Bortezomib, Temozolomide, and Regional Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme or Gliosarcoma

OBJECTIVES:

Primary

- Estimate the overall survival at 2 years of patients with newly diagnosed glioblastoma
multiforme treated with bortezomib in combination with temozolomide and regional
radiotherapy followed by maintenance therapy comprising bortezomib and temozolomide.

Secondary

- Investigate further the safety and tolerability of this regimen in these patients.

- Determine the molecular characterization of tumor tissue and correlate these findings
with response.

OUTLINE: This is a multicenter study.

- Adjuvant chemotherapy: Patients receive bortezomib IV on days 1, 4, 8, 11, 29, 32, 36,
and 39 and oral temozolomide on days 1-42. Patients undergo external-beam fractionated
regional radiotherapy 5 days a week for 6 weeks in the absence of disease progression or
unacceptable toxicity.

- Maintenance: Beginning 2-6 weeks after radiotherapy, patients receive bortezomib IV on
days 1, 4, 8, and 11 and oral temozolomide on days 1-5. Treatment repeats every 28 days
for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Tumor tissue samples are collected at baseline (from surgery) and periodically during study
for further analysis.

After completion of study therapy, patients are followed up periodically.

Inclusion Criteria:

- Must be >- 18 years old, with a life expectancy > 8 weeks

- Histologically confirmed intracranial glioblastoma multiforme (GBM) or gliosarcoma

- Must submit an unstained paraffin block or slides from surgical procedure

- Patients without prior treatment and with prior diagnosis of lower-grade gliomas that
have been upgraded to GBM after repeated resection allowed

- At least 21 days since cranial MRI or contrast CT scan OR ≥ 96 hours since cranial MRI
or contrast CT scan for patients who underwent surgical resection

- Measurable or assessable disease

- Voluntary written informed consent obtained before performance of any study related
procedure not part of normal medical care.

- Karnofsky performance status > 60%

- WBC ≥ 3,000/mm^3

- ANC ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- Hemoglobin ≥ 10 g/dL (transfusion allowed)

- Bilirubin < 2.5 times upper limit of normal (ULN)

- SGOT < 2.5 times ULN

- Creatinine < 1.5 mg/dL

- Creatinine clearance ≥ 20 mL/minute

- Serum sodium > 130 mmol/L

- Negative pregnancy test

- Fertile patients must use effective contraception

- Patients on EIAED must be transitioned to non-EAIED for ≥ 2 weeks

- Concurrent full-dose warfarin or its equivalent (e.g., unfractionated and/or low
molecular weight heparin) allowed

Exclusion Criteria:

- peripheral neuropathy ≥ grade 2

- Myocardial infarction within the past 6 months

- NYHA class III or IV heart failure

- Uncontrolled angina

- Severe uncontrolled ventricular arrhythmias

- Electrocardiographic evidence of acute ischemia or active conduction system
abnormalities

- hypersensitivity to bortezomib, boron, or mannitol

- serious medical or psychiatric illness that would interfere with study participation
including, but not limited to, any of the following:

- Ongoing or active infection requiring IV antibiotics

- Psychiatric illness and/or social situations that would limit compliance with study
requirements

- Disorders associated with a significant immunocompromised state (e.g., HIV, systemic
lupus erythematosus)

- history of stroke within the past 6 months

- other malignancy within the past 3 years except completely resected basal cell
carcinoma or squamous cell carcinoma of the skin, an in situ malignancy (i.e.,
cervical cancer), or low-risk prostate cancer after curative therapy

- significant medical illness that, in the investigator's opinion, cannot be adequately
controlled with appropriate therapy or would compromise the patient's ability to
tolerate this therapy

- disease that will obscure toxicity or dangerously alter drug metabolism

- viral hepatitis (HBV surface antigen positive) or active hepatitis C infection

- Prior or concurrent corticosteroids, automated external defibrillator, analgesics, and
other drugs to treat symptoms or prevent complications allowed

- concurrent investigational drugs that must be stopped at least 4 months prior to
therapy.

- prior radiotherapy to the brain

- prior cytotoxic or noncytotoxic drug therapy or experimental drug therapy (including
chemotherapy, hormonal therapy, or immunotherapy) directed against the brain tumor

- prior polifeprosan 20 with carmustine implant (Gliadel wafer)

- concurrent stereotactic radiosurgery or brachytherapy

- concurrent sargramostim

- concurrent inducers of CYP450 3A4 (e.g., enzyme-inducing anti-epileptic drugs [EIAED])