Stage 1: Marizomib + Bevacizumab in WHO Gr IV GBM; Stage 2: Marizomib Alone; Stage 3: Combination of Marizomib and Bevacizumab

Inclusion Criteria

• Understand and voluntarily sign and date an informed consent document prior to any study related assessments/procedures are conducted.
• Males and females at least 18 years of age at the time of signing of the informed consent document.
• All subjects must have histologic evidence of G4 MG (including glioblastoma and gliosarcoma) and radiographic evidence of recurrence or disease progression (defined as either a greater than 25% increase in the largest bidimensional product of enhancement, a new enhancing lesion, or significant increase in T2 FLAIR).
• Subjects must have previously completed standard radiation therapy and been exposed to temozolomide. Patients must be in first or second relapse.
• No prior treatment with MRZ or any other proteasome inhibitors or any other anti-angiogenic agents.
• No investigational agent within 4 weeks prior to first dose of study drug.
• At least 4 weeks from surgical resection and 12 weeks from end of radiotherapy prior to enrollment in this study, unless relapse is confirmed by tumor biopsy or new lesion outside of radiation field, or if there are two MRIs confirming progressive disease that are 8 weeks apart.
• Subjects with a history of seizures must be on a stable dose of anti-epileptic drugs (AEDs) and without seizures for 14 days prior to enrollment in patients enrolled prior to Amendment 2. Subjects enrolled after Amendment 2 is approved with a history of seizures must be on a stable dose of anti-epileptic drugs (AEDs) for 7 days prior to enrollment.
• All AEs resulting from prior chemotherapy, surgery, or radiotherapy, must have resolved to at least NCI-CTCAE (v. 4.03) Grade 1 (except for laboratory parameters outlined below).
• Laboratory results within 7 days prior to MRZ administration (transfusions and/or growth factor support may not be used to meet this criteria):
• Platelet count at least 100,000/mm3
• Hemoglobin at least 9 g/dL
• Absolute neutrophil count (ANC) at least 1,500/mm3
• Serum bilirubin at least 1.5 × upper limit of normal (ULN) or at least 3 × ULN if Gilbert's disease is documented
• Aspartate transaminase (AST) at least 2.5 ULN
• Alanine transaminase (ALT) at least 2.5 ULN
• Serum creatinine at least 1.5 × ULN
• Urine protein: creatinine ratio ≤ 1.0 at screening
• Karnofsky Performance Status (KPS) score at least 70%.
• For women of child-bearing potential and for men with partners of child-bearing potential, subject must agree to take contraceptive measures for duration of treatments and 6 months after the last dose of BEV. A female subject of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months).
• Willing and able to adhere to the study visit schedule and other protocol requirements.

Exclusion Criteria

• Co-medication that may interfere with study results, eg, immuno-suppressive agents other than corticosteroids. (Steroid therapy for control of cerebral edema is allowed at the discretion of the Investigator. Subjects should be on a stable dose of steroids for at least 1 week prior to first dose of MRZ. Co-medications must not be taken for 2 hours prior to and up to 2 hours after enteral administration of MRZ (Part 4 Phase 1).
• Evidence of CNS hemorrhage on baseline MRI or CT scan (except for post-surgical, asymptomatic Grade 1 hemorrhage that has been stable for at least 3 months for subjects enrolled prior to Amendment 2 and for at least 4 weeks in subjects enrolled after Amendment 2 is approved).
• History of thrombotic or hemorrhagic stroke or myocardial infarction within 6 months.
• Chemotherapy administered within 4 weeks (except 6 weeks for nitrosoureas, 12 weeks for an implanted nitrosoureas wafer, and 1 week from metronomic chemotherapy, such as daily temozolomide and etoposide) prior to Day 1 of study treatment, unless the subject has recovered from all expected toxicities from the chemotherapy.
• (Part 4 Phase 1) Recent nasal or esophageal surgery, history of GI-related medical conditions, or any other condition which, in the opinion of the investigator, would interfere or cause undue risk with insertion of NG tube or enteral administration of marizomib through the NG tube.
• Pregnancy or breast feeding.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring IV antibiotics & psychiatric illness/social situations that would limit compliance with study requirements, or disorders associated with significant immunocompromised state.
• Known previous/current malignancy requiring treatment within ≤ 3 years except for cervical carcinoma in situ, squamous or basal cell skin carcinoma, and superficial bladder carcinoma.
• Any comorbid condition that confounds the ability to interpret data from the study as judged by the Investigator or Medical Monitor. BEV-Specific Concerns (Note: These exclusion criteria apply to the Part 2 Phase 2 portion of the study even though BEV is not administered so that the subject populations among Part 1, Part 2, Part 3, Part 4, and Part 5 are similar):
• Any prior history of hypertensive crisis or hypertensive encephalopathy.
• Systolic blood pressure (BP) > 150 mmHg or diastolic BP > 100 mmHg.
• Unstable angina.
• New York Heart Association Grade ≥ II congestive heart failure.
• History of myocardial infarction within 6 months.
• Subjects with mean QTcF interval > 500 ms.
• Clinically significant peripheral vascular disease.
• Evidence of bleeding diathesis, coagulopathy as documented by an elevated (≥ 1.5 x ULN) prothrombin time (PT), partial thromboplastin time (PTT), or bleeding time. The use of full-dose oral or parenteral anticoagulants is permitted as long as the PT or aPTT is within therapeutic limits (according to the medical standard of the enrolling institution) and the subject has been on a stable dose of anticoagulants for at least 2 weeks prior to the first study treatment.
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 or anticipation of need for major surgical procedure during course of the study.
• Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to Day 1.
• History of abdominal fistula, GI perforation, or intra-abdominal abscess within 6 months prior to Day 1.
• Serious, non-healing wound, ulcer, or bone fracture requiring surgical intervention.