Tamoxifen and Bortezomib to Treat Recurrent Brain Tumors

• INCLUSION CRITERIA: Patients with histologically proven high-grade gliomas or patients with a clinical andradiographic diagnosis of brainstem glioma will be eligible for this protocol. High-gradegliomas include glioblastoma multiforme (GBM; stratum 1) and its variants such asgliosarcoma and anaplastic gliomas (AG; stratum 2), such as anaplastic astrocytoma (AA),anaplastic oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), or malignantastrocytoma/glioma NOS (not otherwise specified). Patients must have unequivocal evidence for tumor progression by magnetic resonance imaging (MRI) or computerized tomography (CT) scan. This scan should be performed within 14 daysprior to registration and on a steroid dosage that has been stable for at least 5 days. Ifthe steroid dose is increased between the date of imaging and registration a new baselineMR/CT is required. The same type of scan, i.e., MRI or CT must be used throughout theperiod of protocol treatment for tumor measurement. Patients having undergone recent resection of recurrent or progressive tumor will beeligible as long as all of the following conditions apply:

1. They have recovered from the effects of surgery.

2. Residual disease following resection of recurrent tumor is mandated for eligibilityinto the study. To best assess the extent of residual disease post-operatively, a CT/MRI should be done:

• no later than 96 hours in the immediate post-operative period or

• at least 4 weeks post-operatively, and

• within 14 days of registration, and

• on a steroid dosage that has been stable for at least 5 days. If the 96 hour scan is more than 21 days before registration, the scan needs to berepeated. If the steroid dose is increased between the date of imaging andregistration, a new baseline MRI/CT is required on a stable steroid dosage for atleast 5 days. Patients must have failed prior radiation therapy and must have an interval of greaterthan or equal to 4 weeks from the completion of radiation therapy to study entry. Ability of subjects or Legally Authorized Representative (LAR) to understand and thewillingness to sign a written informed consent document. Patients must be greater than or equal to 18 years old, and with a life expectancygreater than 8 weeks. Patients must have a Karnofsky performance status of greater than or equal to 60. Patients must have recovered from the toxic effects of prior therapy: 2 weeks from anyinvestigational agent, 4 weeks from prior cytotoxic therapy, two weeks fromvincristine, 6 weeks from nitrosoureas, 3 weeks from procarbazine administration, and 1 week for non-cytotoxic agents, e.g., interferon, thalidomide, cis-retinoic acid,etc. (radiosensitizer does not count). Any questions related to the definition ofnon-cytotoxic agents should be directed to the Study Chair. Patients must have adequate bone marrow function (white blood cell (WBC) greater thanor equal to 3,000/microl, absolute neutrophil count (ANC) greater than or equal to 1,500/mm^3, platelet count of greater than or equal to 100,000/mm^3, and hemoglobingreater than or equal to 10 gm/dl), adequate liver function (serum glutamicoxaloacetic transaminase (SGOT) and bilirubin less than 2 times ULN), and adequaterenal function (creatinine less than 1.5 mg/dL and/or creatinine clearance greaterthan or equal to 60 cc/min) before starting therapy. These tests must be performedwithin 14 days prior to registration. Eligibility level for hemoglobin may be reachedby transfusion. Patients must not have any significant medical illnesses that in the investigator'sopinion cannot be adequately controlled with appropriate therapy or would compromisethe patients' ability to tolerate this therapy. This study was designed to include women and minorities, but was not designed tomeasure differences of intervention effects. Males and females will be recruited withno preference to gender. No exclusion to this study will be based on race. Minoritieswill actively be recruited to participate. Patients must practice adequate contraception.

EXCLUSION CRITERIA: Patients who, in the view of the treating physician, have significant active cardiac (documented coronary artery disease, congestive heart failure, arrhythmia requiringmedication), hepatic (hepatocellular and/or cholestatic dysfunction as documented byliver biopsy, liver ultrasound, or abnormal liver function blood tests, renal (asdocumented by renal biopsy, ultrasound, CT/MRI scans or reflected in the blood testsor psychiatric diseases (requiring hospitalization or is of significant severity toimpair the patients ability to cooperate with the study instructions). No concurrent use of other standard chemotherapeutics or investigative agents. Patients known to have an active malignancy other than their glioma (exceptnon-melanoma skin cancer or carcinoma in-situ of the cervix). Patients who have an active infection requiring intravenous (IV) antibiotics. Patients who are pregnant or breast feeding. Patients who have any disease that will obscure toxicity or dangerously alter drugmetabolism. Patients who have had clear tumor progression while being treated with tamoxifenand/or patients treated with tamoxifen within the past year. Patients who are taking EIAEDs (enzyme inducing anti-epileptic drugs) are noteligible. Patients who have had documented tumor progression while taking tamoxifen and/or anytreatment with tamoxifen within 6 months of registration. Salicylates ARE permitted. Patients with grade 2 or greater peripheral neuropathy. Invasive procedures defined as follows:

• Major surgical procedures, open biopsy or significant traumatic injury within 28days prior to Day ! therapy

• Anticipation of need for major surgical procedures during the course of the study

• Core biopsy within 7 days prior to D1 therapy