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

One of the few treatment options currently FDA approved for recurrent WHO Grade IV malignant
glioma is BEV. Additional treatment options are needed for these subjects. Published
literature indicates that targeting the proteasome in glioma cells has shown significant
anti-tumor activity.

MRZ is a novel, second generation proteasome inhibitor that prevents the breakdown of
proteins involved in signal transduction which blocks growth and survival of cancer cells.
In-vitro studies of multiple glioma cell lines were highly sensitive to MRZ. MRZ had
relatively little effect on neural stem/progenitor cells suggesting minimal neurotoxicity
while significantly affecting both malignant glioma stem cells and glioma cell lines.

Parts 1 and 2 of this trial have been completed with the Recommended Part 3 (Phase 2) Dose
established at 0.8 mg/m2. Part 3 of this trial is enrolling at the MRZ RP2D determined in
Phase 1 to assess the combination of MRZ and BEV activity and safety.

Parts 1, 2, and 3 of this trial have been completed with the Recommended Dose established at
0.8 mg/m2. Part 4 of this trial is enrolling.

Inclusion Criteria:

1. Understand and voluntarily sign and date an informed consent document prior to any
study related assessments/procedures are conducted.

2. Males and females at least 18 years of age at the time of signing of the informed
consent document.

3. 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).

4. Subjects must have previously completed standard radiation therapy and been exposed to
temozolomide. Patients must be in first or second relapse.

5. Subjects with archival tumor tissue suitable for proteasome activity and genetic
testing must give permission to access and test the tissue; subjects without archival
tumor tissue are eligible.

6. No prior treatment with MRZ or any other proteasome inhibitors or any other
anti-angiogenic agents.

7. No investigational agent within 4 weeks prior to first dose of study drug.

8. 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.

9. 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.

10. 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).

11. 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

12. Karnofsky Performance Status (KPS) score at least 70%.

13. 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.

14. Willing and able to adhere to the study visit schedule and other protocol
requirements.

Exclusion Criteria:

1. 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).

2. 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).

3. History of thrombotic or hemorrhagic stroke or myocardial infarction within 6 months.

4. 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.

5. (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.

6. Pregnancy or breast feeding.

7. 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.

8. 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.

9. 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 Phase 2 portion of
the study even though BEV is not administered so that the patient populations between
Phase 1 and Phase 2 are similar):

10. Any prior history of hypertensive crisis or hypertensive encephalopathy.

11. Systolic blood pressure (BP) > 150 mmHg or diastolic BP > 100 mmHg.

12. Unstable angina.

13. New York Heart Association Grade ≥ II congestive heart failure.

14. History of myocardial infarction within 6 months.

15. Subjects with mean QTcF interval > 500 ms.

16. Clinically significant peripheral vascular disease

17. 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.

18. 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.

19. Minor surgical procedures, fine needle aspirations or core biopsies within 7 days
prior to Day 1.

120 History of abdominal fistula, GI perforation, or intra-abdominal abscess within 6
months prior to Day 1.

21. Serious, non-healing wound, ulcer, or bone fracture requiring surgical intervention.