Study of Marizomib With Temozolomide and Radiotherapy in Patients With Newly Diagnosed Brain Cancer

Gliomas account for ~80% of primary malignant tumors in the Central Nervous System (CNS),
with WHO Grade IV malignant glioma (G4 MG; including glioblastoma and gliosarcoma)
constituting the majority of gliomas, and are essentially incurable. Currently only surgical
resection and radiotherapy (RT) with concomitant and adjuvant temozolomide (TMZ) are
standard-of-care treatment strategies for newly diagnosed G4 MG. However, resistance to
chemotherapy and RT results in a high recurrence rate, with median survival of ~15-16 months.
Since no survival advantage has been demonstrated for the addition of bevacizumab (BEV) to
TMZ and RT (Chinot 2014) in newly diagnosed G4 MG, alternative promising investigational
agents need to be tested.

Targeting the proteasome is a well-validated target for the treatment of multiple myeloma
(MM), and preclinical evidence suggests that targeting the proteasome in glioma cells shows
significant anti-tumor activity. Proteasome activity is elevated in patient-derived
glioblastoma (GBM) tissue in comparison with normal human brain. Importantly, preclinical
evidence demonstrates that proteasome inhibition sensitizes GBM cell lines to irradiation and
to TMZ. Further, the combination of bortezomib (BTZ, one of three proteasome inhibitors [PI]
currently approved for the treatment of MM) with TMZ resulted in synergistic glioblastoma
cell death in vitro, and BTZ reduces glioma cell survival in vitro in cell lines sensitive
and resistant to TMZ.

Despite the activity against GBM cells in vitro, BTZ does not cross the blood brain barrier,
and thus has proven ineffective in animal models and in the clinic. In contrast, marizomib
(MRZ) - a potent and irreversible 20S PI possesses the unique attribute among PIs to cross
the blood brain barrier as shown in previous clinical studies. These data prompted
examination of the combination of MRZ and BEV in an ongoing clinical trial in patients with
recurrent G4 MG. In the dose-escalation portion of this ongoing study (MRZ-108), 12 patients
were dosed with MRZ once weekly for 3 weeks (0.55, 0.7, and 0.8 mg/m2 infused intravenously
(IV) over 10 minutes) and with BEV on weeks 1 and 3 (10 mg/kg IV) of a 28-day cycle. As of
April 2016, of these 12 patients, 7 were on study for over 4 months - 5 with a partial
response (including 2 patients with no radiologic evidence of tumor on 2 or more consecutive
MRI scans) and 2 patients whose best response was stable disease. Four of these 12 patients
were treated for over 6 months, 3 of whom remain on study. The recommended Phase 2 dose
(RP2D) of MRZ was determined to be 0.8 mg/m2. Currently, an expansion cohort of 24 patients
has been enrolled in the Phase 2 portion of the study. The next phase involves treatment with
MRZ alone (no BEV) in patients with recurrent G4 MG, and has begun enrolling patients in the
second quarter of 2016.

Together, the demonstrated activity of PIs in preclinical glioma models, and the synergistic
activity of PIs with TMZ on glioblastoma cells, along with the ability of MRZ to access the
CNS, provides compelling rationale to assess the therapeutic benefit of the combination of
MRZ with TMZ in patients with G4 MG, for whom no brain-penetrant options for proteasome
inhibition are currently available.

Very recently, the FDA has approved a novel treatment device using tumor treating fields
(Optune) in addition to standard of care RTand TMZ as an option to standard of care. Optune
has been shown to significantly improve both progression-free and overall survival in GBM
patients. An additional cohort of 12 patients will be treated with Optune in combination with
MRZ and TMZ In North America, the Optune arm is offered only for the US trial sites, and is
not offered for the Canadian trial sites.

Inclusion Criteria:

- Signed Informed Consent Form

- Males and females of age ≥ 18 years or of age ≥ 22 years for those assigned to Optune™
at the time of signing of the informed consent document.

- Histologically confirmed newly diagnosed G4 MG

- Karnofsky Performance Status (KPS) score ≥ 70%

- For Concomitant Treatment: Prior tumor resection or biopsy up to 8 weeks prior to
first MRZ dose

- For Adjuvant Treatment: All AEs resulting from surgery must have resolved to NCI-CTCAE
(v. 4.03) Grade ≤ 1

- Stable or decreasing dose of corticosteroids over 14 days prior to first MRZ dose

- For Concomitant Treatment: No prior treatment with MRZ or any other PIs, including
BTZ, carfilzomib (CFZ), or ixazomib (IXZ)

- For Adjuvant Treatment: No prior treatment with BTZ, CFZ, or IXZ

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

- Adequate hematological, renal, and hepatic function

- Patients must be without seizures for at least 14 days prior to enrollment, and
patients who receive treatment with AEDs must be on stable doses for at least 14 days
prior to enrollment

- Absence of known HIV infection, chronic hepatitis B, or hepatitis C infection; absence
of any other serious medical condition which could interfere with oral medication
intake

- Patients with archival tumor tissue suitable for measurement of proteasome activity
and biomarker status must give permission to access and test the tissue. Patients
without archival tumor tissue are eligible for the Dose-Escalation stage, but not the
Dose-Expansion stage of the study

- For women of child-bearing potential and for men with partners of child-bearing
potential, patient must agree to take contraceptive measures for duration of
treatments and for one month after last study treatment

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

Exclusion Criteria:

- Co-medication or concomitant therapy that may interfere with study results

- History of thrombotic or hemorrhagic stroke or myocardial infarction within 6 months

- Other chemotherapy or anti-tumor treatment for brain tumor (other than therapies
required by the inclusion criteria of this protocol)

- Pregnant or breast feeding

- Uncontrolled intercurrent illness that would limit compliance with study requirements,
or disorders associated with significant immunocompromised state

- Known other previous/current malignancy requiring treatment within ≤ 3 years except
for liited disease treated with curative intent

- Any comorbid condition that confounds the ability to interpret data from the study as
judged by the Investigator or Medial Monitor

- For those enrolled in Adjuvant Treatment with Optune™, patients are excluded if they
are < 22 years of age, have an active implanted medical device, a skull defect, bullet
fragments in the head, sensitivity to conductive hydrogels, a scalp condition that
might interfere with wearing the device, or GBM that is not supratentorial.