Bicalutamide with Brain Re-Irradiation for the Treatment of Relapsed or Refractory Glioblastoma or High Grade Glioma

Inclusion Criteria

• Histopathologically proven diagnosis of relapsed/refractory high grade glioma (HGG) including glioblastoma or variants (gliosarcoma, giant cell glioblastoma etc), World Health Organization (WHO) grade IV, or anaplastic astrocytoma, or anaplastic oligodendroglioma, WHO grade III. Subjects will be eligible if the original histology was lower-grade glioma and a subsequent diagnosis of HGG (secondary HGG) is made
• Subjects who did not have surgery for their HGG within 5 weeks prior to enrollment must have shown unequivocal radiographic evidence for tumor progression by contrast-enhanced MRI scan (or CT scan for subjects with non-compatible devices). Imaging completed prior to enrollment will be acceptable for eligibility purposes if completed within 4 weeks prior to enrollment. If imaging was not completed within 4 weeks prior to enrollment then imaging must be completed within 14 days after enrollment and prior to the start of RT * Subjects unable to undergo MR imaging because of non-compatible devices can be enrolled provided CT scans are obtained and are of sufficient quality. Subjects without non-compatible devices may not use CT scans performed to meet this requirement
• Subjects must have passed an interval of 6 months or greater between completion of prior radiotherapy and registration. If subjects have not passed an interval of at least 6 months, they may still be eligible if they meet one or more of the following criteria that rule out pseudo-progression: * New areas of tumor outside the original radiotherapy fields as determined by the investigator, or * Histologic confirmation of tumor through biopsy or resection, or * Nuclear medicine imaging, MR spectroscopy, or MR perfusion imaging consistent with true progressive disease, rather than radiation necrosis obtained within 28 days of registration AND an interval of at least 90 days between completion of previous radiotherapy and registration
• Prior history of standard dose central nervous system (CNS) radiation of 60 Gy in 30 fractions or 59.4 Gy in 1.8 Gy fractions, or equivalent or lower doses
• Subjects must have recovered from the toxic effects of prior chemotherapy, and there must be a minimum time of 14 days prior to registration from the administration of any investigational agent or prior cytotoxic therapy with the following exceptions: * 14 days from administration of vincristine * 42 days from administration of nitrosoureas * 21 days from administration of procarbazine
• Subjects having undergone recent resection of their glioblastoma (within 5 weeks prior to enrollment) must have recovered from the effects of surgery. For CNS related core or needle biopsies, a minimum of 7 days must have elapsed prior to enrollment * Residual disease following resection of recurrent glioblastoma is not mandated for eligibility into the study
• History/physical examination, including neurologic examination, within 14 days prior to enrollment
• Eastern Cooperative Oncology Group (ECOG) ≤ 2 within 14 days prior to enrollment
• Age ≥ 19 (Age of adults in Nebraska)
• Absolute neutrophil count (ANC) ≥ 1,500 cells/mm^3 (obtained within 14 days of enrollment) * Note: If a complete blood count (CBC) with (w)/differential was not obtained prior to enrollment it must be completed within 14 days of enrollment and prior to the start of bicalutamide
• Platelets ≥ 75,000 cells/mm^3 (obtained within 14 days of enrollment) * Note: If a CBC w/differential was not obtained prior to enrollment it must be completed within 14 days of enrollment and prior to the start of bicalutamide
• Hemoglobin ≥ 9.0 g/dl (obtained within 14 days of enrollment) (Note: The use of transfusion or other intervention to achieve hemoglobin [Hgb] ≥ 9.0 g/dl is acceptable.) * Note: If a CBC w/differential was not obtained prior to enrollment it must be completed within 14 days of enrollment and prior to the start of bicalutamide
• Total bilirubin < 2.0 mg/dL (within 14 days of enrollment) * Note: If labs were not completed prior to enrollment they must be completed within 14 days of enrollment and prior to the start of bicalutamide
• Serum glutamic oxaloacetic transaminase (SGOT) or aspartate aminotransferase (AST) < 2.5 times the upper limit of normal (within 14 days of enrollment) * Note: If labs were not completed prior to enrollment they must be completed within 14 days of enrollment and prior to the start of bicalutamide
• Serum creatinine < 1.8 mg/dL (within 14 days of enrollment) * Note: If labs were not completed prior to enrollment they must be completed within 14 days of enrollment and prior to the start of bicalutamide
• Calculated creatinine clearance > 30 ml/min (Cockroft-Gault) (within 14 days of enrollment) * Note: If labs were not completed prior to enrollment they must be completed within 14 days of enrollment and prior to the start of bicalutamide
• Subjects must not be pregnant (positive pregnancy test) or breast feeding; pregnancy test must be done within 7 days of enrollment and prior to the start of RT. Contraception (men and women), i.e., effective physical barrier methods, must be used in subjects of child-bearing potential while on study treatment and for 6 months after. Oral contraceptives are not allowed as a form of contraception due to potential interference of testosterone levels
• Subject must be able to provide study-specific informed consent prior to study entry

Exclusion Criteria

• Infratentorial, or diffuse leptomeningeal evidence of recurrent disease. If focal leptomeningeal disease (per treating physician’s determination of being “focal”), subjects can be considered eligible
• Ongoing therapy with any androgen deprivation therapy (ADT) such as leuprolide acetate, degarelix, bicalutamide, flutamide, enzalutamide, apalutamide, abiraterone acetate, darolutamide or others per principal investigator’s determination. If ADT has been stopped prior to the enrollment, at least 6 months of ADT-free time is required for eligibility
• Prior allergic reaction to the drug bicalutamide
• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 1 year (for example, carcinoma in situ of the breast, oral cavity, prostate, or cervix are all permissible)
• Severe, active co-morbidity, defined as follows: * Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months prior to registration * Congestive heart failure (New York Heart Association [NYHA] functional capacity class II or greater) * Transmural myocardial infarction within the last 6 months prior to registration * History of stroke or transient ischemic attack within 6 months prior to registration * Ongoing arrhythmias of grade > 2 (Common Terminology Criteria for Adverse Events [CTCAE], version 5.0); Chronic stable atrial fibrillation on stable anticoagulant therapy is allowed * Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism) in the past 6 months * Significant vascular disease (e.g., aortic aneurysm, history of aortic dissection) or clinically significant peripheral vascular disease * Chronic stable atrial fibrillation on stable anticoagulant therapy is allowed
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
• Known Acquired Immune Deficiency Syndrome (AIDS) diagnosis based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude subjects with AIDS from this protocol is necessary because the treatments involved in this protocol may cause significant immunosuppression if requiring steroids for side effects such as radionecrosis
• Immuno-compromised patients with transplant in history are excluded with the same reason as above
• Uncontrolled seizures or controlled seizure in the past 3 months but requires more than levetiracetam 500mg PO twice daily (BID), i.e., with higher dose of levetiracetam or additional antiepileptics (excluding steroids)
• Any prior history of hypertensive crisis or hypertensive encephalopathy
• History of a non-healing wound, ulcer, or bone fracture within 90 days (3 months) prior to enrollment
• Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule, including alcohol dependence or drug abuse
• Subjects who are on testosterone supplement due to medical reasons that cannot be safely discontinued
• Subjects who are on temozolomide treatment and have no plan to stop temozolomide prior to consent or who will be offered temozolomide concurrently with re-RT. Subjects on bevacizumab whose bevacizumab cannot be stopped are not eligible and bevacizumab is not allowed for concurrent use with bicalutamide and re-RT but is allowed after at least two weeks (washout time) after discontinuation of re-RT and bicalutamide