ERC1671/GM-CSF/Cyclophosphamide and Bevacizumab in Treating Patients with Relapsed Glioblastoma Multiforme

Inclusion Criteria

• Patients must have histologically confirmed diagnosis of a recurrent/progressive World Health Organization (WHO) grade IV malignant glioma (glioblastoma and gliosarcoma) and meet the following inclusion criteria
• Karnofsky performance status (KPS) of >= 70%
• Life expectancy > 12 weeks
• First or second relapse of glioblastoma
• Previous treatment for glioblastoma must include surgery (biopsy, partial resection, or full surgical resection), conventional radiation therapy and temozolomide (TMZ)
• Magnetic resonance imaging (MRI) record must be obtained showing the MRI was done at least 4 weeks after any salvage surgery, and at least 12 weeks after radiation therapy, or at least 4 weeks after radiation for a new lesion outside the prior primary radiation field unless relapse is confirmed by tumor biopsy or new lesion outside of radiation field, or if there are two MRIs confirming progressive disease per Response Assessment in Neuro-Oncology criteria (RANO) that are 8 weeks apart
• If prior therapy with gamma knife or other focal high-dose radiation, must have subsequent histologic documentation of local relapse, or relapse with new lesion outside the irradiated field
• Resolution of all chemotherapy or radiation-related toxicities =< Common Terminology Criteria for Adverse Events (CTCAE) grade 1 severity, except for alopecia and hematologic toxicity; patients taking temozolomide can start study treatment 23 days from the last temozolomide dose; for all other chemotherapy drugs, study treatment can start as long as adverse events related to their prior treatment are no higher than grade 1
• Systemic corticosteroid therapy must be at a dose of =< 4 mg of dexamethasone or equivalent per day during the week prior to day 1
• Pre-surgical bi-dimensionally measurable disease (as per immunotherapy Response Assessment in Neuro-Oncology [iRANO] criteria)
• Hemoglobin (Hbg) > 9 g/dL
• Leukocytes > 1,500/mcL
• Absolute neutrophil count > 1,000/mcL
• CD4 count > 450/mcL
• Platelets > 125,000/mcL
• Serum bilirubin = 1.5 x upper limit of normal (ULN) or = 3 x ULN if Gilbert’s disease is documented
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 x institutional upper limit of normal
• Serum creatinine < 1.5 mg/dl
• Signed informed consent approved by the Institutional Review Board
• If sexually active, patients must agree to take contraceptive measures for the duration of the treatments

Exclusion Criteria

• Subjects unable to undergo an MRI with contrast
• Presence of diffuse leptomeningeal disease
• History, presence, or suspicion of metastatic disease
• Administration of immunosuppressive drugs less than 2 weeks prior to first dose of ERC1671 except dexamethasone for cerebral edema as detailed above
• Prior receipt of bevacizumab, bevacizumab biosimilars, or other vascular endothelial growth factor (VEGF) negative (-) or VEGF receptor-targeted agents
• Known contraindication or hypersensitivity to any component of bevacizumab
• Evidence of recent hemorrhage on screening MRI of the brain with the following exceptions: presence of hemosiderin; resolving hemorrhagic changes related to surgery; presence of punctate hemorrhage in the tumor
• Significant vascular disease (e.g., aortic aneurysm, aortic dissection) or recent peripheral arterial thrombosis within 6 months prior to day 1
• Evidence of bleeding diathesis or coagulopathy as documented by an elevated prothrombin time (PT), partial thromboplastin time (PTT) or bleeding time and clinically significant
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to day 1
• Urine protein:creatinine ratio >= 1.0 at screening
• Anticipation of need for major surgical procedure during the course of the study
• Serious non-healing wound, ulcer, or bone fracture
• Active infection requiring treatment, known immunosuppressive disease, active systemic autoimmune diseases such as lupus, receipt of systemic immunosuppressive therapy, human immunodeficiency virus (HIV) infection, hepatitis B or hepatitis C
• Uncontrolled hypertension, blood pressure of > 150 mmHg systolic and > 100 mmHg diastolic, or history of hypertensive encephalopathy; subjects with any known uncontrolled inter-current illness including ongoing or active infection, symptomatic congestive heart failure (New York Heart Association [NYHA] grade [Gr.]2 or >), myocardial infarction, unstable angina pectoris within the past 6 months
• Stroke, transient ischemic attack, unstable angina, myocardial infarction or congestive heart failure (New York Heart Association grade II or greater) within the past 6 months; unstable or severe intercurrent medical conditions, chronic renal disease, or uncontrolled diabetes mellitus
• Women who are pregnant or lactating; all female patients with reproductive potential must have a negative pregnancy test prior to day 1 and agree to use reliable contraception whilst study participant
• Men refusing to exercise a reliable form of contraception
• History of any malignancy (other than glioblastoma) during the last three years except non-melanoma skin cancer, in situ cervical cancer, treated superficial bladder cancer or cured, early-stage prostate cancer in a patient with prostate specific antigen (PSA) level < ULN
• BEVACIZUMAB-SPECIFIC EXCLUSION CRITERIA:
• Any prior history of hypertensive crisis or hypertensive encephalopathy
• Systolic blood pressure greater than 150 mmHg or diastolic blood pressure greater than 100 mmHg
• Unstable angina
• New York Heart Association (NYHA) grade II or greater congestive heart failure
• History of myocardial infarction within 6 months
• History of stroke within 6 months
• Clinically significant peripheral vascular disease
• Evidence of bleeding diathesis, coagulopathy as documented by an elevated PT, PTT or bleeding time
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to day 0, anticipation of need for major surgical procedure during the course of the study
• Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to day 0
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to day 0
• Serious, non-healing wound, ulcer, or bone fracture
• Known hypersensitivity to any component of Avastin
• Inability to comply with study and/or follow-up procedures