Standard Dose Bevacizumab Versus Low Dose Bevacizumab Plus Lomustine (CCNU) for Recurrent Glioblastoma Multiforme (GBM)
Condition: Brain Cancer; Glioblastoma
MeSH terms: Glioblastoma; Brain Neoplasms
Intervention: Standard Dose Bevacizumab; Low Dose Bevacizumab; Lomustine
Intervention description: 10 mg/kg by vein (IV) over 90 minutes on Days 1, 15, and 29 of 6 week cycle.; 5 mg/kg IV over 90 minutes on Day 1 and 22 (every 3 weeks) of 6 week cycle.; Starting dose of 75 mg/m2 administered orally at sleep time on Day 3 of every 6 week cycle.
Intervention MeSH terms: Bevacizumab; Antineoplastic Agents, Immunological; Lomustine; Antibodies; Immunoglobulins; Antibodies, Monoclonal
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 83.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: CNS; Central Nervous System; malignant brain tumor; Recurrent Glioblastoma Multiforme; GBM; Bevacizumab; Lomustine; CCNU

Summary:

      The goal of this clinical research study is to learn if the combination of bevacizumab and
      lomustine can help to control glioblastoma. The safety of this combination will also be
      studied.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Signed Informed Consent Form

          2. Age >/= 18 years

          3. Histologically confirmed glioblastoma in first, second or third relapse. A pathology
             report constitutes adequate documentation of histology for study inclusion. Subjects
             with an initial diagnosis of a lower grade glioma are eligible if a subsequent biopsy
             is determined to be glioblastoma. The amount of prior systemic therapy for this
             population is, nevertheless, restricted to three regimens, with one including
             temozolomide.

          4. Radiographic demonstration of disease progression following prior therapy

          5. Bi-dimensionally measurable disease with a minimum measurement of 1 cm (10 mm) in one
             diameter on MRI performed within 14 days prior to registration (Day 1). Baseline MRIs
             for subjects who underwent salvage surgery after first or second relapse must be
             obtained >/= 4 weeks after the procedure. If receiving corticosteroids, subjects must
             be on a stable or decreasing dose of corticosteroids for >/= 5 days prior to baseline
             MRI.

          6. Patients having undergone recent resection of recurrent or progressive tumor will be
             eligible as long as all of the following conditions apply: 1) They have recovered from
             the effects of surgery. 2) Evaluable or measurable disease following resection of
             recurrent tumor is not mandated for eligibility into the study. 3) To best assess the
             extent of residual measurable disease post-operatively, a MRI should be done no later
             than 96 hours in the immediate post-operative period or 4-6 weeks post-operatively. .

          7. An interval of >/= 4 weeks since surgical resection is required prior to starting
             protocol therapy.

          8. Prior standard radiation for glioblastoma

          9. Prior chemotherapy: All first-relapse subjects must have received temozolomide. All
             second- and third-relapse subjects must have received temozolomide. Patients may not
             have received prior nitrosoureas.

         10. Recovery from the effects of prior therapy, including the following: Four weeks from
             cytotoxic agents (3 weeks from procarbazine, 2 weeks from vincristine); Four weeks
             from any investigational agent; One week from non-cytotoxic agents(eg accutane,
             thalidomide); Eight weeks from radiotherapy to minimize the potential for MRI changes
             related to radiation necrosis that might be misdiagnosed as progression of disease, or
             4 weeks if a new lesion, relative to the pre-radiation MRI, develops that is outside
             the primary radiation field; Patients may have had gliadel wafers during their
             original surgery but they must be >/= 9 months post their original surgery date.

         11. Prior therapy with gamma knife or other focal high-dose radiation is allowed, but the
             subject must have subsequent histologic documentation of recurrence or positron
             emission tomography (PET) or MR Spectroscopic documentation of tumor, unless the
             recurrence is a new lesion outside the irradiated field

         12. Patients must have adequate bone marrow function (WBC >/= 3,000/µl, absolute
             neutrophil count (ANC) >/= 1,500/mm^3, platelet count of >/= 100,000/mm^3, and
             hemoglobin >/= 10 gm/dl), adequate liver function (SGPT < 3 times normal and alkaline
             phosphatase < 2 times normal, bilirubin <1.5 mg/dl), adequate renal function
             (creatinine </= 1.5 mg/dL or creatinine clearance >/= 60 cc/min/1.73 m^2) and a urine
             protein:creatinine ratio of </=1 before starting therapy. These tests must be
             performed within 14 days prior to registration. Eligibility level for hemoglobin may
             be reached by transfusion.

         13. Patients must have a Karnofsky performance status (KPS) equal or greater than 60

         14. Use of an effective means of contraception in males and in females of childbearing
             potential. Women of childbearing potential must have a negative β-human chorionic
             gonadotropin (HCG) pregnancy test documented within 14 days prior to registration.
             Should a woman become pregnant or suspect she is pregnant while participating in this
             study, she should inform her treating physician immediately.

         15. Ability to comply with study and follow-up procedures

         16. Patients receiving treatment with other antiepileptic medications will not be
             excluded. Patients should preferably be treated with non-enzyme inducing
             anti-epileptic medications to avoid any potential interactions with lomustine.
             However, the use of non-enzyme inducing anti-epileptic medications is not mandatory.
             If enzyme-inducing antiepileptic drugs are used, monitoring of drug levels should be
             considered, as considered clinically appropriate by the treating physician.

         17. Patients on the following medications will be included: Anticoagulants/Anti-platelets:
             Patients on stable dose anticoagulants (e.g. warfarin, low molecular-weight heparin)
             and in-range international normalized ratio (INR) (2-3) are eligible. Patients are
             allowed to take aspirin, clopidogrel, ticlopidine, Aggrenox, ibuprofen and other
             NSAIDS.

         18. Patients must be willing to forego other cytotoxic and non-cytotoxic drug therapy
             against the tumor while enrolled in the study.

         19. 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. No exclusion to this study will be based on race. Minorities
             will actively be recruited to participate.

        Exclusion Criteria:

          1. Prior treatment with anti-angiogenesis (eg bevacizumab, sorafenib, sunitinib) agent or
             nitrosurea (eg. lomustine, carmustine, nimustine).

          2. Prior treatment with polifeprosan 20 with carmustine wafer except for the patients
             with gliadel wafers >/= 9 months post their original surgery date.

          3. Patients must not have received any investigational agents within 28 days prior to
             commencing study treatment.

          4. Prior intracerebral agents

          5. Need for urgent palliative intervention for primary disease (e.g., impending
             herniation)

          6. Evidence of recent hemorrhage on baseline MRI of the brain with the following
             exceptions: (1) Presence of hemosiderin (2) Resolving hemorrhagic changes related to
             surgery (3) Presence of punctate hemorrhage in the tumor

          7. Blood pressure of > 140 mmHg systolic and > 90 mmHg diastolic

          8. History of hypertensive encephalopathy

          9. New York Heart Association (NYHA) Grade II or greater chronic heart failure(CHF)

         10. History of myocardial infarction or unstable angina within 6 months prior to Day 1

         11. History of stroke or transient ischemic attack within 6 months prior to study
             enrollment

         12. Significant vascular disease (e.g., aortic aneurysm, aortic dissection) or recent
             peripheral arterial thrombosis within 6 months prior to Day 1

         13. Evidence of bleeding diathesis or coagulopathy or INR >1.5 unless on a stable dose of
             anticoagulation therapy. History of significant bleeding disorder unrelated to cancer,
             including: (1) Diagnosed congenital bleeding disorders (e.g., von Willebrand's
             disease) (2) Diagnosed acquired bleeding disorder within one year (e.g., acquired
             anti-factor VIII antibodies) (3) Ongoing or recent (</= 3 months) significant
             gastrointestinal bleeding

         14. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
             within 6 months prior to Day 1

         15. History of intracerebral abscess within 6 months prior to Day 1

         16. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
             prior to Day 1, anticipation of need for major surgical procedure during the course of
             the study

         17. Minor surgical procedures (excluding placement of a vascular access device),
             stereotactic biopsy, fine needle aspirations, or core biopsies within 7 days prior to
             Day 1

         18. Serious non-healing wound, ulcer, or bone fracture

         19. Pregnancy (positive pregnancy test) or lactation

         20. Known hypersensitivity to any component of bevacizumab

         21. History of any other malignancy (except non-melanoma skin cancer or carcinoma in situ
             of the cervix), unless in complete remission and off of all therapy for that disease
             for a minimum of 3 years are ineligible

         22. Pregnant or nursing females

         23. Unstable systemic disease, including active infection, uncontrolled hypertension, or
             serious cardiac arrhythmia requiring medication

         24. Subjects unable to undergo an MRI with contrast

         25. Patients with a known allergy to bevacizumab, or a known allergy to nitrosoureas (eg.
             lomustine, carmustine, nimustine) will be excluded

         26. Patient must be able to tolerate the procedures required in this study including
             periodic blood sampling, study related assessments, and management at the treating
             institution for the duration of the study. Inability to comply with protocol or study
             procedures (for example, an inability to swallow tablets) will be an exclusion
             criteria.