Clinical trial NCT02330562
Conditions: Malignant Glioma Glioblastoma
Keywords: Marizomib Bevacizumab Avastin Grade IV malignant glioma proteasome inhibitor glioblastoma brain tumor malignant glioma brain cancer gliosarcoma BEV
Sponsor: Celgene
Start date: 2015-04-15; Completion date: 2021-06-02
Enrollment: 121 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 1/2 clinical trial to evaluate a new combination of drugs, marizomib (MRZ) and bevacizumab (BEV; Avastin®), for the treatment of WHO Grade IV malignant glioma. The study population includes subjects who are in first or second relapse and who have not previously received any bevacizumab or other anti-angiogenic agent or proteasome inhibitor for treatment of malignant glioma. Part 1 Phase 1 evaluates the combination of MRZ and BEV, while Part 2 Phase 2 evaluates single-agent MRZ. Part 3 (Phase 2) includes a combination MRZ using intra-patient dose escalation, and BEV at a fixed dose. Part 4 Phase 1 evaluates MRZ through enteral administration, and BEV at a fixed dose. Part 5 Phase 1 evaluates the repeat-dose pharmacokinetics of MRZ administered IV with ECG.

Detailed description:
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, 3 and 4 of this trial have been completed with the Recommended Dose established at 0.8 mg/m2. Part 5 of this trial is enrolling.

Arms: arm 1: Part1-Phase1: MRZ 10 minute IV infusion on Days 1, 8, and 15 plus BEV IV infusion on Days 1 and 15 of each 28-day cycle.

Part2-Phase2: MRZ 10 minute IV infusion administered on Days 1, 8, and 15 of each 28-day cycle.

Part3-Phase2: All subjects will receive IV MRZ infusion and IV BEV infusion. MRZ will be administered as a 10-minute, IV infusion on Days 1, 8, and 15 of every 28-day cycle using intra-patient dose escalation. Starting dose will be 0.8 mg/m2.

Part4- Phase1: All subjects will receive MRZ enterally by NG tube as a bolus on Days 1, 8 and 15 of the first 28-day cycle and BEV IV infusion on Day 15 of the first 28-day cycle. For subsequent 28-day treatment cycles, MRZ will be administered as an IV at the recommended dose and schedule determined in Part 1, with BEV IV on Days 1 and 15.

Part5-Phase1: All subjects will receive IV MRZ infusion and IV BEV infusion. MRZ will be administered as a 10-minute, IV infusion at 0.8 mg/m2 on Days 1, 8, and 15 of every 28-day cycle 0.8 mg/m2
Interventions: intervention 1: MRZ intervention 2: BEV
Intervention descriptions: intervention 1: MRZ dosing in Phase 1 to range from 0.55 to 0.8 mg/m2. Dose Escalation: MRZ dose-escalation will occur using a standard 3+3 study design.

The RP2D of MRZ (0.8.mg/m2) will be used in a two stage design, with fifteen response-evaluable patients entered in the first stage. If 1 or more responses are observed at the MRZ RP2D, then the second stage will be implemented with an additional 15 response-evaluable patients treated. intervention 2: BEV 10 mg/kg IV infusion administered for all cohorts in Phase 1 only.

Protocol documents:
Prot_SAP_000.pdf: 
EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
1
MRZ-108 Amendment 5 Final: 18 Mar 2020
 
PHASE 1, MULTICENTER, OPEN-LABEL, DOSE-
ESCALATION, COMBINATION STUDY OF MARIZOMIB AND 
BEVACIZUMAB IN BEVACIZUMAB-NAÏVE SUBJECTS WITH 
WHO GRADE IV MALIGNANT GLIOMA FOLLOWED BY 
PHASE 2 STUDIES OF SINGLE AGENT MARIZOMIB AND 
COMBINATION MARIZOMIB AND BEVACIZUMAB, AND 
PHASE 1 DOSE-ESCALATION STUDY OF ENTERALLY-
ADMINISTERED MARIZOMIB WITH BEVACIZUMAB
INVESTIGATIONAL PRODUCT (IP):
Marizomib (CC-92763, NPI-0052)
PROTOCOL NUMBER:
MRZ-108
Original Protocol:
10 October 2014 (Not Implemented)
Amendment 1:
09 January 2015
Amendment 2:
10 January 2016
Amendment 3:
27 March 2017
Amendment 4:
19 April 2018
Amendment 5
18 March 2020
EudraCT NUMBER:
Not applicable
IND NUMBER:
123765
SPONSOR NAME / ADDRESS:
Celgene International II Sàrl
Rue des Moulins 4
Couvet 02108,
Neuchatel
Switzerland
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or consultant for review by you, 
your staff, and ethics committee/institutional review board.  The information contained in this document 
is regarded as confidential and, except to the extent necessary to obtain informed consent, may not be 
disclosed to another party unless such disclosure is required by law or regulations.  Persons to whom the 
information is disclosed must be informed that the information is confidential and may not be further 
disclosed by them.
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EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
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MRZ-108 Amendment 5 Final: 18 Mar 2020
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Name:
Title:
Address: 
Phone:
E-mail:
Note: The back-up 24-hour global emergency contact call center should only be used if you 
are not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls.
Back-up 24-hour Global Emergency Contact Call Center: 
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Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
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MRZ-108 Amendment 5 Final: 18 Mar 2020
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be acceptable.  
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EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
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MRZ-108 Amendment 5 Final: 18 Mar 2020
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
Date
Printed Name of Site Principal Investigator
Institution Name:__________________________________________________
By my signature, I agree to personally supervise the conduct of this study at my study site and 
to ensure its conduct is in compliance with the protocol, informed consent, Institutional 
Review Board (IRB)/Ethics Committee (EC) procedures, instructions from the Sponsor 
representatives, the Declaration of Helsinki, ICH Good Clinical Practice Guidelines, and local 
regulations governing the conduct of clinical studies.
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Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
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MRZ-108 Amendment 5 Final: 18 Mar 2020
PROTOCOL SYNOPSIS
Proposed Title
Phase 1, Multicenter, Open-label, Dose-escalation, Combination Study of 
Marizomib and Bevacizumab in Bevacizumab-Naïve Subjects with WHO 
Grade IV Malignant Glioma Followed by Phase 2 Studies of Single Agent 
Marizomib and Combination Marizomib and Bevacizumab, and Phase 1 Dose-
Escalation Study of Enterally-administered Marizomib With Bevacizumab
Study No.
MRZ-108
Sponsor
Celgene International II Sàrl
Phase
1/2
Indication
WHO Grade IV Malignant Glioma (G4 MG) in bevacizumab-naïve subjects
No. of Sites
5-10 study centers in the United States, Canada, and possibly other regions
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Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
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Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
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MRZ-108 Amendment 5 Final: 18 Mar 2020
Objectives
Part 1 Phase 1
Primary Objective

To determine the maximum tolerated dose (MTD) or Maximum Administered 
Dose (MAD) and recommended Phase 2 dose (RP2D) of the combination of 
marizomib (MRZ) + bevacizumab (BEV), with MRZ as a once weekly dose for 
3 weeks of a 28-day cycle and with a fixed dose and schedule of BEV 
(10 mg/kg administered on Days 1 and 15) in subjects with progressive or 
recurrent G4 MG, who have not previously been treated with either an anti-
angiogenic agent including but not limited to, BEV or a proteasome inhibitor
including, but not limited to, MRZ.
Secondary Objectives

To evaluate the safety of the combination of MRZ + BEV in the subject
population.

To evaluate activity of the combination of MRZ + BEV in the subject
population including:
o
Radiographic Overall Response Rate (ORR) (RANO 2010 criteria)
o
Progression-free Survival (PFS) 
o
Overall Survival (OS)

To evaluate the pharmacokinetics (PK) of MRZ and BEV when administered in 
combination in the subject population.

To assess the blood proteasome inhibition pharmacodynamic (PD) activity of 
the combination of MRZ + BEV in the subject population.
Part 2 Phase 2
Primary Objective

To assess the activity of a once weekly dose for 3 weeks of a 28-day cycle of 
MRZ in subjects with progressive or recurrent G4 MG, who have not previously 
been treated with either an anti-angiogenic agent or a proteasome inhibitor.
Secondary Objectives

To evaluate the safety of single agent MRZ in the subject population.
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Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
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MRZ-108 Amendment 5 Final: 18 Mar 2020
Part 3 Phase 2
Primary Objective

To assess the activity of the of the combination of marizomib (MRZ) + 
bevacizumab (BEV), with MRZ as a once weekly dose for 3 weeks of a 28-day 
cycle (with intra-patient dose escalation) and every other week dosing of BEV 
with a fixed dose and schedule of (10 mg/kg administered on Days 1 and 15) in 
subjects with progressive or recurrent G4 MG, who have not previously been 
treated with either an anti-angiogenic agent or a proteasome inhibitor.
Secondary Objectives

To evaluate the safety of combination of MRZ (with intra-patient dose 
escalation) and BEV at a fixed dose in the subject population.
Part 4 Phase 1
Primary Objective – to be assessed during Cycle 1

To determine the maximum tolerated dose (MTD) of marizomib (MRZ) 
administered enterally by NG tube once weekly for 3 weeks of a 28-day cycle 
during the first treatment cycle.  BEV will be administered IV at a fixed dose 
(10 mg/kg administered on Day 15 and Days 1 and 15 of subsequent cycles). 
Subjects are those with progressive or recurrent G4 MG and who have not 
previously been treated with either an anti-angiogenic agent or a proteasome 
inhibitor.
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Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
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MRZ-108 Amendment 5 Final: 18 Mar 2020
Secondary Objectives – to be assessed during Cycle 1

To evaluate the safety (in particular gastrointestinal (GI) tolerability) of 
enterally administered MRZ by NG tube in the subject population.

To assess the frequency of CNS adverse events (including ataxia, dizziness, 
dysarthria, fall, gait disturbances, and hallucinations) after enterally
administered MRZ in the subject population.

To evaluate the pharmacokinetics (PK) of MRZ administered enterally by NG 
tube in the subject population on Cycle 1 Day 1 and Cycle 1 Day 8.

To assess the blood proteasome inhibition pharmacodynamic (PD) activity of 
MRZ administered enterally by NG tube on Cycle 1 Day 1 and Cycle 1 Day 8,
and to compare this with the PD activity of MRZ administered IV in 
combination with IV BEV on Cycle 2 Day 1 and Cycle 2 Day 8 in the subject 
population.
Part 5 Phase 1
Primary Objective

To determine the repeat-dose pharmacokinetics of MRZ administered IV in 
subjects with progressive or recurrent G4 MG, who have not previously been 
treated with either an anti-angiogenic agent or a proteasome inhibitor.
Secondary Objectives

To monitor the safety of the combination of MRZ and BEV at a fixed dose in 
the subject population.

To describe the activity of the combination of MRZ + BEV, with MRZ as a 
once weekly dose for 3 weeks of a 28-day cycle and every other week dosing of 
BEV with a fixed dose and schedule in the study population.

To evaluate MRZ cardiac safety comparing PK to ECG.
Study Design
Part 1 of this protocol is a Phase 1, open-label, 3+3, dose-escalation study in subjects 
with WHO Grade IV Malignant Glioma (G4 MG) who are in first or second relapse 
and who have not previously received any BEV or other anti-angiogenic agent, 
including sorafenib, sunitinib, axitinib, pazopanib, everolimus, or cilengitide or MRZ 
or any other proteasome inhibitor, including BTZ, CFZ, or IXZ.  Three to 6 
evaluable subjects per cohort will be enrolled: approximately 24 subjects, to 
determine the MTD or MAD (Part 1 Dose-escalation) and an addition of at least 12
more subjects to confirm the MTD/MAD and determine the RP2D (Part 2 Expansion
Cohort) and assess preliminary activity to a total of up to 36 subjects.  Subjects may 
not be enrolled in more than 1 cohort and there will be no intra-subject dose 
escalation.
The Phase 1 portion will be followed by Part 2 a Phase 2 study of single agent MRZ 
administered as a 10-minute infusion at a dose of 0.8 mg/m2 (the RP2D from Phase 
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Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
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MRZ-108 Amendment 5 Final: 18 Mar 2020
1) every week for 3 weeks in 28-day cycles.  This part will be conducted as a 2-stage 
sequential design of up to 30 response-evaluable subjects.
The Part 2 Phase 2 will be followed by Part 3, a Phase 2 study of combination MRZ 
using intra-patient dose escalation, and BEV at a fixed dose.  MRZ will be 
administered as a 10-minute infusion every week for 3 weeks in 28-day cycles at a 
starting dose of 0.8 mg/m2 (the RP2D from Part 1 Phase 1).  After the first cycle
without a dose-limiting adverse event (DLAE), the dose of MRZ will be increased to 
1.0 mg/m2 and after 1 more cycle without a DLAE the dose of MRZ will be 
increased to 1.2 mg/m2.  BEV will be administered every 2 weeks (Days 1 and 15 of 
each 28-day cycle) at a fixed dose of 10 mg/kg.
DLAEs are MRZ-related AEs which are: 1) related to disturbances in the cerebellum 
(ie, ataxia, dizziness, dysarthria, fall, gait disturbances) plus hallucinations of any 
grade or 2) Grade ≥ 2 other AEs. This portion of the study will be conducted in 
approximately 40 eligible subjects of which, based on the AEs seen in Part 1 of the 
study, about 24 subjects are expected to be eligible for intra-patient dose escalation.
Part 4 (Phase 1) of this protocol is an open-label, dose-escalation study (during Cycle 
1) in subjects with WHO Grade IV Malignant Glioma (G4 MG) who are in first or 
second relapse and who have not previously received any BEV or other anti-
angiogenic agent, or MRZ or any other proteasome inhibitor.  Subjects will be 
treated with MRZ enterally administered via NG tube for one 28-day treatment 
cycle, with three doses administered on Days 1, 8 and 15.  Subjects must receive at 
least 3 doses of MRZ, with two of them administered enterally during Cycle 1, to be 
evaluable for dose-limiting toxicity (DLT).  One to 6 evaluable subjects per cohort 
will be enrolled in the first 3 dose-escalation cohorts, and 3 to 6 evaluable subjects 
per cohort will be enrolled in the next 6 dose cohorts, to determine the MTD (Part 4
dose-escalation). Approximately 6 additional subjects will be enrolled to confirm the 
MTD (Part 4 dose-expansion) and assess preliminary activity to a total of up to 
approximately 24 subjects.  Subjects may not be enrolled in more than 1 cohort and 
there will be no intra-subject dose escalation.
Part 5 Phase 1 of this protocol is an open-label MRZ PK study in approximately 12 
subjects with WHO Grade IV Malignant Glioma (G4 MG) who are in first or second 
relapse and who have not previously received any BEV or other anti-angiogenic 
agent, or MRZ or any other proteasome inhibitor.  Subjects will be treated with MRZ 
IV (0.8 mg/m2) on Days 1, 8, and 15 of each 28-day treatment cycle.  BEV will be 
administered IV (10 mg/kg) on Day 15 of Cycle 1, after completion of MRZ PK 
sample collection, and subsequently on Days 1 and 15 (10 mg/kg) of each 
subsequent 28-day cycle.
Study 
Treatments
MRZ is an investigational product that will be provided by the Sponsor.  BEV is 
available commercially and will be provided by the Investigator via prescription to 
subjects who are enrolled into the Part 1 Phase 1, Part 3 Phase 2, Part 4 Phase 1, and 
Part 5 Phase 1 portions of this study.
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EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
11
MRZ-108 Amendment 5 Final: 18 Mar 2020
Study Treatment
Part 1 Phase 1
All subjects will receive intravenous (IV) MRZ infusion followed by IV BEV
infusion as follows:
IV MRZ will be administered as a 10-minute (or longer) IV infusion on Days 1, 8, 
and 15 of every 28-day cycle.  IV hydration will be given both before and after the 
infusion.
IV BEV will be administered as an IV infusion (90 minutes 1st dose, 60 minutes
2nd dose and 30 minutes afterward assuming tolerability) at a dose of 10 mg/kg on 
Days 1 and 15 of every 28-day cycle.  BEV will be administered approximately 
10 minutes after the end of the MRZ infusion when co-administered on the same 
day.
Part 2 Phase 2
All subjects will receive IV MRZ infusion.
MRZ will be administered as a 10-minute, IV infusion on Days 1, 8, and 15 of every 
28-day cycle.  IV hydration will be given before the infusion.
Part 3 Phase 2
All subjects will receive IV MRZ infusion and IV BEV infusion.
MRZ will be administered as a 10-minute, IV infusion on Days 1, 8, and 15 of every 
28-day cycle using intra-patient dose escalation.  Starting dose will be 0.8 mg/m2
(RP2D dose).  If the starting dose is tolerated and no DLAE is observed, the dose 
will be increased to 1.0 mg/m2 after 1 cycle.  If the increased dose is tolerated again 
and no DLAE is observed, the dose of MRZ will be increased to 1.2 mg/m2 after 1 
more cycle.  Dose reductions will be applied as necessary and according to the 
toxicities noted.
If the starting dose of 0.8 mg/m2 is not tolerated (after appropriate medical 
treatment of adverse events, if applicable), the dose will be decreased to
0.7 mg/m2. A further reduction to 0.55 mg/m2 is allowed, if necessary.
BEV will be administered as an IV infusion (90 minutes 1st dose, 60 minutes 2nd dose 
and 30 minutes afterward assuming tolerability) at a fixed dose of 10 mg/kg on 
Days 1 and 15 of every 28-day cycle.  BEV will be administered approximately 
10 minutes after the end of the MRZ infusion when co-administered on the same 
day.  Dose reductions of BEV will not be made, but dose delay or discontinuation 
will be made depending upon the observed adverse events.
Part 4 Phase 1
In Cycle 1, all subjects will receive MRZ enterally by NG tube (reconstituted IV 
formulation) as a bolus on Days 1, 8, and 15 of the first 28-day cycle. BEV will be 
administered as an IV infusion on Day 15, approximately 10 minutes after the 
completion of the MRZ enteral dose administration.
In Cycle 2 and all subsequent cycles, MRZ will be administered IV at the 
recommended dose and schedule determined in Phase 1 Part 1: MRZ 0.8 mg/m2 IV 
weekly for three weeks (Days 1, 8 and 15) of a 28-day cycle and BEV 10 mg/kg IV 
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Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
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MRZ-108 Amendment 5 Final: 18 Mar 2020
on Days 1 and 15.  IV MRZ will be infused over 10-minutes, and BEV will be 
administered as an IV infusion (90 minutes 1st dose, 60 minutes 2nd dose and 
30 minutes afterward assuming tolerability) at a dose of 10 mg/kg on Days 1 and 15 
of every 28-day cycle.  BEV will be administered approximately 10 minutes after the 
end of the MRZ IV infusion when co-administered on the same day.
Part 5 Phase 1
In Cycle 1, all subjects will receive MRZ infused over 10-minutes IV at the dose and 
schedule recommended from Phase 1 Part 1: MRZ 0.8 mg/m2 IV weekly for 3 weeks 
(Days 1, 8, and 15) of a 28-day cycle. BEV will be administered as an IV infusion 
over 90 minutes on Day 15, after the completion of the 60-minute MRZ PK blood 
sample collection.
In Cycle 2 and all subsequent cycles, MRZ will be administered IV at the same dose 
and schedule (0.8 mg/m2 IV weekly for 3 weeks (Days 1, 8, and 15) of a 28-day 
cycle), with IV MRZ infused over 10 minutes. BEV will be administered as an IV 
infusion (90 minutes 1st dose, 60 minutes 2nd dose, and 30 minutes afterward 
assuming tolerability) at a dose of 10 mg/kg on Days 1 and 15 of every 28-day cycle.  
In all subsequent cycles, BEV will be administered approximately 10 minutes after 
the end of the MRZ IV infusion.
Dose-Limiting 
Toxicity
Part 1 Phase 1 (only)
For the Phase 1 portion of the study, dose-limiting toxicity (DLT) is defined as the 
occurrence of any of the following adverse events (AEs) related to study treatment
observed during Cycle 1, using National Cancer Institute Common Terminology 
Criteria for Adverse Events version 4.03 (NCI-CTCAE v 4.03) to determine 
severity:

Grade 3 thrombocytopenia or Grade 2 thrombocytopenia with bleeding.

Grade 4 neutropenia or anemia lasting for more than 4 days.

Febrile neutropenia.

Any ≥ Grade 2 neurological event lasting more than 4 days.

Grade 3 or 4 non-hematological toxicity (excluding alopecia) lasting for more 
than 4 days despite adequate supportive therapy or preventing the next 
scheduled dose from being administered within 4 days of scheduled day; for 
≥Grade 3 fatigue to be considered a DLT, it must be present for more than 
7 days.
Subjects without DLT in Cycle 1 who do not receive 3 MRZ doses or 2 BEV doses 
within 5 weeks from first dose will not be evaluable for DLT and will be replaced.
Dose Limiting 
Adverse 
Events
Part 3 Phase 2 only
For the Part 3 Phase 2 portion of the study initiated with Amendment 3, DLAEs are 
defined as MRZ-related AEs observed which are:

related to disturbances in the cerebellum (ie, ataxia, dizziness, dysarthria, fall, 
gait disturbances) plus hallucinations of any grade 

any other AEs of Grade ≥ 2.
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EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
13
MRZ-108 Amendment 5 Final: 18 Mar 2020
Dose-Limiting 
Toxicity
Part 4 Phase 1
Dose-limiting toxicity (DLT) is defined as the occurrence of any of the following 
adverse events (AEs) related to study treatment observed during Cycle 1, using 
National Cancer Institute Common Terminology Criteria for Adverse Events version 
4.03 (NCI-CTCAE v 4.03) to determine severity:

Grade ≥3 non-hematological toxicity (excluding alopecia), including GI 
toxicities such as nausea, vomiting, constipation, and/or diarrhea, lasting for 
more than 4 days despite adequate supportive therapy or preventing the next 
scheduled dose from being administered within 7 days of scheduled day
o
For ≥Grade 3 fatigue to be considered a DLT, it must be present for more 
than 7 days.

Grade 3 thrombocytopenia or Grade 2 thrombocytopenia with bleeding.

Grade 4 neutropenia or anemia lasting for more than 4 days.

Febrile neutropenia.

Any ≥ Grade 2 neurological event lasting more than 4 days.
Subjects who do not have a DLT in the first cycle of a dose cohort will be 
replaced if they do not receive at least two doses of enterally-administered 
MRZ, with the second dose administered no more than 7 days after the 
scheduled dose.  
Part 1 Phase 1 
Dose 
Escalation 
Subjects who have completed Screening procedures and meet all eligibility criteria 
may be enrolled into the study.  
A 3+3 design will be used to define the MTD/MAD for MRZ + BEV combination 
treatment in 28-day cycles, with MRZ administered on Days 1, 8, and 15 and BEV 
on Days 1 and 15.
MRZ dosing will begin at 0.55 mg/m2 once weekly (Cohort 1).  Additional dose 
cohorts are planned as shown below (Table S-1):
Table S-1. Dose Cohorts for MRZ + BEV Combination
Cohort
IV MRZ
Days 1, 8, and 15
IV BEV
Days 1 and 15
-2
0.3 mg/m2
10 mg/kg
-1
0.4 mg/m2
10 mg/kg
1
0.55 mg/m2
10 mg/kg
2
0.7 mg/m2
10 mg/kg
3
0.8 mg/m2
10 mg/kg
4
Additional cohorts with extended 
infusion duration if required
10 mg/kg
Initially 3 subjects will be enrolled into a cohort, commencing with Cohort 1 and the 
doses shown in Table S-1 above.  Dose escalation will proceed as follows:
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Protocol MRZ-108 Amendment 5
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Confidential and Proprietary
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MRZ-108 Amendment 5 Final: 18 Mar 2020

If none of the first 3 evaluable subjects in a dose cohort experience a DLT 
during Cycle 1, then enrollment into the next dose cohort can be initiated.

If ≥2 of the first 3 evaluable subjects in a dose cohort experience a DLT during 
Cycle 1, then the MTD has been exceeded and dose escalation will not proceed.

If 1 of the first 3 evaluable subjects in a dose cohort experiences a DLT during 
Cycle 1, then an additional 3 subjects will be enrolled into the same cohort.

If 1/6 evaluable subjects in the expanded 6-subject cohort experiences a DLT 
during Cycle 1, then the next higher dose cohort can be tested and enrollment of 
the next 3 subjects at the next higher dose level can be initiated.

If ≥2/6 evaluable subjects in the expanded 6-subject cohort experience a DLT 
during Cycle 1, then the MTD has been exceeded and no further dose escalation 
will occur.
The MTD is defined as the dose level below the cohort where DLT is observed in at 
least 2 subjects in the same cohort during Cycle 1.  Intermediate dosing levels may 
be explored if indicated.  If the Sponsor and Investigators agree, then additional 
cohorts starting below the MTD for the 10-minute infusion may be enrolled to 
explore extended infusion lengths.  The dose of 0.8 mg/m2 will not be exceeded and 
will be the MAD.  The RP2D is the MTD/MAD unless further safety information 
suggests a lower dose for future trials.
Teleconferences between Triphase and the clinical study sites will occur at least 
every other week to discuss safety.  Additional teleconferences may be scheduled at 
the end of each cohort to decide on the dose and/or MRZ infusion length of the next 
cohort.  Once the MTD or Maximum Administered Dose (MAD) has been identified, 
a cohort of at least 12 additional, evaluable subjects will be treated at the MTD/MAD
to further confirm the safety and to assess preliminary activity for the combination 
treatment.  This cohort may be used to determine the RP2D.
Part 2 Phase 2 
Dose 
Escalation
Dose escalation of MRZ was not allowed in this portion of the study.
Part 3 Phase 2 
Intra-patient 
Dose 
Escalation
MRZ dosing will start at 0.8 mg/m2 given on Days 1, 8, and 15 in 28-day cycles as a 
10-minute IV infusion.  If the subject tolerates the MRZ dose during the first cycle 
without a DLAE, the dose of MRZ will be increased to 1.0 mg/m2.  After 1 more 
cycle without a DLAE, the dose of MRZ will be increased to 1.2 mg/m2. All dose 
increases require approval by the Sponsor’s Medical Monitor.
DLAEs are MRZ-related AEs 1) related to disturbances in the cerebellum (ie, ataxia, 
dizziness, dysarthria, fall, gait disturbances) plus hallucinations of any grade or 
2) Grade ≥ 2 other AEs. If the MRZ starting dose of 0.8 mg/m2 is not tolerated after 
appropriate medical treatment of AEs in the first cycle, then the dose will be 
decreased to 0.7 mg/m2 with no further dose increases allowed.
BEV will be administered as an IV infusion (90 minutes 1st dose, 60 minutes 2nd dose 
and 30 minutes afterward assuming tolerability) at a dose of 10 mg/kg on Days 1 and 
15 of every 28-day cycle.  BEV will be administered approximately 10 minutes after 
the end of the MRZ infusion when co-administered on the same day.  The dose of 
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
15
MRZ-108 Amendment 5 Final: 18 Mar 2020
BEV will not increase.  No dose adjustments will be made to BEV dosing, although 
doses may be delayed or discontinued.
Part 4 Phase 1 
Dose 
Escalation and 
MTD Dose 
Expansion 
Cohort
Subjects who have completed Screening procedures and meet all eligibility criteria 
may be enrolled into the study.  
A modified 3+3 design will be used to define the MTD for MRZ IV formulation 
reconstituted and administered enterally via NG tube in the first 28-day cycle, with 
MRZ administered on Days 1, 8, and 15 and BEV on Day 15, with initially one 
subject enrolled into each of the first 3 dose cohorts to expedite dose-escalation into 
the anticipated therapeutically effective dose range.
MRZ dosing will begin at 0.075 mg/m2 once weekly (Cohort 1).  Additional dose 
cohorts are planned as shown below (Table S-2):
Table S-2. Dose Cohorts for MRZ + BEV Combination, Part 4 Phase 1
Cohort
Number of 
Subjects
Enteral MRZ 
(mg/m2)
Cycle 1
Days 1, 8, and 15
IV MRZ 
(mg/m2)
Cycle 2+ Days 
1, 8 and 15*
IV BEV (mg/kg)
Cycle 1 Day 15
Cycle 2+ Days 1 
and 15
-1
3-6
0.025
0.8
10
1
1-6
0.075
0.8
10
2
1-6
0.225
0.8
10
3
1-6
0.675
0.8
10
4
3-6
1.0
0.8
10
5
3-6
1.35
0.8
10
6
3-6
1.7
0.8
10
7
3-6
2.0
0.8
10
8
3-6
2.3
0.8
10
9
3-6
2.6
0.8
10
* For Cycle 2 and all subsequent cycles, MRZ will be administered IV at 0.8 mg/m2 given on 
Days 1, 8, and 15 in 28-day cycles as a 10-minute IV infusion.
Initially 1 subject will be enrolled into the first three dose cohorts and 3 subjects will 
be enrolled into the next 6 dose cohorts.  Enteral MRZ dose escalation will proceed 
as follows:

If the first DLT-evaluable subject in dose cohort 1 does not experience a DLT or
intermediate toxicity during Cycle 1, then enrollment into the next dose cohort 
can be initiated.

If the first DLT-evaluable subject in a 1-subject dose cohort experiences a DLT 
during Cycle 1, then up to 5 additional subjects will be enrolled into the same 
cohort.

The 1-subject cohorts will be expanded to 3 subjects with the second instance of 
first-cycle intermediate toxicity.  Intermediate toxicity is defined as any Grade 2 
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
16
MRZ-108 Amendment 5 Final: 18 Mar 2020
or higher adverse event that is deemed clinically significant by the Investigator 
and which cannot be clearly identified as being related to the underlying 
condition, comorbid condition, or concomitant medication.  Once a 1-subject 
cohort has been expanded, all subsequent cohorts will have at least 3 subjects 
(unless the first 2 subjects have DLT prior to the enrollment of a third subject).

If there are 2 subjects with DLT in Cohort 1, then 3 subjects can be enrolled in 
Cohort -1.  The decision to explore Cohort -1 will be made by the participating 
Investigators and Sponsor’s Medical Monitor(s).  If Cohort -1 proceeds without 
any subject with a DLT, participating Investigators and Sponsor’s Medical 
Monitor(s) may decide to revisit Cohort 1 and, if tolerated, continue with the 
escalation as shown in Table S-2, or with intermediate dose levels.

If 1 of the first 3 evaluable subjects in a 3-subject dose cohort experiences a 
DLT during Cycle 1, then an additional 3 subjects will be enrolled into the same 
cohort.  

If no more than 1 of the 6 DLT-evaluable subjects in an expanded dose cohort
experiences a DLT during Cycle 1, then the next higher dose cohort can be 
initiated with 3 subjects enrolled at the next higher dose level.

If ≥ 2/6 evaluable subjects in an expanded dose cohort experiences a DLT 
during Cycle 1, then the MTD has been exceeded and no further dose escalation 
will occur.
The MTD is defined as the dose level below the cohort where DLT is observed in at 
least 2 subjects in the same cohort during Cycle 1.  Intermediate dosing levels may 
be explored if indicated.
The dose of 2.6 mg/m2 is expected to be above the MTD for enterally-administered 
MRZ.  If this is not the case, additional cohorts can be explored with dose escalations 
between cohorts kept at approximately 20%.
Once the MTD has been determined, a cohort of approximately 6 additional, 
response-evaluable subjects will be enrolled in the Part 4 Phase 1 Expansion Cohort, 
to further explore the safety profile of enterally-administered MRZ combined with 
IV BEV.
Teleconferences between Sponsor and the clinical study sites will occur at least 
every other week to discuss safety.  Additional teleconferences may be scheduled at 
the end of each cohort to decide on the dose of the next cohort.
No. Subjects
Part 1 Phase 1: 36 subjects were enrolled in the study at multiple centers.
Part 2 Phase 2: Up to 30 response-evaluable subjects will be enrolled in the study at 
multiple centers.
Part 3 Phase 2: Up to 40 eligible subjects will be enrolled in the study at multiple 
centers.
Part 4 Phase 1: Up to 24 eligible subjects will be enrolled in the study at multiple 
centers.
Part 5 Phase 1: Approximately 12 eligible subjects will be enrolled in the study at a 
single center.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
17
MRZ-108 Amendment 5 Final: 18 Mar 2020
Study 
Population 
The study population includes subjects with G4 MG (including glioblastoma and 
gliosarcoma) who are in first or second relapse and who have not previously received 
any BEV or other anti-angiogenic agent, including sorafenib, sunitinib, axitinib, 
pazopanib, everolimus, or cilengitide or MRZ or any other proteasome inhibitor, 
including BTZ, CFZ, or IXZ.  The eligibility criteria are the same for both Phase 1 
and Phase 2 portions of the study except where noted.
Inclusion Criteria (applicable for all Parts including Part 5):
Subjects must meet the following criteria to be eligible for study participation:
1.
Understand and voluntarily sign and date an informed consent document 
prior to any study related assessments/procedures are conducted.
2.
Males and females of age 18 years 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).  Subjects must have at least 1 measurable 
lesion by RANO criteria (≥10 mm in 2 perpendicular diameters).
4.
Subjects must have previously completed standard radiation therapy and 
been exposed to temozolomide.  Subjects must be in first or second relapse.
5.
No prior treatment with MRZ or any other proteasome inhibitors, including 
BTZ, CFZ, or IXZ or BEV or any other anti-angiogenic agents, including 
sorafenib, sunitinib, axitinib, pazopanib, everolimus, or cilengitide.
6.
No investigational agent within 4 weeks prior to first dose of study drug.
7.
At least 4 weeks from surgical resection and at least 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 approximately 8 weeks apart.
8.
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.
9.
All AEs resulting from prior chemotherapy, surgery, or radiotherapy, must 
have resolved to NCI-CTCAE (v. 4.03) Grade 1 (except for laboratory 
parameters outlined below).
10. 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 100 × 109/L.

Hemoglobin 9 g/dL.

Absolute neutrophil count (ANC) 1.5 × 109/L.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
18
MRZ-108 Amendment 5 Final: 18 Mar 2020

Serum bilirubin 1.5 × upper limit of normal (ULN) or 3 × ULN if 
Gilbert’s disease is documented.

Aspartate transaminase (AST) 2.5 ULN.

Alanine transaminase (ALT) 2.5 ULN.

Serum creatinine 1.5 × ULN.

Urine protein: creatinine ratio ≤ 1.0 at screening.
11. Karnofsky Performance Status (KPS) score 70%.
12. 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 for 3 months after the last dose of MRZ or 
6 months after the last dose of BEV, whichever is longer. 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).
13. Willing and able to adhere to the study visit schedule and other protocol 
requirements.
Exclusion Criteria (applicable for all Parts including Part 5):
Subjects with any of the following will be excluded from participation in the study:
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, of 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.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
19
MRZ-108 Amendment 5 Final: 18 Mar 2020
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 (All Parts) (Note: These exclusion criteria also 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):
1.
Any prior history of hypertensive crisis or hypertensive encephalopathy.
2.
Systolic blood pressure (BP) > 150 mmHg or diastolic BP > 100 mmHg.
3.
Unstable angina.
4.
New York Heart Association Grade ≥II congestive heart failure.
5.
History of myocardial infarction within 6 months.
6.
Subjects with mean QTcF interval > 500 ms.
7.
Clinically significant peripheral vascular disease
8.
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.
9.
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.
10. Minor surgical procedures, fine needle aspirations or core biopsies within 
7 days prior to Day 1.
11. History of abdominal fistula, GI perforation, or intra-abdominal abscess 
within 6 months prior to Day 1.
12. Serious, non-healing wound, ulcer, or bone fracture requiring surgical 
intervention.
Length of 
Study 
Participation
Subjects may continue on study treatment until disease progression, unacceptable 
toxicity, withdrawal of consent, or termination of the study.  For subjects who 
discontinue study drug for reasons other than disease progression, whenever 
possible, tumor assessment will continue as per protocol until disease progression.  
After disease progression, subjects will be followed for survival and the start of first 
new anti-GBM therapy and its outcome.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
20
MRZ-108 Amendment 5 Final: 18 Mar 2020
Investigational 
Product/ 
Background 
Therapy/ 
Route/ 
Regimen
Part 1 Phase 1
MRZ will be administered IV over 10 minutes.  Other infusion lengths may be 
explored.  Volume of administration will vary based on assigned dose (Table S-1) 
and subject body surface area (BSA).  To mitigate the possibility of renal 
dysfunction, subjects will receive normal saline administered at 350 mL/hour for 
1 hour before and for 2 hours after the MRZ infusion. The MRZ infusion will be 
started after approximately 350 mL of saline have been given over 1 hour.  After the 
MRZ infusion has been completed, approximately 700 mL of saline will be given 
over 2 hours, for a total volume of saline infusion equal to approximately 1 L.  Post 
infusion hydration may be reduced at the discretion of the Investigator.  The 
lyophilized drug product contains 2 mg API and 60 mg sucrose bulk excipient.  
Cartons contain one vial of lyophile together with a Diluent vial containing 
55% propylene glycol, 5% ethanol, and 40% citrate buffer pH 5 (20 mL fill; 10 mL 
intended for use).
BEV will be administered as an IV infusion (90 minutes 1st dose, 60 minutes 2nd dose 
and 30 minutes afterward assuming tolerability) as described in the current package 
insert.  BEV will be administered approximately 10 minutes after the end of the 
MRZ infusion when co-administered on the same day.
Part 2 Phase 2
MRZ will be administered IV over 10 minutes at a dose of 0.8 mg/m2.  To mitigate 
the possibility of renal dysfunction, subjects will receive normal saline administered 
at 250 mL for 30 minutes before the MRZ infusion.  The lyophilized drug product is 
the same as used in the Phase 1 portion.
Part 3 Phase 2
MRZ will be administered IV over 10 minutes at a starting dose of 0.8 mg/m2.  
Based on the subject’s tolerability, the dose of MRZ may be increased after the first 
cycle without a dose-limiting adverse event (DLAE) and again after 1 more cycle 
without a DLAE. The lyophilized drug product is the same as used in the other 
portions of the study.  In Amendment 3, pre and post MRZ dose hydration is not 
required, except where assessed as clinically necessary by Investigator.
BEV will be administered as an IV infusion (90 minutes 1st dose, 60 minutes 2nd dose 
and 30 minutes afterward assuming tolerability) as described in the current package 
insert.  BEV will be administered approximately 10 minutes after the end of the 
MRZ infusion when co-administered on the same day.
Part 4 Phase 1
MRZ IV formulation will be reconstituted and administered enterally via NG tube in 
a dose-escalation design on Days 1, 8, and 15 of the first 28-day treatment cycle.  
BEV will be administered IV on Day 15 during Cycle 1.  For the subsequent 28-day 
treatment cycles, MRZ will be administered as an IV at the recommended dose and 
schedule determined in Phase 1 Part 1: MRZ 0.8 mg/m2 IV weekly for three weeks 
(Days 1, 8 and 15, 10 min infusion) of a 28-day cycle, with BEV 10 mg/kg IV on 
Days 1 and 15.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
21
MRZ-108 Amendment 5 Final: 18 Mar 2020
BEV will be administered as an IV infusion (90 minutes 1st dose, 60 minutes 2nd dose 
and 30 minutes afterward assuming tolerability) as described in the current package 
insert.  BEV will be administered approximately 10 minutes after the end of the 
MRZ administration when co-administered on the same day.
Volume of MRZ administration will vary based on assigned dose (Table S-2) and 
subject body surface area (BSA).  The volume of MRZ administration is calculated 
by: Volume = Dose (mg) * BSA (m2) / 0.2 (conc. of MRZ in solution in mg/mL). 
The lyophilized drug product contains 2 mg API and 60 mg sucrose bulk excipient.  
Cartons contain one vial of lyophile together with a Diluent vial containing 55%
propylene glycol, 5% ethanol, and 40% citrate buffer pH 5 (20 mL fill; 10 mL 
intended for use).
Part 5 Phase 1
MRZ will be administered IV over 10 minutes at a dose of 0.8 mg/m2.  In 
Amendment 5, pre and post MRZ dose hydration is not required, except where 
assessed as clinically necessary by Investigator. BEV will be administered as an IV 
infusion over 90 minutes on Cycle 1 Day 15 immediately following the completion 
of the 60-minute MRZ PK blood sample collection.
Beginning with Cycle 2, BEV will be administered as an IV infusion (60 minutes on 
Cycle 2 Day 1 if tolerated at 90 min on Cycle 1 Day 15, and 30 minutes on Cycle 2 
Day 15 and afterwards assuming tolerability at 60 min on Cycle 2 Day 1) as 
described in the current package insert. BEV will be administered approximately 10 
minutes after the end of the MRZ infusion when co-administered on the same day in 
Cycle 2 and all subsequent cycles.
Procedures
For Part 1 Phase 1, Part 2 Phase 2, and Part 3 Phase 2, study visits and procedures 
will be performed as outlined in Table 1. For Part 4 Phase 1, study visits and 
procedures will be as outlined in Table 2.  For Part 5 Phase 1, study visits and 
procedures will be as outlined in Table 3.  The study will consist of Screening, 
Baseline, Treatment, and Follow-up periods.
Screening
The screening period may not exceed a 28-day window (with an extra 3-day window 
for unavoidable delays) prior to start of study treatment (Cycle 1 Day 1). 
Assessments will include medical history, cancer history including previous 
treatments, and tumor assessments.  Tumor assessment must have a baseline MRI 
scan with contrast within 14 (+3) days prior to first treatment with investigational 
product.  
Baseline
Physical examination including Karnofsky Performance Status (KPS), neurological 
evaluation, vital signs measurement, electrocardiogram (ECG), and laboratory tests 
are to be conducted within 7 (+2) days prior to Cycle 1 Day 1.
 
 
 
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
22
MRZ-108 Amendment 5 Final: 18 Mar 2020
Treatment
Subjects may continue on study treatment until disease progression, unacceptable 
toxicity, withdrawal of consent, or termination of the study.  Assessment will include 
MRI scans at the end of every even numbered cycle (± 7 days) using RANO 2010 
criteria for assessment.  Responses (complete response [CR] and partial response 
[PR]) should be confirmed by repeat scans performed 4 weeks (± 2 days) later.  
Subjects in Parts 2, 3, 4, and 5 may continue treatment with MRZ for 1 or 2 cycles 
after an MRI indicates progression of disease, if according to the Investigator’s 
judgement, the MRI is interpreted as showing possible pseudo-progression, and there 
is no significant clinical deterioration of the subject.
Functional status using the KPS
 
 will be 
assessed regularly
.
Subjects who discontinue study drug for reasons other than disease progression 
whenever possible will continue tumor assessment as per protocol schedule until 
progression.
End-of-Treatment Visit
Subjects will be followed for safety for 28 (+ 7) days after discontinuation of study 
therapy (Part 1 Phase 1, Part 3 Phase 2, Part 4 Phase 1, and Part 5 Phase 1: both 
MRZ and BEV; Part 2 Phase 2: MRZ).
Post Study Follow-up
All subjects will be followed in the long-term survival follow-up period for as long 
as they are alive.  Long-term follow-up will occur every 3 months (± 7 days) after the 
End-of-Treatment visit.  Telephone contact will be sufficient to document survival 
status.  During the follow-up period, the following information will be collected: 
survival, and first subsequent anti-malignant glioma regimens (regimen, start and end 
date, and treatment outcome).
Overview of 
Assessments  
Activity (Efficacy) Assessments
Tumor response, including progressive disease, will be assessed with MRI every 
2 cycles (at the end of each even-numbered cycle of therapy) according to the RANO 
2010 criteria, including:

Radiographic Response Rate 

Progression-free Survival (PFS) 

Overall Survival (OS)
Pharmacokinetic (PK) Assessments: MRZ (Part 1 Phase 1, Part 4 Phase 1, and 
Part 5 Phase 1)
In Part 1 Phase 1, blood samples will be taken for peak and trough measurements, 
pre-dose and immediately prior to (end of infusion) EOI, on Cycle 1 Day 1.  
In Part 1 Phase 1, on Cycle 1 Day 15 full PK sampling will be done: pre-dose, 
immediately prior to EOI and then 2, 5, 15, 30, 45, 60, 90 and 120 minutes post 
infusion.  
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
23
MRZ-108 Amendment 5 Final: 18 Mar 2020
In Part 4 Phase 1, full PK sampling will be done on Cycle 1 Day 1 and on Cycle 1 
Day 8: pre-dose, immediately prior to EOI and then 2, 5, 15, 20, 30, 45, 60, 90 and 
120 minutes post administration.
In Part 5 Phase 1, full PK sampling will be done on Cycle 1 Day 1, Cycle 1 Day 8, 
and Cycle 1 Day 15, with blood samples collected pre-dose, immediately prior to the 
end of infusion (EOI), and then 2, 5, 15, 20, 30, 45, and 60 minutes post-EOI.
Pharmacokinetic Assessments: BEV (Part 1 Phase 1 only)
Pre-dose and immediately prior to EOI serum samples will be taken on Cycle 1 
Days 1 and 15 to assess BEV peak and trough levels in plasma. 
Blood Pharmacodynamic (PD) Assessments (Part 1 Phase 1 and Part 4 Phase 1)
In Part 1 (Phase 1), proteasome activity levels in packed whole blood (PWB) lysates 
and peripheral blood mononuclear cell (PBMC) lysates, comparing pre- and post-
MRZ administration levels, will be determined on Days 1, 8, and 15 of Cycle 1; 
Days 1 and 15 of each cycle thereafter; and at the End-of Treatment Visit.
In Part 4 (Phase 1), proteasome activity levels in packed whole blood (PWB) lysates 
and peripheral blood mononuclear cell (PBMC) lysates, comparing pre- and post-
MRZ administration levels, will be determined on Days 1 and 8 of Cycle 1 and Cycle 
2.
Statistical 
Analyses
Overview
Part 1 Phase 1
A 3 + 3 design will be utilized to determine the MTD/MAD for MRZ + BEV 
combination treatment in 28-day cycles.  (Subjects who do not have a DLT will be 
replaced if they discontinue treatment with MRZ or BEV in Cycle 1 for any other 
reasons.)  After MTD/MAD has been determined in the dose-escalation part of the 
study, at least 12 additional subjects will be treated at the MTD/MAD to confirm the 
safety and assess the preliminary activity for the combination of MRZ + BEV.
For all analyses by dose cohorts, the MTD/MAD confirmation cohort subjects will 
be combined with the corresponding dose cohort in the MTD/MAD determination 
phase as one single dose cohort.
Part 2 Phase 2
A 2-stage sequential design will be utilized in Phase 2.  Fifteen response-evaluable 
subjects will be in the first stage.  If at least 1 response is observed, then the study
will be expanded, and an additional 15 response-evaluable subjects will be treated.  If 
at least 5 responses are observed in the 30 response-evaluable subjects, then MRZ 
will be considered active as a single agent.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
24
MRZ-108 Amendment 5 Final: 18 Mar 2020
Part 3 Phase 2
Forty eligible subjects will be treated.  Assuming there are 30 deaths observed 
(ie, 25% of the subjects are censored), the resulting 95 % confidence interval (CI) is 
7.2 – 14.8 months, with a width equal to 7.6 months for an estimated median survival 
of 10 months.
Part 4 Phase 1
A modified 3 + 3 design will be utilized to determine the MTD for MRZ
administered enterally via NG tube in the first 28-day treatment cycle.  (Subjects 
who do not have a DLT in Cycle 1 will be replaced if they discontinue treatment 
with enterally administered MRZ in Cycle 1 before receiving at least 2 doses for any 
other reasons.)  After MTD has been determined in the dose-escalation part of the 
study, approximately 6 additional response-evaluable subjects will be treated at the 
MTD to confirm the safety of MRZ administered enterally via NG tube.
For all analyses by dose cohorts, the MTD confirmation cohort subjects will be 
combined with the corresponding dose cohort in the MTD determination (dose-
escalation) phase as one single dose cohort.
Part 5 Phase 1
Tumor response, including progressive disease (PD), progression-free survival 
(PFS), and overall survival (OS) will be assessed.  Tumor response will be assessed 
by the Investigators using RANO 2010 criteria.  The overall confirmed response rate 
will be presented.  Endpoints of response based on tumor assessments will be 
calculated for subjects who received at least 3 doses of MRZ and had at least 1 post-
dose tumor evaluation.  Disease Progression (PD), PFS, and OS will be tabulated for 
Part 5.
Safety (All Parts)
All subjects will be evaluated for safety analysis if they receive at least one dose of 
MRZ (or BEV in Parts 1, 3, 4 and 5).  The safety data will be presented in individual 
listings and summary tables, including frequency tables for adverse events and 
frequency and shift tables for laboratory variables.  The safety population will be all 
subjects who received at least one dose of either study drug in any part of the study.
Pharmacokinetics (PK) (Part 1 Phase 1, Part 4 Phase 1, and Part 5 Phase 1)
Non-compartmental analyses will be performed.  The following PK parameters will 
be calculated using standard non-compartmental analysis: maximum observed blood 
drug concentration (Cmax), time of maximum blood concentration (Tmax), elimination 
half-life (T1/2), area under the blood concentration-time curve (AUC0-inf), clearance 
(CL), and volume of distribution.  Blood concentrations and computed PK 
parameters for MRZ will be listed and summarized by cohort (mean, geometric 
mean, standard deviation, coefficient of variation, minimum, maximum and number 
of observations).  Subject population for PK will be all subjects who received at least
one dose of either study drug and had at least one post-MRZ administration sample 
analyzed. Compartmental PK modeling may be conducted, as appropriate.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
25
MRZ-108 Amendment 5 Final: 18 Mar 2020
Pharmacodynamics (Part 1 Phase 1 and Part 4 Phase 1)
Change in proteasome activity levels in PWB lysates and PBMC lysates, comparing 
pre- and post-MRZ administration.  
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
26
MRZ-108 Amendment 5 Final: 18 Mar 2020
Table 1: Schedule of Assessments and Procedures, Part 1 Phase 1 and Parts 2 and 3 Phase 2: All Cycles
Screen 1
Baseline 1
Cycle 1
Cycle 2+
End of 
Treatment 22
Post Study
Follow-up 23
Study Day
-28 to -1
-7 to -1
1
8
15
1
8
15
Window Up to Day -31
Up to Day -9
±1
±1
±1
±1
±1
+7
±7
Informed consent
X
Medical history/Demographics
X
Concomitant medications 1
X
X
X
X
X
X
X
X
X
X
Physical examination, height 2
X
Targeted physical, weight, BSA 2
X
X
X
X
Karnofsky Performance Status 
(KPS) 3
X
X
X
X
Toxicity evaluation 6
X
X
X
X
X
X
Vital signs (HR, temp, BP) 7
X
X
X
X
X
X
X
X
ECG 8
X
X
Complete Blood Count,
Differential, Platelets 9
X
X
X
X
X
X
Serum Chemistry 10
X
X
X
X
X
X
PT/PTT 11
X
X
X
Urinalysis12
X
X
X
Marizomib infusion 13
X
X
X
X
X
X
Bevacizumab infusion 14
X
X
X
X
Blood PK sampling (MRZ) 15
X
X
Blood PK sampling (BEV) 16
X
X
Pregnancy test 17
X
X
Blood Proteasome assay 18
X
X
X
X
X
X
Tumor measurement 19
X (-14 to -1)
(3-day window)
At the end of each even numbered cycle
X
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
27
MRZ-108 Amendment 5 Final: 18 Mar 2020
1.
Within 7 (+2) days of starting treatment except Informed Consent, demographics, medical history, concomitant medications, complete physical examination, 
radiographic/tumor assessments, and consent to acquire and test archival tumor tissue samples, which can be obtained within 28 days (+3) prior to the start of treatment.
2.
Height measured at baseline only.  Physical Examination is a complete physical as per institutional guidelines (genitourinary examination not required unless there are related 
signs or symptoms) at baseline, but thereafter as directed by signs and symptoms (targeted physical examination).
3.
Functional assessment using the Karnofsky Performance Status (KPS) is to be completed at baseline, at the beginning of each cycle, and at the end of treatment. See 
Appendix A.
6.
Toxicity evaluation is an assessment of reported and observed adverse events, in all parts of the study compared to pre-dose evaluation.
7.
Vital Signs: (blood pressure, heart rate, and temperature) during the Part 1 Phase 1 and Part 3 Phase 2 portions of the study in Cycle 1, Days 1 and 15: immediately before the 
MRZ infusion and immediately before the BEV infusion and approximately 10 (±2) minutes, 30 (±5) minutes and 1 hour (±5 minutes) following the BEV infusion.  Cycle 2+, 
Days 1 and 15: prior to the MRZ infusion and prior to the BEV infusion and 30 (±5) minutes following each BEV infusion.  In all cycles, Day 8, immediately before the MRZ 
infusion and 30 (±5) minutes following each MRZ infusion.  During the Part 2 Phase 2 portion of the study, in Cycle 1, Days 1, and 15: immediately before the MRZ infusion 
and approximately 10 (±2) minutes, 30 (±5) minutes and 1 hour (±5 minutes) following the MRZ infusion.  Cycle 2+, Days 1, 8, and 15: prior to the MRZ infusion and 30 
(±5) minutes following each MRZ infusion.  In all cycles, Day 8, immediately before the MRZ infusion and 30 (±5) minutes following each MRZ infusion.  For all portions 
of the study vital signs are also collected as part of the physical examination.
8.
ECG: Eligibility ECGs must be performed within 7 (+2) days prior to Day 1.  In Part 1 and Part 2 Phase 2 ECGs will be collected on Cycle 1 only (Days 1 and 15), within 60 
minutes prior to the MRZ infusion and within 5 (±1) minutes following the MRZ infusion.  An End-of-Treatment ECG is to be collected.  Additional ECGs should be 
obtained if clinically indicated.  In Part 3 Phase 2, only Screening and End-of-Treatment ECGs will be conducted unless others are clinically indicated. (Cycle 1 Day 1 Cycle 
1 Day 15 ECGs will not be collected.)
9.
Hemoglobin (Hgb), hematocrit (Hct), red blood cell (RBC) count, white blood cell (WBC) count with differential, and platelets. Hematology tests can be performed within 
72 hours of scheduled dosing on Days 1 and 15 except prior to Cycle 1, which can be done within 7 (+2) days prior to dosing.  Should a subject experience a Grade 4 
hematologic toxicity, the appropriate test will be monitored in accordance with institutional guidelines (at minimum: weekly) until Grade ≤2.  The following tests should 
meet minimum stipulations prior to entry into Cycle 2+: Hgb ≥8 g/dL; platelets ≥75 x 109 /L.
10. Sodium, potassium, chloride, bicarbonate, calcium, magnesium, glucose, BUN, serum creatinine, uric acid, ALT, AST, alkaline phosphatase, total protein, albumin, and total 
bilirubin.  Chemistry will be performed within 72 hours of scheduled dosing, on Days 1 and 15 except prior to Cycle 1, which can be done within 7 (+2) days prior to dosing.  
Minimum re-treatment criterion prior to the beginning of each new cycle: creatinine ≤1.5 x ULN.
11. Coagulation tests will be performed within 72 hours of scheduled dosing on Day 1, except prior to Cycle 1, which can be done within 7 (+2) days prior to dosing. Prothrombin 
time (PT) or International Normalized Ratio (INR) and partial thromboplastin time (PTT) may be performed more often if clinically indicated.  
12. Urinalysis: protein, blood, glucose, pH; microscopic (RBC, WBC, casts) if abnormal urinalysis. Urinalysis performed within 72 hours of scheduled dosing on Day 1, except 
prior to Cycle 1, which can be done within 7 (+2) days prior to dosing.
13. Subjects are to be encouraged to maintain good oral hydration during the study (eg, 2 liters per day, as considered appropriate by the Investigator).  Part 1 MRZ infusion: 
injected over 10 minutes (or longer depending upon cohort).  The volume of infusate will vary per subject depending on dose and BSA.  In Part 1 Phase 1 subjects will receive 
normal saline starting prior to and following the infusion administered at ~350 mL/hour, with the infusion to occur after ~350 mL have been given with a total volume of 
infusion to equal one liter.  In Part 2 Phase 2 subjects will receive 250 mL normal saline over 30 minutes prior to the MRZ infusion.  At the discretion of the Investigator, 
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
28
MRZ-108 Amendment 5 Final: 18 Mar 2020
additional normal saline can be given after the MRZ infusion is complete.  Part 3 Phase 2: No pre or postdose hydration is required unless re-instituted after safety review by 
the Medical Monitor, representatives of the Sponsor, and the Investigators.  In each subject the dose will be increased if tolerated to 1.0 mg/m2 after Cycle 1 and to 1.2 mg/m2
after Cycle 2.  Dose escalation after dose reduction is not recommended but will be allowed only with the approval of the Sponsor’s Medical Monitor.
14. BEV administered as an IV infusion.  First dose should be infused over 90 minutes and if tolerated, the second infusion may be given over 60 minutes, and if tolerated, 
subsequent infusions may be given over 30 minutes.  Infusions may be interrupted or lengthened to treat or prevent infusion-related reactions.  BEV is administered 
approximately 10 minutes after the end of the MRZ infusion.  BEV is not given during Part 2 Phase 2.
15. Blood PK Sampling (MRZ) (during Part 1 Phase 1 dose escalation only): On Cycle 1 Day 1, MRZ samples will be obtained before treatment and just prior to end of infusion.  
On Cycle 1 Day 15, MRZ samples will be obtained before treatment, just prior to end of infusion, and 2, 5, 15, 30, 45, 60, 90, and 120 minutes after the infusion.  Every effort 
should be made to collect samples at the prescribed times, but deviations up to 10% of the time point are allowed.  Additional samples may be collected if the subject 
experiences a potentially drug-related SAE.  Use Sponsor-provided PK kits.  Process, store and ship samples per instructions in Study Reference Manual.
16. Blood PK Sampling (BEV) (during Part 1 Phase 1 dose escalation only): For BEV Cycle 1 Day 1 and 15, BEV plasma samples will be obtained before treatment and just 
prior to end of infusion.  Use Sponsor-provided PK kits.  Every effort should be made to collect samples at the prescribed times, but deviations up to 10% of the time point are 
allowed.  Use Sponsor-provided PK kits.  Process, store and ship samples per instructions in Study Reference Manual.
17. Pregnancy test (serum or urine) to be performed at Baseline, End-of-Treatment visit, and more frequently if clinically indicated.
18. Blood proteasome assay (during Part 1 Phase 1 dose escalation only): Cycle 1 Day 1 (before treatment and 1 hour post MRZ infusion), Day 8 (before treatment and 1 hour 
post MRZ infusion), and Day 15 (before treatment and 1 hour post MRZ infusion).  Starting Cycle 2 and thereafter, Day 1 (before treatment and 1 hour post MRZ infusion) 
and on Day 15 (before treatment and 1 hour post MRZ infusion).  A sample will be drawn at the End of Treatment visit.  On Cycle 2 Day 1 (pre MRZ infusion or on Cycle 1 
Day 29 if the subject does not go on to Cycle 2 or Cycle 2 is delayed.  A sample will be drawn at the time that a complete response or partial response or disease progression 
is determined.
19. Tumor assessment: Baseline tumor assessments are to be made within 14 days (+3-day window) prior to Cycle 1 Day 1.  Response should be assessed (RANO 2010) during 
the rest period of Cycle 2 and during the rest period of every 2 cycles thereafter (± 7 days).  If a subject is determined to have an overall disease response of CR or PR, then 
disease assessments should be repeated approximately 4 (± 2 days) weeks later to confirm the response.  If tumor assessments have not been performed in the 4 weeks prior to 
the End-of Treatment Visit, then tumor assessments are to be done at the End-of Treatment Visit.  If a subject has a standard of care tumor assessment done prior to giving 
Informed Consent, but within the 14 day (+3-day window), that is available to the Investigator, then that tumor assessment can serve as a baseline and another screening MRI 
is not required.
22. Subjects with drug-related AEs of Grade ≥2 observed at the End-of-Treatment assessment should be followed-up at least monthly until the AE has resolved to Grade 1, the 
event is believed to be chronic or subject receives other anticancer therapy.
23. Post Study Follow-up visits may be made in person or other means of communication.  Purpose of the follow up, which should occur every 3 months (±7 days), is to 
determine survival and the start of first new anti-GBM systemic treatment and its outcome.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
29
MRZ-108 Amendment 5 Final: 18 Mar 2020
Table 2:
Schedule of Assessments and Procedures, Part 4 Phase 1: All Cycles
Screen 1
Baseline 1
Cycle 1
Cycle 2+
End of 
Treatment19
Post 
Study 
Follow-
up20
Study Day
-28 to -1
-7 to -1
1
8
15
1
8
15
Window
Up to Day -31
Up to Day -9
±1
±1
±1
±1
±1
+7
±7
Informed consent
X
Medical history/Demographics
X
Concomitant medications 1
X
X
X
X
X
X
X
X
X
X
Physical examination, height 2
X
Targeted physical, weight, BSA 2
X
X
X
X
Karnofsky Performance Status 
(KPS) 3
X
X
X
X
Toxicity evaluation 4
X
X
X
X
X
X
Vital signs (HR, temp, BP) 5
X
X
X
X
X
X
X
X
ECG 6
X
X
Complete Blood Count, 
Differential, Platelets 7
X
X
X
X
X
X
Serum Chemistry 8
X
X
X
X
X
X
PT/PTT 9
X
X
X
Urinalysis 10
X
X
X
Marizomib administration 11
X
X
X
X
X
X
Bevacizumab infusion 12
X
X
X
Blood PK sampling (MRZ) 13
X
X
Pregnancy test 14
X
X
Blood Proteasome assay 15
Pre & 1h Post 
MRZ
Pre & 1h Post 
MRZ
Pre & 1h 
Post MRZ
Cycle 2
Pre & 1h 
Post MRZ
Cycle 2
Tumor measurement 16
X (-14 to -1)
(3-day window)
At the end of each even numbered 
cycle
X
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
30
MRZ-108 Amendment 5 Final: 18 Mar 2020
1.
Within 7 (+2) days of starting treatment except Informed Consent, demographics, medical history, concomitant medications, complete physical examination, 
radiographic/tumor assessments, and consent to acquire and test archival tumor tissue samples, which can be obtained within 28 days (+3) prior to the start of treatment.
2.
Height measured at baseline only.  Physical Examination is a complete physical as per institutional guidelines (genitourinary examination not required unless there are related 
signs or symptoms) at baseline, but thereafter as directed by signs and symptoms (targeted physical examination). 
3.
Functional assessment using the Karnofsky Performance Status (KPS) is to be completed at baseline, at the beginning of each cycle, and at the end of treatment. See 
Appendix A.
4.
Toxicity evaluation is an assessment of reported and observed adverse events, in all parts of the study compared to pre-dose evaluation.
5.
Vital Signs: (blood pressure, heart rate, and temperature) in Cycle 1, Day 1: immediately before the MRZ enteral administration and approximately 10 (±2) minutes, 30 (±5) 
minutes and 1 hour (±5 minutes) following the MRZ infusion.  Cycle 1, Day 15: immediately before the MRZ enteral administration and immediately before the BEV 
infusion and approximately 10 (±2) minutes, 30 (±5) minutes and 1 hour (±5 minutes) following the BEV infusion. Cycle 2+, Days 1 and 15: prior to the MRZ infusion and 
prior to the BEV infusion and 30 (±5) minutes following each BEV infusion.  In all cycles, Day 8, immediately before the MRZ administration and 30 (±5) minutes following 
each MRZ administration.  For all portions of the study vital signs are also collected as part of the physical examination.
6.
ECG: Eligibility ECGs must be performed within 7 (+2) days prior to Day 1.  ECGs will be collected on Cycle 1 only (Days 1 and 15), within 60 minutes prior to the MRZ 
enteral administration and within 5 (±1) minutes following the MRZ enteral administration.  An End-of-Treatment ECG is to be collected.  Additional ECGs should be 
obtained if clinically indicated.
7.
Hemoglobin (Hgb), hematocrit (Hct), red blood cell (RBC) count, white blood cell (WBC) count with differential, and platelets.  Hematology tests can be performed within 
72 hours of scheduled dosing on Days 1 and 15 except prior to Cycle 1, which can be done within 7 (+2) days prior to dosing. Should a subject experience a Grade 4 
hematologic toxicity, the appropriate test will be monitored in accordance with institutional guidelines (at minimum: weekly) until Grade ≤ 2.  The following tests should 
meet minimum stipulations prior to entry into Cycle 2+: Hgb ≥ 8 g/dL; platelets ≥ 75 x 109 /L.
8.
Sodium, potassium, chloride, bicarbonate, calcium, magnesium, glucose, BUN, serum creatinine, uric acid, ALT, AST, alkaline phosphatase, total protein, albumin, and total 
bilirubin.  Chemistry will be performed within 72 hours of scheduled dosing, on Days 1 and 15 except prior to Cycle 1, which can be done within 7 (+2) days prior to dosing.  
Minimum re-treatment criterion prior to the beginning of each new cycle: creatinine ≤ 1.5 x ULN.
9.
Coagulation tests will be performed within 72 hours of scheduled dosing on Day 1, except prior to Cycle 1, which can be done within 7 (+2) days prior to dosing. Prothrombin 
time (PT) or International Normalized Ratio (INR) and partial thromboplastin time (PTT) may be performed more often if clinically indicated.  
10. Urinalysis: protein, blood, glucose, pH; microscopic (RBC, WBC, casts) if abnormal urinalysis. Urinalysis performed within 72 hours of scheduled dosing on Day 1, except 
prior to Cycle 1, which can be done within 7 (+2) days prior to dosing.
11. Enteral administration of MRZ in Cycle 1 requires insertion of NG tube on Days 1, 8, and 15.  Subjects should not eat or drink for 2 hours prior to and 2 hours after enteral
administration of MRZ via NG tube. Subjects are to be encouraged to maintain good oral hydration during the study (eg, 2 liters per day, as considered appropriate by the 
Investigator).  Part 4 Phase 1: No pre or postdose hydration is required unless re-instituted after safety review by the Medical Monitor, representatives of the Sponsor, and the 
Investigators (See Footnote 13 in Table 1).  
12. BEV administered as an IV infusion.  First dose should be infused over 90 minutes and if tolerated, the second infusion may be given over 60 minutes, and if tolerated, 
subsequent infusions may be given over 30 minutes.  Infusions may be interrupted or lengthened to treat or prevent infusion-related reactions.  BEV is administered 
approximately 10 minutes after the end of the MRZ infusion.  BEV is not given during Part 2 Phase 2.
13. Blood PK Sampling (MRZ) (Part 4 Phase 1): On Cycle 1 Day 1 and on Cycle 1 Day 8, MRZ samples will be obtained before treatment, just prior to end of infusion, and 2, 5, 
15, 20, 30, 45, 60, 90, and 120 minutes after the infusion.  Every effort should be made to collect samples at the prescribed times, but deviations up to 10% of the time point 
are allowed.  Additional samples may be collected if the subject experiences a potentially drug-related SAE.  Use Sponsor-provided PK kits.  Process, store and ship samples 
per instructions in Study Reference Manual.
14. Pregnancy test (serum or urine) to be performed at Baseline, End-of-Treatment visit, and more frequently if clinically indicated.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
31
MRZ-108 Amendment 5 Final: 18 Mar 2020
15. Blood proteasome assay (Part 4 Phase 1): Before treatment and 1 hour after the end of MRZ enteral administration on Cycle 1 Day 1, Cycle 1 Day 8, Cycle 2 Day 1, and
Cycle 2 Day 8.
16. Tumor assessment: Baseline tumor assessments are to be made within 14 days (+3-day window) prior to Cycle 1 Day 1.  Response should be assessed (RANO 2010) during 
the rest period of Cycle 2 and during the rest period of every 2 cycles thereafter (± 7 days).  If a subject is determined to have an overall disease response of CR or PR, then 
disease assessments should be repeated approximately 4 (± 2 days) weeks later to confirm the response.  If tumor assessments have not been performed in the 4 weeks prior to 
the End-of Treatment Visit, then tumor assessments are to be done at the End-of Treatment Visit.  If a subject has a standard of care tumor assessment done prior to giving 
Informed Consent, but within the 14-day (+3-day window), that is available to the Investigator, then that tumor assessment can serve as a baseline and another screening MRI 
is not required.
19. Subjects with drug-related AEs of Grade ≥2 observed at the End-of-Treatment assessment should be followed-up at least monthly until the AE has resolved to Grade 1, the 
event is believed to be chronic or subject receives other anticancer therapy.
20. Post Study Follow-up visits may be made in person or other means of communication.  Purpose of the follow up, which should occur every 3 months (±7 days), is to 
determine survival and the start of first new anti-GBM systemic treatment and its outcome.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
32
MRZ-108 Amendment 5 Final: 18 Mar 2020
Table 3:
Schedule of Assessments and Procedures, Part 5 Phase 1: All Cycles
Screen 1
Baseline 1
Cycle 1
Cycle 2+
End of 
Treatment15
Post 
Study 
Follow-
up16
Study Day
-28 to -1
-7 to -1
1
8
15
1
8
15
Window
Up to Day -31
Up to Day -9
±1
±1
±1
±1
±1
+7
±7
Informed consent 1
X
Medical history/Demographics 1
X
Concomitant medications 1
X
X
X
X
X
X
X
X
X
X
Physical examination, height 2
X
Targeted physical, weight, BSA 2
X
X
X
X
Karnofsky Performance Status 
(KPS) 3
X
X
X
X
Toxicity evaluation 4
X
X
X
X
X
X
Vital signs (HR, temp, BP) 5
X
X
X
X
X
X
X
X
ECG 6
X
X
X
X
X
Complete Blood Count, 
Differential, Platelets 7
X
X
X
Serum Chemistry 8
X
X
X
PT or INR and PTT 9
X
X
X
Urinalysis 10
X
Marizomib administration
X
X
X
X
X
X
Bevacizumab infusion 11
X
X
X
Blood PK sampling (MRZ) 12
X
X
X
Pregnancy test 13
X
X
Tumor measurement 14
X (-14 to -1)
(3-day window)
At the end of each even numbered 
cycle
X
1.
Within 7 (+2) days of starting treatment except Informed Consent, demographics, medical history, concomitant medications, complete physical examination, and 
radiographic/tumor assessments.
2.
Height measured at baseline only.  Physical Examination is a complete physical as per institutional guidelines (genitourinary examination not required unless there are 
related signs or symptoms) at baseline, but thereafter as directed by signs and symptoms (targeted physical examination). Body Surface Area (BSA).
3.
Functional assessment using the Karnofsky Performance Status (KPS) is to be completed at baseline, at the beginning of each cycle, and at the end of treatment. See 
Appendix A.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
33
MRZ-108 Amendment 5 Final: 18 Mar 2020
4.
Toxicity evaluation is an assessment of reported and observed adverse events, in all parts of the study compared to pre-dose evaluation.
5.
Vital Signs: (blood pressure, heart rate, and temperature) in Cycle 1, on Days 1 and 8, immediately before the MRZ enteral administration and approximately 1 hour (±5 
minutes) following the MRZ infusion, and on Day 15 immediately before the MRZ infusion and immediately before the BEV infusion and approximately 1 hour (±5 
minutes) following the BEV infusion. In Cycle 2+, on Days 1 and 15, immediately prior to the MRZ infusion and immediately before the BEV infusion and 
approximately 30 (±5) minutes following each BEV infusion.  In all cycles, on Day 8, immediately before the MRZ administration and 30 (±5) minutes following each 
MRZ administration.  For all portions of the study, vital signs are also collected as part of the physical examination.
6.
ECG: Eligibility ECGs must be performed within 7 (+2) days prior to Day 1.  ECGs will be collected on Days 1, 8, and 15 of Cycle 1 only, within 60 minutes prior to the 
MRZ IV infusion and within 5 (±1) minutes following the MRZ IV infusion.  An End-of-Treatment ECG is to be collected. Additional ECGs should be obtained if 
clinically indicated. On Cycle 1 Day 1, continuous 12-Lead ECG recording will be collected using a Holter recorder through the 60-minute PK blood collection, and by 
bedside 12-Lead ECG monitor at all other visits (see footnote 12). Cycle 1 Day 1 Holter recorder will be sent to central ECG vendor and replicate ECGs will be extracted 
at 3 time points prior to infusion (-45, -30, and -15 minutes) and at the end of infusion, and 2, 5, 15, 20, 30, 45, and 60 minutes after the infusion. Subjects should be 
supinely or semi-recumbently resting for at least 10 minutes prior to the time points of the ECG extractions.
7.
Hemoglobin (Hgb), hematocrit (Hct), red blood cell (RBC) count, white blood cell (WBC) count with differential, and platelets.  Hematology tests can be performed 
within 72 hours of scheduled dosing on Day 1 except prior to Cycle 1, which can be done within 7 (+2) days prior to dosing.  Should a subject experience a Grade 4 
hematologic toxicity, the appropriate test will be monitored in accordance with institutional guidelines (at minimum: weekly) until Grade ≤ 2.  The following tests should 
meet minimum stipulations prior to entry into Cycle 2+: Hgb ≥ 8 g/dL; platelets ≥ 75 x 109 /L.
8.
Sodium, potassium, chloride, bicarbonate, calcium, magnesium, glucose, BUN, uric acid, creatinine, ALT, AST, alkaline phosphatase, total protein, albumin, and total 
bilirubin.  Chemistry will be performed within 72 hours of scheduled dosing, on Day 1 except prior to Cycle 1, which can be done within 7 (+2) days prior to dosing.  
Minimum re-treatment criterion prior to the beginning of each new cycle: creatinine ≤ 1.5 x ULN.
9.
Coagulation tests will be performed within 72 hours of scheduled dosing on Day 1, except prior to Cycle 1, which can be done within 7 (+2) days prior to dosing. 
Prothrombin time (PT) or International Normalized Ratio (INR) and partial thromboplastin time (PTT) may be performed more often if clinically indicated.  
10. Urinalysis: protein, blood, glucose, pH; microscopic (RBC, WBC, casts) if abnormal urinalysis. Urinalysis performed within 7 (+2) days prior to dosing on Cycle 1 Day 
1.  Additional urinalysis should be obtained if clinically indicated.
11. BEV administered as an IV infusion.  Cycle 1 Day 15 dose should be infused over 90 minutes and if tolerated, the second infusion (Cycle 2 Day 1) may be given over 60 
minutes, and if tolerated, subsequent infusions may be given over 30 minutes.  Infusions may be interrupted or lengthened to treat or prevent infusion-related reactions.  
The first dose of BEV is administered on Cycle 1 Day 15 immediately following the 60-minute PK blood collection, and approximately 10 minutes after the end of the 
MRZ infusion at all subsequent visits.
12. On Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 1 Day 15, MRZ PK samples will be obtained before treatment, just prior to end of infusion, and 2, 5, 15, 20, 30, 45, and 
60 minutes after the infusion.  Every effort should be made to collect samples at the prescribed times, but excursions up to 10% of the time point are allowed.  Additional 
samples may be collected if the subject experiences a potentially drug-related SAE.  Use Sponsor-provided PK kits.  Process, store, and ship samples per instructions in 
Study Reference Manual.
13. Pregnancy test (serum or urine) to be performed at Baseline, End-of-Treatment visit, and more frequently if clinically indicated.
14. Tumor assessment: Baseline tumor assessments are to be made within 14 days (+3-day window) prior to Cycle 1 Day 1.  Response should be assessed (RANO 2010) 
during the rest period of Cycle 2 and during the rest period of every 2 cycles thereafter (± 7 days).  If a subject is determined to have an overall disease response of CR or 
PR, then disease assessments should be repeated approximately 4 (± 2 days) weeks later to confirm the response.  If tumor assessments have not been performed in the 4 
weeks prior to the End-of-Treatment Visit, then tumor assessments are to be done at the End-of-Treatment Visit.  If a subject has a standard of care tumor assessment 
done prior to giving Informed Consent, but within the 14-day (+3-day) window, that is available to the Investigator, then that tumor assessment can serve as a baseline 
and another screening MRI is not required.
15. Subjects with drug-related AEs of Grade ≥2 observed at the End-of-Treatment Visit assessment should be followed-up at least monthly until the AE has resolved to 
Grade 1, the event is believed to be chronic or subject receives other anticancer therapy.
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16. Post Study Follow-up visits may be made in person or other means of communication.  Purpose of the follow up, which should occur every 3 months (±7 days), is to 
determine survival and the start of first new anti-GBM systemic treatment and its outcome.
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TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SYNOPSIS............................................................................................................5
1.
INTRODUCTION..................................................................................................42
1.1.
Glioblastoma: Current Clinical Outcome ................................................................42
1.2.
Anti-angiogenic Therapy ........................................................................................42
1.3.
Bevacizumab Clinical Experience...........................................................................42
1.4.
Marizomib..............................................................................................................43
1.4.1.
Pharmacology.........................................................................................................44
1.4.2.
Pharmacokinetics....................................................................................................46
1.4.3.
Toxicology .............................................................................................................47
1.4.3.1.
IV MRZ..................................................................................................................47
1.4.3.2.
Oral MRZ...............................................................................................................48
1.4.4.
Clinical Experience.................................................................................................49
1.4.5.
Pharmacodynamics.................................................................................................53
1.4.6.
Pharmacokinetics....................................................................................................54
2.
STUDY OBJECTIVES...........................................................................................63
2.1.
Primary Objective...................................................................................................63
2.2.
Secondary Objectives .............................................................................................63
3.
STUDY ENDPOINTS............................................................................................66
3.1.
Primary Endpoint(s) ...............................................................................................66
3.2.
Secondary Endpoint(s)............................................................................................66
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4.
OVERALL STUDY DESIGN ................................................................................68
4.1.
Study Design ..........................................................................................................68
4.3.
Study Duration .......................................................................................................70
4.4.
End of Study...........................................................................................................70
5.
PROCEDURES......................................................................................................71
5.1.
Screening................................................................................................................71
5.2.
Baseline..................................................................................................................71
5.3.
Treatment ...............................................................................................................71
5.4.
End-of-Treatment Visit...........................................................................................72
5.5.
Post Study Follow-up .............................................................................................72
5.6.
Activity Assessments..............................................................................................72
5.7.
Pharmacokinetic (PK) Assessments: MRZ (Part 1 Phase 1, Part 4 Phase 1, 
and Part 5 Phase 1) .................................................................................................72
5.8.
PK Assessments: BEV (Part 1 Phase 1 only)...........................................................73
5.9.
Pharmacodynamic (PD) Assessments (Part 1 Phase 1 and Part 4 Phase 1)...............73
5.12.
Karnofsky Performance Status................................................................................74
6.
STUDY POPULATION.........................................................................................76
6.1.
Number of Subjects and Sites .................................................................................76
6.2.
Inclusion Criteria....................................................................................................76
6.3.
Exclusion Criteria...................................................................................................77
7.
DESCRIPTION OF STUDY TREATMENTS........................................................80
7.1.
Description of Investigational Product(s)................................................................80
7.2.
Treatment Administration and Schedule .................................................................80
7.2.1.
Administration of MRZ in Part 1 Phase 1 ...............................................................80
7.2.2.
Administration of BEV in Part 1 Phase 1, Part 3 Phase 2, Part 4 Phase 1, and 
Part 5 Phase 1 .........................................................................................................80
7.2.3.
Administration of MRZ in Part 2 Phase 2 ...............................................................80
7.2.4.
Administration of MRZ in Part 3 Phase 2 ...............................................................81
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7.2.5.
Administration of MRZ in Part 4 Phase 1 ...............................................................81
7.2.6.
Administration of MRZ in Part 5 Phase 1 ...............................................................82
7.2.6.1.
Dose Schedules.......................................................................................................82
7.2.7.
Dose-Limiting Toxicity ..........................................................................................90
7.2.8.
Dose Escalation Process and MTD/MAD Determination ........................................91
7.3.
Method of Treatment Assignment...........................................................................93
7.4.
Packaging and Labeling..........................................................................................94
7.5.
Investigational Product Accountability and Disposal ..............................................94
7.6.
Investigational Product Compliance........................................................................94
8.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................95
8.1.
Permitted Concomitant Medications and Procedures...............................................95
8.2.
Prohibited Concomitant Medications and Procedures..............................................95
8.3.
Required Concomitant Medications and Procedures................................................95
9.
STATISTICAL ANALYSES..................................................................................96
9.1.
Overview................................................................................................................96
9.2.
Study Population Definitions ..................................................................................97
9.3.
Sample Size............................................................................................................97
9.4.
Background and Demographic Characteristics........................................................98
9.5.
Subject Disposition.................................................................................................98
9.6.
Activity (Efficacy) Analysis ...................................................................................98
9.7.
Safety Analysis.......................................................................................................98
9.8.
Pharmacokinetic Analysis (Part 1 Phase 1, Part 4 Phase 1, and Part 5 
Phase 1)..................................................................................................................99
9.9.
Pharmacodynamic Analysis (Part 1 Phase 1 and Part 4 Phase 1) .............................99
9.10.
Interim Analysis .....................................................................................................99
10.
ADVERSE EVENTS............................................................................................100
10.1.
Monitoring, Recording and Reporting of Adverse Events .....................................100
10.2.
Evaluation of Adverse Events...............................................................................100
10.2.1.
Seriousness...........................................................................................................101
10.2.2.
Severity / Intensity................................................................................................102
10.2.3.
Causality ..............................................................................................................102
10.2.4.
Duration ...............................................................................................................102
10.2.5.
Action Taken........................................................................................................103
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10.2.6.
Outcome...............................................................................................................103
10.3.
Abnormal Laboratory Values................................................................................103
10.4.
Pregnancy.............................................................................................................103
10.4.1.
Females of Childbearing Potential: .......................................................................103
10.4.2.
Male Subjects.......................................................................................................104
10.5.
Reporting of Serious Adverse Events....................................................................104
10.5.1.
Safety Queries ......................................................................................................105
10.6.
Expedited Reporting of Adverse Events................................................................105
11.
DISCONTINUATIONS .......................................................................................106
12.
EMERGENCY PROCEDURES...........................................................................107
12.1.
Emergency Contact...............................................................................................107
12.2.
Emergency Identification of Investigational Products ...........................................107
13.
REGULATORY CONSIDERATIONS.................................................................108
13.1.
Good Clinical Practice..........................................................................................108
13.2.
Investigator Responsibilities .................................................................................108
13.3.
Protocol Amendments...........................................................................................109
13.4.
Subject Information and Informed Consent...........................................................109
13.5.
Confidentiality......................................................................................................109
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ..............................................................................................................109
13.7.
Ongoing Information for Institutional Review Board / Ethics Committee..............110
13.8.
Termination of the Study ......................................................................................110
14.
DATA HANDLING AND RECORDKEEPING...................................................112
14.1.
Data/Documents ...................................................................................................112
14.2.
Data Management.................................................................................................112
14.3.
Record Retention..................................................................................................112
15.
QUALITY CONTROL AND QUALITY ASSURANCE......................................114
15.1.
Study Monitoring and Source Data Verification....................................................114
15.2.
Audits and Inspections..........................................................................................114
16.
PUBLICATIONS .................................................................................................115
17.
REFERENCES.....................................................................................................116
18.
APPENDICES......................................................................................................119
APPENDIX A.
KARNOFSKY PERFORMANCE STATUS SCALE...................................119
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LIST OF TABLES
Table 1:
Schedule of Assessments and Procedures, Part 1 Phase 1 and Parts 2 and 3 
Phase 2: All Cycles.................................................................................................26
Table 2:
Schedule of Assessments and Procedures, Part 4 Phase 1: All Cycles.......................29
Table 3:
Schedule of Assessments and Procedures, Part 5 Phase 1: All Cycles......................32
Table 4:
Central Nervous System Adverse Events With Worse Severity Grade 
Occurring in ≥5 Subjects in Part 1 (Phase 1)...........................................................58
Table 5:
Dose Cohorts for MRZ + BEV Combination ..........................................................82
Table 6:
Marizomib Dose Modification Guidelines for Part 1 Phase 1 Expansion and 
Part 2 Phase 2 .........................................................................................................83
Table 7:
Marizomib Dose Modification Guidelines in Part 3 Phase 2, Part 4 Phase 1, 
and Part 5 Phase 1...................................................................................................84
Table 8:
Dose Cohorts for Enteral (Cycle 1) and IV (Cycles 2) MRZ + IV BEV 
Combination...........................................................................................................87
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LIST OF FIGURES
Figure 1:
Chemical Structure of Marizomib (NPI-0052/CC-92763) .......................................43
Figure 2:
In Vitro Activity of Marizomib in Primary Cell Cultures Derived from 
Human Brain Tumors (High-grade and Low-grade Gliomas and 
Meningiomas), Normal Neural Stem/progenitor Cells (NSC) and the 
Established Malignant Glioma Lines, U251-MG and D54-MG...............................45
Figure 3:
Marizomib Inhibits Migration and Invasion of Glioblastoma Cells .........................46
Figure 4:
PFS and OS in Subjects with Adverse Event Terms of Ataxia, Gait 
Disturbance, Fall, Dysarthria, Dizziness, Balance Disorder, or Hallucinations ........59
Figure 5:
Overall Study Design..............................................................................................69
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1.
INTRODUCTION
1.1.
Glioblastoma: Current Clinical Outcome
There is an unmet clinical need for the therapy of progressive or recurrent malignant gliomas 
(MG) with a median survival of < 12 months despite available chemotherapy.  Recurrence 
following current “standard of care” surgery, radiation therapy and adjuvant chemotherapy is 
nearly universal. The traditional therapies rely on DNA damage and disruption of mitotic 
machinery, with limited effect in prolonging subject survival (Stupp 2005). The reported data 
show a 6 month progression-free-survival of 15% and median progression-free survival of only 
9 weeks among 225 subjects with recurrent glioblastoma (GBM) (Wong 1999). Upon 
progression, subjects typically develop progressive physical and mental debilitation culminating 
in death 40 to 50 weeks from diagnosis. Novel therapies are being developed in an attempt to 
target specific molecular mechanisms involved in abnormal signaling and resistance to apoptosis. 
1.2.
Anti-angiogenic Therapy
Malignant gliomas have long been known to be one of the most densely vascularized tumors
(Brem 1972). Malignant gliomas express high levels of vascular endothelial growth factor 
(VEGF), a key regulator of angiogenesis. Levels of VEGF expression correlate with both tumor 
grade and microvessel density (Plate 1992; Schmidt 1999; Samoto 1995). These findings 
suggest that therapeutic strategies targeting VEGF may provide an effective approach to suppress 
MG growth. Several preclinical studies in MG have shown promising antitumor activity of 
targeting VEGF and its cognate receptors (Kunkel 2001; Rubenstein 2000). In addition, 
inhibition of VEGF receptor signaling was shown to reverse the resistance of GBM to radiation 
therapy in a preclinical study (Geng 2001).
Avastin® (bevacizumab, BEV) (Genentech Inc., South San Francisco, CA), an anti-VEGF,
humanized, monoclonal antibody, has been examined extensively in preclinical models
(Avastin® Prescribing Information 2014 and 2015). These studies found that single-agent 
therapy with BEV resulted in tumor growth inhibition of 20 different human tumor cell lines 
(13 tumor types) implanted into nude mice irrespective of the route of administration or tumor 
location (Gerber 2005). A murine equivalent of BEV, A4.6.1 was shown to decrease tumor 
vascularity, enhance tumor apoptosis and prolong survival of rats intracranially implanted with 
glioblastoma cells (Rubenstein 2000). Various studies have examined the feasibility of 
combining anti-VEGF therapy with cytotoxic or biological agents. Combining BEV with 
doxorubicin, topotecan, paclitaxel, docetaxel, or radiotherapy resulted in additive or synergistic 
tumor growth inhibition. Changes in vascular functions were frequently reported, including 
decreased vessel diameter, density, and permeability in response to treatment. A reduction in 
interstitial fluid pressure was also observed. In some studies, these improvements resulted in an 
increase in intratumoral uptake of chemotherapy, implying that the most effective use of 
anti-VEGF therapy is in combination with chemotherapy (Chauhan 2005).
1.3.
Bevacizumab Clinical Experience
BEV has been studied in at least 5000 subjects in a number of Phase 1, 2, and 3 clinical trials.  
BEV is indicated in the United States for a variety of cancer indications including GBM, as a 
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single agent for adult subjects with progressive disease following prior therapy (Avastin® 
Prescribing Information 2014 and 2015).
The efficacy and safety of BEV was evaluated in an open-label, multicenter, randomized, 
non-comparative study of subjects with previously treated GBM (Friedman 2009).  Subjects 
received BEV (10 mg/kg IV) alone or BEV plus irinotecan every 2 weeks until disease 
progression or until unacceptable toxicity.  All subjects received prior radiotherapy (completed at 
least 8 weeks prior to receiving BEV) and temozolomide.  Subjects with active brain hemorrhage 
were excluded.  Of the 85 subjects randomized to the BEV arm, the median age was 54 years, 
32% were female, 81% were in first relapse, Karnofsky performance status (KPS) was 90−100 
for 45% and 70−80 for 55%.  The efficacy of BEV was demonstrated using response assessment 
based on both WHO radiographic criteria and by stable or decreasing corticosteroid use, which 
occurred in 25.9% (95% CI 17.0%, 36.1%) of the subjects. Median duration of response was 
4.2 months (95% CI 3.0, 5.7).  Radiologic assessment was based on MRI imaging (using T1 and 
T2/flair). MRI does not necessarily distinguish between tumor, edema, and radiation necrosis.
Another study was a single-arm, single institution trial with 56 subjects with GBM. All subjects
had documented disease progression after receiving temozolomide and radiation therapy
(Avastin® Prescribing Information 12/2016). Subjects received BEV 10 mg/kg IV every 
2 weeks until disease progression or unacceptable toxicity.  The median age was 54, 54% were 
male, 98% Caucasian, and 68% had a KPS of 90−100.  The efficacy of BEV was supported by 
an objective response rate of 19.6% (95% CI 10.9%, 31.3%) using response assessment based on 
both WHO radiographic criteria and by stable or decreasing corticosteroid use. Median duration 
of response was 3.9 months (95% CI 2.4, 17.4).
1.4.
Marizomib
Marizomib (MRZ, also known as NPI-0052, Salinosporamide A, or CC-92763) is a highly potent 
20S proteasome inhibitor originally derived from a marine actinomycete (Figure 1).  
Pharmacology data support the clinical development of this investigational agent in the treatment 
of a variety of solid tumors (including MG) and hematologic malignancies (including multiple 
myeloma).
Figure 1:
Chemical Structure of Marizomib (NPI-0052/CC-92763)
H
N
O
O
O
CH3
H
H
Cl
OH
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Pharmacology and toxicology studies were performed to support initial dosing in subjects with 
advanced malignancies.  The pharmacology program consisted of single- and multiple-dose 
testing in the mouse, rat, and monkey; cytochrome P450 inhibition studies; and a variety of 
in vitro mechanism-of-action and in vivo tumor-efficacy studies.  Toxicology studies included 
dose-range finding, Good Laboratory Practice (GLP) repeat-dose safety studies, and pivotal 
long-term toxicity studies in rats and primates with toxicokinetics and assessment of 
pharmacodynamics by proteasome inhibition.  Cardiovascular safety parameters, such as blood 
pressure, heart rate, electrocardiogram (ECG), troponin I, and creatine kinase (CK) isoforms, 
have been measured as part of the GLP toxicology studies.  No-observed-adverse-effect levels 
(NOAELs) and severely toxic doses have been identified in the rat and primate to establish a safe 
starting human dose in the initial Phase 1 trials of single agent MRZ.
1.4.1.
Pharmacology
MRZ inhibits proteasome activities with a significantly different profile and at different 
concentrations compared to bortezomib (BTZ).  Initial in vitro studies demonstrated that MRZ is 
a potent inhibitor of the CT-L (IC50 3.5 nM) and T-L (IC50 29 nM) activities of human 
erythrocyte-derived derived 20S proteasomes but is less potent at inhibiting the C-L activity 
(IC50 430 nM).  Bortezomib exhibited a similar inhibition of CT-L activity compared to MRZ
(IC50 8 nM) but different profiles on the T-L (IC50 590 nM) and C-L (IC50 53 nM) activities. 
MRZ is also a more potent inhibitor of NF-κB activation and cytokine synthesis compared to 
bortezomib (Chauhan 2005). 
Proteasome inhibition holds potential for therapeutic activity in incurable brain tumors such as 
GBM.  Due to high mutation rates, malignant cells generate excessive amounts of misfolded 
proteins in comparison to normal cells, a situation that is exacerbated, particularly in brain 
tumors, by reactive oxygen species (ROS).  Upon reduction or elimination of proteasome 
activity, these waste products accumulate, leading to cellular stress and apoptosis.  Thus, to 
prevent cell death, cancer cells rely on the residual proteasome activity, rendering them 
potentially more vulnerable to proteasome inhibition in comparison to normal cells.  Thus, 
apoptosis may be selectively induced in cancer cells by inhibiting their proteasome activity.  
Bortezomib has been evaluated as a potential anti-GBM drug.  Although showing good activity 
against GBM cells in vitro (Bota 2013), bortezomib does not cross the blood brain barrier 
(Yu 2006) and thus has proven ineffective in animal models and in the clinic (Labussiere 2008;
Phuphanich 2006).
Bota and coworkers (Bota 2013) investigated the in vitro activity of MRZ in primary cell 
cultures derived from human brain tumors (high-grade and low-grade glioma and meningioma), 
normal neural stem/progenitor cells (NSC) and the established MG lines, U251-MG and 
D54-MG.  Malignant glioma stem cells (GSCs) and the two cells lines were highly sensitive to 
MRZ (IC50 20-50 nM) (Figure 2-AB), in contrast to the low-grade glioma, meningioma, and 
NSC-derived cells (no effect at 60 nM) (Figure 2-A).  Treatment with MRZ at 60 nM for 4 hours 
inhibited proteasome activity by 89-90% in U251-MG and D54-MG cells (Figure 2-C).  MRZ
cytotoxicity was dependent upon increased free radical production and apoptosis in glioma cells 
since these effects were partially suppressed by the ROS quenching agent N-acetyl cysteine 
(Figure 2-D).
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MRZ has relatively little effect on neural stem/progenitor cells (Figure 2-A), suggesting minimal 
neurotoxicity while severely affecting both MG stem cells and glioma cell lines (Di 2014).
Figure 2:
In Vitro Activity of Marizomib in Primary Cell Cultures Derived from 
Human Brain Tumors (High-grade and Low-grade Gliomas and 
Meningiomas), Normal Neural Stem/progenitor Cells (NSC) and the 
Established Malignant Glioma Lines, U251-MG and D54-MG
High-grade and low-grade glioma and meningioma cells, normal neural stem/progenitor cells (NSC) and primary 
glioma stem cells (GSC) (A) or glioma cell lines (B) were treated with MRZ at the indicated concentrations for 72h 
and viability assessed by XTT assay. (C) CT-L proteasome activity was inhibited by up to 80% by brief treatment 
with 60 nM MRZ. (D) D54-MG glioma cell killing by MRZ was dependent in part on ROS generation, as it could 
be partially reversed by the ROS quenching agent N-acetyl cysteine (NAC). 
Glioblastomas rarely metastasize, causing death through local growth in the CNS alone, so a 
particularly important factor in progression of GBM is the colonization of the surrounding brain 
tissue by invasive tumor cells.  As shown in Figure 3, MRZ potently and robustly inhibited 
A
B
C
% survival
NSC-SC27
NSC-DB31
Meningioma-SC-M1
Meningioma-SC-M2
LG-GSC-DB29
LG-GSC-DB30
HG-GSC-DB17
HG-GSC-DB26
HG-GSC-DB32
HG-GSC-DB33
0
50
100
150
20nM
60nM
log[M]
% survival
-10
-9
-8
-7
-6
-5
-20
0
20
40
60
80
100
120
U-251 MG
D-54 MG
IC50
U-251 MG
5.196e-008
D-54 MG
1.955e-008
Marizomib 60nM
% Proteasome activity
untreated
2h
4h
0
50
100
150
U-251 MG
D-54 MG
Marizomib
Concentration(nM)
% survival
none
20
60
180
1620
0
20
40
60
80
100
120
-NAC
+NAC
D
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migration and invasion of human GBM cell lines in two assays.  In the ‘wound healing’ assay 
with U251-MG cells, 60 nM MRZ partially prevented wound closure for > 24 hours (Panel A)
and in the more physiological Matrigel invasion assay, treatment with the proteasome inhibitor 
decreased matrix invasion by either of two GBM lines by approximately 90%, a highly 
significant effect (Panel B).
Figure 3:
Marizomib Inhibits Migration and Invasion of Glioblastoma Cells
Wound closure assay was performed using U-251 MG cells with or without 60 nM MRZ treatment. The 
time required for ‘wound closure’ was monitored and photographed at indicated time points. (B) Invasion 
capability of the cells treated or untreated with 60 nM MRZ for 24 hours was analyzed using Matrigel 
Invasion chambers. The average of invaded cells for each counting grid is shown in lower panel. 
***p < 0.001. 
1.4.2.
Pharmacokinetics
In animal models, MRZ distributes rapidly (within 2 to 5 minutes) from whole blood into tumors 
and other tissues; however, penetration into central and peripheral nervous system organs was 
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low at the dose studied (0.6 mg/m2).  The terminal half-life in whole blood is short, in the range 
of 7 to 15 minutes for both humans and monkeys, although some individuals may exhibit a 
half-life of up to 30 minutes.
The short half-life is consistent with the very rapid clearance from the vascular compartment, in 
the range of several liters/min in man.  Clearance is independent of dose level and duration of 
administration.  A rapid clearance is also observed in monkeys. The volume of distribution (Vd) 
is large, approaching or exceeding total body mass. 
In an animal model using [3H]-MRZ, MRZ is excreted via both the urinary and fecal routes.  
Blood levels of radioactivity decrease rapidly and attain a baseline plateau within 10 minutes; 
parent compound is detected in blood for at least 1 hour. Tissues with high levels of 
radioactivity include lung, small intestine wall, kidney, adrenal gland and liver.  Tissues with 
lower levels of radioactivity include brain (approximately 10% of peak blood levels), spinal 
cord, testis and skin, whereas no radioactivity was detected in adipose tissue or bone.  
Radioactivity remains in the body for at least 10 days, consistent with the irreversible binding of 
MRZ to proteasomes and other tissue components.
Protein binding could not be determined due to the short half-life or MRZ.  The disappearance of 
MRZ in vitro in human liver microsomes does not appear to be P450-mediated.  Based on 
in vitro cytochrome P450 isoform inhibition studies, the potential for clinically important in vivo
drug interactions with substrates for CYP1A2, 2C9, 2C19, 2D6, and 3A4 is considered to be low.
1.4.3.
Toxicology
1.4.3.1.
IV MRZ
The toxicity profile of MRZ following IV injection to rats and monkeys was similar between the 
2 species as the same general array of treatment-related effects occurred in both species.  These 
included lack of adverse in-life signs, changes in RBCs (decrease) and leukocytes (increase) and 
serum chemistry parameters (notably increases in indices of hepatic and renal functions), organ 
weight effects, and histopathological alterations.  The data from the rat study suggested target 
organs of kidney, liver, spleen and adrenal gland whereas in the monkey study the target organs 
were kidney, nerve fibers in deep cerebellar white matter and spinocerebellar tracts pathways and 
pancreas. The effects occurred mainly in the high dose groups (0.60 increased to 
0.75 mg/m2/dose in the rat and 0.45 increased to 0.60 mg/m2/dose in the monkey).  In addition, 
inhibition of proteasome activity was noted, with CT-L activity being the most sensitive 
indicator of exposure to MRZ and exhibiting inhibition at all doses.
The observations from the pivotal toxicity studies suggest that 6 to 9 month prolonged exposure 
to MRZ is not associated with an increased incidence or severity of toxicity, or the induction of 
any new toxicity as compared to the findings from the previous 1-month studies. In fact fewer 
target organs were noted in the long-term studies.
Based on the findings observed in the pivotal GLP studies, the following dose levels were 
determined: a NOAEL in rats of 0.30 mg/m2 and in monkeys of 0.225 mg/m2; a highest 
non-severely toxic dose (HNSTD) or maximally tolerated dose (MTD) was determined to be 
0.75 mg/m2 in rats and 0.6 mg/m2 in monkeys. 
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The genotoxic potential of MRZ has been investigated in vitro in the bacterial reverse mutation 
assay and in the micronucleus test in human lymphocytes.  In the bacterial reverse mutation 
assay, no signs of toxicity and no evidence of mutagenic activity were observed following 
exposure to MRZ with or without added S9 mix. In the micronucleus test, concentrations of up 
to 70 nM in the absence of S9 mix and 150 nM in the presence of S9 mix did not induce 
significant induction of micronuclei; at higher concentrations MRZ showed evidence of causing 
an increase in the induction of micronuclei in cultured human lymphocytes.  It should be noted 
that the concentrations inducing micronuclei in this study are considerably higher (by a factor of 
≥20-fold) than the IC50 values observed for inhibition of human proteasome inhibition (3.5 nM).  
Thus, one possible interpretation of the data is that the induction of micronuclei may be related 
to cellular cytotoxicity as it is not observed at non-cytotoxic, yet pharmacologically active, 
concentrations of MRZ.
In summary, the toxicological effects profile for IV administered MRZ has been well established 
in rats and monkeys.  No unique species or gender effects were observed.  In addition, any 
potential safety concerns for the clinical studies (as identified in the toxicology studies) have 
been addressed in the current clinical protocols via an extensive monitoring schedule.
1.4.3.2.
Oral MRZ
The toxicological effects profile of orally administered MRZ have also been established in the 
nonhuman primate.  In a GLP study in cynomolgus monkeys (ITR 30948), the toxicity, 
toxokinetic (TK), and PD profiles of MRZ were determined following oral capsule
administration to the cynomolgus monkey on Days 1, 8 and 15, as well as the reversibility of any 
changes following a 14-day recovery period.  The test and Control/Excipient items were 
administered to groups of 7 monkeys per gender per dose (4 monkeys/gender/dose terminated 
one day after the last dose, 3 monkeys/gender/dose terminated after the 14-day recovery period).  
Dosages administered were 0, 0.0083, 0.025, and 0.0375 mg/kg/dose (corresponding to 0, 0.1, 
0.3 and 0.45 mg/m2, respectively).
Parameters evaluated in this study included daily mortality and clinical signs and observations
along with weekly body weight measurements. Serial blood samples were obtained on Days 1
and 15 of treatment for quantification of marizomib and the bioanalytical data obtained were 
used for toxicokinetic parameter evaluation. Blood samples were also collected for
pharmacodynamics on Days 1 and 15 for evaluation of chymotrypsin-like, caspase-like and 
trypsin-like proteolytic activities. Blood and urine samples were also obtained for clinical 
pathology evaluation (hematology, clinical chemistry and coagulation parameters) prior to start 
of treatment, on Day 2 and prior to necropsy for all main animals as well as at the end of 
recovery. Fecal occult blood collections and analysis were performed on Days 2, 3, 7, 9, 10, 14 
and 16 as well as prior to termination on Day 30 for recovery animals. At termination, a gross 
external and internal evaluation was conducted, selected organs were weighed and 
histopathology evaluation was performed.
Treatment of cynomolgus monkeys with oral capsule administration of MRZ on Days 1, 8, and 
15 was well tolerated at a dose level of 0.0083 mg/kg/dose. Treatment of cynomolgus monkeys 
with MRZ at dose levels of 0.025 and 0.0375 mg/kg/dose caused significant clinical signs of 
emesis and diarrhea a few hours after dosing and were related to the microscopic changes noted 
in the stomach and small intestines (see below), such as edema, hemorrhage, necrosis, erosion 
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Protocol MRZ-108 Amendment 5
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MRZ-108 Amendment 5 Final: 18 Mar 2020
and inflammation in the mucosa and submucosa.  The inflammation in the stomach and small 
intestines correlated with an increase in circulating white blood cells populations, most notably 
neutrophils and monocytes and changes in the spleen (sinus neutrophilia and/or histiocytosis), 
mesenteric lymph node (sinus neutrophilia), and/or bone marrow (myeloid hypercellularity). All 
findings were completely reversed following a 14-day recovery period.
In this study, no gender differences in marizomib pharmacokinetics were observed following 
once a week oral capsule administration of marizomib in cynomolgus monkeys. Although there 
was a dose related increase in Cmax and AUClast on both treatment days, the Cmax and AUClast
estimates obtained on Day 15 were lower than those obtained on Day 1 in the low (0.0083 
mg/kg) and mid dose (0.025 mg/kg) group, but were comparable on both treatment days in the 
high dose group (0.0375 mg/kg). Since the exposure on both treatment days was similar in the 
high dose group (the likely therapeutic dose), the observed trend of change in accumulation 
index with dose is not likely to have any impact on the pharmacodynamics/efficacy in a clinical 
setting using higher therapeutically relevant doses.
Macroscopic and microscopic findings in the stomach and small intestines were considered to be 
related to the administration of MRZ at dose levels of ≥ 0.0083 mg/kg/occasion including 
inflammation, edema/hemorrhage, epithelial degeneration/necrosis, and/or erosion noted in the 
mucosa and/or submucosa of the cardia, fundus, and pylorus portions of the stomach and 
inflammation, edema/hemorrhage, and/or villous atrophy noted in the mucosa of the duodenum 
and jejunum. The incidence and severity of microscopic changes were proportional to dose of 
MRZ and reversed completely following a 14-day recovery period. The microscopic changes in 
the stomach and small intestines were considered adverse based on the incidence and severity of 
change at dose levels of 0.025 and 0.0375 mg/kg/occasion of MRZ.  
The No Observed Adverse Effect Level (NOAEL) of MRZ administered orally was considered 
to be the 0.0083 mg/kg/dose, based on the adverse findings of the clinical signs, microscopic
changes (stomach, small intestines and spleen) and hematology changes that resulted from the
administration of marizomib at the two higher dose levels tested on this study. Changes that were 
noted in the low dose animals were considered to be of low magnitude and reversible. The
Highest Non-Severely Toxic Dose (HNSTD) was considered to be the high dose, 0.0375 
mg/kg/occasion (0.45 mg/m2), based on the absence of mortality and reversibility of the adverse 
findings following the 14-day recovery period.
1.4.4.
Clinical Experience 
As of 05 Feb 2020, under IND 123765, a total of 465 subjects have received one or more doses 
of MRZ in Phase 1 and Phase 1/2 studies evaluating MRZ as a single agent or in combination 
with other anticancer drugs, including 185 subjects in clinical studies for newly diagnosed and 
recurrent glioblastoma.
In the first 4 Phase 1 dose ranging studies in subjects with Multiple Myeloma (MM), lymphoma 
and solid tumors where MRZ was infused at doses ranging from 0.0125 to 0.9 mg/m2 over 1 to 
120 minutes (n=242), the most common AEs related to study drug were fatigue, nausea, diarrhea, 
headache, vomiting, dizziness, infusion site pain, and anorexia with the most common serious 
adverse events (SAEs) related to study drug including coordination abnormal, confusional state, 
nausea, and pneumonia (Protocols NPI-0052-100, NPI-0052-101, NPI-0052-102, and 
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Protocol MRZ-108 Amendment 5
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Confidential and Proprietary
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NPI-0052-103). In the NPI-0052-107 study in subjects with relapsed and refractory multiple 
myeloma, where MRZ was given in combination with pomalidomide (POM) and low-dose 
dexamethasone (Lo-DEX), the duration of the MRZ infusion was 2 hours on days 1, 4, 8 and 11 
of a 28-day cycle to minimize the risk of central nervous system (CNS) toxicity (n=38). The 
most common AEs related to MRZ in this study were fatigue, neutropenia, thrombocytopenia, 
anemia, and nausea. CNS AEs were relatively uncommon and when they occurred did not 
present a substantial safety concern. In addition, the incidence of hematologic AEs related to 
any of the study drugs in this study was comparable to large-scale studies evaluating the 
combination of POM/ dexamethasone (DEX) in subjects with MM. Therefore, MRZ does not 
appear to increase the incidence or severity of hematologic AEs reported for the POM/DEX 
combination.
Preliminary Results from Ongoing Studies in G4 MG
To date, 187 subjects have been enrolled in 3 completed and 2 ongoing studies in subjects with 
glioblastoma under IND 123765. Additional information can be found in the Investigator’s
Brochure.
Study MRZ-108 Amendment 1 (NCT02330562, Recurrent Glioblastoma)
In Part 1 (Phase 1) of this MRZ-108 study, subjects received MRZ IV 0.55 to 0.8 mg/m2 on days 
1, 8, and 15 and BEV IV 10 mg/kg on days 1 and 15 of each 28-day cycle.  The RP2D for 
dose-expansion was MRZ 0.8 mg/m2.  As of 04 January 2018, 36 of the target 36 subjects 
enrolled had discontinued for AEs (3), subject decision (5), and disease progression (28).  
Subjects received an average of 5 cycles of MRZ and BEV, the MRZ dose was reduced in 36% 
of subjects predominantly for AEs (10 of 14 reductions), and 17% of subjects had MRZ 
discontinued for an AE.  
The most common AEs related to MRZ are fatigue (67%), nausea (64%), vomiting (50%), 
headache (47%), and hallucinations (36%).  The most common AEs related to BEV are 
fatigue (64%), hypertension (42%), headache (31%), and dysphonia (31%).  The only MRZ-
related Grade ≥ 3 AEs that occurred in 2 or more subjects are headache (3), confusional state (3), 
fatigue (2), and hallucination (2).  There was one dose-limiting toxicity (DLT) during Cycle 1 for 
a subject in Cohort 1 (MRZ 0.5 mg/m2): Grade 3 fatigue, dysarthria, and weakness.  There were 
4 Grade 4 treatment-emergent adverse events (TEAEs): optic nerve disorder (BEV-related), 
hypertension (BEV-related), appendicitis perforated (not related) and depressed level of 
consciousness (not related). There were 3 Grade 5 TEAEs: intracranial hemorrhage (BEV-
related) and disease progression x 2 (not related).  Four subjects had MRZ-related SAEs: one 
subject with hallucinations and confusional state, one subject with confusion, fatigue, and muscle 
weakness, one subject with confusional state, and one subject with cough and dyspnea (subject
hospitalized primarily for a 
 – not related).  Twenty-five of 36 subjects died 
from progressive disease, while one subject died from an intracranial hemorrhage related to BEV 
in Cycle 1, and two subjects died from unknown causes, one 113 days after the last MRZ dose
and the other 281 days after the last MRZ dose.
Overall, the combination of MRZ + BEV has demonstrated encouraging efficacy in this 
completed study.  The best overall Response Assessment in Neuro-Oncology Criteria (RANO) 
response for the 36 subjects as determined by the investigators included: 1 complete response 
(CR), 15 partial responses (PRs), and 11 stable diseases (SDs) with an overall response rate 
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(ORR) of 44%.  The median PFS and overall survival (OS) were 3.9 and 9.4 months, 
respectively, and the 6-month PFS and 9-month OS rates were 34% and 60%, respectively.
Study MRZ-108 Amendment 2 (NCT02330562, Recurrent Glioblastoma)
In Part 2 (Phase 2) of this MRZ-108 study, subjects received MRZ monotherapy at a dose of 
0.8 mg/m2; MRZ was administered as a 10-minute infusion on Days 1, 8, and 15 of every 28-day 
cycle.  As of 04 January 2018, 30 of the 30 target subjects enrolled on study had discontinued for 
disease progression (27), subject decision (2), or other (1).  Subjects received a median of 2 
cycles of MRZ (range 1 to 11 cycles), the MRZ dose was reduced in 17% of subjects 
predominantly for AEs (5 of 30 subjects), and 7% of subjects had MRZ discontinued for an AE.
The most common AEs related to MRZ were fatigue (67%), headache (43%), hallucination 
(37%), nausea (30%), vomiting (27%).  The only MRZ-related Grade ≥3 AEs that occurred in 2 
or more subjects were fatigue (2) and hallucination (2).  There was 1 Grade 4 AE of hallucination 
related to MRZ and no Grade 5 AEs.  Three subjects had MRZ-related SAEs: one subject with 
hallucination Grade 4 and delusion Grade 3, one subject with hypertension Grade 3, mental 
disorder Grade 2 and lethargy Grade 3, and one subject with ataxia Grade 2.  All three subjects 
recovered with supportive therapy.  One subject died 70 days after his last dose of MRZ due to 
increased intracranial pressure leading to herniation related to disease progression.  Four subjects 
died from unknown causes 360, 157, 97, and 252 days following the last MRZ dose.
This portion of the trial was a 2-stage sequential design with 15 response-evaluable subjects in 
each stage for a total of 30 subjects.  In the first stage of the study, one subject had a partial 
response, so the second stage was opened.  As of 04 January 2018, all subjects completed the 
study.  Out of 30 subjects enrolled in Phase 2, Part 2 of Study MRZ-108, 1 subject (3%) had a 
PR; 7 subjects (23%) had stable disease, 21 subjects (70%) had progressive disease, and 1 
subject (3%) was not response evaluable.
Study MRZ-108 Amendment 3 (NCT02330562, Recurrent Glioblastoma)
MRZ-108 Amendment 3 was designed to determine the maximally tolerated dose for MRZ by 
intra-subject dose escalation.  Forty-one subjects with progressive or recurrent WHO Grade IV 
GBM, were enrolled in MRZ-108 Phase 2, Amendment 3 and received the combination of MRZ 
and BEV, with MRZ administered as a 10-minute IV infusion every week for three weeks in 28-
day cycles (on Days 1, 8 and 15) at a starting dose of 0.8 mg/m2. As of 04 January 2018, 33 
subjects completed the study.  After the first cycle without a dose-limiting adverse event (DLAE) 
the dose of MRZ was increased to 1.0 mg/m2, and after one more cycle without a DLAE the dose 
of MRZ was to be increased to 1.2 mg/m2.  BEV was administered every 2 weeks on Days 1 and 
15 of each 28-day cycle, at a fixed dose of 10 mg/kg.  
DLAEs are MRZ-related AEs which are: 1) related to disturbances in the cerebellum (ie, ataxia, 
dizziness, dysarthria, fall, gait disturbances) plus hallucinations of any grade or 2) Grade ≥ 2 
other AEs.  
Out of the first 36 subjects, 10 were escalated in Cycle 2 to a dose of MRZ 1.0 mg/m2; no 
subjects were escalated to a dose of MRZ 1.2 mg/m2.  The MRZ dose was reduced in 37% of 
subjects at 0.8 mg/m2 and 80% of subjects at 1.0 mg/m2, predominantly due to AEs. The most 
common TEAEs related to MRZ were fatigue (63%), confusional state (44%), vomiting (41%), 
nausea (41%) and hallucination (41%).  The frequency of these AEs was generally higher for 
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subjects who were escalated to the 1.0 mg/m2 dose level as compared to those who were not 
escalated to the higher dose. Ninety percent of subjects who were dose escalated to the 1.0 
mg/m2 dose of MRZ had at least 1 Grade ≥ 3 TEAE, compared to 63% of subjects who received 
the 0.8 mg/m2 dose of MRZ.  Most CNS-related AEs of special interest were Grades 1 and 2 in 
severity.  None of the 33 subjects who had completed the study were discontinued due to an 
adverse event.  In this ongoing study, the RP2D for MRZ was determined to be 0.8 mg/m2 in 
recurrent GBM (in agreement with Part 1 of the study).  
Study MRZ-108 Amendment 4 (NCT02330562, Recurrent Glioblastoma)
Part 4 of the study was added to assess the feasibility of enterally-administered MRZ. The MRZ 
IV formulation was reconstituted and administered enterally via NG tube for the first 28-day 
treatment cycle. In Cycle 2 and all subsequent cycles, MRZ was administered IV at the 
recommended dose and schedule determined in Part 1. Fourteen subjects have been enrolled in 
Part 4 of this ongoing study.
Study MRZ-112 (NCT02903069; Newly Diagnosed Glioblastoma (ndGBM)
The study is examining the effect of the addition of MRZ to standard of care treatment utilizing 
two study arms: Concomitant Treatment in which MRZ is combined with temozolomide (TMZ)
+ radiation therapy (RT) and Adjuvant Treatment in which MRZ is combined with TMZ.  The 
study is being conducted as follows: 

Stage 1 (Dose-Escalation): 3 to 6 evaluable subjects per MRZ dose cohort were 
enrolled in each study arm (MRZ 0.55 to 1.2 mg/m2). A total of 33 subjects were 
enrolled.

Stage 2 (Dose-Expansion):  Concomitant Treatment was followed by Adjuvant Treatment 
to confirm the MTD for each treatment regimen as determined in the Dose-Escalation 
(Stage 1), and to assess preliminary activity of the RP2D.

Stage 2, Amendment 2:  The protocol was amended (Amendment 2) to add another 
treatment arm to include MRZ 0.8 mg/m2 + TMZ + Optune®.
As of 10 Jul 2019, 66 subjects have been enrolled in Study MRZ-112 (35 in the concomitant 
treatment arm, 18 in the adjuvant treatment arm, and 13 in the Optune arm). Twenty-five of the 
35 subjects enrolled in the concomitant treatment arm also continued to receive adjuvant 
treatment. Overall, 47 (71.2%) subjects experienced at least 1 Grade ≥ 3 TEAE. Fatigue, 
vomiting, ataxia, and hypertension were the most frequently reported Grade ≥ 3 TEAEs. Grade 3 
or higher TEAEs occurred most frequently in the SOCs of nervous system disorders, general 
disorders and administration site conditions, psychiatric disorders, and gastrointestinal disorders.
Six (6) DLTs occurred during dose-escalation, with 5 of the 6 DLTs occurring in the 1.0 mg/m2
cohort: 

In adjuvant Cohort 2 (0.7 mg/m2), one subject experienced Grade 3 fatigue for > 7 
days; 

In concomitant Cohort 4 (1.0 mg/m2), DLTs included Grade 3 ataxia/diarrhea 
(1 subject), Grade 3 ataxia/confusion (1 subject), and Grade 3 myocardial infarction 
(1 subject) for which the relationship to MRZ could not be excluded; 
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Protocol MRZ-108 Amendment 5
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
In adjuvant Cohort 4 (1.0 mg/m2), DLTs included Grade 3 delirium/ataxia (1 subject) 
and Grade 3 ataxia/fatigue (1 subject). 
A total of 7 subjects (21%) had a TEAE that led to discontinuation of MRZ treatment of which 
five of these subjects received MRZ at 1.0 mg/m2.  Eleven of the 12 subjects (92%) dosed at 1.0 
mg/m2 experienced at least one Grade ≥ 3 TEAE.  In contrast, 5 of the 21 subjects in the lower 
dose cohorts experienced at least one Grade ≥ 3 TEAE, including 2 subjects (33%) at 0.55 
mg/m2, 2 subjects (22%) at 0.7 mg/m2, and 1 subject (17%) at the 0.8 mg/m2 dose.  Based on the 
totality of these data, the RP2D for MRZ was determined to be 0.8 mg/m2 added to the standard 
of care radiation and TMZ in newly diagnosed GBM.
1.4.5.
Pharmacodynamics
Pharmacodynamic (PD) data demonstrate that MRZ is a potent inhibitor of all 3 proteasome 
activities and that the inhibition pattern is dose-, cycle-, and schedule-dependent.  The PD profile 
of MRZ-induced proteasome inhibition has been assessed in clinical studies at 10 dose levels 
(0.0125 to 0.9 mg/m2).  Importantly, preliminary clinical PD activity detected in early trials of 
MRZ closely mirrored the encouraging data from preclinical studies in rodents and primates.  In 
the first-in-human trial Study NPI-0052-100, where sample sizes were small and PD activity was 
collected only during Cycle 1, CT-L activity was inhibited modestly (up to 20%) even in the first 
cohort (0.025 mg/m2), more robustly at intermediate doses (eg, 50-80% at 0.25 mg/m2) and was 
completely inhibited at high doses of 0.7 mg/m2 and above.  For T-L activity, inhibition was 
observed at lower doses (up to 20% at 0.25 mg/m2) but a robust effect (over 50%) was noted at 
doses of 0.7 mg/m2 and above, even by C1D15.  The C-L activity was the least affected, with 
little to no inhibition seen within the first cycle at doses up to 0.55 mg/m2, although several 
subjects receiving at least 0.7 mg/m2 achieved a 30-40% inhibition of C-L activity.
In trials NPI-0052-101 and -102, partial or complete inhibition of all three proteasome subunits 
was achieved with both once- and twice-weekly MRZ dosing, with the rank order of sensitivity 
(CT-L > T-L > C-L; Levin, 2016) consistent with the biochemical potency of MRZ 
(Teicher, 2015). For CT-L activity, both initial (C1D1) and peak proteasome inhibition was 
dose-dependent, with complete (100%) inhibition of CT-L activity in PWB, and maximal 
(60-80%) inhibition of CT-L activity in PBMC, within the first dosing cycle. Increasing MRZ 
dose exposure resulted in increasing inhibition of CT-L activity in PWB, with estimated 50% 
inhibitory dose levels of 0.3 and 0.8 mg/m2 in the once- and twice-weekly infusion arms, 
respectively (95% Confidence Intervals: AM, 0.02 – 4.3; MM, 0.14 – 4.5), indicating equivalent 
proteasomal inhibitory activity of MRZ in PWB between tumor types or infusion regimens. 
Importantly, proteasome inhibition in the nucleated cells (PBMCs) was comparable at all dose 
levels to that observed in PWB samples after both a single dose or repeated doses. These data 
suggest that the irreversible binding mode of MRZ can overcome the resynthesis of proteasome 
subunits in nucleated cells, as expected for an irreversible proteasome inhibitor. 
In contrast to the rapid and robust inhibition of CT-L activity, C-L and T-L activities were 
unchanged or increased in the first cycle of MRZ dosing, suggesting compensatory 
hyperactivation in response to effective blockade of CT-L activity (Levin, 2016). Importantly, 
this response was overcome by further treatment with MRZ, with inhibition of T-L and C-L 
activity noted across dose levels with repeated dosing. These data suggest that initial potent 
inhibition of CT-L activity leads to a compensatory hyperactivation of the C-L and T-L subunits. 
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Protocol MRZ-108 Amendment 5
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As CT-L activity becomes fully inhibited by the irreversible activity of MRZ, progressive 
inhibition of the hyperactivated C-L and T-L subunits occurs, ultimately resulting in robust pan-
proteasome inhibition within 2 cycles in the majority of subjects.
Similar patterns of pan-proteasome inhibition by MRZ have been observed in more recent, 
multiple agent studies, as in the single agent studies detailed above. In Study NPI-0052-107, in 
which MRZ is administered twice weekly in combination with pomalidomide and DEX, mean 
CT-L inhibition of 80% is observed in Cycle 1 at the 0.4 mg/m2 dose, and ~100% inhibition of 
CT-L is observed by the last infusion of Cycle 1 (Day 11) at the 0.5 mg/m2 dose (RP2D). As in 
the single agent studies, minimal inhibition with some activation of T-L and C-L activity were 
observed during Cycle 1, however with repeated administration of MRZ, inhibition of these 
hyperactivated subunits becomes apparent in Cycles 2 and 3.  Similarly, preliminary data
demonstrate pan-proteasome inhibition of MRZ in subject samples of PWB and PBMC in 
subjects with Grade IV malignant glioma (MRZ-108). In this ongoing study, MRZ is infused 
once weekly, in combination with bevacizumab. Preliminary data from the RP2D MRZ dose 
cohort (0.8 mg/m2) demonstrate pan-proteasome inhibition of MRZ in subject samples of PWB 
and PBMC, with mean CT-L inhibition of ~70% was observed after the first MRZ dose of 
Cycle 1, and persisted at the time of the second MRZ dose of Cycle 1.  Subsequent MRZ doses 
resulted in 100% inhibition of CT-L post-infusion, and 60-80% inhibition prior to the next 
infusion.  A slight increase in T-L and C-L activity in PWB samples was observed after the first 
MRZ infusion, after which inhibition of T-L (up to 70% post-infusion) and of C-L (up to 50% 
post-infusion) through Cycle 6.  Persistent inhibition of T-L and C-L was observed at the time of 
the next MRZ dose, demonstrating the irreversible nature of pan-proteasome inhibition induced 
by MRZ in these non-nucleated cells.  Pre- and post-infusion inhibition of T-L and C-L was less 
robust in the PBMC samples as compared with PWB specimens, with maximum levels of 
40-60% inhibition observed for both T-L and C-L activity.
1.4.6.
Pharmacokinetics
The whole blood human pharmacokinetics (PK) of MRZ administered as a single agent have 
been assessed in clinical Studies NPI-0052-100, NPI-0052-101, and NPI-0052-102.  Blood levels 
have been measured following intravenous (IV) doses of MRZ from 0.025 to 0.9 mg/m2.  
Depending on the study, doses were administered either as a bolus over 1 minute or as a bolus 
and as an infusion with a nominal infusion time of 10 to 120 minutes.  Preliminary PK analyses 
indicate the PK profile in humans is similar to the profile observed in animal studies, ie, the drug 
has a short half-life in whole blood with initial t1/2 estimates in the range of 3.6 ± 0.6 to 8.7 ± 
6.8 min following a 1-10 min IV infusion.  Similar t1/2 values were observed (range 
6-15 minutes) following a 120-minute infusion. 
More recently, the PK of MRZ in whole blood were assessed in Study NPI-0052-107, in which 
MRZ is administered twice weekly as an infusion for 120 min on Days 1, 4, 8, and 11 of a 
28-day cycle, in combination with pomalidomide (administered orally, 3 or 4 mg/day, days 1-21) 
and DEX (administered orally, 5 or 10 mg, Days 1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22, and 23). 
Blood levels have been measured following IV MRZ doses of 0.3, 0.4, and 0.5 mg/m2 (lyophile 
formulation) on Study Day 8. Noncompartmental pharmacokinetic analysis of these data 
revealed similar parameter estimates to those obtained from prior clinical studies. MRZ 
demonstrated a very short half-life (6-11 min), with a very rapid clearance and large volume of 
distribution of MRZ, implying extensive metabolism and the involvement of extra hepatic 
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
55
MRZ-108 Amendment 5 Final: 18 Mar 2020
clearance or non-CYP mediated biotransformation mechanisms, and a wide tissue distribution or 
binding of MRZ to blood components. MRZ did not appear to affect the PK of either 
co-administered pomalidomide or DEX. 
PK of MRZ in whole blood were also assessed in Study MRZ-108, in which MRZ is 
administered once weekly as an infusion for 10 min on Days 1, 8, and 15 of a 28-day cycle, in 
combination with bevacizumab (BEV, administered IV at a dose of 10 mg/kg). Blood MRZ 
levels were measured following IV MRZ doses of 0.55, 07, and 0.8 mg/m2 (lyophile 
formulation) on Study Days 1 (pre-dose and end-of-infusion only) and 15 (full PK sampling).  
Serum BEV concentrations were measured on Days 1 and 15, pre-dose and at the end-of-
infusion. Noncompartmental analysis of the MRZ PK data revealed similar T1/2, Vd, and CL 
parameter estimates to those obtained from in the NPI-0052-107 study, and again these 
parameter estimates appeared to be dose-independent. Earlier Tmax values and higher Cmax values 
were observed in MRZ-108 than in NPI-0052-107, which were anticipated based on the shorter 
MRZ infusion time. MRZ did not appear to affect the PK of co-administered BEV.  
The PK of MRZ in whole blood was also assessed in Study MRZ-112 in which MRZ was 
administered as a 10 min IV infusion on Days 1, 8, 15, 29 and 36 of the 6-week concomitant 
treatment cycle, in combination with temozolomide (TMZ), administered orally at a dose of 75 
mg/m2/day and radiotherapy delivered 5 days/week for 6 weeks. Blood MRZ levels were 
measured following IV MRZ doses of 0.55, 0.7, 0.8, and 1.0 mg/m2 on study Days 1 and 8. 
Blood samples were taken at pre-dose, immediately prior to the end of infusion, and then at 5 
and 60 minutes post-infusion on Day 1; and pre-dose and immediately prior to end of infusion, 
and then 2, 5, 15, 30, 45, and 60 minutes post-infusion on Day 8. PK parameters (Cmax, Tmax, 
t1/2, AUC0-t, AUC0-inf, CL, Vd) were estimated from the Day 8 data by non-compartmental 
analysis (NCA). Serum TMZ concentrations were measured on Days 1 and 15, pre-dose, 1-hour 
post-dose, and 24 hours post-dose (prior to the next TMZ dose). Plasma TMZ concentrations 
were measured to assess TMZ peak and trough levels.  Analysis of the MRZ PK data revealed 
similar t1/2 (6.6 to 15.4 min), Vd (64 to 122 L), and CL (341 to 4164 L/hr) parameter estimates 
to those obtained in previous clinical studies with MRZ administered as a single agent, and again 
these parameter estimates appeared to be dose-independent.  MRZ did not appear to affect the 
PK of co-administered TMZ.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
56
MRZ-108 Amendment 5 Final: 18 Mar 2020
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
57
MRZ-108 Amendment 5 Final: 18 Mar 2020
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
58
MRZ-108 Amendment 5 Final: 18 Mar 2020
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
59
MRZ-108 Amendment 5 Final: 18 Mar 2020
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
60
MRZ-108 Amendment 5 Final: 18 Mar 2020
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
61
MRZ-108 Amendment 5 Final: 18 Mar 2020
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
62
MRZ-108 Amendment 5 Final: 18 Mar 2020
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
63
MRZ-108 Amendment 5 Final: 18 Mar 2020
2.
STUDY OBJECTIVES
2.1.
Primary Objective
Part 1 Phase 1
The primary objective of the study is:

To determine the maximum tolerated dose (MTD) or maximum administered dose 
(MAD) and recommended Phase 2 dose (RP2D) of the combination of marizomib
(MRZ) + bevacizumab (BEV) with MRZ as a once weekly dose for 3 weeks of a 28-day 
cycle and a fixed dose and schedule of BEV (10 mg/kg administered on Days 1 and 15) 
in subjects with WHO Grade 4 malignant glioma (G4 MG), who have not previously 
been treated with either an anti-angiogenic agent including, but not limited to, BEV or a 
proteasome inhibitor including, but not limited to, MRZ.
Part 2 Phase 2

To assess the activity of a once weekly dose for 3 weeks of a 28-day cycle of MRZ in 
subjects with progressive or recurrent G4 MG, who have not previously been treated 
with either an anti-angiogenic agent or a proteasome inhibitor.
Part 3 Phase 2

To assess the activity of the combination of once weekly MRZ dosing for 3 weeks
(allowing for intra-patient dose escalation) and every other week dosing of BEV at 
10 mg/kg in a 28-day cycle in subjects with progressive or recurrent G4 MG, who have 
not previously been treated with either an anti-angiogenic agent or a proteasome 
inhibitor.
Part 4 Phase 1

To determine the maximum tolerated dose (MTD) of marizomib (MRZ) administered 
enterally by NG tube once weekly for 3 weeks of a 28-day cycle during the first
treatment cycle.  BEV will be administered IV at a fixed dose (10 mg/kg administered on 
Day 15 and Days 1 and 15 of subsequent cycles). Subjects are those with progressive or 
recurrent G4 MG, who have not previously been treated with either an anti-angiogenic 
agent or a proteasome inhibitor.
Part 5 Phase 1

To determine the repeat-dose pharmacokinetics of MRZ administered IV in subjects with 
progressive or recurrent G4 MG, who have not previously been treated with either an 
anti-angiogenic agent or a proteasome inhibitor.
2.2.
Secondary Objectives
Part 1 Phase 1
The secondary objectives of the study are:

To evaluate the safety of the combination of MRZ + BEV in the subject population.

To evaluate activity of the combination of MRZ + BEV in the subject population:
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
64
MRZ-108 Amendment 5 Final: 18 Mar 2020

Radiographic Response Rate 

Progression-free Survival (PFS) 

Overall Survival (OS) 

To evaluate the pharmacokinetics (PK) of MRZ and BEV when administered in 
combination in the subject population.

To assess the whole blood proteasome pharmacodynamic (PD) activity of the 
combination of MRZ + BEV in the subject population.
Part 2 Phase 2

To evaluate the safety of single agent MRZ in the subject population.
Part 3 Phase 2

To evaluate the safety of combination of MRZ and BEV with intra-patient dose 
escalation and BEV at a fixed dose in the subject population.
Part 4 Phase 1

To evaluate the safety (in particular GI tolerability) of MRZ administered enterally by 
NG tube in the subject population.

To assess the frequency of CNS adverse events (including ataxia, dizziness, 
dysarthria, fall, gait disturbances, and hallucinations) after enterally administered 
MRZ in the subject population.

To evaluate the pharmacokinetics (PK) of MRZ administered enterally by NG tube in 
the subject population on Cycle 1 Day 1 and Cycle 1 Day 8.

To assess the blood proteasome inhibition pharmacodynamic (PD) activity of MRZ 
administered enterally by NG tube on Cycle 1 Day 1 and Cycle 1 Day 8, and to 
compare this with the PD activity of MRZ administered IV in combination with IV 
BEV on Cycle 2 Day 1 and Cycle 2 Day 8 in the subject population.
Part 5 Phase 1

To monitor the safety of the combination of MRZ and BEV at a fixed dose in the subject 
population.

To describe the activity of the of the combination of MRZ + BEV, with MRZ as a once 
weekly dose for 3 weeks of a 28-day cycle and every other week dosing of BEV with a 
fixed dose and schedule in the study population.

To evaluate MRZ cardiac safety comparing PK to ECG.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
65
MRZ-108 Amendment 5 Final: 18 Mar 2020
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
66
MRZ-108 Amendment 5 Final: 18 Mar 2020
3.
STUDY ENDPOINTS
3.1.
Primary Endpoint(s)
Part 1 Phase 1

Maximum tolerated dose (MTD) or Maximum Administered Dose (MAD)

Recommended Phase 2 Dose (RP2D)
Part 2 Phase 2

Best response
Part 3 Phase 2

Overall survival (OS)
Part 4 Phase 1

Maximum tolerated dose (MTD)
Part 5 Phase 1

Pharmacokinetics for MRZ
-
Maximum observed blood drug concentration (Cmax) 
-
Time of maximum blood concentration (tmax) 
-
Elimination half-life (t1/2) 
-
Area under the blood concentration-time curve (AUC0-t, AUC0-inf) 
-
Clearance (CL)
-
Volume of distribution (Vd)
3.2.
Secondary Endpoint(s)
Part 1 Phase 1 and Part 2 Phase 2
Safety

Type, incidence and severity of adverse events (AEs)

Type, incidence and severity of serious adverse events (SAEs)

Type, incidence and severity of dose-limiting toxicities (DLTs)
Activity

Radiographic overall response rate (ORR)

Progression-free survival (PFS)

Overall survival (OS)
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
67
MRZ-108 Amendment 5 Final: 18 Mar 2020
Part 3 Phase 2 and Part 4 Phase 1
Safety

Type, incidence and severity of adverse events (AEs)

Type, incidence and severity of serious adverse events (SAEs)

Type, incidence and severity of dose-limiting adverse events (DLAEs)(Part 3 Phase 
2)

Type, incidence and severity of dose-limiting toxicities (DLTs)(Part 4 Phase 1)
Activity

Radiographic overall response rate (ORR)

Progression-free survival (PFS)
Part 5 Phase 1
Safety

Type, incidence and severity of adverse events (AEs)

Type, incidence and severity of serious adverse events (SAEs)

MRZ cardiac safety comparing PK to ECG
Activity

Radiographic overall response rate (ORR)

Progression-free survival (PFS)
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
68
MRZ-108 Amendment 5 Final: 18 Mar 2020
4.
OVERALL STUDY DESIGN
4.1.
Study Design
Part 1 is a Phase 1, multicenter, open-label, 3+3, dose-escalation study in subjects with G4 MG
who are in first or second relapse and who have not previously received any BEV or other anti-
angiogenic agent, including: sorafenib, sunitinib, axitinib, pazopanib, everolimus, or cilengitide 
or MRZ or any other proteasome inhibitor, including bortezomib (BTZ), carfilzomib (CFZ), or 
ixazomib (IXZ).  Three to 6 evaluable subjects per cohort will be enrolled: up to 24 subjects to 
determine the MTD/MAD (Part 1 dose-escalation) and an addition of 12 or more subjects to 
confirm the MTD/MAD (Part 2 MTD/MAD expansion) and assess preliminary activity, to a total 
of up to 36 subjects.  Subjects may not be enrolled in more than 1 cohort.
The Part 1 Phase 1 portion will be followed by a Part 2 Phase 2 study of single agent MRZ 
administered as a 10-minute infusion at a dose of 0.8 mg/m2 (the MAD) every week for 3 weeks 
in 28-day cycles.  This portion of the study will be conducted as a 2-stage sequential design of up 
to 30 response-evaluable subjects.
Part 2 Phase 2 will be followed by Part 3 Phase 2 study of combination MRZ and BEV.  MRZ 
will be administered as a 10-minute infusion every week for 3 weeks in 28-day cycles at a 
starting dose of 0.8 mg/m2 (the RP2D from Phase 1).  After 1 cycle without a DLAE, the dose of 
MRZ will be increased to 1.0 mg/m2.  If the increased dose is tolerated with no DLAEs, the dose 
will be further increased to 1.2 mg/m2 in the next cycle.  BEV will be administered every 2 
weeks (Days 1 and 15 of each 28-day cycle) at a fixed dose of 10 mg/kg.  
DLAEs are MRZ-related AEs which are: 1) related to disturbances in the cerebellum (ie, ataxia, 
dizziness, dysarthria, fall, gait disturbances) plus hallucinations of any grade or 2) Grade ≥ 2 
other AEs.  
This portion of the study will be conducted in approximately 40 eligible subjects of which, based 
on the AEs seen in Part 1 of the study, about 24 subjects are expected to be eligible for intra-
patient dose escalation.
Part 4 Phase 1 will also study the combination of MRZ and BEV.  MRZ IV formulation will be 
reconstituted and administered enterally via NG tube for the first 28-day treatment cycle, with 
three doses administered on Days 1, 8 and 15. BEV will be administered as an IV infusion on 
Day 15, approximately 10 minutes after the completion of the MRZ enteral dose administration.  
In Cycle 2 and all subsequent cycles, MRZ will be administered IV at the recommended dose 
and schedule determined in Phase 1 Part 1: MRZ 0.8 mg/m2 IV weekly for three weeks (Days 1, 
8 and 15) of a 28-day cycle and BEV 10 mg/kg IV on Days 1 and 15.
Subjects must receive at least 2 doses of MRZ via NG tube during Cycle 1 to be evaluable.  One 
to six evaluable subjects per cohort will be enrolled in the first 3 dose-escalation cohorts, and 
three to six evaluable subjects per cohort will be enrolled in the next 6 dose cohorts, to determine 
the MTD (Part 4 dose-escalation). Approximately 6 additional subjects will be enrolled to 
confirm the MTD (Part 4 dose-expansion) and assess preliminary activity to a total of up to 
approximately 24 subjects.  Subjects may not be enrolled in more than 1 cohort and there will be 
no intra-subject dose escalation. This portion of the study will be conducted in approximately 24 
eligible subjects.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
69
MRZ-108 Amendment 5 Final: 18 Mar 2020
In Part 5 Phase 1 of the study, all subjects will receive MRZ infused over 10-minutes IV at the 
dose and schedule recommended from Phase 1 Part 1: MRZ 0.8 mg/m2 IV weekly for 3 weeks 
(Days 1, 8, and 15) of a 28-day cycle. Full PK sampling will be done on Cycle 1 Day 1, Cycle 1 
Day 8, and Cycle 1 Day 15, with blood samples collected at pre-dose, immediately prior to end 
of infusion (EOI), and then 2, 5, 15, 20, 30, 45, and 60 minutes post-EOI, for determination of 
blood MRZ concentrations.  BEV will be administered as an IV infusion over 90 minutes on 
Cycle 1 Day 15, immediately following the MRZ PK blood sample collection.
In Cycle 2 and all subsequent cycles, MRZ will be administered IV at the same dose and 
schedule (0.8 mg/m2 IV weekly for 3 weeks (Days 1, 8, and 15) of a 28-day cycle), with IV 
MRZ infused over 10 minutes.  BEV will be administered as an IV infusion (90 minutes 1st dose, 
60 minutes 2nd dose, and 30 minutes afterward assuming tolerability) at a dose of 10 mg/kg on 
Days 1 and 15 of every 28-day cycle.  BEV will be administered approximately 10 minutes after 
the end of the MRZ IV infusion. Approximately 12 eligible subjects will be enrolled in the study 
at a single center.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
70
MRZ-108 Amendment 5 Final: 18 Mar 2020
4.3.
Study Duration 
Subjects may continue on study treatment until disease progression, unacceptable toxicity, 
withdrawal of consent, or termination of the study. Once discontinued from the study treatment, 
subjects will enter a long-term follow-up period (Post Study Follow-Up) for documentation of 
survival and the start of first new anti-GBM therapy and its outcome.  Post Study Follow-up will 
occur every 3 months (± 7 days) after the 28-day post-treatment discontinuation visit (End-of-
Treatment visit).
4.4.
End of Study
The End of Study is defined as the date of receipt of the last data point from the last remaining 
subject that is required for primary, secondary 
analysis.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
71
MRZ-108 Amendment 5 Final: 18 Mar 2020
5.
PROCEDURES
Study visits and procedures will be performed as outlined in Table 1 for subjects in Parts 1, 2, 
and 3, Table 2 for subjects in Part 4 Phase 1, and Table 3 for subjects in Part 5 Phase 1.
The study will consist of Screening, Baseline, Treatment, and Follow-up periods.  Except where 
otherwise stated, the procedures apply to all Phase 1 and Phase 2 parts of the study. Neurological 
coordination assessment and quality of life assessment will not be done in Part 4 Phase 1.
5.1.
Screening
Screening procedures may not be done prior to the signing and dating of the Informed Consent 
Form (ICF).  However, the results of tumor assessments done as part of standard of care that are 
within the 14-day (+3 days) screening period do not have to be repeated if they were done at the 
participating site.  However, if results are not available, then tumor assessments are to be 
conducted within 14 days prior to Cycle 1 Day 1.  The screening period for assessments that 
include medical history (including demographics and cancer history), prior medications and 
procedures may not exceed a 28 day (+3 days for scheduling conflicts) window prior to start of 
study treatment (Cycle 1 Day 1).
5.2.
Baseline
Physical examination including height, weight, and vital signs, Karnofsky Performance Status 
(KPS) scale (see Appendix A), ECGs, laboratory tests including hematology, coagulation, 
chemistry, urinalysis; and, as appropriate, pregnancy tests. 
 
 
5.3.
Treatment
Safety tests and procedures will be performed according to the Schedule of Assessments and 
Procedures (Table 1 for Part 1 Phase 1, Part 2 Phase 2, and Part 3 Phase 2; Table 2 for Part 4 
Phase 1; Table 3 for Part 5 Phase 1).  PK samples correlated with ECG will be obtained prior to 
the start of treatment and then after dosing at selected time points for Part 1 Phase 1, Part 4 Phase 
1, and Part 5 Phase 1. Part 5 Cycle 1 Day 1 ECGs will be collected by Holter monitor 
continuously through completion of the 60-minute PK blood collection. Tumor assessments will 
include MRI scans at the end of every even numbered cycle (± 7 days) using RANO 2010 
criteria for assessment.  Subjects may continue treatment with MRZ for 1 or 2 cycles after an 
MRI indicates progression of disease, if according to the Investigator’s judgement, the MRI is 
interpreted as showing possible pseudo-progression, and there is no significant clinical 
deterioration of the subject or if it is in the best interest of the subject. 
Functional status using the KPS will be conducted in both Phases.  
 
 
Subjects may continue on study treatment until disease progression, unacceptable toxicity, 
withdrawal of consent, or termination of the study.  
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
72
MRZ-108 Amendment 5 Final: 18 Mar 2020
5.4.
End-of-Treatment Visit
An End-of-Treatment Visit should occur when a subject discontinues study treatment.  Tests are 
primarily to ensure there are no late occurring AEs and that AEs have resolved or have 
stabilized.  Additional follow-up visits may be conducted to follow ongoing AEs that are 
resolving.  If a subject cannot or will not make this visit, attempts to gather information on the 
status of AEs should be made by telephone or other means.
5.5.
Post Study Follow-up
All subjects will be followed for survival during the follow-up period for as long as they are 
alive.  Post Study follow-up will occur every 3 months (± 7 days) after the End-of-Treatment
Visit.  During long-term follow-up, the following information will be collected: survival, first 
subsequent anti-GBM systemic regimens, and treatment outcomes.
5.6.
Activity Assessments
Tumor response, including progressive disease, will be assessed with MRI at the end of every
2 cycles of therapy according to the RANO criteria (Wen 2010), including:

Radiographic Overall Response Rate 

Progression-free Survival (PFS) 

Overall Survival (OS)
Confirmation of response at 4 weeks (± 2 days) after the response is to be performed.
If the Investigator believes that an MRI indicating tumor progression by RANO criteria may 
reflect pseudo-progression, and there is no significant clinical deterioration of the subject, the 
subject may be continued for 1 or 2 additional cycles (at the discretion of the Investigator based 
on the subject’s clinical condition) before another MRI assessment is conducted.  If a subject is 
taken off study for progressive disease by imaging and subsequent biopsy or surgical resection 
shows no evidence of disease, the subject will be counted as a responder.  In this case, the 
subject may return to the study for additional treatment with MRZ, using a post-procedure MRI 
as the new baseline.
5.7.
Pharmacokinetic (PK) Assessments: MRZ (Part 1 Phase 1, Part 4 
Phase 1, and Part 5 Phase 1)
Blood should be drawn from the contralateral arm to the infusion site and using an indwelling 
catheter to avoid multiple needle sticks is recommended.  Sample collection time should be 
recorded on the tube label and Case Report Form (CRF) as day: hour: minute.  Nominal time of 
blood collection are given as “time points”; it is critical that an accurately collected actual time 
of the sample is written on the CRF and on the blood tubes (date entered as dd:mm:yyyy; time 
entered using a 24-hour clock, hh:mm).

In Part 1 Phase 1, MRZ samples will be obtained before treatment and just prior to end of 
infusion on Cycle 1 Day 1. In Part 1 Phase 1, on Cycle 1 Day 15, MRZ blood samples 
will be obtained before treatment, just prior to end of infusion, and 2, 5, 15, 30, 45, 60, 
90, and 120 minutes after the infusion.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
73
MRZ-108 Amendment 5 Final: 18 Mar 2020

In Part 4 Phase 1, MRZ blood samples will be obtained before treatment and just prior to 
the end of infusion, and 2, 5, 15, 20, 30, 45, 60, 90 and 120 minutes after the infusion on 
Cycle 1 Day 1 and on Cycle 1 Day 8.

In Part 5 Phase 1, MRZ blood samples will be obtained before treatment (pre-dose) and 
just prior to the end of infusion (EOI), and then 2, 5, 15, 20, 30, 45, and 60 minutes post-
EOI, on Days 1, 8, and 15 of Cycle 1.  Every effort should be made to collect samples at 
the prescribed times, but excursions up to 10% of the time point are allowed. Additional 
samples may be collected if the subject experiences a potentially drug-related SAE.  After 
blood collection, neutralizing solution must be added.  Use Sponsor-provided PK kits. 
Process, store and ship samples per instructions in Study Reference Manual.
PK parameters that will be determined include:

Maximum observed blood drug concentration (Cmax)

Time of maximum blood concentration (tmax)

Elimination half-life (t1/2)

Area under the blood concentration-time curve (AUC0-t, AUC0-inf)

Clearance (CL)

Volume of distribution (Vd)
5.8.
PK Assessments: BEV (Part 1 Phase 1 only)
For BEV pre-dose and immediately prior to EOI, plasma samples will be taken on Days 1 and 15 
to assess BEV peak and trough levels. Process, store and ship samples per instructions in Study 
Reference Manual.  PK assessment of BEV is not done in Phase 2.
5.9.
Pharmacodynamic (PD) Assessments (Part 1 Phase 1 and Part 4 
Phase 1)
Change in proteasome activities (whole blood lysates and PBMC lysates), comparing pre-drug 
and post drug levels
The laboratory correlates include assessment of the percentage inhibition of proteasome function 
(evaluated by measurement of CT-L, T-L and C-L activity in blood isolates such as whole blood 
and PBMC lysates.
In Part 4 (Phase 1), proteasome activity levels in packed whole blood (PWB) lysates and 
peripheral blood mononuclear cell (PBMC) lysates, comparing pre- and post-MRZ 
administration levels, will be determined on Days 1 and 8 of Cycle 1 and Cycle 2.
Process, store and ship samples per instructions in Study Reference Manual.
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5.12.
Karnofsky Performance Status
The Karnofsky Performance Status (KPS) allows subjects to be classified as to their functional 
impairment (Schag 1984).  This can be used to measure changes in a subject’s ability to function.  
The Karnofsky Performance Status scores range from 0 to 100. A higher score signifies the 
subject is better able to carry out daily activities. The KPS questionnaire is provided in 
Appendix A.
 
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6.
STUDY POPULATION
The study population includes subjects with G4 MG (including glioblastoma and gliosarcoma) 
who are in first or second relapse and who have not previously received any BEV or other anti-
angiogenic agent, including sorafenib, sunitinib, axitinib, pazopanib, everolimus, or cilengitide 
or MRZ or any other proteasome inhibitor, including BTZ, CFZ, or IXZ. The eligibility criteria 
are the same for both Phase 1 and Phase 2 portions of the study except where noted.
6.1.
Number of Subjects and Sites
Thirty-six subjects were enrolled in the study at multiple sites in Part 1 Phase 1 and 30 response-
evaluable subjects will be enrolled in Part 2 Phase 2.  Forty-one (41) response-evaluable subjects
in Part 3 Phase 2 were enrolled in Amendment 3.  Fourteen (14) response-evaluable subjects 
were enrolled in Amendment 4.  Approximately twelve (12) response-evaluable subjects will be 
enrolled at a single site in Amendment 5. 
6.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study.  These criteria apply to the 
Part 5 Phase 1 portion under Amendment 5 (see earlier versions of the protocol for criteria for 
Parts 1, 2, 3, and 4). 
1. Understand and voluntarily sign and date an informed consent document prior to any 
study related assessments/procedures are conducted.
2. Males and Females 18 years of age at the time of signing 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 bi-dimensional product of enhancement, 
a new enhancing lesion, or significant increase in T2 FLAIR).  Subjects must have at 
least 1 measurable lesion by RANO criteria (≥ 10 mm in 2 perpendicular diameters).
4. Subjects must have previously completed standard radiation therapy and been exposed to 
temozolomide. Subjects must be in first or second relapse. 
5. No prior treatment with MRZ or any other proteasome inhibitors, including BTZ, CFZ, 
and IXZ or BEV or any other anti-angiogenic agents, including sorafenib, sunitinib, 
axitinib, pazopanib, everolimus or cilengitide.
6. No investigational agent within 4 weeks prior to first dose of study drug.
7. At least 4 weeks from surgical resection and at least 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 approximately 8 weeks apart.
8. 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 subjects enrolled prior to 
Amendment 2.  Subjects enrolled after Amendment 2 is approved with a history of 
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seizures must be on a stable dose of anti-epileptic drugs (AEDs) for 7 days prior to 
enrollment.
9. All AEs resulting from prior chemotherapy, surgery, or radiotherapy, must have resolved 
to US National Cancer Institute Common Terminology Criteria for Adverse Events 
Version 4.03 (NCI-CTCAE v. 4.03) Grade 1 (except for laboratory parameters outlined 
below).
10. 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 100 × 109/L. 

Hemoglobin 9 g/dL. 

Absolute neutrophil count (ANC) 1.5 × 109/L.

Serum bilirubin 1.5 × upper limit of normal (ULN) or 3 x ULN if Gilbert’s 
disease is documented.

Aspartate transaminase (AST) 2.5 ULN.

Alanine transaminase (ALT) 2.5 ULN.

Serum creatinine 1.5 × ULN.

Urine protein: creatinine ratio ≤1.0
11. Karnofsky Performance Status (KPS) score 70%.
12. 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 treatment and 
for 3 months after the last dose of MRZ or 6 months after the last dose of BEV, 
whichever is longer. 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).
13. Willing and able to adhere to the study visit schedule and other protocol requirements.
6.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment in Part 4 Phase 1 
under Amendment 4 (see earlier versions of the protocol for criteria for Parts 1, 2, and 3).  
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 
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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 nitrosourea 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, basal cell 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 (All Parts) (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):
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 or 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.
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19. Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to 
Day 1.
20. 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.
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7.
DESCRIPTION OF STUDY TREATMENTS
7.1.
Description of Investigational Product(s)
MRZ is an investigational product that will be provided by the Sponsor.  BEV is available 
commercially and will be provided by the Investigator via prescription to subjects who are 
enrolled into this study.
7.2.
Treatment Administration and Schedule
7.2.1.
Administration of MRZ in Part 1 Phase 1
MRZ will be administered IV over 10 minutes or longer depending upon cohort (refer to 
Directions for Use regarding directions for administration time).  Volume of administration will 
vary based on assigned dose and subject body surface area (BSA).  To mitigate the possibility of 
renal dysfunction, subjects will receive normal saline administered at 350 mL/hour for 1 hour 
before and for 2 hours after the MRZ infusion. The MRZ infusion will be started after 
approximately 350 mL of saline have been given over 1 hour.  After the MRZ infusion has been 
completed, approximately 700 mL of saline will be given over 2 hours, for a total volume of 
saline infusion equal to approximately 1 L.  
Subjects should maintain good oral hydration during the study (eg, 2 L/day).  The volume and 
duration of hydration may be reduced at the discretion of the Investigator, especially for subjects 
with low body weight or with conditions sensitive to fluid overload.
Subjects must not drive a vehicle or operate heavy machinery while on this study.
The lyophilized drug product contains 2 mg API and 60 mg sucrose bulk excipient.  Cartons 
contain one vial of lyophile together with a Diluent vial containing 55% propylene glycol, 5% 
ethanol, and 40% citrate buffer pH 5 (20 mL fill; 10 mL intended for use).  The lyophile drug 
product reconstituted with 10 mL diluent results in a dosing solution comprised of 
55% propylene glycol, 40% citrate buffer and 5% ethanol, with 6 mg/mL sucrose as a 
pharmaceutical excipient.  The drug is delivered at 0.2 mg/mL at a final dosing solution of 
pH ~6.  A dose of 0.7 mg/m2 will result in approximately 7 mL of infusate.
7.2.2.
Administration of BEV in Part 1 Phase 1, Part 3 Phase 2, Part 4 Phase 1, and 
Part 5 Phase 1
BEV will be administered as an IV infusion (90 minutes 1st dose, and if tolerated 60 minutes 2nd
dose and 30 minutes on subsequent doses if tolerated) as described in the current package insert.  
During Part 5 Phase 1, the first dose of BEV will be administered on Cycle 1 Day 15
immediately following the 60-minute PK blood collection.  During all other treatment cycles,
BEV will be administered approximately 10 minutes after the end of the MRZ administration 
when co-administered on the same day.
7.2.3.
Administration of MRZ in Part 2 Phase 2
MRZ (0.8 mg/m2) will be administered IV over 10 minutes (refer to Directions for Use).  To 
mitigate the possibility of renal dysfunction, subjects will receive normal saline administered at 
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250 mL over ~30 minutes before the MRZ infusion.  The lyophilized drug product is the same as 
used in Phase 1.
Subjects should maintain good oral hydration during the study (eg, 2 L/day).  The volume and 
duration of hydration may be reduced at the discretion of the Investigator, especially for subjects 
with low body weight or with conditions sensitive to fluid overload.  
Subjects must not drive a vehicle or operate heavy machinery while on this study.
7.2.4.
Administration of MRZ in Part 3 Phase 2
MRZ will be administered IV over 10 minutes (refer to Directions for Use).  The lyophilized 
drug product is the same as used in previous parts.
Starting dose in each subject will be 0.8 mg/m2.  Intra-patient dose escalation will be used.  After 
the first cycle without a DLAE, the dose will be increased by 0.2 mg/m2 to 1.0 mg/m2 (an 
increase of 25%).  After one more cycle without a DLAE the dose of MRZ will be increased to 
1.2 mg/m2 (an increase of 20%) for that cycle and subsequent cycles.
Subjects should be encouraged to maintain good oral hydration during the study (eg, 2 L/day).  
Renal dysfunction has not been observed during the conduct of the study, including in Part 2 
Phase 2 where volume and duration of pre and post dose hydration was reduced.  It is therefore 
not considered a safety concern and will not be required in Part 3 Phase 2.  Should renal function 
become a safety issue, pre-dose hydration will be reinstated if thought necessary by the 
Sponsor’s medical monitor and study team and the Investigators.
Subjects must not drive a vehicle or operate heavy machinery while on this study.
7.2.5.
Administration of MRZ in Part 4 Phase 1
Subjects should not eat or drink for 2 hours prior to and 2 hours after enteral administration of 
MRZ via NG tube.
In Cycle 1, MRZ IV formulation will be reconstituted and administered enterally via NG tube 
over up to 10 minutes (refer to Directions for Use).  Volume of administration will vary based on 
assigned dose and subject body surface area (BSA).  The volume of MRZ administration is 
calculated by: Volume = Dose (mg) * BSA (m2) / 0.2 (conc. of MRZ in solution in mg/mL). The 
lyophilized drug product is the same as used in previous parts of the protocol.
In Cycle 2 and all subsequent cycles, MRZ (0.8 mg/m2) will be administered IV over 10 minutes 
(refer to Directions for Use).  
Subjects should be encouraged to maintain good oral hydration during the study (eg, 2 L/day).  
Renal dysfunction has not been observed during the conduct of the clinical studies in GBM, 
including in Part 2 Phase 2 where volume and duration of pre and post dose hydration was 
reduced, and in Part 3 Phase 2 where pre and post dose hydration was not required.  It is 
therefore not considered a safety concern and will not be required in Part 4 Phase 1.  
Subjects must not drive a vehicle or operate heavy machinery while on this study.
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7.2.6.
Administration of MRZ in Part 5 Phase 1
MRZ will be administered IV at the dose of 0.8 mg/m2 over 10 minutes.  Volume of 
administration will vary based on subject BSA.  The volume of MRZ administration is calculated 
by: Volume = Dose (mg) * BSA (m2) / 0.2 (conc. of MRZ in solution in mg/mL). The 
lyophilized drug product is the same as used in previous parts of the protocol.
Subjects must not drive a vehicle or operate heavy machinery while on this study.
7.2.6.1.
Dose Schedules
Part 1 Phase 1
All subjects will receive MRZ + BEV as follows:
IV Marizomib (MRZ)

MRZ will be administered as a 10-minute IV infusion on Days 1, 8, and 15 of every 
28-day cycle.  Infusion durations may be lengthened to ameliorate toxicity for 
individual subjects or for cohorts with agreement between the Investigators and the 
Sponsor.  For dosing details, see Table 5.

Minimum re-treatment criterion prior to the beginning of each new cycle: 
creatinine ≤1.5 x ULN, Hgb ≥8 g/dL, platelets ≥75 x 109/L.
IV BEV
BEV will be administered as an IV infusion (90 minutes 1st dose, 60 minutes 2nd dose and 30 
minutes afterward) at a dose of 10 mg/kg on Days 1 and 15.  BEV will be administered 
approximately 10 minutes after the end of the MRZ infusion when co-administered on the same 
day.
In the case of dosing delay, BEV should always be given on the day that MRZ is administered.  
If BEV is discontinued for AEs, the subject may continue on MRZ alone.  If MRZ is 
discontinued, then the subject will be discontinued from the trial.  If MRZ is delayed, BEV 
should also be delayed.  Both drugs will be discontinued once disease progression is 
documented.
MRZ dosing will begin at 0.55 mg/m2 once weekly (Cohort 1).  Additional dose cohorts are 
planned as shown in Table 5.
Table 5:
Dose Cohorts for MRZ + BEV Combination
Cohort
IV MRZ
Day 1, 8, and 15 of Each 28-Day Cycle
IV BEV
Day 1 and 15 of Each 28-Day Cycle
-2
0.3 mg/m2
10 mg/kg
-1
0.4 mg/m2
10 mg/kg
1
0.55 mg/m2
10 mg/kg
2
0.7 mg/m2
10 mg/kg
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Table 5:
Dose Cohorts for MRZ + BEV Combination (Continued)
Cohort
IV MRZ
Day 1, 8, and 15 of Each 28-Day Cycle
IV BEV
Day 1 and 15 of Each 28-Day Cycle
3
0.8 mg/m2
10 mg/kg
4
Additional cohorts with extended infusion 
duration if required
10 mg/kg
Part 1 Phase 1 Expansion Cohort and Part 2 Phase 2
IV Marizomib (MRZ)
MRZ (0.8 mg/m2) will be administered as a 10-minute IV infusion on Days 1, 8, and 15 of every 
28-day cycle.  Infusion durations may be lengthened to ameliorate toxicity for individual subjects 
with agreement between the Investigator and the Sponsor.
Detailed instructions for MRZ dose modifications and actions are provided in Table 6.
Table 6:
Marizomib Dose Modification Guidelines for Part 1 Phase 1 Expansion and 
Part 2 Phase 2
Toxicity 
MRZ Dose Modification & Action 
Grade 2 Central Nervous System Disorders 
Consider holding MRZ until toxicity resolves. When 
toxicity resolves, consider reinitiating with reduced dose 
of MRZ (to be determined in discussion with the 
Medical Monitor, but at least a decrease of 0.1 mg/m2). 
Grade 3 Nervous System Disorder AEs 
Hold MRZ until toxicity resolves. When toxicity 
resolves, reinitiate with reduced dose of MRZ (to be 
determined in discussion with the Medical Monitor, but 
at least a decrease of 0.1 mg/m2 at start of next cycle). 
Other Grade 3 MRZ-related AEs 
Hold MRZ until toxicity resolves. When toxicity 
resolves, reinitiate with reduced dose of MRZ (to be 
determined in discussion with the Medical Monitor, but 
at least a decrease of 0.1 mg/m2 at start of next cycle). 
Grade 4 Hematologic MRZ-related AEs 
Hold MRZ until toxicity resolves. When toxicity 
resolves, reinitiate with reduced dose of MRZ (to be 
determined in discussion with the Medical Monitor, but 
at least a decrease of 0.1 mg/m2 at start of next cycle). 
Nonhematological Grade 4 MRZ-related 
AEs 
Permanently discontinue all study treatment. 
This table was added with Amendment 2 and applies to subjects entered under Amendment 2 whether in the Phase 1 
Dose Expansion or Phase 2 portions of the study.
In addition to the guidelines in Table 6 if a subject has a drug-related event that requires a 14-day 
delay in therapy, then MRZ dose reduction is appropriate. If recovery from toxicities is 
prolonged beyond 14 days, then the dose of MRZ will be decreased by 0.1 mg/m2 when dosing 
resumes. After MRZ dose interruption, reassessment of safety laboratory tests is required prior 
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to resuming MRZ treatment. Prior to initiation of subsequent cycles, results for the following 
tests must meet study entry criteria: liver functions tests (LFTs), serum creatinine, and complete 
blood count. 
The minimum permitted dose level for MRZ is 0.5 mg/m2. If toxicity recurs at the minimum 
permitted dose of MRZ, all study treatment should be discontinued. Dose re-escalation is not 
permitted for MRZ.
Part 3 Phase 2
IV Marizomib

MRZ will be administered as a 10-minute IV infusion on Days 1, 8, and 15 of every 
28-day cycle.

Starting dose for each subject will be 0.8 mg/m2.

Doses will be rounded to the nearest tenth of a mg.

After the first cycle without a dose-limiting adverse event (DLAE), the dose of MRZ 
will be increased to 1.0 mg/m2 and after 1 more cycle without a DLAE the dose of 
MRZ will be increased to 1.2 mg/m2.

DLAEs are MRZ-related AEs 1) related to disturbances in the cerebellum (ie, ataxia, 
dizziness, dysarthria, fall, gait disturbances) plus hallucinations of any grade or 
2) Grade ≥2 other AEs.

Doses will be delayed and/or reduced or discontinued for DLAEs related to MRZ as 
described in Table 7.
Table 7:
Marizomib Dose Modification Guidelines in Part 3 Phase 2, Part 4 Phase 1, 
and Part 5 Phase 1
Marizomib-Related 
Adverse Event
Severity
Recommended MRZ Dose Modification
Central Nervous System
Common CNS AEs 
include:
Hallucinations, ataxia, 
dizziness, gait 
disturbance, balance 
disorder, fall, 
dysarthria, confusion
Grade 1
Maintain current MRZ dose schedule without dose 
modification.
Grade 2
Consider other supportive treatment; generally no dose-
reductions are recommended.
Dose-reduction is recommended if intolerable by patient due 
to interference with daily routine and/or if duration of event 
lasts longer than 3 days.
Grade 3
At the next scheduled MRZ dose administration, dose-reduce 
one dose level. If AE has not resolved to ≤Grade 1 (or 
baseline), skip the MRZ dose and resume with the next 
scheduled dose at reduced level.
In addition, consider other supportive treatment.
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Table 7:
Marizomib Dose Modification Guidelines in Part 3 Phase 2, Part 4 Phase 1, 
and Part 5 Phase 1 (Continued)
Marizomib-Related 
Adverse Event
Severity
Recommended MRZ Dose Modification
Grade 4 
Stop MRZ until resolution to ≤ Grade 1 (or baseline).
Discuss with Medical Monitor.
If re-challenge is an option, reduce MRZ dose level (see MRZ 
dose reduction table) in agreement with Medical Monitor.
Gastrointestinal
Nausea, Vomiting 
Grade 1 or 2
Implement prophylactic anti-emetic regimen according to 
local guidelines.
Maintain current MRZ dose schedule without dose 
modification.
If (re)occurrence despite appropriate prophylaxis, dose-reduce 
one dose level (see MRZ dose reduction table) at the next 
scheduled MRZ dose administration.
Grade 3 or 4
Implement prophylactic anti-emetic regimen according to 
local guidelines.
If (re)occurrence despite appropriate prophylaxis, dose-reduce 
one dose level (see MRZ dose reduction table) at the next 
scheduled MRZ dose administration.
In addition, consider other supportive treatment per local 
guidelines.
Other Adverse Events
Grade 2
Maintain current MRZ dose schedule without dose 
modification.
Consider dose-reduction if intolerable by patient due to 
interference with daily routine and/or not resolved to ≤ Grade 
1 (or baseline) at the next scheduled MRZ dose administration. 
Grade 3
At the next scheduled MRZ dose administration, dose-reduce 
one dose level (see MRZ dose reduction table). If AE has not 
resolved to ≤ Grade 1 (or baseline), skip the MRZ dose and 
resume with the next scheduled dose at reduced level.
Grade 4
Stop MRZ until resolution to ≤ Grade 1 (or baseline).
Discuss with Medical Monitor.
If re-challenge is an option, reduce MRZ dose level (see MRZ 
dose reduction table) in agreement with Medical Monitor.
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
In addition to the guidelines in Table 7, if a subject has an MRZ-related event that requires a 14-day delay in 
therapy (calculated from the scheduled date of the next dose), then MRZ dose reduction is appropriate.  If 
recovery from MRZ-related AEs is prolonged beyond 14 days, then the dose of MRZ will be decreased by 
0.1 mg/m2 when dosing resumes unless an alternative plan is approved by the Sponsor’s Medical Monitor.

Dose re-escalation is not permitted for MRZ unless approved by the Sponsor’s Medical Monitor.

All dose increases (Part 3 Phase 2 only) require approval of the Sponsor’s Medical Monitor.
IV BEV
BEV will be administered as an IV infusion (90 minutes 1st dose, 60 minutes 2nd dose, and 30 
minutes afterward) at a dose of 10 mg/kg on Days 1 and 15.  BEV will be administered 
approximately 10 minutes after the end of the MRZ infusion when co-administered on the same 
day.
In the case of dosing delay, BEV should always be given on the day that MRZ is administered.  
If MRZ is delayed, BEV should also be delayed.  If BEV is discontinued for AEs, the subject 
may continue on MRZ alone.  If MRZ is discontinued, the subject will be discontinued from the
study.  Both drugs will be discontinued once disease progression is documented.
There are no recommended dose reductions.  According to the Warnings and Precautions and 
Dose Modification sections of the Avastin® United States Prescribing Information, the following 
actions are recommended:

Perforation or Fistula: Discontinue BEV if perforation or fistula occurs.

Wound Healing: Discontinue BEV for wound dehiscence and wound healing 
complications requiring medical intervention

Hemorrhage:  Discontinue BEV in subjects with serious hemorrhage

Arterial Thromboembolic Events (ATE) (eg, myocardial infarction, cerebral 
infarction): Discontinue BEV for severe ATE.

Venous Thromboembolic Events (VTE): Discontinue BEV for life-threatening 
(Grade 4) VTE, including pulmonary embolism

Hypertension: Monitor blood pressure and treat hypertension.  Temporarily suspend 
BEV if not medically controlled.  Discontinue BEV for hypertensive crisis or 
hypertensive encephalopathy.

Posterior Reversible Encephalopathy Syndrome (PRES): Discontinue BEV.

Proteinuria: Monitor proteinuria by dipstick urine analysis for the development or 
worsening of proteinuria with serial urinalyses during BEV therapy. Subjects with a 
2+ or greater urine dipstick reading should undergo further assessment with a 24-hour 
urine collection.  Suspend BEV administration for ≥ 2 grams of proteinuria/24 hours 
and resume when proteinuria is < 2 gm/24 hours. Discontinue BEV in subjects with 
nephrotic syndrome.

Infusion Reactions: Stop BEV for severe infusion reactions and administer 
appropriate medical therapy.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
87
MRZ-108 Amendment 5 Final: 18 Mar 2020
Part 4 Phase 1
Enterally Administered Marizomib

MRZ will be administered enterally as a bolus over ≤10 min via NG tube on Days 1, 
8, and 15 of the first 28-day cycle.

MRZ dosing will begin at 0.075 mg/m2 once weekly (Cohort 1).  Additional dose 
cohorts are planned as shown in Table 8.

Doses will be rounded to the nearest tenth of a mg.
Table 8:
Dose Cohorts for Enteral (Cycle 1) and IV (Cycles 2) MRZ + IV BEV 
Combination
Cohort
Number of 
Subjects
Enteral MRZ (mg/m2)
Cycle 1
Days 1, 8, and 15
IV MRZ (mg/m2)
Cycle 2+ Days 1, 8 
and 15*
IV BEV (mg/kg)
Cycle 1 Day 15
Cycle 2+ Days 1 and 15
-1*
3-6
0.025
0.8
10
1
1-6
0.075
0.8
10
2
1-6
0.225
0.8
10
3
1-6
0.675
0.8
10
4
3-6
1.0
0.8
10
5
3-6
1.35
0.8
10
6
3-6
1.7
0.8
10
7
3-6
2.0
0.8
10
8
3-6
2.3
0.8
10
9
3-6
2.6
0.8
10
* Refer to Section 7.2.8, Part 4 Phase 1.

Doses will be delayed and/or reduced or discontinued for DLTs related to MRZ as 
described in Table 7.

Subjects must receive at least 3 doses of MRZ during Cycle 1, with 2 MRZ doses 
administered enterally during Cycle 1 to be evaluable for DLT.
IV Marizomib

For Cycle 2 and all subsequent cycles, MRZ will be administered as a 10-minute IV 
infusion on Days 1, 8, and 15 of every 28-day cycle.

Starting dose for each subject will be 0.8 mg/m2.  No dose increases are permitted.

Doses will be rounded to the nearest tenth of a mg.

Doses will be delayed and/or reduced or discontinued for adverse events related to 
MRZ as described in Table 7.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
88
MRZ-108 Amendment 5 Final: 18 Mar 2020

In addition to the guidelines in Table 7, if a subject has a MRZ-related event that 
requires a 14-day delay in therapy (calculated from the scheduled date of the next 
dose), then MRZ dose reduction is appropriate.  If recovery from MRZ-related AEs is 
prolonged beyond 14 days, then the dose of MRZ will be decreased by 0.1 mg/m2
when dosing resumes unless an alternative plan is approved by the Sponsor’s Medical 
Monitor.
Dose re-escalation is not permitted for MRZ unless approved by the Sponsor’s Medical Monitor.
IV BEV
BEV will be administered as an IV infusion (90 minutes 1st dose, 60 minutes 2nd dose, and 30 
minutes afterward) at a dose of 10 mg/kg on Day 15 of Cycle 1, and on Days 1 and 15 of Cycle 2 
and all subsequent cycles.  BEV will be administered approximately 10 minutes after the end of 
the MRZ infusion when co-administered on the same day.
In the case of dosing delay, BEV should always be given on the day that MRZ is administered.  
If MRZ is delayed, BEV should also be delayed.  If BEV is discontinued for AEs, the subject 
may continue on MRZ alone.  If MRZ is discontinued, the subject will be discontinued from the 
study.  Both drugs will be discontinued once disease progression is documented.
There are no recommended dose reductions.  According to the Warnings and Precautions and 
Dose Modification sections of the Avastin® United States Prescribing Information, the following 
actions are recommended:

Perforation or Fistula: Discontinue BEV if perforation or fistula occurs.

Wound Healing: Discontinue BEV for wound dehiscence and wound healing 
complications requiring medical intervention

Hemorrhage:  Discontinue BEV in subjects with serious hemorrhage

Arterial Thromboembolic Events (ATE) (eg, myocardial infarction, cerebral 
infarction): Discontinue BEV for severe ATE.

Venous Thromboembolic Events (VTE): Discontinue BEV for life-threatening 
(Grade 4) VTE, including pulmonary embolism

Hypertension: Monitor blood pressure and treat hypertension.  Temporarily suspend 
BEV if not medically controlled.  Discontinue BEV for hypertensive crisis or 
hypertensive encephalopathy.

Posterior Reversible Encephalopathy Syndrome (PRES): Discontinue BEV.

Proteinuria: Monitor proteinuria by dipstick urine analysis for the development or 
worsening of proteinuria with serial urinalyses during BEV therapy. Subjects with a 
2+ or greater urine dipstick reading should undergo further assessment with a 24-hour 
urine collection.  Suspend BEV administration for ≥ 2 grams of proteinuria/24 hours 
and resume when proteinuria is < 2 gm/24 hours. Discontinue BEV in subjects with 
nephrotic syndrome.

Infusion Reactions: Stop BEV for severe infusion reactions and administer 
appropriate medical therapy.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
89
MRZ-108 Amendment 5 Final: 18 Mar 2020
Part 5 Phase 1

All subjects will receive MRZ + BEV as follows:
IV Marizomib (MRZ)

MRZ will be administered as a 10-minute IV infusion on Days 1, 8, and 15 of every 
28-day cycle. Infusion durations may be lengthened to ameliorate toxicity for 
individual subjects with agreement between the Investigator and the Sponsor.

Starting dose for each subject will be 0.8 mg/m2.

Doses will be rounded to the nearest tenth of a mg.

Doses will be delayed and/or reduced or discontinued for AEs related to MRZ as 
described in Table 7.

Intra-patient dose escalation is not permitted in Part 5 Phase 1.

In Part 5 Phase 1, an additional subject(s) will be enrolled for any subject(s) who has 
a reduction in their MRZ dose in Cycle 1.  
IV BEV
BEV will be administered as an IV infusion (90 minutes 1st dose, 60 minutes 2nd dose and 30 
minutes afterward) at a dose of 10 mg/kg on Day 15 of Cycle 1, and on Days 1 and 15 of Cycle 2 
and all subsequent cycles.  BEV will be administered approximately 10 minutes after the 
collection of the last MRZ PK blood sample on Day 15 of Cycle 1, and approximately 10 
minutes after the end of the MRZ infusion when co-administered on the same day in Cycle 2 and 
all subsequent cycles.
In the case of dosing delay, BEV should always be given on the day that MRZ is administered.  
If MRZ is delayed, BEV should also be delayed.  If BEV is discontinued for AEs, the subject 
may continue on MRZ alone.  If MRZ is discontinued, the subject will be discontinued from the 
study.  Both drugs will be discontinued once disease progression is documented.
There are no recommended dose reductions.  According to the Warnings and Precautions and 
Dose Modification sections of the Avastin® United States Prescribing Information, the following 
actions are recommended:

Perforation or Fistula: Discontinue BEV if perforation or fistula occurs.

Wound Healing: Discontinue BEV for wound dehiscence and wound healing 
complications requiring medical intervention

Hemorrhage:  Discontinue BEV in subjects with serious hemorrhage

Arterial Thromboembolic Events (ATE) (eg, myocardial infarction, cerebral 
infarction): Discontinue BEV for severe ATE.

Venous Thromboembolic Events (VTE): Discontinue BEV for life-threatening 
(Grade 4) VTE, including pulmonary embolism

Hypertension: Monitor blood pressure and treat hypertension.  Temporarily suspend 
BEV if not medically controlled.  Discontinue BEV for hypertensive crisis or 
hypertensive encephalopathy.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
90
MRZ-108 Amendment 5 Final: 18 Mar 2020

Posterior Reversible Encephalopathy Syndrome (PRES): Discontinue BEV.

Proteinuria: Monitor proteinuria by dipstick urine analysis for the development or 
worsening of proteinuria with serial urinalyses during BEV therapy. Subjects with a 
2+ or greater urine dipstick reading should undergo further assessment with a 24-hour 
urine collection.  Suspend BEV administration for ≥ 2 grams of proteinuria/24 hours 
and resume when proteinuria is < 2 gm/24 hours. Discontinue BEV in subjects with 
nephrotic syndrome.

Infusion Reactions: Stop BEV for severe infusion reactions and administer 
appropriate medical therapy.
7.2.7.
Dose-Limiting Toxicity
Part 1 Phase 1
Dose-limiting toxicity (DLT) is defined as the occurrence of any of the following AEs related to 
one of the drugs or the combination observed during Cycle 1, using NCI-CTCAE (v 4.03):

≥ Grade 3 thrombocytopenia or Grade 2 thrombocytopenia with bleeding.

Grade 4 neutropenia or anemia lasting for more than 4 days.

Febrile neutropenia.

Any ≥ Grade 2 neurological event lasting more than 4 days.

Grade 3 or 4 non-hematologic toxicity (excluding alopecia), lasting for more than 4 
days despite adequate supportive therapy or preventing the next scheduled dose from 
being administered within 4 days of scheduled day; for ≥Grade 3 fatigue to be 
considered a DLT, it must be present for more than 7 days.
Subjects without DLT in Cycle 1 who do not receive 3 MRZ doses or 2 BEV doses within 
5 weeks from first dose will not be evaluable for DLT and will be replaced.
Part 2 Phase 2
If at any time after 3 subjects are enrolled, the incidence of AEs that fit the definition of DLT 
from Phase 1 occurs in >33% of the subjects, then enrollment will be paused.  Available data 
will be reviewed and a decision regarding continuing to enroll subjects at the 0.8 mg/m2 over 
10 minutes dose in Phase 2 is agreed between the Sponsor and Investigators.  Adjustment 
downward on dose or lengthening infusion duration will be considered and the Phase 2 portion 
restarted at the selected dose and infusion time.
Part 3 Phase 2
The term DLT is not applicable to this portion of the study.  DLAEs, defined as MRZ-related 
AEs which are: 1) related to disturbances in the cerebellum (ie, ataxia, dizziness, dysarthria, fall, 
gait disturbances) plus hallucinations of any grade or 2) Grade ≥ 2 other AEs will be used to 
determine if MRZ doses should be delayed, reduced, or discontinued.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
91
MRZ-108 Amendment 5 Final: 18 Mar 2020
Part 4 Phase 1
Dose-limiting toxicity (DLT) is defined as the occurrence of any of the following AEs related to 
one of the drugs or the combination observed during Cycle 1, using NCI-CTCAE (v 4.03) to 
determine severity:

Grade ≥3 non-hematological toxicity (excluding alopecia), including GI toxicities 
such as nausea, vomiting, constipation, and/or diarrhea, lasting for more than 4 days 
despite adequate supportive therapy or preventing the next scheduled dose from being 
administered within 7 days of scheduled day

For ≥Grade 3 fatigue to be considered a DLT, it must be present for more than 
7 days.

Grade 3 thrombocytopenia or Grade 2 thrombocytopenia with bleeding.

Grade 4 neutropenia or anemia lasting for more than 4 days.

Febrile neutropenia.

Any ≥ Grade 2 neurological event lasting more than 4 days.
Subjects who do not have a DLT in the first cycle of a dose cohort will be replaced if they do not 
receive at least two doses of enterally-administered MRZ, with the second dose administered no 
more than 7 days after the scheduled dose.  Subjects who demonstrate intolerability to enteral 
MRZ administration for any reason may continue to receive subsequent MRZ treatments 
intravenously.
Part 5 Phase 1
Amendment 5 does not include an assessment of dose-limiting toxicity, as MRZ will be 
administered by IV infusion at the MTD as confirmed in Part 3 Phase 2 (0.8 mg/m2 on Days 1, 8, 
and 15 of each 28-day cycle).
7.2.8.
Dose Escalation Process and MTD/MAD Determination
Part 1 Phase 1 
Initially 3 subjects will be enrolled into a cohort, commencing with Cohort 1 and the doses 
shown in Table 5. Dose escalation will proceed as follows:

If none of the first 3 evaluable subjects in a dose cohort experience a DLT during 
Cycle 1, then enrollment into the next dose cohort can be initiated.

If ≥2 of the first 3 evaluable subjects in a dose cohort experience a DLT during Cycle 
1, then the MTD has been exceeded and dose escalation will not proceed.

If 1 of the first 3 evaluable subjects in a dose cohort experiences a DLT during Cycle 
1, then an additional 3 subjects will be enrolled into the same cohort.  

If 1/6 evaluable subjects in the expanded 6-subject cohort experiences a DLT during 
Cycle 1, then the next higher dose cohort can be tested and enrollment of the next 
3 subjects at the next higher dose level can be initiated.

If ≥2/6 evaluable subjects in the expanded 6-subject cohort experience a DLT during 
Cycle 1, then the MTD has been exceeded and no further dose escalation will occur.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
92
MRZ-108 Amendment 5 Final: 18 Mar 2020
The MTD is defined as the dose level below the cohort where DLT is observed in at least 
2 subjects in the same cohort during Cycle 1.  Intermediate dosing levels may be explored if 
indicated.  The dose of 0.8 mg/m2 will not be exceeded and will be the MAD.
During the dose escalation phase of the protocol, if 2 DLTs are noted in the first 2 subjects of a 
cohort prior to the third subject being enrolled, the third subject will not be enrolled in that 
cohort.  If there is 1 DLT in the first 3 subjects and the cohort is expanded and another DLT is 
noted prior to enrolling all 6 subjects in the cohort, further enrollment in that cohort will be 
halted.  If during the dose expansion phase there are ≥3 DLTs in the first 6 or fewer subjects 
then the MTD will be reassessed by the Investigators and Sponsor.
Teleconferences between Triphase and the clinical study sites will occur at least every other 
week to discuss safety.  Once the MTD/MAD has been identified, a cohort of at least 
12 additional, evaluable subjects for a total of 36 subjects will be treated at the MTD/MAD to 
further confirm the safety and to assess preliminary activity for the combination treatment.  This 
cohort may be used to determine the RP2D.
Part 4 Phase 1 
A modified 3+3 design will be used to define the MTD for MRZ IV formulation reconstituted 
and administered enterally via NG tube in the first 28-day cycle, with MRZ administered on 
Days 1, 8, and 15 and BEV on Day 15. Initially one subject will be enrolled into each of the first 
3 dose cohorts to expedite dose-escalation into the anticipated therapeutically effective dose 
range, followed by enrollment of 3 subjects each into the next 6 dose cohorts. 
Enteral MRZ dose escalation will proceed as follows:

If the first DLT-evaluable subject in dose cohort 1 does not experience a DLT or 
intermediate toxicity during Cycle 1, then enrollment into the next dose cohort can be 
initiated. Intermediate toxicity is defined as any Grade 2 or higher adverse event that 
is deemed clinically significant by the Investigator and which cannot be clearly 
identified as being related to the underlying condition, comorbid condition, or 
concomitant medication.

If the first DLT-evaluable subject in a 1-subject dose cohort experiences a DLT 
during Cycle 1, then up to 5 additional subjects will be enrolled into the same cohort.

The 1-subject cohorts will be expanded to 3 subjects with the second instance of first-
cycle intermediate toxicity.  Intermediate toxicity is defined as any Grade 2 or higher 
adverse event that is deemed clinically significant by the Investigator and which 
cannot be clearly identified as being related to the underlying condition, comorbid 
condition, or concomitant medication.  Once a 1-subject cohort has been expanded, 
all subsequent cohorts will have at least 3 subjects (unless the first 2 subjects have 
DLT prior to the enrollment of a third subject).

If there are 2 subjects with DLT in Cohort 1, then 3 subjects can be enrolled in Cohort 
-1.  The decision to explore Cohort -1 will be made by the participating Investigators 
and Sponsor’s Medical Monitor(s).  If Cohort -1 proceeds without any subject with a 
DLT, participating Investigators and Sponsor’s Medical Monitor(s) may decide to 
revisit Cohort 1 and, if tolerated, continue with the escalation as shown in Table S-2, 
or with intermediate dose levels.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
93
MRZ-108 Amendment 5 Final: 18 Mar 2020

If 1 of the first 3 evaluable subjects in a 3-subject dose cohort experiences a DLT 
during Cycle 1, then an additional 3 subjects will be enrolled into the same cohort.  

If no more than 1 of the 6 DLT-evaluable subjects in an expanded dose cohort 
experiences a DLT during Cycle 1, then the next higher dose cohort can be initiated 
with 3 subjects enrolled at the next higher dose level.

If ≥ 2/6 evaluable subjects in an expanded dose cohort experiences a DLT during 
Cycle 1, then the MTD has been exceeded and no further dose escalation will occur.
The MTD is defined as the dose level below the cohort where DLT is observed in at least 2 
subjects in the same cohort during Cycle 1.  Intermediate dosing levels may be explored if 
indicated.
The dose of 2.6 mg/m2 is expected to be above the MTD for enterally-administered MRZ. If this 
is not the case, additional cohorts can be explored with dose escalations between cohorts kept at 
approximately 20%.
Once the MTD has been identified, a cohort of approximately 6 additional, evaluable subjects 
will be treated at the MTD to further confirm the safety of the combination treatment.
Teleconferences between Sponsor and the clinical study sites will occur at least every other week 
to discuss safety.  Additional teleconferences may be scheduled at the end of each cohort to 
decide on the dose of the next cohort.
7.3.
Method of Treatment Assignment
Part 1 Phase 1
Treatments consist of IV doses of MRZ and BEV.  Subjects will enter the study sequentially and 
be assigned to a cohort (dose level) based on the evaluation of subjects who were previously 
treated according to the dose escalation scheme.  Once the RP2D is determined, subjects will be 
treated at the RP2D in the expansion cohort unless the Investigators and Sponsor agree to a lower 
dose for safety reasons.
Part 2 Phase 2
Treatments consist of IV doses of MRZ.  Subjects will enter the study sequentially.
Part 3 Phase 2
Treatment consists of IV doses of MRZ and BEV.  Subjects will enter the study sequentially.
Part 4 Phase 1
Treatments consist of once-weekly enterally administered doses of MRZ IV formulation 
reconstituted and administered via NG tube (Days 1, 8, and 15), with a single IV dose of BEV on 
Day 15.  Subjects will enter the study sequentially and be assigned to a cohort (dose level) based 
on the evaluation of subjects who were previously treated according to the dose escalation 
scheme.  Once the MTD is determined, subjects will be treated at the MTD in the expansion 
cohort unless the Investigators and Sponsor agree to a lower dose for safety reasons.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
94
MRZ-108 Amendment 5 Final: 18 Mar 2020
Part 5 Phase 1
Treatments consist of IV doses of MRZ administered by IV infusion at the MTD as confirmed in 
Part 3 Phase 2 (0.8 mg/m2 on Days 1, 8, and 15 of each 28-day cycle), and BEV.
7.4.
Packaging and Labeling
The label(s) for Investigational Product (IP) MRZ will include Sponsor name, address and 
telephone number, the protocol number, IP name, dosage form and strength (where applicable), 
amount of IP per container, lot number, expiry date (where applicable), medication 
identification/kit number, dosing instructions, storage conditions, and required caution 
statements and/or regulatory statements as applicable. Additional information may be included 
on the label as applicable per local regulations.
7.5.
Investigational Product Accountability and Disposal 
Triphase (or designee) will review with the Investigator and relevant site personnel the process 
for Investigational Product return, disposal, and/or destruction including responsibilities for the 
site vs. Triphase (or designee).
7.6.
Investigational Product Compliance
Both investigational products are given intravenously by trained site personnel and records of 
administration are maintained at the site.  Subjects will be monitored for adherence to visit days 
for drug administration.  Dosing delays for AEs or administrative reasons (eg, clinical closure for 
holidays) will not be considered protocol deviations.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
95
MRZ-108 Amendment 5 Final: 18 Mar 2020
8.
CONCOMITANT MEDICATIONS AND PROCEDURES
8.1.
Permitted Concomitant Medications and Procedures
Concomitant medications to treat comorbid conditions and adverse events are permitted.  
Enzyme-inducing anti-epileptic drugs (EIAEDs) are allowed.  Steroids are allowed and dosing is 
at the discretion of the Investigator.  Consideration should be given to treating hallucinations 
with anti-psychotic drugs such as olanzapine or quetiapine and fatigue with stimulating agents 
such as methylphenidate.
In studies to date, MRZ has caused clinically significant nausea and vomiting requiring the use 
of antiemetics as therapy and also as prophylaxis.  Therefore, both the therapeutic and 
prophylactic use of antiemetics is allowed in this study at the discretion of the Investigator.
8.2.
Prohibited Concomitant Medications and Procedures
Medications to treat the underlying malignancy are not permitted and their use constitutes 
progressive disease and subjects must discontinue study treatment.  Investigational agents of any 
kind are not permitted.
8.3.
Required Concomitant Medications and Procedures
There are no required concomitant medications or procedures.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
96
MRZ-108 Amendment 5 Final: 18 Mar 2020
9.
STATISTICAL ANALYSES
9.1.
Overview
Part 1 Phase 1
A 3 + 3 design will be utilized to determine the MTD/MAD for combination treatment of MRZ + 
BEV in each 28-day cycle.  Subjects who do not have a DLT in the first cycle of a dose cohort
will be replaced if they discontinue treatment with MRZ or BEV in Cycle 1 for any other reason.  
Subjects who miss a dose of MRZ or BEV or cannot receive all doses within 5 weeks from first 
dose during Cycle 1 and do not have a DLT will not be evaluable for DLT and will be replaced.  
After MTD/MAD has been determined in the dose-escalation part of the study, at least 
12 additional subjects will be treated at the MTD/MAD in an expansion cohort to confirm the 
safety and assess the preliminary activity for the combination of MRZ + BEV administered up to 
a total of 36 subjects.
For all analyses by dose cohorts, the MTD/MAD confirmation cohort subjects will be combined 
with the corresponding dose cohort in the MTD/MAD determination phase as one single dose 
cohort.
Part 2 Phase 2
Subjects enrolled in the Part 2 Phase 2 portion of the protocol will receive 0.8 mg/m2 MRZ IV on 
Days 1, 8, and 15 of 28-day cycles. A minimum of 15 response-evaluable subjects will be 
enrolled in Stage 1, and up to 15 additional response-evaluable subjects will be enrolled in Stage 
2, for a maximum of 30 response-evaluable subjects.  After the first 15 response-evaluable 
subjects in the first stage have received 2 or more cycles of therapy, available study data will be 
reviewed by the Phase 2 Review Committee consisting of the Investigators at each study center, 
the Medical Monitor, and the Sponsor’s Chief Medical and Scientific Officers and Study 
Coordinator. The Phase 2 Review Committee will recommend whether to enroll the second stage 
based on an assessment of both safety and efficacy.  If there are no safety concerns and clinical 
benefit is demonstrated with evidence of disease response, defined as at least one response 
(partial response (PR) or better) as determined by RANO criteria, in 15 response-evaluable 
subjects, then 15 additional response-evaluable subjects will be enrolled in Phase 2.  Otherwise, 
there will be no further enrollment into the study.
Efforts will be made to ensure the correct number of subjects is accrued, and enrollment will be 
carefully monitored and communicated with the sites.  There may be instances where, as a result 
of simultaneous screening activities, subjects may qualify for the study at the same time, 
resulting in slight over-enrollment.
Part 3 Phase 2
A sample size of 40 eligible subjects is based on wanting a reasonably precise estimate of 
median OS.
Efforts will be made to ensure the correct number of subjects is accrued, and enrollment will be 
carefully monitored and communicated with the sites.  There may be instances where, as a result 
of simultaneous screening activities, subjects may qualify for the study at the same time, 
resulting in slight over-enrollment.
Approved
3.0
v
Approved
1.0
v


EDMS Doc. Number: 
EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Protocol MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
97
MRZ-108 Amendment 5 Final: 18 Mar 2020
Part 4 Phase 1
A modified 3 + 3 design will be utilized to determine the MTD for MRZ IV formulation 
reconstituted and administered enterally via NG tube on Days 1, 8, and 15 of a 28-day cycle, 
with BEV administered IV on Day 15.  Subjects who do not have a DLT in the first cycle of a 
dose cohort will be replaced if they do not receive at least two doses of enterally-administered 
MRZ, with the second dose administered no more than 7 days after the scheduled dose.  After 
MTD has been determined in the dose-escalation part of the study, approximately 6 additional 
subjects will be treated at the MTD in an expansion cohort to confirm the safety and assess the 
PK and pharmacodynamic activity for enterally administered MRZ, for up to a total of 
approximately 24 subjects.
For all analyses by dose cohorts, the MTD confirmation cohort subjects will be combined with 
the corresponding dose cohort in the MTD determination phase as one single dose cohort.
Part 5 Phase 1
A subject who has at least 1 full PK profile in Cycle 1 with quantifiable PK parameters will be 
included in the PK analysis.  PK parameters from noncompartmental analysis will be 
summarized by study day across subjects, and by subject across study days using simple 
summary statistics presented in tables and graphs.
In Amendment 5, any subject that discontinues treatment in Cycle 1 without completing all PK 
assessments will be replaced.  Further, an additional subject(s) will be enrolled for any subject(s) 
who has a reduction in their MRZ dose in Cycle 1.
9.2.
Study Population Definitions
All subjects who receive at least one dose of study medication (MRZ or BEV) will be considered 
enrolled in the study and will be in the Safety Population.  All subjects who receive at least one 
dose of study medication and have at least 1 post dose PK sample will be in the PK Population.  
All subjects who receive at least 1 cycle of therapy and have at least 1 post treatment tumor 
assessment will be in the Activity (Efficacy) Population (Response-evaluable Population).  
9.3.
Sample Size
Part 1 Phase 1
Up to 36 subjects will be enrolled in the MTD/MAD determination and confirmation (expansion 
cohort) parts of the study.
Part 2 Phase 2
Fifteen response-evaluable subjects will be enrolled in the first stage of a 2-stage design
(Green 1992).  If there is at least 1 PR or better and there are no safety concerns in the first 
15 response-evaluable subjects, then the second stage of 15 response-evaluable subjects will be 
opened.  If ≥5 subjects respond by the end of the second accrual stage (n = 30), the conclusion 
can be drawn that MRZ is promising, unless other considerations indicate otherwise.
Assuming the effect size of interest is at least 20%, a sample size of 30 subjects for Phase 2 will 
have 80% power to reject the null hypothesis of H0: response rate is ≤ 5% in favor of the 
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alternative hypothesis (H1) that the effective size is > 5% with a 0.050 two-sided significance 
level.
Part 3 Phase 2
A sample size of 40 subjects is based on wanting a reasonably precise estimate of OS.  Assuming 
10 subjects will be alive at the time of statistical analysis, there will be 30 deaths observed (ie, 
25% of the subjects are censored).  The resulting 95% confidence interval (CI) is 7.2 –
14.8 months, with a width equal to 7.6 months, around an estimated median survival of 
10 months.
Part 4 Phase 1
Approximately 24 subjects will be enrolled in the MTD determination and confirmation 
(expansion cohort) parts of the study.
Part 5 Phase 1
The sample size of 12 was determined to provide sufficient PK exposure data to quantify the 
between and within subject variability.  A subject who has at least 1 full PK profile with 
quantifiable PK parameters will be included in the PK analysis. Any subject that discontinues 
treatment in Cycle 1 without completing all PK assessments will be replaced.  Further, an 
additional subject(s) will be enrolled for any subject(s) who has a reduction in their MRZ dose in 
Cycle 1.
9.4.
Background and Demographic Characteristics
Subjects’ age, height, weight, and baseline characteristics will be summarized using descriptive 
statistics, while gender, race and other categorical variables will be provided using frequency 
tabulations.  Medical history data including cancer history will be listed.  Results of Phase 1 and 
Phase 2 portions of the study will not be combined.
9.5.
Subject Disposition
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percent for both treatment 
and follow-up phases.  A summary of subjects enrolled by site will be provided. Protocol 
deviations will be summarized using frequency tabulations.  Results of the two Phase 1 and the 
two Phase 2 portions of the study will not be combined.
9.6.
Activity (Efficacy) Analysis
Tumor response including PD, progression-free survival (PFS), and overall survival (OS) will be 
assessed by the Investigators using RANO 2010 criteria.  The overall confirmed response rate 
will be examined.  The overall response rate, PFS, and OS will also be tabulated by dose cohorts.  
Results of Phase 1 and the two Phase 2 portions of the study will not be combined.
9.7.
Safety Analysis
All subjects in all parts of the study will be evaluated for safety analysis if they receive at least 
one dose of MRZ (or BEV for subjects in Parts 1, 3, 4 and 5).  The safety data will be presented 
in individual listings and summary tables, including frequency tables for adverse events and 
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listings of abnormalities for laboratory variables. Results of Phase 1 and Phase 2 portions of the 
study will not be combined.
9.8.
Pharmacokinetic Analysis (Part 1 Phase 1, Part 4 Phase 1, and Part 5 
Phase 1)
Non-compartmental analyses will be performed.  The following PK parameters will be 
calculated: maximum observed blood drug concentration (Cmax), time of maximum blood 
concentration (Tmax), elimination half-life (T1/2), area under the blood concentration-time curve 
(AUC0-inf), clearance (CL), and volume of distribution (Vd).
Blood concentrations and computed PK parameters for MRZ will be listed and summarized by 
cohort (mean, geometric mean, standard deviation, coefficient of variation, minimum, maximum 
and number of observations). Compartmental PK modeling may be conducted, as appropriate.
9.9.
Pharmacodynamic Analysis (Part 1 Phase 1 and Part 4 Phase 1)
In Part 1 (Phase 1), PD analysis will include change in proteasome activities (whole blood 
lysates and PBMC lysates) by comparing levels of proteasome activity pre-drug and post-drug 
on Days 1, 8, and 15 (ie, for each dose) of Cycle 1 and Days 1 and 15 (ie, for the first and last 
doses) of each cycle thereafter.
In Part 4 (Phase 1), PD analysis will include change in proteasome activities (whole blood 
lysates and PBMC lysates) by comparing levels of proteasome activity pre-drug and post-drug 
on Days 1 and 8 of Cycles 1 and 2.
9.10.
Interim Analysis
Part 1 Phase 1
This is a Phase 1 study and no interim analysis is planned.
Part 2 Phase 2
Response to MRZ will be assessed in the 15 response-evaluable subjects in Stage 1 of the 2-stage 
design.  Once at least 1 response (PR or better) has been determined, the second stage will be 
implemented.  If no confirmed, objective responses have been observed after all subjects have 
received at least 2 cycles of therapy, Phase 2 will end without implementing the second stage.  If 
the second stage is implemented, an additional 15 response-evaluable subjects will be enrolled.
Part 3 Phase 2
No interim analysis is planned.
Part 4 Phase 1
This is a Phase 1 study and no interim analysis is planned.
Part 5 Phase 1
This is a Phase 1 study and no interim analysis is planned.
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10.
ADVERSE EVENTS
10.1.
Monitoring, Recording and Reporting of Adverse Events
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may 
appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a 
worsening concomitant illness, an injury, or any concomitant impairment of the subject’s health, 
including laboratory test values (as specified by the criteria in Section 10.3), regardless of 
etiology. Any worsening (ie, any clinically significant adverse change in the frequency or 
intensity of a pre-existing condition) should be considered an AE.  A diagnosis or syndrome 
should be recorded on the AE page of the CRF rather than the individual signs or symptoms of 
the diagnosis or syndrome. 
Overdose (accidental or intentional), abuse, withdrawal, sensitivity or toxicity to study treatment 
should be reported as an AE.  If an overdose is associated with an AE, the overdose and AE 
should be reported as separate terms. Any sequelae of an accidental or intentional overdose of 
an investigational product should be reported as an AE on the AE CRF. If the sequelae of an 
overdose are an SAE, then the sequelae must be reported on an SAE report form and on the AE 
CRF. The overdose resulting in the SAE should be identified as the cause of the event on the 
SAE report form and CRF but should not be reported as an SAE itself. Medication errors, 
defined as an overdose with > 105% of drug administered, or underdose, defined as < 95% of 
dose administered, are to be reported as AEs.  Prescribed dose reductions for AEs are not 
considered medication errors. On a schedule or frequency basis, an overdose is defined as 
anything more frequent than the protocol required schedule or frequency. On an infusion rate 
basis, an overdose is defined as any rate faster than the protocol-specified rate. Complete data 
about drug administration, including any overdose, regardless of whether the overdose was 
accidental or intentional, should be reported in the case report form. 
All subjects will be monitored for AEs during the study.  Assessments may include monitoring 
of any or all of the following parameters:  the subject’s clinical symptoms, laboratory, 
pathological, radiological or surgical findings, physical examination findings, or findings from 
other tests and/or procedures.
All SAEs will be recorded by the Investigator from the time the subject signs informed consent 
until 28 days after the last dose of study treatment and those SAEs made known to the 
Investigator at any time thereafter that are suspected of being related to study treatment.  AEs are 
recorded from the start of the first infusion of study treatment.  AEs occurring before the first 
infusion of IP are considered medical history and should be recorded on the medical history 
CRF.  AEs and serious adverse events (SAEs) will be recorded on the AE page of the CRF and in 
the subject’s source documents.  All SAEs must be reported to Celgene Drug Safety within 24 
hours of the Investigator’s knowledge of the event by facsimile, or other appropriate method, 
using the SAE Report Form, or approved equivalent form.  
10.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all adverse events as to: 
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10.2.1.
Seriousness 
A serious adverse event (SAE) is any AE occurring at any dose that:

Results in death;

Is life-threatening (ie, in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE);

Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);

Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions);

Is a congenital anomaly/birth defect;

Constitutes an important medical event.
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
Events not considered to be SAEs are hospitalizations for:

A standard procedure for protocol therapy administration. However, hospitalization 
or prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE. 

Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.

The administration of blood or platelet transfusion as routine treatment of studied 
indication.  However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE.

A procedure for protocol/disease-related investigations (eg, surgery, scans, 
endoscopy, sampling for laboratory tests, bone marrow sampling).  However, 
hospitalization or prolonged hospitalization for a complication of such procedures 
remains a reportable SAE.

Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE.

A procedure that is planned (ie, planned prior to starting of treatment on study); must 
be documented in the source document and the CRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.

An elective treatment of or an elective procedure for a pre-existing condition 
unrelated to the studied indication. 

Emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
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If an AE is considered serious, both the AE page of the CRF and the SAE Report Form must be 
completed.
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to study treatment, action taken regarding study treatment, and outcome.
10.2.2.
Severity / Intensity
For both AEs and SAEs, the Investigator must assess the severity/intensity of the event. 
The severity / intensity of AEs will be graded based upon the subject’s symptoms according to 
the current active minor version of the Common Terminology Criteria for Adverse Events (NCI-
CTCAE, Version 4.03).
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning.  
Seriousness, not severity, serves as a guide for defining regulatory obligations.
10.2.3.
Causality 
The Investigator must determine the relationship between the administration of study treatment
and the occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
Means a causal relationship of the adverse event to study treatment
administration is unlikely or remote, or other medications, therapeutic 
interventions, or underlying conditions provide a sufficient explanation for 
the observed event.
Suspected:
Means there is a reasonable possibility that the administration of study
treatment caused the adverse event.  ‘Reasonable possibility’ means there 
is evidence to suggest a causal relationship between the study treatment
and the adverse event.
Causality should be assessed and provided for every AE/SAE based on currently available 
information.  Causality is to be reassessed and provided as additional information becomes 
available.  For regulatory purposes, it is the Sponsor that is responsible for making the final 
causality assessment.
10.2.4.
Duration
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event.  For AEs that become SAEs, the start date of the SAE will be when the seriousness criteria 
are met.  The original AE will have a stop date the same as the start date of the SAE.  The SAE
will have a stop date of when the seriousness criteria are no longer met.  If the AE continues after 
the seriousness criteria are no longer met, then a new AE will be recorded with a start date the 
same as the SAE stop date and a stop date when the AE is completely resolved.  In all cases, the 
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AE must have the same verbatim term throughout.  Within the duration of the SAE or AE, the 
maximum grade should be used to categorize severity.
10.2.5.
Action Taken
The Investigator will report the action taken with each study drug as a result of an AE or SAE, as 
applicable (eg, discontinuation, interruption, or reduction of study treatment, as appropriate) and 
report if concomitant and/or additional treatments were given for the event. 
10.2.6.
Outcome
The Investigator will report the outcome of the event for both AEs and SAEs.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered, recovered with sequelae, returned to baseline, stabilized, or 
died (due to the SAE or due to another cause). 
10.3.
Abnormal Laboratory Values
An abnormal laboratory value is to be considered an AE if the abnormality:

results in discontinuation from the study;

requires treatment, modification/ interruption of IP dose, or any other therapeutic 
intervention; or

is judged to be of significant clinical importance.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event.
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page of the CRF.  If the abnormality was not a part of 
a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. If 
possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets).
10.4.
Pregnancy
All pregnancies or suspected pregnancies occurring in either a female subject or partner of a 
male subject are immediately reportable events.
10.4.1.
Females of Childbearing Potential:
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on study treatment or within 28 
days of the subject’s last dose of MRZ or 6 months of the subject’s last dose of BEV are 
considered immediately reportable events.  Study treatment is to be discontinued immediately.  
The pregnancy, suspected pregnancy, or positive pregnancy test must be reported to Celgene 
Drug Safety immediately by facsimile, or other appropriate method, using the Pregnancy Initial 
Report Form, or approved equivalent form.  
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The female subject should be referred to an obstetrician-gynecologist, preferably one 
experienced in reproductive toxicity for further evaluation and counseling.  
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form.
If the outcome of the pregnancy was abnormal (eg, spontaneous abortion), the Investigator 
should report the abnormal outcome as an AE.  If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the SAE Report 
Form, or approved equivalent form.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety by 
facsimile, or other appropriate method, within 24 hours of the Investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form.
10.4.2.
Male Subjects
If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking study treatment should notify the Investigator, and the pregnant female partner 
should be advised to call her healthcare provider immediately.
10.5.
Reporting of Serious Adverse Events
Any AE that meets any serious criterion requires reporting as an SAE within 24 hours of the 
Investigator’s knowledge of the event.  This instruction pertains to initial SAE reports as well as 
any follow-up reports.
This requirement applies to all SAEs (regardless of relationship to IP) that occur during the study 
(from the time the subject signs informed consent until 28 days after the last dose of IP)  or any 
SAE made known to the Investigator at any time thereafter that are suspected of being related to 
IP.  Serious adverse events occurring prior to treatment (after signing the ICF) are to be recorded 
within the CRF, but do not require reporting to Celgene Drug Safety.
Where required by local legislation, the Investigator is responsible for informing the Institutional 
Review Board/Ethics Committee (IRB/EC) of the SAE and providing them with all relevant 
initial and follow-up information about the event. The Investigator must keep copies of all SAE 
information on file including correspondence with Celgene and the IRB/EC.
The SAE is reported directly to Celgene Drug Safety by facsimile, or other appropriate method 
using the SAE Report Form or approved equivalent form. The SAE report should provide a 
detailed description of the SAE and include a concise summary of hospital records and other 
relevant documents. If a subject died and an autopsy has been performed, results of the autopsy 
report and/or death certificate are to be reported to Celgene Drug Safety as soon as these become 
available. Any follow-up data, including responses to safety queries, should be detailed in a 
subsequent SAE Report Form, or approved equivalent form, and sent to Celgene Drug Safety. 
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via 
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facsimile or electronic mail.  Urgent queries (eg, missing causality assessment) may be handled 
by phone.
10.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via 
facsimile or electronic mail.  The response time is expected to be no more than five (5) business 
days.  Urgent queries (eg, missing causality assessment) may be handled by phone.
10.6.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to MRZ based on the Investigator Brochure and BEV based on 
the local prescribing information.
In the United States, all suspected unexpected serious adverse reactions (SUSARs) will be 
reported in an expedited manner in accordance with 21 CFR 312.32.
Celgene Drug Safety or its authorized representative shall notify the Investigator of the following 
information:

Any AE suspected of being related to the use of IP in this study or in other studies 
that is both serious and unexpected (ie, SUSAR);

Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.
Where required by local legislation, the Investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to subjects.
The Investigator must keep copies of all pertinent safety information on file including 
correspondence with Triphase/Celgene Drug Safety and the IRB/EC.  (See Section 14.3 for 
record retention information).
Drug Safety Contact Information:
For Celgene Drug Safety contact information, please refer to the Serious Adverse Event Report 
Form Completion Guidelines or to the Pregnancy Report Form Completion Guidelines.
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11.
DISCONTINUATIONS
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product and/or from the study:

Protocol Violation

Non-Compliance

Adverse Event

Subject Developed a DLT

Subject Decision

Withdrew Consent

Investigator Decision

Disease Progression

Pregnancy

Death

Other
The reason for discontinuation should be recorded in the CRF and in the source documents.
The decision to discontinue a subject remains the responsibility of the treating physician, which 
will not be delayed or refused by the Sponsor.  However, prior to discontinuing a subject, the 
Investigator may contact the Medical Monitor and forward appropriate supporting documents for 
review and discussion.
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12.
EMERGENCY PROCEDURES
12.1.
Emergency Contact
In emergency situations, the Investigator should contact the responsible Clinical Research 
Physician/Medical Monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page).
12.2.
Emergency Identification of Investigational Products
This is an open-label study; therefore, this section is not applicable.
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13.
REGULATORY CONSIDERATIONS
13.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the Sponsor, its authorized 
representative, and Investigator abide by Good Clinical Practice (GCP), as described in 
International Conference on Harmonization (ICH) Guideline E6 and in accordance with the 
general ethical principles outlined in the Declaration of Helsinki. The study will receive 
approval from an IRB/EC prior to commencement. The Investigator will conduct all aspects of 
this study in accordance with applicable national, state, and local laws of the pertinent regulatory 
authorities.
13.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in 
the local regulations.  Celgene staff or an authorized representative will evaluate and approve all 
Investigators who in turn will select their staff.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions. 
The Investigator should maintain a list of Sub-Investigators and other appropriately qualified 
persons to whom he or she has delegated significant study-related duties.
The Investigator is responsible for keeping a record of all subjects who sign an informed consent 
document and are screened for entry into the study.  Subjects who fail screening must have the 
reason(s) recorded in the subject’s source documents.
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (eg, 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification. The Investigator must ensure timely and accurate completion of CRFs and queries.
The information contained in the protocol and amendments (with the exception of the 
information provided by Celgene on public registry websites) is considered Celgene confidential 
information.  Only information that is previously disclosed by Celgene on a public registry 
website may be freely disclosed by the Investigator or its institution, or as outlined in the Clinical 
Trial Agreement.  Celgene protocol, amendment and IB information is not to be made publicly 
available (for example on the Investigator’s or their institution’s website) without express written 
approval from Celgene.  Information proposed for posting on the Investigator’s or their 
institution’s website must be submitted to Celgene for review and approval, providing at least 5 
business days for review.
At the time results of this study are made available to the public, Celgene will provide 
Investigators with a summary of the results that is written for the lay person.  The Investigator is 
responsible for sharing these results with the subject and/or their caregiver as agreed by the 
subject.
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13.3.
Protocol Amendments
Any amendment to this protocol must be approved by the Sponsor and submitted to appropriate 
Regulatory Authority by the Sponsor.  Amendments will be submitted to the IRB/EC for written 
approval.  Written approval must be obtained before implementation of the amended version 
occurs.  The written signed approval from the IRB/EC should specifically reference the
Investigator name, protocol number, study title and amendment number(s) that is applicable. 
Amendments that are administrative in nature do not require IRB/IEC approval but will be 
submitted to the IRB/IEC for information purposes.
13.4.
Subject Information and Informed Consent
The Investigator must obtain informed consent of a subject and/or a subject’s legal representative 
prior to any study related procedures.
Documentation that informed consent occurred prior to the study subject’s entry into the study 
and of the informed consent process should be recorded in the study subject’s source documents 
including the date.  The original informed consent document signed and dated by the study 
subject and by the person consenting the study subject prior to the study subject’s entry into the 
study, must be maintained in the Investigator’s study files and a copy given to the study subject.  
In addition, if a protocol is amended and it impacts on the content of the informed consent, the 
informed consent document must be revised.  Study subjects participating in the study when the 
amended protocol is implemented must be re-consented with the revised version of the informed 
consent document.  The revised informed consent document signed and dated by the study 
subject and by the person consenting the study subject must be maintained in the Investigator’s 
study files and a copy given to the study subject.  
13.5.
Confidentiality
Celgene and its authorized representatives affirm the subject's right to protection against invasion 
of privacy and to be in compliance with ICH and other local regulations (whichever is most 
stringent). Celgene requires the Investigator to permit Celgene and its authorized representatives 
and, when necessary, representatives from regulatory authorities, to review and/or copy any 
medical records relevant to the study in accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed informed consent document, it is the responsibility of the Investigator to obtain 
such permission in writing from the appropriate individual.
13.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, informed consent document, and any other 
appropriate documents will be submitted to the IRB/EC with a cover letter or a form listing the 
documents submitted, their dates of issue, and the site (or region or area of jurisdiction, as 
applicable) for which approval is sought. If applicable, the documents will also be submitted to 
the authorities in accordance with local legal requirements.
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Study treatment can only be supplied to an Investigator by Celgene and/or Triphase or its 
authorized representative after documentation on all ethical and legal requirements for starting 
the study has been received by Celgene and/or Triphase or its authorized representative. This 
documentation must also include a list of the members of the IRB/EC and their occupation and 
qualifications. If the IRB/EC will not disclose the names, occupations and qualifications of the 
committee members, it should be asked to issue a statement confirming that the composition of 
the committee is in accordance with GCP. For example, the IRB General Assurance Number 
may be accepted as a substitute for this list. Formal approval by the IRB/EC should mention the 
protocol title, number, amendment number (if applicable), study site (or region or area of 
jurisdiction, as applicable), and any other documents reviewed. It must mention the date on 
which the decision was made and must be officially signed by a committee member. Before the 
first subject is enrolled in the study, all ethical and legal requirements must be met.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the informed consent document 
should also be revised.
The Investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a Coordinating Investigator and the IRB/EC. This statement also applies to any 
communication between the Investigator (or Coordinating Investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by Celgene and/or 
Triphase and the IRB/EC prior to use.
13.7.
Ongoing Information for Institutional Review Board / Ethics 
Committee
If required by legislation or the IRB/EC, the Investigator must submit to the IRB/EC:

Information on serious or unexpected adverse events as soon as possible;

Periodic reports on the progress of the study;

Deviations from the protocol or anything that may involve added risk to subjects.
13.8.
Termination of the Study
The Sponsor reserves the right to terminate this study at any time for reasonable medical or 
administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (eg, IRB/EC, regulatory authorities, etc.).
In addition, the Investigator or the Sponsor has the right to discontinue a single site at any time 
during the study for medical or administrative reasons such as:

Unsatisfactory enrollment;

GCP noncompliance;

Inaccurate or incomplete data collection;

Falsification of records;
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Failure to adhere to the study protocol.
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14.
DATA HANDLING AND RECORDKEEPING 
14.1.
Data/Documents
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed and 
retained.  Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of CRFs or CD-ROM.
14.2.
Data Management
Data will be collected via CRF and entered into the clinical database per Triphase SOPs, or if 
delegated to a vendor, according to the vendor’s SOPs. This data will be electronically verified 
through use of programmed edit checks specified by the clinical team.  Discrepancies in the data 
will be brought to the attention of the clinical team, and investigational site personnel, if 
necessary.  Resolutions to these issues will be reflected in the database.  An audit trail within the 
system will track all changes made to the data.
14.3.
Record Retention
Essential documents must be retained by the Investigator for a minimum of 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IP. The investigator must retain these 
documents for the time period described above or according to local laws or requirements, 
whichever is longer.  Essential documents include, but are not limited to, the following:

Signed informed consent documents for all subjects;

Subject identification code list, screening log (if applicable), and enrollment log;

Record of all communications between the Investigator and the IRB/EC;

Composition of the IRB/EC;

Record of all communications between the Investigator, the Sponsor, and their 
authorized representative(s);

List of Sub-Investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in 
the study, curriculum vitae, and their signatures;

Copies of CRFs (if paper) and of documentation of corrections for all subjects;

IP accountability records;

Record of any body fluids or tissue samples retained;

All other source documents (subject records, hospital records, laboratory records, 
etc.); 
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
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial).
The Investigator must notify Celgene if he/she wishes to assign the essential documents to 
someone else, remove them to another location or is unable to retain them for a specified period.  
The Investigator must obtain approval in writing from Celgene prior to destruction of any 
records. If the Investigator is unable to meet this obligation, the Investigator must ask Celgene 
for permission to make alternative arrangements. Details of these arrangements should be 
documented. 
All study documents should be made available if required by relevant health authorities. 
Investigator/Institution should take measures to prevent accidental or premature destruction of 
these documents.
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15.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Triphase or its authorized representative 
for compliance with applicable government regulations with respect to current GCP and standard 
operating procedures.
15.1.
Study Monitoring and Source Data Verification
Triphase ensures that appropriate monitoring procedures are performed before, during and after 
the study.  All aspects of the study are reviewed with the Investigator and the staff at a study 
initiation visit and/or at an Investigator meeting.  Prior to enrolling subjects into the study, a 
Triphase representative will review the protocol, CRFs, procedures for obtaining informed 
consent, record keeping, and reporting of AEs/SAEs with the Investigator.  Monitoring will 
include on-site visits with the Investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone.  During monitoring visits, the facilities, 
investigational product storage area, CRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the Triphase representative in accordance with the 
Study Monitoring Plan.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the CRFs against the appropriate source documentation.  Any resulting 
discrepancies will be reviewed with the Investigator and/or his/her staff.  Any necessary 
corrections will be made directly to the CRFs or via queries by the Investigator and/or his/her 
staff. Monitoring procedures require that informed consents, adherence to inclusion/exclusion 
criteria and documentation of SAEs and their proper recording be verified.  Additional 
monitoring activities may be outlined in a study-specific monitoring plan.
15.2.
Audits and Inspections
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, CRFs, and applicable supporting records of study subject participation for 
audits and inspections by IRB/IECs, regulatory authorities (eg, FDA, EMA, Health Canada) and 
company authorized representatives.  The Investigator should make every effort to be available 
for the audits and/or inspections.  If the Investigator is contacted by any regulatory authority 
regarding an inspection, he/she should contact Celgene and/or Triphase immediately.
A Product Quality Complaint (PQC) is any written, electronic, or oral communication that 
alleges deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, 
purity, or performance of any drug product manufactured by or on behalf of Celgene Corporation 
after it is released for distribution.  PQCs may reduce the usability of the product for its intended 
function or affect performance of the product and therefore pose a significant risk to the subject.  
Examples of PQCs include (but are not limited to): mixed product, mislabeling, lack of effect, 
seal/packaging breach, product missing/short/overage, contamination, suspected falsified, 
tampered, diverted or stolen material, and general product/packaging damage. If you become 
aware of a suspected PQC, you are obligated to report the issue immediately. You can do so by 
emailing customercomplaints@celgene.com or by contacting the Celgene Customer Care Center 
(1-888-423-5436).
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16.
PUBLICATIONS
The results of this study may be published in a medical publication, journal, or may be used for 
teaching purposes.  Additionally, this study and its results may be submitted for inclusion in all 
appropriate health authority study registries, as well as publication on health authority study 
registry websites, as required by local health authority regulations.  Selection of first authorship 
will be based on several considerations, including, but not limited to study participation, 
contribution to the protocol development, analysis and input into the manuscript, related 
abstracts, and presentations in a study.  Individual Investigators or a subset of Investigators may 
not publish their experience until a report of the total experience by all Investigators has been 
published.
As described in Section 13.2, all protocol- and amendment-related information, with the 
exception of the information provided by Celgene on public registry websites, is considered 
Celgene confidential information and is not to be used in any publications.  Celgene protocol-
related information proposed for use in a publication must be submitted to Celgene for review 
and approval, and should not be utilized in a publication without express written approval from 
Celgene, or as described in the Clinical Trial Agreement.
Celgene will ensure Celgene-sponsored studies are considered for publication in the scientific 
literature in a peer-reviewed journal, irrespective of the results.  At a minimum, this applies to 
results from all Phase 3 clinical studies, and any other study results of significant medical 
importance.  This also includes results relating to investigational medicines whose development 
programs have been discontinued.
Study results may also be presented at one or more medical congresses, and may be used for 
scientific exchange and teaching purposes.  Additionally, this study and its results may be 
submitted for inclusion in all appropriate health authority study registries, as well as publication 
on health authority study registry websites, as required by local health authority regulations.
Eligibility for external authorship, as well as selection of first authorship, will be based on 
several considerations, including, but not limited to, contribution to protocol development, study 
recruitment, data quality, participation in data analysis, participation in study steering committee 
(when applicable) and contribution to abstract, presentation and/or publication development
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17.
REFERENCES
Avastin Prescribing Information (12/2017) at 
http://www.gene.com/download/pdf/avastin_prescribing.pdf.
Bota DA, Alexandru D, Keir ST, et al. Proteasome inhibition with bortezomib induces cell death 
in GBM stem-like cells and temozolomide-resistant glioma cell lines, but stimulates GBM stem-
like cells’ VEGF production and angiogenesis. J Neurosurg 119(6):1415-23, 2013.
Brem S, Cotran R, Folkman J. Tumor angiogenesis: a quantitative method for histologic grading. 
J Natl Cancer Inst 48:347-56, 1972.
 
 
 
Chauhan D, Catley L, Li G, et al.  A novel orally active proteasomes inhibitor induces apoptosis 
in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell 8:407-419, 
2005.
 
Di K, Gong X, Curticiu DM, Palladino M, Bota DA. Marizomib (NPI-0052) activity as a single 
agent in glioblastoma. AACR 2014.
Friedman HS, Prados MD, Wen PY, et al.  Bevacizumab alone and in combination with 
irinotecan in recurrent glioblastoma. J Clin Oncol 27(28):4733-40, 2009.
Geng L, Donnelly E, McMahon G, et al: Inhibition of vascular endothelial growth factor receptor 
signaling leads to reversal of tumor resistance to radiotherapy. Cancer Res 61:2413-9, 2001.
Gerber HP, Ferrara N: Pharmacology and pharmacodynamics of bevacizumab as monotherapy or 
in combination with cytotoxic therapy in preclinical studies. Cancer Res 65:671-80, 2005.
Green SJ and Dahlberg S. Planned Versus Attained Design in Phase II Clinical Trials. Statistics 
in Medicine 11:853-862. 1992.
Kunkel P, Ulbricht U, Bohlen P, et al: Inhibition of glioma angiogenesis and growth in vivo by 
systemic treatment with a monoclonal antibody against vascular endothelial growth factor 
receptor-2. Cancer Res 61:6624-8, 2001.
Labussiere M, Pinel S, Delfortrie S, et al. Proteasome inhibition by bortezomib does not translate 
into efficacy on two malignant glioma xenografts. Oncol Rep 20: 1283-1287, 2008.
Levin N, Spencer A, Harrison S et al. Marizomib irreversibly inhibits proteasome to overcome 
compensatory hyperactivation in Multiple Myeloma and solid tumor patients. Br J Haematol 
174:711-720, 2016.
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National Cancer Institute: Common Terminology Criteria for Adverse Events, Version 4.03, 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. 
Oxford Textbook of Palliative Medicine, Oxford University Press. 109, 1993.
Phuphanich S, Supko JG, Carson K, et al. Phase I trial of bortezomib in adults with reccurent 
malignant glioma. J Clin Oncol 24: 1567, 2006.
Plate KH, Breier G, Weich HA, et al: Vascular endothelial growth factor is a potential tumour 
angiogenesis factor in human gliomas in vivo. Nature 359:845-8, 1992.
Report MPI 2202-005. Marizomib (Pharmatek Dry Blend #1): An Oral Capsule Dose Range-
Finding Toxicity Study in Monkeys. MPI Research, Inc.
Report MPI 2202-007. Marizomib (Pharmatek Formulation): An Oral Capsule Dose Range-
Finding Toxicity Study in Monkeys. MPI Research, Inc.
Report ITR 30948: Marizomib-NPI-0052: A Repeat Dose Oral Toxicity Study Followed by a 14-
Day Recovery Period in Cynomolgus Monkeys. ITR Laboratories.
Rubenstein JL, Kim J, Ozawa T, et al: Anti-VEGF antibody treatment of glioblastoma prolongs 
survival but results in increased vascular cooption. Neoplasia 2:306-14, 2000.
Samoto K, Ikezaki K, Ono M, et al: Expression of vascular endothelial growth factor and its 
possible relation with neovascularization in human brain tumors. Cancer Res 55:1189-93, 1995.
Schag CC, Heinrich RL, Ganz PA. Karnofsky performance status revisited: reliability, validity, 
and guidelines. J Clin Oncol Mar;2(3):187-93, 1984.
Schmidt NO, Westphal M, Hagel C, et al: Levels of vascular endothelial growth factor, 
hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and 
their relation to angiogenesis. Int J Cancer 84:10-8, 1999.
 
 
 
Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapy plus concomitant and adjuvant 
temozolomide for glioblastoma. N Engl J Med 352:987-96, 2005.
Teicher, BA, Tomaszewski JE. Proteasome inhibitors. Biochem Pharmacol 96: 1-9, 2015.
 
  
 
Wen PY, Macdonald DR, Reardon DA, et al.  Updated response assessment criteria for high-
grade gliomas: Response assessment in Neuro-Oncology Working Group.  Clin Oncol 28:1963-
1972, 2010.
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Wong ET, Hess KR, Gleason MJ, et al: Outcomes and prognostic factors in recurrent glioma 
patients enrolled onto phase II clinical trials. J Clin Oncol 17:2572-8, 1999.
Yu LJ, Riordan B, Hatsis P et al. Study of brain and whole blood PK/PD of bortezomib 
(VELCADE®) in rat models. J Clin Oncol ASCO Annual Meeting Proceedings Part I. 
Vol 24:12036, 2006.
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18.
APPENDICES
APPENDIX A. KARNOFSKY PERFORMANCE STATUS SCALE
Oxford Textbook of Palliative Medicine, Oxford University Press. 109, 1993.
Schag CC, Heinrich RL, Ganz PA. Karnofsky performance status revisited: reliability, validity, and guidelines. 
J Clin Oncol Mar;2(3):187-93, 1984.
Activity Level
Score
Normal, no complaints
100
Able to carry on normal activity; minor signs or symptoms of disease 
90
Normal activity with effort
80
Unable to carry on normal activity or perform active work; cares for self
70
Requires occasional assistance but is able to care for most own needs
60
Requires considerable assistance and frequent medical care
50
Disabled; requires special medical care and assistance
40
Severely disabled; hospitalization indicated although death not imminent
30
Very sick; hospitalized and requires active supportive care.
20
Moribund; fatal processes progressing rapidly
10
Dead
0
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Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
UserName: 
Title:  
Date: Friday, 20 March 2020, 09:40 AM   Eastern Daylight Time
Meaning: Approved, no changes necessary.
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This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
UserName: 
Title:  
Date: Wednesday, 01 April 2020, 12:47 PM   Eastern Daylight Time
Meaning: Approved, no changes necessary.
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1.
JUSTIFICATION FOR AMENDMENT
The purpose of this amendment is to include Part 5 (Phase 1) further characterizing
pharmacokinetics (PK) in correlation with time-matched electrocardiogram (ECG) to further 
evaluate the cardiovascular safety of intravenous (IV) Marizomib administered at 0.8 mg/m2.
In the Part 5 (Phase 1) portion of the study, full PK sampling will be done on Cycle 1 Day 1, 
Cycle 1 Day 8, and Cycle 1 Day 15, with blood samples collected pre-dose, immediately prior to 
the end of infusion (EOI), and then 2, 5, 15, 20, 30, 45, and 60 minutes post-EOI. ECGs will be 
continuously collected via Holter monitor throughout the Cycle 1 Day 1 visit for correlation with 
PK.
Changes directly associated with the addition of Part 5 (Phase 1) are as follows:
Objectives
Primary and Secondary Objectives were added for Part 5 (Phase 1).
Revised sections include the protocol Synopsis and Sections 2.1 and 2.2
Study Endpoints
Primary Endpoint and Secondary Endpoints including pharmacokinetics and ECG were added
for Part 5 (Phase 1).  Revised sections include the protocol Synopsis and Sections 3.1 and 3.2.
Study Design
Study Design was updated to include Part 5 (Phase 1).
Revised sections include the protocol Synopsis and Sections 4.1 
.
Table of Events
A new Table of Events was created for Part 5 labeled Table 3: Schedule of Assessments and 
Procedures, Part 5 Phase 1: All Cycles; all subsequent table numbering was updated as 
appropriate.
Procedures
Study procedures were clarified and added for Part 5 (Phase 1).
Revised sections include protocol Synopsis, Table 3, protocol Sections 5, 5.3, 5.7, 
.
Number of Subjects and Sites (Study Population)
Number of subjects were updated in accordance with Part 5 (Phase 1).
Revised sections include the protocol Synopsis and Sections 6.1 and 9.3.
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Inclusion Criteria
Clarification of the patient population specific to Part 5 (Phase 1) were made in Sections 6.1 and
6.2.
Exclusion Criteria
Clarification of the patient population specific to Part 5 (Phase 1) were made in Section 6.3.
Treatment Administration and Schedule
Study Treatment Administration and Schedule were updated to include Part 5 (Phase 1).
Revised sections include protocol Synopsis and Sections 7.2.2 and 7.2.6.
Dose Schedules
Part 5 (Phase 1) dose schedule was included in Section 7.2.6.1.
Revised sections include the protocol Synopsis and Section 7.2.6.1 and Table 7.
The volume of MRZ administration formula was corrected to Volume = Dose (mg) * BSA (m2) / 
0.2 (conc. of MRZ in solution in mg/mL) throughout the protocol.
Dose Limiting Toxicity
Clarified that Part 5 (Phase 1) will not be evaluated for DLT.
Revised Section 7.2.7.
Method of Treatment Assignment
Method of Treatment Assignment was updated to include Part 5 (Phase 1) will be IV only.
Revised sections include Section 7.3.
Statistical Analysis
Statistical Analysis was updated for Part 5 (Phase 1).
Revised sections include the protocol Synopsis and Sections 9.1, 9.3, 9.8, and 9.10.
Overview of Assessments
Assessments were described for Part 5 (Phase 1) in the protocol Synopsis.
This amendment also includes other clarifications and minor corrections unrelated to the 
addition of Part 5 (Phase 1):

Medical Monitor / Emergency Contact Information was updated to reflect the address of 
the Medical Monitor. 

Clinical Experience Section 1.4.4 was updated to reflect the most recent information from 
previous and ongoing studies with MRZ; Table 3 in Amendment 4 was removed.

Reporting of Serious Adverse Events Section 10.5 was updated with the most recent 
Celgene standard language.

Section 9.3 Sample Size. Part 2 Phase 2, second paragraph edited to include the following
for clarity.
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EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Summary of Changes MRZ-108 Amendment 5
Celgene International II Sàrl
Confidential and Proprietary
5
MRZ-108 Amendment 5 Final: 18 Mar 2020
Assuming the effect size of interest is at least 20%, a sample size of 30 subjects for Phase 
2 will have 80% power to reject the null hypothesis of H0: response rate is ≤ 5% in favor 
of the alternative hypothesis (H1) that the effective size is > 5% with a 0.050 two-sided 
significance level.

Previous recommendations for hydration in earlier Parts of the study are no longer
required; hydration recommendations were not included with Part 5 Phase 1.

Clarified throughout protocol, where appropriate, Part 5 Phase 1 will not collect
 
 GBM tumor tissue, and blood for pharmacodynamics (PD) and 
proteasome activity.

Typos and punctuation were corrected throughout the document as appropriate.
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EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Summary of Changes Protocol MRZ-108 Amendment 4
Celgene International II Sàrl
Confidential and Proprietary
3
MRZ-108 Amendment 4:  19 Apr 2018
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
Addition of Part 4 (Phase 1) Dose-Escalation Study of Enterally-Administered Marizomib
With Bevacizumab
A Part 4 (Phase 1) portion of the study (added with Amendment 4) is to determine the safety 
profile of dose-escalated enterally-administered marizomib (MRZ) with bevacizumab.  In order 
to administer MRZ in a manner consistent with that used in the nonclinical safety assessment, 
MRZ will be reconstituted in the intravenous (IV) formulation and administered via naso gastric 
(NG) tube.  The safety and tolerability information collected in this study, combined with 
pharmacodynamic assessments, will inform further development of a pharmaceutically 
appropriate oral dosage form (eg, capsule or tablet).
Changes directly associated with the addition of Part 4 (Phase 1) are as follows:
Study Title
The study title has been updated accordingly throughout the document.
Introduction
A description of previous studies with oral MRZ was added as Section 1.4.3.2.
Objectives
Primary and Secondary Objectives were added for Part 4 (Phase 1)
 
.
Revised sections include the protocol synopsis and Sections 2.1, 2.2, 
Study Endpoints
Primary Endpoint and Secondary Endpoints including pharmacokinetics and pharmacodynamics, 
were added for Part 4 (Phase 1) 
.  Revised sections 
include Sections 3.1, 3.2, 
.
Study Design
Study Design was updated to include Part 4 (Phase 1).
Revised sections include the protocol synopsis and Sections 4.1 
.
Procedures
Study procedures were clarified and added for Part 4 (Phase 1).
Revised sections include Sections 5, 5.3, 5.7, and 5.9.
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EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Summary of Changes Protocol MRZ-108 Amendment 4
Celgene International II Sàrl
Confidential and Proprietary
4
MRZ-108 Amendment 4:  19 Apr 2018
Number of Subjects and Sites (Study Population)
Number of Subjects were updated in accordance with Part 4 (Phase 1).
Revised sections include the protocol synopsis and Sections 6.1 and 9.3.
Inclusion Criteria
Clarification of the patient population specific to Part 4 (Phase 1) were made in Section 6.2.
Exclusion Criteria
Clarification of the patient population specific to Part 4 (Phase 1), along with the addition of two 
Exclusion Criteria, were made in Section 6.3.
Revised sections include the protocol synopsis (Study Population) and Section 6.3.
Treatment Administration and Schedule
Study Treatment Administration and Schedule were updated to include Part 4 (Phase 1).
Revised sections include protocol synopsis, Sections 7.2.2 and 7.2.5, and the addition of Table 8.
Investigational Product/Background Therapy/Route/Regimen
A description of the Part 4 (Phase 1) investigational products was added.
Revised sections include the protocol synopsis and Section 7.2.5.
Dose Limiting Toxicity
Dose Limiting Toxicity was expanded to include Part 4 (Phase 1).
Revised sections include the protocol synopsis and Section 7.2.7.
Dose Escalation and Expansion
The Dose Escalation, Expansion, and DLT description for Part 4 (Phase 1) was added.
Revised sections include the protocol synopsis, Section 7.2.8, and the addition of Table S-2 and 
Table 8.
Method of Treatment Assignment
Method of Treatment Assignment was updated to include Part 4 (Phase 1).
Revised sections include Section 7.3.
Statistical Analysis
Statistical Analysis was updated for Part 4 (Phase 1).
Revised sections include the protocol synopsis and Sections 9.1, 9.3, 9.8, 9.9 and 9.10.
Schedule of Assessments
A separate Schedule of Assessments was added for Part 4 (Phase 1).
Revised section includes Table 2.
Overview of Assessments
Assessments were described for Part 4 (Phase 1) in the protocol synopsis.
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EDMS Doc. Number: 
Marizomib (CC-92763, NPI-0052)
Summary of Changes Protocol MRZ-108 Amendment 4
Celgene International II Sàrl
Confidential and Proprietary
5
MRZ-108 Amendment 4:  19 Apr 2018
This amendment also includes several other clarifications and minor corrections unrelated
to the addition of Part 4 (Phase 1):

Marizomib compound identification NPI-0052 has been changed to NPI-0052/CC-92763 
to include Celgene nomenclature. 

On November 17, 2016, Triphase Research and Development I Corporation and 
marizomib were acquired by Celgene Corporation. Effective March 30, 2018, Celgene 
International II, Sàrl (CIS II), a wholly-owned subsidiary of Celgene Corporation, 
became the sponsor for all clinical trials for which Triphase was previously named 
sponsor.  Sponsor Name/Address and Header has been updated from Triphase Research 
and Development I Corporation to Celgene International II Sàrl to reflect the change in 
Sponsor. Throughout Protocol Amendment 4 and associated documents, Celgene has 
been listed as the sponsor where appropriate, and continued responsibilities specific to 
Triphase are noted as such.

Medical Monitor/Emergency Contact Information has been updated.

Triphase Officer Signature Page has been replaced with Celgene Therapeutic Area Head 
Signature Page and updated.

The collection of Vital Signs was clarified in Schedule of Assessments and Procedures 
table.  Revised footnote in Table 1.

Clinical Experience Section 1.4.4 was updated to reflect the most recent information from 
ongoing studies MRZ-108 and MRZ-112.

Pharmacokinetics Section 1.4.6 was updated to include additional information from the 
ongoing study MRZ-112.

Based on the data generated in MRZ-108 and MRZ-112, revised MRZ dose modification 
guidelines have been developed that consider the adverse event, duration and potential 
impact on patient’s daily routine. Table 5 has been replaced with the revised guidance for 
Marizomib Dose Modifications as per memo dated 21 December 2017 sent to all 
Investigators for MRZ-108 and MRZ-112.

The reporting of Serious Adverse Events has been assumed by Celgene Corporation as of 
30MAR2018 and is described in Sections 10.1, 10.4.1, 10.5, 10.5.1, and 10.6.

References were updated to include recent prescribing information for bevacizumab and 
three additional toxicology studies.

This Summary of Changes document focuses on changes to scientific content or study 
design. Unless incidentally shown or otherwise specified, administrative changes (ie, 
formatting, spelling, punctuation corrections, hyphenations, or the spelling out of 
numbers or symbols or abbreviations for clarity) will not be individually identified with a 
rationale.
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Marizomib 
Protocol MRZ-108 Amendment 3 Summary 
Triphase R&D I Corp. 
Confidential and Proprietary 
1 
27 March 2017 
AMENDMENT SUMMARY 
Protocol MRZ-108 Amendment 3 
1. 
AMENDMENT RATIONALE AND DESCRIPTION 
Summary 
In Amendment 3, all subjects will receive IV MRZ infusion followed by IV BEV infusion.  MRZ 
will be administered as a 10-minute, IV infusion on Days 1, 8, and 15 of every 28-day cycle using 
intra-patient dose escalation.  Starting dose will be 0.8 mg/m2 (RP2D dose).  If the starting dose is 
tolerated and no Dose Limiting Adverse Event (DLAE) is observed, the dose will be increased to 
1.0 mg/m2 after1 cycle.  If the increased dose is tolerated again and no DLAE is observed, the dose 
of MRZ will be increased to 1.2 mg/m2 after 1 more cycle.  Dose reductions will be applied as 
necessary and according to the toxicities noted.  DLAEs are defined as MRZ related AEs observed 
which are: 1) related to disturbances in the cerebellum (i.e. ataxia, dizziness, dysarthria, fall, gait 
disturbances) plus hallucinations of any grade. 2) Any other AEs of Grade  ≥ 2. 
If the starting dose of 0.8mg/m2 is not tolerated (after appropriate medical treatment of adverse 
events, if applicable), the dose will be decreased to 0.7 mg/m2.  A further reduction to 
0.55 mg/m2 is allowed, if necessary. 
Rationale 
Central nervous system (CNS) AEs were noted during the early development of MRZ in subjects 
with solid tumors, lymphoma, and multiple myeloma.  Based on this early data the assumption 
was made that the drug was blood-brain barrier penetrant, and this assumption led to exploring 
MRZ in G4 MG. 
In Part 1 of this study, conducted under Amendment 1 (note: original protocol was not 
implemented), the combination of MRZ and a fixed dose of BEV was studied in a Phase 1 study; 
the maximum dose level for MRZ to be studied was set at 0.8 mg/m2 because of the CNS AEs 
observed in the early studies. The RP2D of MRZ was determined to be 0.8 mg/m2 with BEV, 
however a MTD for MRZ + BEV (as defined in the protocol) was not determined.   
In Part 2 of this study (Amendment 2) MRZ was studied as a single agent in the same subject 
population in order to explore whether MRZ has activity as a single agent in relapsed or 
recurrent G4 MG.  A Phase 2, 2-stage design was used to assess the activity of MRZ as a single 
agent.  The preliminary results of the Phase 2 portion (Part 2) of the study, determined that single 
agent MRZ at a starting dose of 0.8 mg/m2 is active with 1 partial response documented in 
15 subjects the first stage of the 2-stage design.  The second stage is ongoing/recruiting at 
present, for a total of 30 subjects. 
Analysis of safety and efficacy data from the MRZ + BEV combination (Part 1 of this protocol) 
suggests that subjects experiencing certain AEs associated with the central nervous system 
(CNS) have a better outcome in terms of ORR, PFS, and OS than subjects not experiencing any 
of these CNS AEs.  The assumption and justification for adding Part 3 to this protocol is that 
these CNS AEs are indicative of higher MRZ concentrations in the brain leading to both toxicity 
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27 March 2017 
and efficacy.  It seems reasonable that CNS AEs may be a marker for higher drug concentrations 
in the brain. 
On 4 January 2017, an analysis of data from all 36 subjects enrolled in Part 1 with a median 
follow up of 9.2 months for surviving subjects was performed.  Interestingly, when a group of 6 
AEs related to disturbances in the cerebellum (plus hallucinations), were combined (i.e. ataxia, 
dizziness, dysarthria, fall, gait disturbances and hallucinations) and related to efficacy 
parameters, an apparent difference was observed between the 23 subjects with any of these AEs 
of any grade during treatment as compared to the 13 subjects without occurrence of any of these 
AEs at any time; the median PFS was 5.5 months as compared to 2.8 months, and the median OS 
was 10.4 months as compared to 6.3 months respectively.  
When further analyzing this group of 6 AEs, it was the case that 19/23 (83%) of subjects 
experienced one of more of these AEs during Cycle 1 or Cycle 2, and 15/23 subjects (65%) 
experienced one or more of these AEs during the first cycle of MRZ + BEV treatment.  These 
AEs were generally reversible with treatment delay and/or dose reduction. 
This analysis of a fairly mature dataset from all subjects included in Part 1 of this study 
generated the hypothesis that subjects with certain CNS events do better than those without, 
which suggests that those with the highest MRZ levels in the brain, as suggested by these AEs, 
do better than those without these events, which suggests lower brain levels of MRZ.  This 
portion of the study (Part 3) presented in Amendment 3 is designed to deliver to each subject a 
high dose of MRZ as long as they can tolerate it and to get point estimates for efficacy 
parameters including ORR, PFS, and OS.  For the same reason that the Part 2 Phase 2 was added 
to this study rather than as a separate protocol (namely, to keep the population homogenous), the 
results from subjects in this Part 3 can be compared to those in Part 1.  
Revisions are shown in detail in the sections that follow.  Significant changes introduced with 
Amendment 3 are as follows: 
1. The title page, headers and footers were revised to reflect the addition of this Amendment. 
2. Table 1 Schedule of Assessments and Procedures, updated to reflect increased 
Screening and Baseline window, removal of Cycle 1 ECGs, allowance for PT/PTT and 
Urinalysis to be collected up to 7 days prior to Cycle 1 Day1, clarification of when vital 
signs should be taken on Day 8 of each cycle, and removal of hydration. 
3. Section 1.4.4 Clinical Experience updated with more recent safety information. 
4. Section 1.4.5 Pharmacodynamics updated to include more recent PD findings. 
5. Section 1.4.6 Pharmacokinetics updated to include more recent PK findings. 
7. Section 2.1 Primary Objective was added to describe the primary objective in Part 3 Phase 2 
8. Section 2.2 Secondary Objective was added to describe the secondary objective in Part 3 
Phase 2 
9. Section 3.2 Secondary Endpoint(s) was added to describe the secondary endpoints of 
Part 3 Phase 2 
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10. Section 4.1 Study Design describes the intra-patient dose escalation of MRZ and Dose 
Limiting Adverse Events (DLAEs)
12. Section 5.1 Screening, updated to allow for a +3 day window due to scheduling conflicts
13. Section 5.2 Baseline update to allow +2 day window for scheduling conflicts
14. Section 5.3 Treatment updated to allow for continued treatment if the investigator 
believes the patient has pseudoprogression.
15. Section 5.4 End of Treatment Visit updated EOT timeframe.
16. Section 5.6 Activity Assessments updated to reflect changes made in Amendment 3.
17. Section 6.1 Number of Subjects and Sites  updated to reflect an additional 40 subjects 
for Part 3 Phase 2.
18. Section 6.2 Inclusion Criteria
a.
#3 revised wording that all enrolling patients must have measurable lesions per 
RANO criteria,
b.
#8 revised to clarify time from end of radiotherapy and time between MRIs 
confirming progression
c.
#13 added that contraceptive measures are to be continued for 6 months after the last 
dose of BEV or 3 months after the last dose of MRZ, whichever is longer
19. Section 6.3 Exclusion Criteria revised to reflect clinically insignificant deviations from 
these criteria are acceptable if approved by the Sponsor’s Medical Monitor.
20. Section 7.2.4 Administration of MRZ in Part 3 Phase 2 added to describe intra-patient 
dose escalation in Amendment 3.
21. Section 7.2.5 Dose Schedules revised to reflect MRZ and BEV dosing schedules in Part 
3 Phase 2, Table 5 added to define dose modification guidelines in Part 3.
22. Section 7.3 Method of Treatment Assignment, updated to include Amendment 3
23. Section 8.1 Permitted Concomitant Medications and Procedures, updated to include 
the treatment of hallucinations.
24. Section 9.1 Statistical Analysis Overview, Part 3 Phase 2 was added to reflect the 
samples size of 40 subjects for OS
25. Section 9.3 Sample Size was added to describe the significance of 40 subjects.
26. Section 9.7 Safety Analysis updated to add Amendment 3.
27. Section 9.10 Interim Analysis Phase 2 updated to reflect that Part 3 Phase 2 will be 
implemented.
28. Section 17 References updated Avastin Prescribing Information date, added Levin 2016 
and Teicher 2015. 
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Marizomib 
Protocol MRZ-108 Amendment 2 Summary 
Triphase R&D I Corp. 
Confidential and Proprietary 
1 
10 January 2016 
AMENDMENT SUMMARY 
Protocol MRZ-108 Amendment 2 
1. 
AMENDMENT RATIONALE AND DESCRIPTION 
Amendment 2 was to amend the study to a Phase 1/2 study and add up to 30 response-evaluable 
patients.  During the Phase 1 dose-escalation portion of the study, responses to treatment were 
demonstrated.  These responses justify the expansion cohort within the Phase 1 portion of the 
study to obtain a preliminary estimate of the response rate to the combination of MRZ and BEV.  
However, it will take a larger randomized study to determine if the combination of MRZ and 
BEV has greater activity than BEV alone.  Prior to undertaking such a trial, it would be 
important to determine if MRZ as a single agent has activity in relapsed or recurrent Grade 4 
malignant glioma (G4 MG).  A small Phase 2 study, at the dose and schedule of MRZ 
determined in Phase 1, is warranted to assess the activity of MRZ as a single agent.  The results 
of the Phase 2 will help determine if it is worthwhile developing MRZ as a single agent or in 
combination with BEV in relapsed or recurrent G4 MG. 
Because the dose level of 0.8 mg/m2 was tolerated in the Phase 1, dose escalation portion of the 
study where MRZ was combined with BEV, it is expected that the single agent will also be 
tolerated at this dose.  Because this and other MRZ trials do not suggest renal damage as a direct 
result of MRZ, the IV hydration will be shortened to 250 mL infused over 30 minutes prior to 
MRZ dosing in the Phase 2 portion.  Renal function will continue to be monitored and, if 
necessary, hydration can be increased in specific patients at the discretion of the investigator. 
Revisions are shown in detail in the sections that follow.  Significant changes introduced with 
Amendment 2 are as follows: 
1. The title was changed accordingly to include the Phase 2 portion of the trial: Phase 1,
Multicenter, Open-Label, Dose-Escalation, Combination Study of Marizomib and
Bevacizumab in Bevacizumab-Naïve Subjects with WHO Grade IV Malignant Glioma
followed by a Phase 2 Trial of Single Agent Marizomib.
2. Avastin® (bevacizumab, BEV) prescribing information updated to reflect most recent
December 2015 update.
3. Section 1.4.4 Clinical Experience updated to reflect preliminary response data in the
Dose Escalation portion of this study.
5. Section 2 Study Objectives and Section 3 Endpoints updated to include the Phase 2
portion of the study.
6. Section 4 Overall Study Design updated to include the Phase 2 portion of the study. The
study is a modified 2-stage design (Green 1992).  Standard evaluations for safety and
activity are employed.  Fifteen response-evaluable patients will be entered in the first
stage.  If no objective responses are observed, the trial will be terminated.  If 1 or more
responses are observed, then the second stage will be implemented with an additional
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Protocol MRZ-108 Amendment 2 Summary 
Triphase R&D I Corp. 
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10 January 2016 
15 response-evaluable patients treated.  If at least 5 responses are observed, MRZ will be 
considered active as a single agent. 
8. Section 6.2 Inclusion Criteria was updated for the Phase 2 portion of the study. 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.
9. Section 6.3 Exclusion Criteria was updated for the Phase 2 portion of the study.
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).  BEV-Specific Exclusion Criteria only applies to patients
dosed with BEV as in the Phase 1 portion of the study.
10. Section 7.2.4 Dose Schedule updated to include Phase 2 portion of the study. MRZ
(0.8 mg/m2) will be administered as a 10-minute IV infusion on Days 1, 8, and 15 of
every 28-day cycle.  Infusion durations may be lengthened to ameliorate toxicity for
individual subjects with agreement between the Investigator and the Sponsor.
11. Section 9.1 Statistical Analysis Overview updated to include the Phase 2 portion of the
study.  Patients enrolled in the Phase 2 portion of the protocol will receive 0.8 mg/m2
MRZ IV on Days 1, 8, and 15 of 28-day cycles.  A minimum of 15 response-evaluable
patients will be enrolled in Stage 1, and up to 15 additional response-evaluable patients
will be enrolled in Stage 2, for a maximum of 30 response-evaluable patients.  After the
first 15 response-evaluable patients in the first stage have received 2 or more cycles of
therapy, available study data will be reviewed by the Phase 2 Review Committee
consisting of the Principal Investigators at each study center, the Medical Monitor, and
the Sponsor’s Chief Medical and Scientific Officers and Study Coordinator. The Phase 2
Review Committee will recommend whether to enroll the second stage based on an
assessment of both safety and efficacy.  If there are no safety concerns and clinical
benefit is demonstrated with evidence of disease response, defined as at least one
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response (partial response (PR) or better) as determined by RANO criteria, in 
15 response-evaluable patients, then 15 additional response-evaluable patients will be 
enrolled in Phase 2.  Otherwise, there will be no further enrollment into the study. 
12. Section 9.3 Sample Size updated to include the Phase 2 portion of the study.  Fifteen
response-evaluable patients will be enrolled in the first stage of a 2-stage design
(Green 1992).  If there is at least 1 PR or better and there are no safety concerns in the
first 15 response-evaluable patients, then the second stage of 15 response-evaluable
patients will be opened.  If ≥ 5 patients respond by the end of the second accrual stage
(n = 30), the conclusion can be drawn that MRZ is promising, unless other considerations
indicate otherwise.
13. Section 9.7 Safety Analysis updated to include the Phase 2 portion of the study. All
subjects will be evaluated for safety analysis if they receive at least one dose of MRZ.
The safety data will be presented in individual listings and summary tables, including
frequency tables for adverse events and listings of abnormalities for laboratory variables.
Results of Phase 1 and Phase 2 portions of the study will not be combined.
14. Section 9.10 Interim Analysis updated to include the Phase 2 portion of the study.
Response to MRZ will be assessed in the 15 response-evaluable patients in Stage 1 of the
2-stage design.  Once at least 1 response (PR or better) has been determined, the second
stage will be implemented.  If no confirmed, objective responses have been observed
after all patients have received at least 2 cycles of therapy, Phase 2 will end without
implementing the second stage.  If the second stage is implemented, an additional
15 response-evaluable patients will be enrolled.
15. Section 17 References updated to reflect changes in the document accordingly.
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Marizomib 
Protocol MRZ-108 Amendment Summary 
 
Triphase R&D I Corp. 
AMENDMENT SUMMARY 
Protocol MRZ-108 Amendment 1 
1. 
AMENDMENT RATIONALE AND DESCRIPTION 
 
 Revisions are shown in detail in the sections that 
follow.  Significant changes introduced with Amendment 1 are as follows: 
1. The frequency and rationale of the Karnofsky Performance Status was clarified in 
Table 1, and Section 3. 
 
4. Dexamethasone (DEX) dosing requirement removed from protocol:  The use of steroids 
to ameliorate toxicities of MRZ including nausea and vomiting and some of the central 
nervous system effects was suggested by an investigator on the multiple myeloma 
studies.  However, no formal analysis of the ability of steroids to counteract these effects 
was under taken.  This requirement has been removed from Table 1.  Adverse events 
requiring treatment will be treated with standard of care procedures and/or medications.  
Steroids may be used if such standard of care treatments are unsuccessful.  Section 8.1 
was amended to include the use of antiemetic steroids, such as dexamethasone. 
5. Inclusion criteria: 
• The study population was clarified to include subjects with glioblastoma and 
gliosarcoma. 
• 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.  
• Transfusions and/or growth factor support may not be used in order to meet 
laboratory inclusion criteria. 
• Alanine transaminase (ALT) ≤ 2.5 ULN was added to the laboratory inclusion 
criteria. 
Section 6.2 was amended accordingly. 
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Marizomib 
Protocol MRZ-108 Amendment Summary 
 
Triphase R&D I Corp. 
6. Subjects must not drive a vehicle or operate heavy machinery while on this study.  
Section 7.2.1 was amended accordingly. 
7. Dose-limiting toxicity (DLT) was amended to include: 
• ≥ Grade 3 thrombocytopenia or Grade 2 thrombocytopenia with bleeding. 
• Febrile neutropenia. 
• Any ≥ Grade 2 neurological event lasting more than 4 days. 
Section 7.2.3 was amended accordingly. 
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