Avastin/Radiation (XRT)/Temozolomide (Temodar) Followed by Avastin/Temodar/Topotecan for Glioblastoma
Avastin/Radiation (XRT)/Temozolomide (Temodar) Followed by Avastin/Temodar/Topotecan for Glioblastoma
This is a phase II study of the combination of radiation therapy, temozolomide and Avastin
 followed by Avastin, temozolomide, and topotecan in grade IV malignant glioma patients.
The primary objective of this study is to use 6-month progression-free survival to assess the
 efficacy of the combination of radiation therapy, temozolomide and Avastin followed by
 Avastin, temozolomide, and topotecan in the treatment of grade IV malignant glioma patients
 following surgical resection. Secondary objectives are to determine the overall survival
 following the combination of radiation therapy, temozolomide and Avastin followed by Avastin,
 temozolomide, and topotecan and to describe the toxicity of radiation therapy, temozolomide
 and Avastin followed by Avastin, temozolomide, and topotecan.

 The study will have survival and toxicity endpoints. Patients will be treated with standard
 radiation therapy and daily temozolomide for 6 and a half weeks of radiation. Avastin will be
 administered every other week beginning a minimum of 28 days after the last major surgical
 procedure, open biopsy, or significant traumatic injury. Following completion of radiation
 therapy, patients will have a MRI and if there is no evidence of disease progression,
 patients will receive 12 cycles of Avastin, temozolomide, and topotecan (beginning a minimum
 of 14 days after the last radiation treatment). Subjects will be identified by the
 investigator as those patients who have newly diagnosed grade 4 malignant glioma
 (glioblastoma multiforme or gliosarcoma), and be within 6 weeks of the last major surgical
 procedure, craniotomy, open biopsy, or stereotactic biopsy.

 Fifty (50) patients will initially be accrued to the study and the overall efficacy of the
 treatment regimen assessed. Analyses will be conducted within subgroups defined by
 methylation status.

 Early side effects of radiation that may start during radiation include hair loss, scalp
 redness, inflammation of the ear canals, and fatigue. There is a small chance of long-term
 effects from radiation, occurring after months or years after completion. These may include
 worsening of mental function, hearing, vision, strength and coordination. In initial Phase I
 and II clinical trials, four potential Avastin-associated safety signals were identified:
 hypertension, proteinuria, thromboembolic events, and hemorrhage. Temozolomide has been well
 tolerated by both adults and children with the most common toxicity being mild
 myelosuppression. Other, less likely, potential toxicities include nausea and vomiting,
 constipation, headache, alopecia, rash, burning sensation of skin, esophagitis, pain,
 diarrhea, lethargy, and hepatotoxicity. With topotecan, reversible myelosuppression with
 leukopenia and thrombocytopenia is dose limiting. Nausea and vomiting, as well as diarrhea
 and alopecia, are frequent. Moderate fatigue, transient elevation of hepatic transaminase
 levels, stomatitis, anemia, fever, mucositis, flu-like symptoms, and rash have been reported.
Inclusion Criteria:

 -  Patients must have histologically confirmed diagnosis of WHO grade IV primary
 malignant glioma (glioblastoma multiforme or gliosarcoma). Patients have to be within
 6 weeks of the last major surgical procedure.

 -  Age > or = to 18 years.

 -  An interval of at least 2 weeks and not > 6 weeks between prior major surgical
 procedure and study enrollment.

 -  No prior radiotherapy or chemotherapy for a brain tumor

 -  Karnofsky > or = to 60%.

 -  Hemoglobin ≥ 9.0 g/dl, absolute neutrophil count (ANC) ≥ 1,500 cells/microliter,
 platelets ≥ 125,000 cells/microliter.

 -  Serum creatinine ≤ 1.5 mg/dl, serum glutamic oxaloacetic transaminase (SGOT) and
 bilirubin ≤ 1.5 times upper limit of normal.

 -  Signed informed consent approved by the Institutional Review Board

 -  If sexually active, patients must agree to use appropriate contraceptive measures for
 the duration of the study and for 6 months afterwards as stated in the informed
 consent.

 Exclusion Criteria:

 -  Pregnancy or breast feeding.

 -  Co-medication that may interfere with study results; e.g. immuno-suppressive agents
 other than corticosteroids.

 -  Active infection requiring IV antibiotics.

 -  Prior treatment with radiotherapy or chemotherapy for a brain tumor, irrespective of
 the grade of the tumor.

 -  Evidence of > grade 1 central nervous system (CNS) hemorrhage on baseline MRI on CT
 scan.

 Avastin-specific Exclusion Criteria:

 -  Inadequately controlled hypertension (defined as systolic blood pressure > 150 and/or
 diastolic blood pressure > 100 mmHg)

 -  Prior history of hypertensive crisis or hypertensive encephalopathy

 -  New York Heart Association (NYHA) Grade II or greater congestive heart failure

 -  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

 -  Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or
 recent peripheral arterial thrombosis) within 6 months prior to study enrollment

 -  History of hemoptysis (≥ ½ teaspoon of bright red blood per episode) within 1 month
 prior to study enrollment

 -  Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic
 anticoagulation)

 -  Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
 prior to study enrollment or 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

 -  History of abdominal fistula, gastrointestinal perforation within 6 months prior to
 study enrollment

 -  Serious, non-healing wound, active ulcer, or untreated 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

 -  Pregnant (positive pregnancy test) or lactation. Use of effective means of
 contraception (men and women) in subjects of child-bearing potential