Clinical trial NCT03345095
Conditions: Newly Diagnosed Glioblastoma
Keywords: Marizomib Temozolomide Glioblastoma Phase III
Sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Start date: 2018-07-26; Completion date: 2023-06-30
Enrollment: 749 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The standard of care for newly diagnosed glioblastoma includes surgery, involved-field radiotherapy, and concomitant and six cycles of maintenance temozolomide chemotherapy, however the prognosis remains dismal. Marizomib has been tested in patients with newly diagnosed and recurrent glioblastoma in phase I and phase II studies. In patients with recurrent glioblastoma, marizomib was administered as a single agent or in combination with bevacizumab (NCT02330562). Based on encouraging observations, a phase I/II trial of marizomib in combination with Temozolomide+Radiotherapy(TMZ/RT) followed by Temozolomide (TMZ) in newly diagnosed glioblastoma has been launched (NCT02903069) which explores safety and tolerability of this triple combination and which shall help to determine the dose for further clinical trials in glioblastoma. In this context, given that marizomib has been established as a safe addition to the standard TMZ/RT --\>TMZ, a phase III study is considered essential to establishing its impact on overall survival.

Detailed description:

Arms: arm 1: Radiotherapy + Temozolomide + Marizomib followed by adjuvant Temozolomide + Marizomib arm 2: Radiotherapy + Temozolomide followed by adjuvant Temozolomide
Interventions: intervention 1: Marizomib intervention 2: Temozolomide intervention 3: radiotherapy
Intervention descriptions: intervention 1: Intravenous administration of Marizomib intervention 2: Oral Administration of Temozolomide intervention 3: 60 Gy in 30 fractions over 6 weeks

Protocol documents:
Prot_000.pdf: 
EORTC 
Avenue E. Mounierlaan 83/11 
Brussel 1200 Bruxelles 
België – Belgique 
Tel: +32 2 774 16 11 
e-mail: eortc@eortc.org 
www.eortc.org 
Intergroup Study (EORTC-1709-BTG) 
A phase III trial of marizomib in combination with standard 
temozolomide-based radiochemotherapy versus standard 
temozolomide-based radiochemotherapy alone in patients 
with newly diagnosed glioblastoma 
MIRAGE 
(EudraCT 2017-003908-50) 
(NCT03345095) 
Coordinating Group: 
EORTC Brain Tumor Group 
Collaborating Groups: 
Canadian Cancer Trials Group (CCTG) 
EORTC Study Coordinator: 
Patrick Roth 
EORTC Study Co-Coordinator: 
Jaap Reijneveld  
This document contains confidential information. The information is provided to you and your study staff in 
confidence and cannot be used for any other purpose than the evaluation or conduct of the project described in 
this protocol. The information contained in the protocol should not be disclosed to others, without the prior 
written approval from EORTC, unless required to be made public by any applicable law. 
Version 9.0 / June 20, 2022 
©Copyright EORTC 2022 


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Document history 
Protocol version 
Date of PRC 
approval/notification 
Amendment reference 
N° 
Classification  
Outline 
July 18, 2017 
--- 
--- 
1.0 
November 13, 2017 
--- 
--- 
1.1 
December 12, 2017 
1 
Administrative 
2.0 
February 19, 2018 
2 
Scientific 
3.0 
March 16, 2018 
3 
Scientific 
4.0 
December 21, 2018 
4 
Scientific 
5.0 
January 22, 2019 
5 
Scientific 
5.1 
February 05, 2019 
6 
Administrative 
6.0 
September 12, 2019 
7 
Scientific 
7.0 
October 22, 2019 
8 
Scientific 
8.0 
September 30, 2020 
10 
Scientific 
9.0 
June 20, 2022 
11 
Scientific 
 
Warning: 
This is an Intergroup study coordinated by the EORTC. The present protocol is written according to the EORTC 
template and is fully applicable to all collaborative groups (with the exception of EORTC specific sections or 
other collaborative group(s) specific appendix and unless otherwise specified). 
The chapters 19 to 21 and the PIS/IC are fully applicable to EORTC investigators only. 
Corresponding items and contact addresses for non EORTC investigators are provided in their Group specific 
appendix that supersedes the contents of chapters 19-21 (unless otherwise specified). 
Study Coordinators: 
Coordinating group 
EORTC Study Coordinator: 
EORTC Study Co-Coordinator: 
Roth Patrick 
Reijneveld Jaap 
Collaborating group(s) 
CCTG: Warren Mason 
 


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Steering Committee: 
Dhermain F., Gustave Roussy, Villejuif, France 
Gorlia T., EORTC HQ 
Le Rhun E., CHRU de Lille, Lille, France 
Mason W., PMH, Toronto ON, Canada 
Roth P., University Hospital, Zurich, Switzerland  
Van den Bent MJ., Erasmus MC, Rotterdam, The Netherlands 
Vanlancker M., EORTC HQ 
Weller M., University Hospital, Zurich, Switzerland 
Writing Committee: 
Dhermain F., Gustave Roussy, Villejuif, France 
Reijneveld J., VU University, Amsterdam, The Netherlands  
Roth P., University Hospital, Zurich, Switzerland  
Weller M., University Hospital, Zurich, Switzerland 
EORTC Headquarters Team, Brussels, Belgium  
Contacts for EORTC 
Study Coordinator: 
Patrick Roth 
Phone: (+41) 44 255 5511 
E-Mail: patrick.roth@usz.ch 
Study co-Coordinator: 
Jaap Reijneveld 
Phone: +31 204442821 / +31 205669111 
E-Mail: JC.Reijneveld@amsterdamumc.nl 
Clinical Research Physician/ 
Medical Monitor: 
Sandrine Marréaud 
Phone: (+32) 2 774 1685 
E-Mail: sandrine.marreaud@eortc.org 
Clinical Scientist:  
Beatrice Fournier 
Phone: (+32) 2 774 15 23 
E-Mail: beatrice.fournier@eortc.org 
Project Manager: 
Sarah Nuyens 
Phone: (+32) 2 774 10 89 
E-Mail: sarah.nuyens@eortc.org 
Clinical Operation Manager 
Tina Verschuere  
Phone: (+32) 2 774 15 04 
E-Mail: tina.verschuere@eortc.org 
Data Manager: 
Sven Janssen 
Phone: (+32) 2 774 16 09 
E-Mail: sven.janssen@eortc.org 
Statistician: 
Thierry Gorlia 
Phone: (+32) 2 774 16 52 
E-Mail: thierry.gorlia@eortc.org 
Pharmacovigilance Unit: 
Phone: (+32) 2 774 16 76 
Fax: 
(+32) 2 772 80 27 
E-Mail: pharmacovigilance@eortc.org 
Contacts for other groups: see group specific appendices 


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Sponsor signatory page 
Protocol 1709 
 
Sponsor: 
 
___________________________________________________ __________________ 
Vassilis Golfinopoulos  
 
 
 
 
(Date) 
Director, EORTC Headquarters 
EORTC 
European Organisation for Research and Treatment of Cancer 
AISBL-IVZW 
Avenue E. Mounierlaan 83/11 
Brussel 1200 Bruxelles 
België - Belgique 
Phone: +32 (0)2 774 16 65 
E-mail:  vassilis.golfinopoulos@eortc.org 
Website: http://www.eortc.org 
 
 
Study Coordinator: 
 
___________________________________________________ __________________ 
Patrick Roth 
 
 
 
 
 
 
(Date) 
University Hospital Zurich  
Department of Neurology  
Frauenklinikstrasse 26  
CH-8091 Zurich  
phone: +41 (0)44 255 5511  
fax: +41 (0)44 255 4507  
email: patrick.roth@usz.ch  
 
 
Investigator:  
 
___________________________________ 
 
________________ 
 
__________________ 
Investigator’s full name (in capitals) 
 
 
(Signature) 
 
 
(Date) 
 
 
01 July 2022 | 10:00:29 MESZ
04 July 2022 | 10:53:42 CEST


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Table of contents 
Protocol summary ........................................................................................................................................................ 10 
Trial organization .......................................................................................................................................................... 16 
1 
Background and introduction .............................................................................................................................. 17 
1.1 
Proteasome inhibitor - Marizomib ............................................................................................................... 18 
1.2 
Assessment of Risks and Benefits ................................................................................................................ 21 
1.2.1 
Review by the IDMC ............................................................................................................................. 21 
1.2.2 
COVID-19 .............................................................................................................................................. 21 
1.3 
Rationale for pharmacodynamics ................................................................................................................ 21 
2 
Objectives of the trial .......................................................................................................................................... 21 
2.1 
General objectives ........................................................................................................................................ 21 
2.2 
End-points .................................................................................................................................................... 22 
3 
Patient Selection criteria ..................................................................................................................................... 22 
3.1 
Inclusion Criteria ........................................................................................................................................... 22 
3.2 
Exclusion Criteria .......................................................................................................................................... 23 
4 
Trial Design .......................................................................................................................................................... 24 
5 
Therapeutic regimens, expected toxicity, dose modifications ............................................................................ 25 
5.1 
Drug information .......................................................................................................................................... 25 
5.1.1 
Marizomib ............................................................................................................................................ 25 
5.1.2 
Temozolomide ...................................................................................................................................... 26 
5.2 
Initial dose and schedule .............................................................................................................................. 27 
5.3 
Treatment duration ...................................................................................................................................... 27 
5.4 
Withdrawal criteria ...................................................................................................................................... 27 
5.5 
Dose and schedule modifications................................................................................................................. 28 
5.5.1 
MRZ ...................................................................................................................................................... 28 
5.5.2 
RT Delays .............................................................................................................................................. 31 
5.5.3 
TMZ ....................................................................................................................................................... 31 
5.6 
Concomitant treatments .............................................................................................................................. 32 
5.6.1 
General ................................................................................................................................................. 32 
5.6.2 
Supportive care in case of toxicity........................................................................................................ 32 
5.6.3 
Prohibited therapies ............................................................................................................................. 32 
5.6.4 
ECG with use of Marizomib .................................................................................................................. 32 
5.6.5 
Covid-19 vaccines ................................................................................................................................. 33 
5.7 
Radiotherapy ................................................................................................................................................ 33 
5.7.1 
Facility and Equipment ......................................................................................................................... 33 
5.7.2 
Patient position and data acquisition ................................................................................................... 34 


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5.7.3 
Volume definition ................................................................................................................................. 34 
5.7.4 
Dose ...................................................................................................................................................... 35 
5.7.5 
Treatment planning .............................................................................................................................. 35 
5.7.6 
Treatment verification and accuracy.................................................................................................... 36 
5.7.7 
Complications ....................................................................................................................................... 36 
5.7.8 
Treatment interruptions/modifications ............................................................................................... 36 
6 
Clinical evaluation, laboratory tests and follow-up ............................................................................................. 36 
6.1 
Before treatment start ................................................................................................................................. 36 
6.2 
During treatment .......................................................................................................................................... 37 
6.2.1 
During the 6 weeks of RT and TMZ ± MRZ ........................................................................................... 37 
6.2.2 
During TMZ maintenance ± MRZ .......................................................................................................... 38 
6.2.3 
During Marizomib maintenance (experimental arm, after stopping TMZ maintenance).................... 39 
6.3 
After the end of treatment (Follow-up) ....................................................................................................... 40 
6.3.1 
End-of-Treatment Visit ......................................................................................................................... 40 
6.3.2 
Post Treatment Follow-up (every 12 weeks ± 7 days) ......................................................................... 40 
6.4 
Summary table ............................................................................................................................................. 42 
7 
Criteria of evaluation ........................................................................................................................................... 47 
7.1 
Evaluation of efficacy ................................................................................................................................... 47 
7.1.1 
General method of response assessment ............................................................................................ 47 
7.1.2 
Overall Survival ..................................................................................................................................... 50 
7.1.3 
Progression Free Survival ..................................................................................................................... 50 
7.1.4 
Overall Response .................................................................................................................................. 50 
7.1.5 
Mini Mental State Examination ............................................................................................................ 51 
7.2 
Evaluation of safety ...................................................................................................................................... 51 
7.2.1 
Adverse events ..................................................................................................................................... 51 
7.2.2 
General evaluation of adverse events .................................................................................................. 51 
7.2.3 
Serious adverse events ......................................................................................................................... 51 
7.2.4 
Toxic deaths .......................................................................................................................................... 51 
7.2.5 
Evaluability for safety ........................................................................................................................... 52 
7.3 
Evaluation of MGMT status .......................................................................................................................... 52 
7.4 
Evaluation of frailty using the G8 geriatric screening tool ........................................................................... 52 
7.4.1 
Background ........................................................................................................................................... 52 
7.4.2 
Assessments ......................................................................................................................................... 52 
7.4.3 
Objective............................................................................................................................................... 52 
8 
Statistical considerations ..................................................................................................................................... 53 
8.1 
Statistical design ........................................................................................................................................... 53 


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8.1.1 
Sample size ........................................................................................................................................... 53 
8.1.2 
Randomization and stratifications ....................................................................................................... 53 
8.2 
Statistical analysis plan ................................................................................................................................. 54 
8.2.1 
Analysis populations ............................................................................................................................. 54 
8.2.2 
Primary and secondary endpoints ........................................................................................................ 54 
8.2.3 
Statistical methods ............................................................................................................................... 55 
8.2.4 
Pre-planned sensitivity or exploratory analyses .................................................................................. 57 
8.2.5 
Prognostic factor analyses .................................................................................................................... 57 
8.2.6 
Data recording and display ................................................................................................................... 57 
8.3 
Interim analyses ........................................................................................................................................... 58 
8.4 
Follow-up analysis ........................................................................................................................................ 59 
8.5 
End of study .................................................................................................................................................. 59 
9 
Trial Governance and Data Monitoring ............................................................................................................... 59 
9.1 
Study committees ......................................................................................................................................... 59 
9.1.1 
Study Management Group (SMG) ........................................................................................................ 59 
9.1.2 
Study Steering committee (SSC) ........................................................................................................... 60 
9.1.3 
Independent data monitoring committee (IDMC) ............................................................................... 60 
9.2 
Data Monitoring ........................................................................................................................................... 60 
9.2.1 
Monitoring during medical review meetings ....................................................................................... 60 
9.2.2 
Monitoring by the IDMC ....................................................................................................................... 60 
10 
Quality of life assessment .................................................................................................................................... 61 
10.1 
Rationale....................................................................................................................................................... 61 
10.2 
Objective ...................................................................................................................................................... 61 
10.3 
HRQoL instrument ........................................................................................................................................ 61 
10.4 
Study design ................................................................................................................................................. 62 
10.4.1 
HRQoL schedule ................................................................................................................................... 62 
10.5 
Statistical considerations .............................................................................................................................. 62 
10.5.1 
Primary analysis .................................................................................................................................... 63 
10.5.2 
Sensitivity analysis ................................................................................................................................ 63 
10.5.3 
Missing data ......................................................................................................................................... 63 
11 
Translational research ......................................................................................................................................... 64 
11.1 
Objective and projects description .............................................................................................................. 64 
11.2 
Sample Collection ......................................................................................................................................... 65 
11.2.1 
Tumor samples ..................................................................................................................................... 65 
11.2.2 
Blood samples ...................................................................................................................................... 65 
11.2.3 
Sample overview .................................................................................................................................. 66 


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11.3 
Data storage, transfer and development of analysis plans .......................................................................... 66 
11.4 
General principles for human biological material (HBM) collection ............................................................ 67 
11.5 
Ancillary Radiotherapy related research projects ........................................................................................ 68 
11.5.1 
Artificial Intelligence for Automated QUality Assurance in RadioTherapy for glioblastoma target 
volume and organs at risk delineation - AQUA RT .............................................................................................. 68 
11.5.2 
Optimizing CTV margins for Radiotherapy in GBM by Machine Learning ........................................... 70 
12 
Results dissemination policy ................................................................................................................................ 72 
12.1 
Study disclosure............................................................................................................................................ 72 
12.1.1 
Trial Registration .................................................................................................................................. 72 
12.1.2 
Final Analysis Report ............................................................................................................................ 72 
12.2 
Publication policy ......................................................................................................................................... 72 
12.3 
Data sharing.................................................................................................................................................. 73 
13 
Investigator authorization procedure ................................................................................................................. 73 
14 
Patient registration & randomization procedure ................................................................................................ 74 
14.1 
General procedure ....................................................................................................................................... 74 
14.2 
Randomization ............................................................................................................................................. 74 
14.3 
Stock management process ......................................................................................................................... 74 
15 
Forms and procedures for collecting data ........................................................................................................... 75 
15.1 
Case report forms and schedule for completion.......................................................................................... 75 
15.2 
Data flow ...................................................................................................................................................... 75 
15.3 
HBM* sample registration and tracking ....................................................................................................... 75 
16 
Reporting of Serious Adverse Events................................................................................................................... 76 
16.1 
Definitions .................................................................................................................................................... 76 
16.2 
Exceptions .................................................................................................................................................... 77 
16.3 
Severity assessment ..................................................................................................................................... 77 
16.4 
Causality assessment .................................................................................................................................... 77 
16.5 
Expectedness assessment ............................................................................................................................ 78 
16.6 
Reporting procedure for investigators ......................................................................................................... 78 
16.7 
Reporting responsibilities of the Sponsor .................................................................................................... 79 
16.8 
Pregnancy reporting ..................................................................................................................................... 79 
17 
Quality assurance ................................................................................................................................................ 79 
17.1 
Control of data consistency .......................................................................................................................... 79 
17.2 
On-site monitoring ....................................................................................................................................... 80 
17.3 
Audits ............................................................................................................................................................ 80 
17.4 
Other central review procedures ................................................................................................................. 80 
17.4.1 
Quality assurance in radiotherapy ....................................................................................................... 80 


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17.4.2 
Scan submission Quality Assurance and Quality Control in imaging ................................................... 82 
17.4.3 
Imaging QA/QC level description ......................................................................................................... 82 
17.4.4 
Scan submission ................................................................................................................................... 82 
18 
Ethical considerations .......................................................................................................................................... 83 
18.1 
Patient protection ........................................................................................................................................ 83 
18.2 
Subject identification ................................................................................................................................... 83 
18.3 
Informed consent ......................................................................................................................................... 83 
19 
Administrative responsibilities ............................................................................................................................ 86 
19.1 
The study coordinator .................................................................................................................................. 86 
19.2 
The EORTC Headquarters ............................................................................................................................. 86 
19.3 
The EORTC group .......................................................................................................................................... 86 
20 
Trial sponsorship and financing ........................................................................................................................... 87 
21 
Trial insurance ..................................................................................................................................................... 87 
 
 
Table of appendices 
Appendix A: References ............................................................................................................................................... 88 
Appendix B: Abbreviations ........................................................................................................................................... 92 
Appendix C: New York Heart Association (NYHA) classification of heart failure ......................................................... 95 
Appendix D: Common Terminology Criteria for Adverse Events ................................................................................. 96 
Appendix E: Karnofsky scale for performance status ................................................................................................... 97 
Appendix F: EORTC Quality of Life evaluation: guidelines for administration of questionnaires ................................ 98 
Appendix G: G8 geriatric screening tool (Version 1.0 - December 2010) .................................................................. 100 
Appendix H: Acceptable birth control methods ......................................................................................................... 102 
Appendix I: Mini Mental State Examination (MMSE)................................................................................................. 103 
Appendix J: Neurocognitive test battery .................................................................................................................... 104 
Appendix K: Certification Worksheet for test administrator ..................................................................................... 113 
Appendix L: Specific protocol instructions during the COVID-19 pandemic .............................................................. 114 
 
 
 
 


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Protocol summary 
Title of the Study 
A phase III trial of marizomib in combination with standard temozolomide-based 
radiochemotherapy versus standard temozolomide-based radiochemotherapy alone 
in patients with newly diagnosed glioblastoma - MIRAGE 
Objective(s) 
The primary objective of this study is to compare overall survival (OS) in patients 
receiving marizomib in combination with standard treatment (temozolomide (TMZ) 
with concomitant radiotherapy (RT), followed by TMZ maintenance therapy: 
TMZ/RT→TMZ) with patients receiving standard treatment only (TMZ/RT→TMZ). The 
testing strategy is defined to assess this objective in both the whole population and 
the subgroup of unmethylated MGMT (O-6-methylguanine-DNA methyltransferase) 
patients with adequate statistical power. 
Secondary objective is to compare progression free survival (PFS) in the two 
treatment arms in the whole population.  
Further secondary objectives are: 
• 
To assess the safety and tolerability of marizomib combined with TMZ/RTTMZ. 
• 
To assess objective and self-perceived neurocognitive function and quality of life 
of patients treated with this approach. 
• 
Descriptive and correlative translational research. 
• 
To evaluate pharmacokinetics in the MRZ arm 
Methodology 
This is a multicenter, randomized, controlled, open label phase III superiority trial with 
an early stopping rule for futility. 
After signing the informed consent form and upon confirmation of the patient 
eligibility, patients will be randomized 1:1 to the experimental arm (addition of 
marizomib to the standard treatment) or the standard arm. 
Stratification factors are: Institution; Age (≤55, >55 years); Karnofsky performance 
status (70/80, 90/100); Extent of surgery (partial/open biopsy, gross total).  
Number of patients  
Number planned 
(Statistical design) 
Number analyzed 
For this study, we assumed that in the whole trial population, the standard treatment 
plus marizomib presents with a superior OS efficacy compared to the standard 
treatment alone estimated by a hazard ratio equal to 0.74 (26% reduction of the 
hazard of death). This corresponds to a median OS of 16 months in the standard 
treatment alone compared to 21.6 months for standard treatment plus MRZ. We also 
assume that at the time of final analysis, the MGMT methylation status will be 
distributed 60% unmethylated, 30% methylated and 10% undetermined. We also 
hypothesized that the MRZ effect would be mainly present in the unmethylated 
MGMT subgroup where it would display a HR=0.70 (median OS of 13 months in the 
control arm and compared to 18.6 months for marizomib). The effect in the 
methylated MGMT subgroup would be HR>0.80 and in the undetermined cases which 
are assumed to be a balanced mixture of unmethylated and methylated MGMT cases 
the effect would be in the line with the overall population, i.e. HR=0.74.  
Based on the network of institution, it should be possible to recruit 400 patients/year 
(150 patients in the first year, and then 400 patients per year).  


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For the primary endpoint OS, the formal statistical testing is based on comparisons 
between two treatment groups in both ITT population and unmethylated subgroup. 
We will use a graphical method to control overall Type 1 error at one-sided 2.5%. We 
have to recruit 750 patients to show the OS difference with 86% power (taking into 
account the interim analysis for futility) and overall one-sided 1.5% significance in the 
whole population and with 80.7% power and one sided 1% significance in the 
unmethylated MGMT subgroup (uMGMT). We will recruit these patients in about 30 
months and will follow them up for about 19 months, the time necessary to observe 
the required 488 deaths (320 in uMGMT). We will perform the test in the ITT 
population and in the uMGMT subgroup simultaneously. If one of them is significant, 
we will attribute the assigned alpha to the other. At the final analysis, we will provide 
treatment effect estimates in the uMGMT and in the methylated MGMT (mMGMT) 
subgroups.  
In order to avoid exposing too many patients to a possibly ineffective and/or toxic 
treatment, a non-binding futility analysis will be conducted on the whole population.  
Diagnosis and main 
criteria for inclusion 
Inclusion Criteria 
• 
Histologically confirmed newly diagnosed glioblastoma (WHO grade IV) 
• 
Tumor resection (gross total or partial), or open biopsy only (no stereotactic 
biopsy)  
• 
Availability of FFPE tumor block or 24 unstained slides for MGMT analysis  
• 
Patient must be eligible for standard TMZ/RT→TMZ 
• 
Karnofsky performance score (KPS) ≥ 70 
• 
Recovered from effects of surgery, postoperative infection and other 
complications of surgery (if any)  
• 
The patient is at least 18 years of age on day of signing informed consent 
• 
Stable or decreasing dose of steroids for at least 1 week prior to inclusion 
• 
The patient has a life expectancy of at least 3 months 
• 
Patient has undergone a brain MRI within 14 days of randomization but after 
intervention (resection or biopsy) 
• 
The patient shows adequate organ functions as assessed by the specified 
laboratory values within 2 weeks prior to randomization defined as adequate 
bone marrow, renal and hepatic function within the following ranges:  
• 
WBC ≥ 3×109/L  
• 
ANC ≥ 1.5×109/L  
• 
Platelet count of ≥ 100×109/L independent of transfusion  
• 
Hemoglobin ≥ 10 g/dl  
• 
Total Bilirubin ≤ 1.5 ULN  
• 
ALT, AST, alkaline phosphatase (ALP) ≤ 2.5 × ULN  
• 
Serum creatinine < 1.5 x ULN or creatinine clearance (CrCl) > 30 mL/min 
(using the Cockcroft-Gault formula) 
• 
Women of child bearing potential (WOCBP) must have a negative urine or 
serum pregnancy test within 7 days prior to randomization 
• 
Patients of childbearing / reproductive potential must agree to use adequate 
birth control measures, as defined by the investigator, during the study 


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treatment period and for at least 6 months after the last study treatment. A 
highly effective method of birth control is defined as those which result in low 
failure rate (i.e. less than 1% per year) when used consistently and correctly. 
Patients must also agree not to donate sperm during the study and for 6 
months after receiving the last dose of study treatment. 
• 
Women who are breast feeding must agree to discontinue nursing prior to the 
first dose of study treatment and until 6 months after the last study 
treatment. 
• 
Ability to take oral medication  
• 
Ability to understand the requirements of the study, ability to provide written 
informed consent and authorization of use and disclosure of protected health 
information, and agree to abide by the study restrictions and return for the 
required assessments.  
• 
Before patient registration/randomization, written informed consent must be 
given according to ICH/GCP, and national/local regulations. 
Exclusion Criteria 
• 
Patients with known IDH mutation (IDH mutation testing should be conducted 
for younger patients (<55years old), patients with tumors with atypical 
features, or with history or present concurrent lower grade gliomas. 
• 
Prior treatment for glioblastoma other than surgery; prior RT to brain and/or 
prior chemotherapy for lower grade glioma. Placement of BCNU wafer during 
surgery is not allowed  
Planned additional treatment with Tumor-Treating Fields 
• 
Known hypersensitivity to the active substance or any of the excipients in the 
IV formulation 
• 
History of thrombotic or hemorrhagic stroke or myocardial infarction in past 6 
months 
• 
Congestive heart failure (New York Heart Association Class III to IV), 
symptomatic ischemia, conduction abnormalities uncontrolled by 
conventional intervention, and myocardial infarction within 6 months prior to 
first dose  
• 
Concurrent severe or uncontrolled medical disease (e.g., active systemic 
infection, diabetes, hypertension, coronary artery disease, psychiatric 
disorder) that, in the opinion of the investigator, would compromise the 
safety of the patient or compromise the ability of the patient to complete the 
study  
• 
Known history or current evidence of active Hepatitis B (e.g., positive HBV 
surface antigen) or C (e.g., HCV RNA [qualitative] is detected) 
• 
Known or current evidence of Human Immunodeficiency Virus (HIV) (positive 
HIV-1/2 antibodies)  
• 
Prior or second invasive malignancy, except non-melanoma skin cancer, 
completely resected cervical carcinoma in situ, low risk prostate cancer (cT1-
2a N0 and Gleason score ≤ 6 and PSA < 10 ng/mL), either totally resected or 
irradiated with curative intent (with PSA of less than or equal to 0.1 ng/mL) or 
under active surveillance as per ESMO guidelines Other cancers for which the 


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subject has completed potentially curative treatment more than 3 years prior 
to study entry are allowed.  
• 
Presence of any psychological, familial, sociological or geographical condition 
potentially hampering compliance with the study protocol and follow-up 
schedule; those conditions should be discussed with the patient before 
registration in the trial. 
Treatment 
Test product, dose and 
mode of administration 
Duration of treatment 
Experimental arm: Standard radiotherapy ( RT)(60 Gy in 30 fractions over 6 weeks) + 
TMZ 75 mg/m2 p.o. daily for 6 weeks (during radiotherapy) and marizomib (MRZ) dose 
0.8 mg/m2 IV at days 1, 8, 15, 29 and 36. 
This is followed, after 4-week break, by up to 6 cycles of maintenance TMZ 150-200 
mg/m2 p.o. on days 1-5 of a 28-day cycle and up to 18 cycles of maintenance MRZ 
treatment (0.8 mg/m2 IV) at days 1, 8, 15 of a 28-day cycle until disease progression, 
unacceptable toxicity or withdrawal of consent.  
Standard arm: Standard radiotherapy (RT) (60 Gy in 30 fractions over 6 weeks) + TMZ 
75 mg/m2 p.o. daily for 6 weeks (during radiotherapy) then (after 4-week break) up to 
6 cycles of maintenance TMZ 150-200 mg/m2 p.o. on days 1-5 of a 28-day cycle.  
All patients will have regular follow-up by MRI, 4 weeks after the end of radiotherapy 
(RT), then every 8 weeks thereafter until progression. 
Once patients stop study treatment, they will be followed as per institution's 
standard. 
Criteria for evaluation 
Efficacy 
 
Safety 
Response and progression will be assessed by RANO criteria as determined by the 
local investigator. 
OS is defined as the number of days from date of randomization to the date of death 
due to any cause. If a patient has not died, the data will be censored at the last date 
documented to be alive. 
PFS is defined as the number of days from date of randomization to the date of 
earliest disease progression or to the date of death due to any cause, if disease 
progression does not occur.  
MMSE is a brief, standardized tool to grade patients’ neurocognitive function. It is an 
11-question measure that tests five areas of neurocognitive function: orientation, 
registration, attention and calculation, recall, and language. 
This study will use the International Common Terminology Criteria for Adverse Events 
(CTCAE), version 5.0, for adverse event reporting. 


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Statistical methods 
We will conduct all efficacy analyses in the intent-to-treat (ITT) population. In the 
primary analyses, differences between the treatment groups in OS will be assessed by 
a stratified LogRank test adjusted for the stratification factors assessed at 
randomization (except institution). 
We consider this test as confirmatory and will perform it at a 1-sided significance level 
α=0.015 in the ITT population and α=0.01 in the uMGMT subgroup. If one of them is 
significant, the assigned alpha will be transferred to the other and the overall Type 1 
error will be controlled at one-sided 2.5% by graphical method. 
Kaplan-Meier survival curves will be presented by treatment group, in the ITT 
population and by MGMT subgroup, together with a summary of associated statistics 
including the corresponding two-sided 95% confidence intervals.  
The hazard ratio (including two sided 97% and 95 % confidence interval in the ITT 
population and two sided 98% and 95 % confidence interval in the uMGMT subgroup) 
of the Marizomib group over the control group will be calculated by Cox's 
proportional hazards model stratified by the stratification factors assessed at 
randomization (except institution).  
A re-randomization-test analysis will be performed to support the primary analysis in 
the ITT population and in uMGMT.  
Secondary analyses of efficacy are supportive and will be analyzed in a non-
confirmatory sense. Therefore no adjustments for multiplicity will be done. The 
following analyses will be performed. 
For PFS, the same analyses as for OS will be performed in the ITT population.  
For PFS and OS, Kaplan-Meier estimates will be calculated and unstratified Cox’s 
proportional hazards model will be fit for various subgroups. Forest Plot will be 
displayed with a subgroup by treatment interaction test. 
The distribution of the MMSE at each time point of evaluation will be described on the 
two treatment arms separately using means and their associated standard error (a 
graphical display will be considered). Median and range will also be provided. The 
proportion of patients with ‘normal’ and ‘impaired’ MMSE score at baseline and at key 
timepoints of evaluation will also be displayed. Longitudinal analysis might also be 
performed and detailed in the SAP. 


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Translational research 
FFPE tumor tissue will be prospectively collected for central testing of the MGMT 
status. Since MGMT status will be used in the primary OS analysis to determine if 
there is a difference in treatment effect which is dependent on this variable, this initial 
tumor tissue is a mandatory requirement within this protocol.  
We will also collect mandatory plasma and serum samples at study entry, after 
completion of RT and, every 3 cycles and at progression, as well as plasma samples for 
extracellular vesicle isolation (optional) for biomarker discovery.  
In this study, we plan to investigate the proteasomal activity in patients with sufficient 
amount of tissue available for these analyses. We have 2 objectives: firstly, we would 
like to confirm baseline proteasome activity and clinical response (PFS and OS), and 
secondly we want to see if the proteasome activity is modulated by marizomib in 
patients with tissue at baseline and at salvage surgery.  
To perform proteasome activity measurement, frozen tumor tissue, at study entry and 
after salvage surgery, should it occur, will be collected. Moreover, proteasomal 
activity will also be measured in PBMCs, collected at study entry, after completion of 
RT and, every 3 cycles and at progression.  
Future research might include isolation of ctDNA and gDNA from plasma. Depending 
on the study results, we may look for soluble factors in the serum which may be of 
interest as potential biomarkers. The ultimate goal of such work would be to define a 
tumor specific signature in the peripheral blood which could be used to monitor and 
predict response to therapy. Exploratory research may also include evaluation of a 
multigene signature to predict benefit from marizomib. 
FFPE samples will be stored at the EORTC BTG Tissue Repository (Rotterdam, NL) and 
blood derivates will be stored at the Intergrated BioBank Luxembourg (Luxembourg, 
LU). 
Quality of Life 
The main objective of QOL assessment within this trial is to determine the impact of 
addition of marizomib to temozolomide (TMZ) and radiation therapy (RT) on five 
chosen domains being primarily global QOL, with fatigue, physical function, 
neurocognitive function, communication and motor dysfunction as secondary QOL 
outcomes. It is expected that these are likely to be most affected in patients, based on 
the toxicity profiles and information of previous studies.  
Quality of life will be assessed through the EORTC Quality of Life Questionnaire (QLQ-
C30) version 3 and the EORTC Brain Cancer module (QLQ-BN20), designed for use in 
brain tumor patients undergoing protocol treatment or radiotherapy. They will be 
collected every 16 weeks (± 7 days) until death, end of study, start of new anticancer 
treatment or lost to follow-up whichever comes first 
 
 
 


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Trial organization 
• 
This trial is an intergroup trial, jointly conducted by the Canadian cancer trials group (CCTG)  
• 
Each participating group is the Sponsor for their participants (unless otherwise agreed).  
In summary: 
Country 
Recruiting group(s) 
Sponsor 
US & Canada 
CCTG 
CCTG 
Europe 
EORTC 
EORTC 
 
• 
The EORTC is the coordinating group in this trial and therefore centrally manage trial design and activation, 
attribution of duties and responsibilities between participating research groups, data collection and quality 
control of data, statistical analysis and publication. 
• 
Each Sponsor locally manages the notification/submission of all necessary documents to their regulatory 
bodies and receives the confirmation of the review by IRB/IEC following the applicable national law. 
• 
This protocol is to be followed by all participating groups. Chapters 1 to 18 are fully applicable to all groups. 
Chapters 19-21 are specific to the EORTC participants (members of the EORTC covered by the sponsorship of 
the EORTC). All particularities of participation of each individual group are included is the Group Specific 
Appendixes annexed at the end of the protocol.  
• 
The patient information sheet and informed consent templates are applicable as such only for participants 
under the sponsorship of the EORTC (participants under a different sponsorship should refer to the 
corresponding Group Specific Appendix or to their group). 
• 
The participation to this trial is only possible through one of the participating clinical cancer research groups. 
For contacts and addresses please refer to the Group Specific Appendix of the group of your membership on 
which behalf you are going to participate (see below). 
• 
Investigators members of several groups participating to the trial should select one of these groups for the 
framework of this trial and have to include all patients through this group. In some cases, because of the 
national legal framework the choice may be imposed. For EORTC members all patients will be accounted for 
the membership independently from the group they choose to participate through (see EORTC Policy 10). In 
case of any difficulties in a group selection, please contact the EORTC Headquarters. 
• 
The investigational drug Marizomib will be supplied by the industry  
This trial is an academic trial with an educational grant support from the industry. 
 
 


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1 Background and introduction 
The group of gliomas is divided into World Health Organisation (WHO) grades I-IV (Ref. 28). Glioblastoma, a grade 
IV glioma, is not only the most malignant but also the most common primary brain tumor in adults. Glioblastoma is 
a tumor thought to be of neuroglial origin, typically characterized by astrocytic differentiation and additional 
histological features such as microvascular proliferation and necrosis. Glioblastomas are diagnosed throughout all 
age groups with a median age at diagnosis of approximately 64 years. According to age-adjusted analyses, the 
incidence of glioblastoma is continuously increasing from young to old subjects with a highest incidence rate in 
patients aged 75 to 84 years (Ref. 32).  
Mutations of the isocitrate dehydrogenase IDH1 and IDH2 genes are frequent in WHO grade II and III gliomas (Ref. 
57). Furthermore, they are present in nearly all glioblastomas that have progressed from grade II or III tumors. 
Accordingly, these tumors have been called "secondary glioblastomas". Since IDH mutations are the best way to 
define the occurrence of a glioblastoma from a less malignant precursor lesion, these tumors are now separately 
classified in the 2016 WHO classification and called "IDH-mutated glioblastomas" which represent approximately 
5% of all glioblastomas. IDH-mutated glioblastomas have a better prognosis than their IDH wild-type counterparts 
(Ref. 22). The clear majority of glioblastoma arise de novo which means that no lower-grade precursor lesion has 
been known. These tumors, sometimes also referred to as "primary glioblastoma", typically harbor no IDH 
mutation and have been named “IDH-wildtype glioblastoma” in the 2016 WHO classification (Ref. 28). Accordingly, 
the updated WHO classification indicates that IDH-mutant glioblastoma should be considered a distinct entity.  
The median survival of glioblastoma patients is in the range of one year in population-based studies  
(Ref. 20) and is in the range of 15-16 months in clinical trial populations (Ref. 8, Ref. 17). Glioblastomas are 
paradigmatic for their propensity to deeply infiltrate adjacent brain areas, precluding definitive surgical 
resection and limiting the efficacy of other local therapies. The results achieved with traditional cancer 
therapies are poor because of defects in the apoptotic machinery of glioma cells, accounting for their 
resistance to irradiation and chemotherapy.  
Younger age, better performance status and extent of resection have repeatedly been shown to be positive 
prognostic factors in glioblastoma patients. Furthermore, data from the EORTC 26981/22981-NCIC CE3 trial 
indicate that a Mini-Mental State Examination (MMSE) score of 27 or higher is associated with better outcome 
(Ref. 19). The majority of glioblastomas does not harbor molecular factors associated with a better prognosis in 
gliomas such as IDH mutation or 1p/19q co-deletion (Ref. 50). The DNA repair protein O-6-methylguanine-DNA 
methyltransferase (MGMT) removes the alkylation at the O⁶-position of guanine induced by alkylating agents. 
Thereby, MGMT confers resistance to alkylating chemotherapeutic drugs such as nitrosoureas or temozolomide. 
MGMT is expressed if the gene promoter is unmethylated. In contrary, a methylated MGMT promoter leads to 
gene silencing and is associated with sensitivity to alkylating agents (Ref. 23). In glioblastoma patients who are 
treated with alkylating drug chemotherapy, MGMT promoter methylation is associated with prolonged 
progression-free and overall survival (Ref. 42; Ref. 29; Ref. 54). 
Biopsy or surgical resection is mandatory to allow for a histopathological characterization of the tumor tissue. The 
emergence of various molecular markers stresses the importance of having sufficient amount of tissue in order to 
be able to perform all desired analyses. Results obtained in various retrospective analyses stress the hypothesis 
that gross total resection results in prolonged survival in glioblastoma patients (Ref. 7). Furthermore, data from 
prospective trials which took advantage of the fluorescent dye, 5-aminolevulinic acid (5-ALA), or intraoperative 
MRI in order to improve the extent of resection, showed that patients with more complete resections of malignant 
gliomas had an improved progression free survival (Ref. 40, Ref. 39).  
Radiotherapy has been a standard treatment for patients with newly diagnosed glioblastoma for decades. Data 
from a prospective trial comparing best supportive care alone with best supportive care and additional 


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radiotherapy demonstrated prolonged progression free survival (PFS) and overall survival (OS) with the 
administration of radiotherapy (Ref. 25). Since 2005, patients with newly diagnosed glioblastoma aged 70 years or 
younger are treated with maximal safe surgery followed by involved-field radiotherapy (RT) with concomitant 
temozolomide (TMZ) therapy followed by up to 6 cycles of maintenance temozolomide therapy (TMZ/RT→TMZ) 
according to results of the EORTC 26981/22981-NCIC CE3 trial (Ref. 42, Ref. 51). The situation is similar in elderly 
patients with newly diagnosed glioblastoma but only a fraction of patients might be eligible for combined 
radiochemotherapy (Ref. 33). Patients not considered eligible for combined modality treatment, e.g. frail subjects, 
may be treated based on the O-6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status 
with radiotherapy alone or temozolomide alone (Ref. 54, Ref. 29).  
Since 2005, various attempts have failed to further improve the outcome of patients with newly diagnosed 
glioblastoma. Dose intensification of TMZ during the maintenance part using a regimen consisting of 21 days of 
temozolomide administration out of 28 days did not result in prolonged survival (Ref. 18). Several retrospective 
analyses also suggest that there is no clinical benefit from the extended administration of maintenance TMZ 
beyond 6 cycles (Ref. 3; Ref. 21). Efforts to improve overall survival results obtained with TMZ/RT-->TMZ have also 
failed, including the addition of antiangiogenic compounds such as bevacizumab (Ref. 17, Ref. 8) or cilengitide (Ref. 
41) which were explored in randomized phase 3 trials. More recently, the vaccine rindopepimut, the first 
immunotherapeutic approach in the treatment of brain cancers, was assessed in a randomized, placebo-controlled 
phase 3 trial in patients with newly diagnosed glioblastoma harboring a mutation in the epidermal growth factor 
receptor (EGFR) gene called EGFRvIII. The addition of rindopepimut to TMZ/RT-->TMZ did not improve PFS or OS 
compared to placebo-treated patients (Ref. 50). Tumor-Treating Fields (TTFields) are alternating electric fields 
delivered through transducer arrays directly applied onto the scalp of patients. TTFields are supposed to exert anti-
tumor effects by targeting dividing tumor cells while sparing other cells in the brain that are not undergoing 
division. The addition of TTFields to maintenance temozolomide has resulted in prolonged survival in patients with 
newly diagnosed glioblastoma (Ref. 43). This trial, however, enrolled only patients who had stable disease after 
completion of radiotherapy. Several questions on how to potentially incorporate this novel treatment modality 
which is not yet reimbursed in many countries into standards of care remain unanswered.  
1.1 
Proteasome inhibitor - Marizomib 
The proteasome is a central cellular structure for the turnover of proteins. Its activity is constituted by multiple 
proteases assembled in a large multi-protein complex. Cancer cells often exhibit enhanced proteasome activity and 
inhibition of proteasome activity may preferentially affect the viability of cancer cells, including glioblastoma cells 
(Ref. 48, Ref. 49, Ref. 36).  
Marizomib displays a unique pharmacologic profile among proteasome inhibitors characterized by high potency 
and irreversible pan-proteasome inhibition. It inhibits all 3 major catalytic activities of the 20S core particle by 
rapidly entering cells and covalently binding to all three active enzyme sites (Ref. 27). Preclinically, marizomib has 
been shown to induce apoptotic cell death in stable human glioma tumor cell lines and in glioma stem cells, as well 
as in intracranial glioblastoma models in vivo (Ref. 4; Ref. 30;  
Ref. 12). In vitro studies indicate that glioma stem (tumor-initiating) cells are rather resistant to irradiation and 
chemotherapeutic agents such as temozolomide, but are still sensitive to proteasome inhibitors, whereas neural 
stem cells are sensitive to irradiation and temozolomide, but resistant to proteasome inhibitors (Ref. 4). 
Proteasome inhibition though knockdown of the PSMA1 component of the core 20S proteasome radiosensitizes 
non-small cell lung cancer cells, resulting in impairment of radiation-induced DNA double strand break repair, and 
the combination of proteasome inhibition by PSMA1 knockdown with irradiation enhanced tumor control in vivo 
(Ref. 10). In glioblastoma, proteasome inhibition by bortezomib enhanced apoptosis in combination with 
temozolomide (Ref. 47) and with irradiation (Ref. 31) as shown for several glioma cell lines. These data 
demonstrate that proteasome inhibition through a variety of modalities (e.g. bortezomib, marizomib, and gene 


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silencing) consistently results in anti-glioma activity. Together, these data suggest that proteasome inhibition 
should result in synergistic activity against various glioma cells when combined with temozolomide or irradiation. 
Bortezomib has been assessed in phase 1 and 2 trials in patients with recurrent glioblastoma. However, there was 
no clear signal of clinical activity, most likely because the drug does not cross the blood brain barrier (BBB) (Ref. 34; 
Ref. 16). In contrast, data from several preclinical studies demonstrate the unique ability of marizomib to cross the 
blood brain barrier (BBB). In a study measuring the 20S proteasome activity in mouse whole brain lysates with 
either marizomib or bortezomib, brain proteasome activity was inhibited by marizomib from 41-52% to 94-98% 
(peak), while bortezomib had no effect on brain proteasome activity (Ref. 56). Second, in a quantitative whole-
body autoradiography study in rats, after a single intravenous dose of radiolabeled marizomib, radioactivity was 
found throughout the central nervous system (CNS) (cerebrum, cerebellum, and medulla) from 2 min to 24 h after 
injection (Ref. 12). Thirdly, the proteasome activity in the prefrontal cortex of monkeys was reduced by 26-28% 
after once- or twice weekly oral doses of marizomib (MRZ) (Ref. 12). Finally, biweekly intravenous administration 
of marizomib to mice bearing intracranial glioma xenografts significantly prolonged survival in comparison with 
vehicle-treated controls (Ref. 12). Taken together, the clinical and preclinical data strongly support the conclusion 
that marizomib is brain penetrant. In clinical studies with MRZ IV, the duration of MRZ administration varied from 1 
to 120 min over the dose range 0.025 to 0.9 mg/m2. MRZ exhibited similar PK properties in both once and twice-
weekly infusion studies, with a short t1/2 (generally ranging from 3 to 15 min), a very high volume of distribution, 
and a very high clearance rate. Together, these parameters account for the observation that little-to-no 
accumulation of MRZ is observed with repeat dosing. Generally, dose-proportional increases in MRZ exposure are 
noted with increased dose. The pharmacodynamic effects of MRZ on subunit-specific activity of the proteasome 
were measured in whole blood samples and mononuclear cells collected from patients with solid and hematologic 
malignancies across several clinical trials. Partial or complete inhibition of all three proteasome subunits [CT-L 
(chymotrypsin-like, β5); T-L (trypsin-like, β2) and C-L (caspase-like, β1)] was achieved with both once- and 
twice-weekly MRZ dosing, with the rank order of sensitivity (CT-L > T-L > C-L) consistent with the biochemical 
potency of MRZ (Ref. 46). For CT-L activity, both initial on Cycle 1, Day 1 (C1D1) and peak proteasome inhibition 
was dose-dependent, with complete (100%) inhibition of CT-L activity in packed whole blood (PWB), and maximal 
(60 to 80%) inhibition of CT-L activity in peripheral blood mononuclear cells (PBMC), within the first dosing cycle. In 
contrast, 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. 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. 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 patients (Ref. 27). As of 01 August 2018, a total of 451 
subjects have received one or more doses of MRZ in 7 Phase 1 and Phase 1/2, dose-escalating clinical studies 
evaluating MRZ as a single agent or in combination with other anticancer drugs, including 171 subjects in Phase 1b 
and Phase 1/2 clinical studies for newly diagnosed and recurrent glioblastoma, respectively. In patients with 
recurrent glioblastoma, marizomib was administered (10 minute infusion) as a single agent or in combination with 
bevacizumab (Study MRZ-108, NCT02330562); the study was conducted in 4 parts. In all 4 parts of the study, 
patients were at their second or third relapse and were required to have had documented progressive disease and 
no prior therapy with bevacizumab. Part 1 evaluated MRZ at escalating doses, in order to establish the 
recommended dose, in combination with BEV (Cohorts 1 to 3) with an expansion cohort (Cohort 4) in subjects with 
relapsed GBM. The Part 2 portion of the study explored the activity of single-agent MRZ (Cohort 5) at the 
recommended dose of 0.8 mg/m2. Upon evaluation of the efficacy data in conjunction with the safety data from 
Cohorts 1 to 4, the decision was taken to attempt an intrapatient dose-escalation of MRZ in order to evaluate 
higher doses in combination with BEV in the Part 3 portion of the study (Cohort 6) in the same patient population. 
Part 4 of the study was added to assess the feasibility of enterally-administered MRZ. 


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In Parts 1 and 3 of the study, in subjects with MRZ administered a dose up to 0.8 mg/m2 in combination with 
bevacizumab, the best overall response by RANO criteria is 34.3%, with 23 of 67 subjects achieving a best response 
of CR (n = 2) or PR (n = 21), as well as a progression free survival rate at 6 months (PFS6) of 28.8% in all patients. 
Overall survival rates at 9 months (OS9) was 51.6%; in 37 patients with MGMT promoter-unmethylated tumors 
OS9 was 40.5%, and 70.2% in 21 patients with MGMT promoter-methylated tumors. Results as of 01 Aug 2018 
indicate progression-free (PFS) and overall survival (OS) at the high end of any bevacizumab monotherapy study 
(Ref. 44). In the Taal et al. study, PFS6 and OS9 were 16% and 38%, respectively, for bevacizumab alone group. 
In Part 2 of Study MRZ-108 (30 patients included), marizomib was administered as a single agent at the 
recommended phase II dose (RP2D) of 0.8 mg/m2 as a 10-minute intravenous infusion on days 1, 8, 15 every four 
weeks. Single agent MRZ activity was clearly observed but was limited: Eight subjects (26.7%) had SD (duration 
ranging from 0.7 to 9.5 months for 7 subjects; 1 subject discontinued prior to PD). Four subjects clearly benefited 
from single-agent treatment with MRZ, including the 1 subject with a confirmed PR, and 3 subjects with durable 
clinical stabilization (1 subject for 8 cycles, another 2 subjects for 12 cycles). The median PFS was 1.8 months and 
the median OS was 11.4 months.  
In the ongoing Study MRZ-108 in recurrent GBM, at MRZ doses ranging from 0.55 to 0.8 mg/m2 in combination 
with BEV (n=67) and 0.8 mg/m2 in the monotherapy arm (n=30), the most common treatment emergent adverse 
events (TEAEs) in both arms are fatigue, nausea, headache, vomiting, hallucination, hypertension, constipation and 
insomnia. Grade 3 and higher MRZ related TEAEs occurred in 51 subjects (76%) in the combination arm and in 17 
subjects (57%) in the monotherapy arm with the majority of events occurring in the system organ classes (SOCs) of 
nervous system disorders, and psychiatric disorders and vascular disorders. The incidence of serious adverse 
events (SAEs) in combination therapy at MRZ doses up to 0.8 mg/m2 and in subjects for MRZ monotherapy was 
40% and 33%, respectively. 
Based on these encouraging observations, a phase Ib trial of marizomib in combination with standard doses and 
schedules of TMZ/RT→TMZ in newly diagnosed glioblastoma has been ongoing (Study MRZ-112, NCT02903069) 
which explores safety and tolerability of this triple combination and which forms the basis for dosing for further 
clinical trials in newly diagnosed glioblastoma. During the dose escalation part of the study (MRZ dose levels of 
0.55, 0.7, 0.8, and 1.0 mg/m2), patients were enrolled in parallel to the concomitant modality cohort (TMZ/RT + 
MRZ on D1, 8, 15, 29, and 36 – these patients may continue with TMZ + MRZ in the adjuvant setting) and the 
adjuvant cohort (TMZ + MRZ on D1, 8, and 15).  
After the RP2D had been determined in the dose-escalation part of the study for the concomitant treatment and 
adjuvant treatment arms, respectively, additional patients were enrolled in the dose expansion part of the study 
and were to be treated at the RP2D to confirm the safety and assess the preliminary activity for the combination of 
MRZ+TMZ+RT (concomitant treatment) followed by MRZ+TMZ (adjuvant treatment). An additional cohort was 
added to evaluate the safety of the combination of MRZ+TMZ+Optune as adjuvant treatment. 
As of 01 Aug 2018, 63 subjects have been enrolled in Study MRZ-112 (35 in the concomitant treatment arm, 18 in 
the adjuvant treatment arm, and 10 in the Optune arm). Of the 35 subjects enrolled in the concomitant treatment 
arm, 25 of these subjects also continued to receive adjuvant treatment. 
In the on-going study MRZ-112, the most common TEAEs (more than 1/3 patients) are fatigue, nausea, vomiting, 
hallucination, constipation, headache and confusional state. Grade 3 and higher MRZ related TEAEs occurred in 37 
subjects (59%) with the majority of events occurring in the SOCs of general disorders and administration site 
conditions, nervous system disorders, gastrointestinal disorders and psychiatric disorders. Twenty-four of the 
subjects experienced an SAE and there was one TEAE of sudden death where relationship to MRZ could not be 
excluded. 


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As of 10 Jul 2019, 286 subjects have been enrolled in the study with 144 of these subjects enrolled in the MRZ 
treatment arm. As the study is on-going and is a non-company sponsored study, only SAE data are available.  
In this study, 3 SAEs of encephalopathy have been reported, 2 on the MRZ arm and 1 on the standard TMZ-based 
radiochemotherapy arm. One case of encephalopathy on the MRZ arm was fatal with the final autopsy reported as 
leukoencephalopathy. This subject presented with ataxia and hallucinations but rapidly became unconscious 95 
days after start of MRZ/TMZ treatment and 45 days after completing radiotherapy. The investigator considered 
this event to be related to MRZ. The 2 other cases of encephalopathy (1 related to para-influenza virus Type 3 and 
1 related to radiation treatment) were recovered and resolving, respectively. 
1.2 
Assessment of Risks and Benefits 
1.2.1 
Review by the IDMC 
The third IDMC review of the safety of the study and the first interim efficacy analysis (futility) took place in 
September 2020. Although the trial results did not cross the pre-specified futility boundary, the IDMC observed 
that there was as yet no evidence that this treatment provided a benefit in survival. The statistical data presented 
also suggested that it was extremely unlikely that a difference would emerge with additional patients or further 
follow-up. The IDMC observed that marizomib in this combination induced severe neurological and 
neuropsychiatric disorders, as well as other treatment-related grade 3-4 side effects, in a substantial proportion of 
the patients. The IDMC therefore recommended that the study be discontinued from further recruitment and that 
results be disclosed to medical community as soon as possible. However, if patients still on treatment were 
tolerating marizomib, they might be allowed to continue if so wished by the patient and treating physician 
1.2.2 
COVID-19 
The risk/benefit assessment of COVID-19 is included in Appendix L: Specific guidelines during COVID-19 pandemic. 
1.3 
Rationale for pharmacodynamics 
Population PD and exposure-response analyses for efficacy and safety are a fundamental component of the 
benefit/risk information. 
Pharmacodynamics (PD) analysis will be performed on the  blood of patients. This information will be used to 
conduct population PD and exposure-response analyses for efficacy and safety. 
Central nervous system adverse events have been observed with marizomib treatment in previous trials. The PD 
data could be used to assess whether there is an exposure-response relationship for this toxicity. 
2 Objectives of the trial 
To compare the overall survival (OS) of glioblastoma patients treated with standard TMZ-based 
chemoradiotherapy alone or TMZ-based chemoradiotherapy in combination with marizomib.  
2.1 
General objectives 
The primary objective of this study is to compare overall survival in patients receiving Marizomib in combination 
with standard treatment (TMZ with concomitant RT, followed by TMZ maintenance therapy: TMZ/RT→TMZ) with 
patients receiving standard treatment only (TMZ/RT→TMZ). The testing strategy is defined to assess this objective 
in both the whole population and the subgroup of unmethylated MGMT patients with adequate statistical power. 
Secondary objective is to compare PFS in the two treatment arms in the whole population.  
Further secondary objectives are: 


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To assess tumor response in the two treatment arms in the whole population 
• 
To assess the safety and tolerability of marizomib combined with TMZ/RTTMZ. 
• 
To assess objective and self-perceived neurocognitive function and quality of life of patients treated with this 
approach. 
• 
Descriptive and correlative translational research 
• 
To evaluate Pharmacodynamics (PD) of MRZ in newly diagnosed GBM 
2.2 
End-points 
Primary endpoint is OS. 
Secondary endpoints are:  
• 
PFS  
• 
Quality of Life (modified EORTC QLQ C30/BN20) 
• 
Mini Mental State Examination (MMSE) 
• 
Best overall response, objective response, complete response, duration of response  
• 
Frequencies and percentages of worst Adverse Events (AEs) or Laboratory Event grades 
The following are exploratory endpoints: 
• 
Activity of the proteasome in the tumor tissue prior to treatment start and correlation with patient’s 
outcome.  
3 Patient Selection criteria 
Patients must fulfill all the following criteria to be eligible for the study. 
3.1 
Inclusion Criteria 
• 
Histologically confirmed newly diagnosed glioblastoma (WHO grade IV) 
• 
Tumor resection (gross total or partial), or open biopsy only (stereotactic biopsy not allowed)  
• 
Availability of FFPE tumor block or 24 unstained slides for MGMT analysis  
• 
Patient must be eligible for standard TMZ/RT→TMZ 
• 
Karnofsky performance score (KPS) ≥ 70 (Appendix E) 
• 
Recovered from effects of surgery, postoperative infection and other complications of surgery (if any)  
• 
The patient is at least 18 years of age on day of signing informed consent 
• 
Stable or decreasing dose of steroids for at least 1 week prior to inclusion 
• 
The patient has a life expectancy of at least 3 months 
• 
Patient has undergone a brain MRI within 14 days of randomization but after intervention (resection or 
biopsy) 
• 
The patient shows adequate organ functions as assessed by the specified laboratory values within 2 weeks 
prior to randomization defined as adequate bone marrow, renal and hepatic function within the following 
ranges:  
• 
WBC ≥ 3×109/L  
• 
ANC ≥ 1.5×109/L  
• 
Platelet count of ≥ 100×109/L independent of transfusion  
• 
Hemoglobin ≥ 10 g/dl  
• 
Total Bilirubin ≤ 1.5 ULN  
• 
ALT, AST, alkaline phosphatase (ALP) ≤ 2.5 × ULN  


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• 
Serum creatinine < 1.5 x ULN or creatinine clearance (CrCl) > 30 mL/min (using the Cockcroft-Gault 
formula) 
• 
Women of child bearing potential (WOCBP - refer to Appendix H for definition) must have a negative urine 
or serum pregnancy test within 7 days prior to randomization 
• 
Patients of childbearing / reproductive potential must agree to use adequate birth control measures, as 
defined by the investigator, during the study treatment period and for at least 6 months after the last 
study treatment. A highly effective method of birth control is defined as those which result in low failure 
rate (i.e. less than 1% per year) when used consistently and correctly (see Appendix H). Patients must also 
agree not to donate sperm during the study and for 6 months after receiving the last dose of study 
treatment. 
• 
Women who are breast feeding must agree to discontinue nursing prior to the first dose of study 
treatment and until 6 months after the last study treatment. 
• 
Ability to take oral medication  
• 
Ability to understand the requirements of the study, ability to provide written informed consent and 
authorization of use and disclosure of protected health information, and agree to abide by the study 
restrictions and return for the required assessments.  
• 
Before patient registration/randomization, written informed consent must be given according to ICH/GCP, 
and national/local regulations. 
3.2 
Exclusion Criteria 
• 
Patients with known IDH mutation. IDH mutation testing should be conducted for younger patients (< 
55years old0, patients with tumors with atypical features, or with history or present concurrent lower 
grade gliomas  
• 
Prior treatment for glioblastoma other than surgery; prior RT to brain and/or prior chemotherapy for lower 
grade glioma. Placement of BCNU wafer during surgery is not allowed Planned additional treatment with 
Tumor-Treating Fields 
• 
Known hypersensitivity to the active substance or any of the excipients in the IV formulation 
• 
History of thrombotic or hemorrhagic stroke or myocardial infarction in past 6 months 
• 
Congestive heart failure (New York Heart Association Class III to IV, see Appendix C), symptomatic 
ischemia, conduction abnormalities uncontrolled by conventional intervention, and myocardial infarction 
within 6 months prior to first dose  
• 
Concurrent severe or uncontrolled medical disease (e.g., active systemic infection, diabetes, hypertension, 
coronary artery disease, psychiatric disorder) that, in the opinion of the investigator, would compromise 
the safety of the patient or compromise the ability of the patient to complete the study  
• 
Known history or current evidence of active Hepatitis B (e.g., positive HBV surface antigen) or C (e.g., HCV 
RNA [qualitative] is detected) Known or current evidence of Human Immunodeficiency Virus (HIV) infection 
(positive HIV-1/2 antibodies)  
• 
Prior or second invasive malignancy, except non-melanoma skin cancer, completely resected cervical 
carcinoma in situ, low risk prostate cancer (cT1-2a N0 and Gleason score ≤ 6 and PSA < 10 ng/mL), either 
totally resected or irradiated with curative intent (with PSA of less than or equal to 0.1 ng/mL) or under 
active surveillance as per ESMO guidelines. Other cancers for which the subject has completed potentially 
curative treatment more than 3 years prior to study entry are allowed. 
• 
Presence of any psychological, familial, sociological or geographical condition potentially hampering 
compliance with the study protocol and follow-up schedule; those conditions should be discussed with the 
patient before registration in the trial 


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Important note: All eligibility criteria must be adhered to, in case of deviation discussion with Headquarters and 
study coordinator is mandatory. 
4 Trial Design 
This is a multicenter, randomized, controlled, open label phase III superiority trial with an early stopping rule for 
futility. 
After signing the informed consent form and upon confirmation of the patient eligibility, patients will be 
randomized 1:1 to the experimental arm (addition of marizomib to the standard treatment) or the standard arm. 
Experimental arm: Standard radiotherapy (60 Gy in 30 fractions over 6 weeks) + TMZ 75 mg/m2 p.o. daily for 6 
weeks (during radiotherapy) and marizomib (MRZ) dose 0.8 mg/m2 IV at days 1, 8, 15, 29 and 36. 
This is followed, after 4-week break, by up to 6 cycles of maintenance TMZ 150-200 mg/m2 p.o. on days 1-5 of a 28-
day cycle and up to 18 cycles of maintenance MRZ treatment (0.8 mg/m2 IV) at days 1, 8, 15 of a 28-day cycle until 
disease progression, unacceptable toxicity or withdrawal of consent (see section 5.4).  
Continuation of maintenance temozolomide beyond 6 cycles is not encouraged, but will not constitute a protocol 
violation as long as it does not exceed 12 cycles in total. 
Standard arm: Standard radiotherapy (60 Gy in 30 fractions over 6 weeks) + TMZ 75 mg/m2 p.o. daily for 6 weeks 
(during radiotherapy) then (after 4-week break) up to 6 cycles of maintenance TMZ 150-200 mg/m2 p.o. on days 1-
5 of a 28-day cycle.  
Continuation of maintenance TMZ beyond 6 cycles is not encouraged, but will not constitute a protocol violation as 
long as it does not exceed 12 cycles in total. 


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5 Therapeutic regimens, expected toxicity, dose 
modifications 
5.1 
Drug information 
5.1.1 
Marizomib 
5.1.1.1 
General information  
Chemical name: 
(1R,4R,5S)-4-(2-chloroethyl)-1-((1S)-cyclohex-2-enyl(hydroxyl)methyl)-5-
methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione  
Other chemical identifier: 
Salinosporamide A 
Molecular formula: 
C15H20ClNO4 
Molecular weight: 
313.78 
Physical description: 
White crystalline solid 
Pharmacological class: 
Proteasome inhibitor 
Abbreviated names 
NPI-0052, MRZ 


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5.1.1.2 
Drug supply 
Marizomib supplies and re-supplies will be provided by Celgene as long as patients are on protocol treatment. 
Guidelines for drug resupply will be provided in a separate document (see IMP Management Guidelines).  
5.1.1.3 
Packaging, dispensing and storage 
The intravenous (IV) formulation consists of a kit containing 1 vial of marizomib lyophile (2 mg marizomib in 60 mg 
sucrose) presenting as white to light pink powder or cake and 1 vial of marizomib diluent.  
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.  
Kits containing one vial each of marizomib lyophile and marizomib diluent should be stored at 2°C to 8°C in a 
secured area to prevent unauthorized access. A temperature log must be maintained and temperature excursion 
monitored during the study course. Please refer to the Pharmacy Manual and local product label, as applicable, for 
detailed handling instruction for the reconstituted solution. 
5.1.1.4 
Drug reconciliation procedures 
Accountability of the investigational study drug is under the responsibility of the investigator and can be delegated 
to an appropriately qualified person. 
Study drug accountability should be maintained by each site. Accountability records should include receipt date, 
batch numbers, expiry dates, patient SeqID, use by subject, dispensing dates, quantities (lowest unit) and stock 
balance.  
In addition to internal accountability documentation on site, EORTC study-specific accountability and drug 
destruction forms will be supplied for this purpose, if site-specific forms are deemed not sufficiently detailed or do 
not provide enough information, according to EORTC Quality Assurance criteria. 
The drug accountability and destruction forms will be verified during monitoring visits. 
At the end of study, when all patients have stopped protocol treatment, complete drug reconciliation per batch 
should be available at the site for verification by EORTC in order to allow drug destruction or return procedure. 
Both the unused and expired study medication must be destroyed, upon authorization of the sponsor, according to 
local regulations and procedures, and a copy of the destruction form must be returned to the EORTC 
Headquarters.  
The medication provided for this trial is to be used only as indicated in this protocol and only for the patients 
entered in this study. 
5.1.2 
Temozolomide 
Temozolomide (TMZ) is an approved drug for the treatment of patients with newly diagnosed glioblastoma. TMZ is 
available commercially and will therefore be taken off the shelf. 
During radiotherapy, TMZ is administered at a dose of 75 mg/m2 daily, starting at the first day of radiotherapy, 
typically for 42 days and for a maximum of 49 days. Four weeks after the last day of radiotherapy, treatment with 
TMZ is resumed at a dose of 150 mg/m2 (cycle 1) and 200 mg/m2 (subsequent cycles) daily for 5 days every 28 days 
(corresponding to a cycle) for up to 6 cycles. TMZ will be administered and prescribed according to the official label 
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5.2 
Initial dose and schedule 
MRZ will be administered IV over 10 minutes. Volume of administration will vary based on dose (0.8 mg/m2) and 
patient body surface area (BSA). Capping is not allowed, because of potential underdosing. MRZ can be 
administered either through peripheral, PIC-line, central line or port-a-cath at investigator discretion. However, 
infusion site reactions are observed with peripheral administration; infusing by central line reduces the frequency 
and severity of these events (refer to Pharmacy Manual). 
Patients should maintain good oral hydration during the study (e.g., 2 L/day). The volume and duration of 
hydration may be reduced at the discretion of the Investigator, especially for patients with low body weight or with 
conditions sensitive to fluid overload.  
Patients should not drive a vehicle or operate heavy machinery while on this study.  
MRZ will be administered as a 10-minute IV infusion on Days 1, 8, 15, 29 and 36 during the concomitant treatment 
(with TMZ+RT), and on Days 1, 8, and 15 of each 28-day cycle in adjuvant treatment (with TMZ) for a total of 6 
cycles. After 6 cycles of TMZ have been completed, marizomib is administered on Days 1, 8, and 15 of each 28-day 
cycle for another 12 cycles. 
Minimum re-treatment criterion prior to the beginning of each new cycle in the adjuvant treatment: creatinine ≤ 
1.5 x ULN, Hgb ≥ 8 g/dL, platelets ≥ 75 x 109/L.  
5.3 
Treatment duration 
In the standard arm, patients will receive up to 6 cycles of TMZ as maintenance at a dose of 150-200 mg/m2 daily 
for 5 days every 28 days, unless treatment is discontinued for disease progression, unacceptable toxicity, or 
withdrawal of consent. 
Continuation of maintenance temozolomide beyond 6 cycles (e.g., for a maximum of 12 cycles) is not encouraged 
but is left to the discretion of the Investigator and the interest of the patient.  
In the experimental arm, patients will receive up to 6 cycles of MRZ+TMZ in the maintenance setting, followed by 
another 12 cycles of MRZ alone, unless treatment is discontinued for disease progression, unacceptable toxicity, 
withdrawal of consent, or the patient has completed the 18 cycles of MRZ as planned. In the event that one drug 
(TMZ or MRZ) is discontinued for reasons other than disease progression, the other will then continue as a single 
agent.  
At study closure, all study participants may continue to receive study treatment as planned in the protocol (see 
chapter 4) provided that they benefit from it and all protocol-specified criteria for continuing study treatment are 
met. For all patients who discontinue treatment for reasons other than disease progression, whenever possible, 
tumor assessment will continue as per protocol until disease progression, or start of a new treatment regimen.  
After disease progression, treatment will be left to the discretion of the treating physician. Any further anti-cancer 
therapy will not be considered as part of the protocol treatment. However, patients will be followed for survival 
and the start of first new anti-GBM therapy and its outcome.  
5.4 
Withdrawal criteria 
The principal investigator should discontinue study treatment for a patient in the event of: 
• 
Progressive disease 
• 
Unacceptable overall toxicity for all drugs. 
• 
Protocol violation  
• 
Loss to follow-up  


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• 
Patient significant non-compliance 
• 
Pregnancy 
• 
Physician/Patient decision 
• 
Death 
An end of treatment visit should be performed, and follow-up for survival, subsequent therapy and date of 
progressive disease (PD) collected, whenever feasible. 
Patients have the right to withdraw from the study at any time for any reason.  
In the case that the patient decides to prematurely discontinue study treatment, the patient must be followed for 
disease assessments and survival follow-up, unless the patient decides to withdraw consent for the collection of 
these data. In the case that the patient withdraws consent, the patient must be asked if can still be contacted for 
survival follow-up only. The outcome of these discussions should be documented in both the medical records and 
in the eCRF. 
5.5 
Dose and schedule modifications 
Treatment (MRZ +TMZ) may be administered -1 / +3 days of a scheduled dose for reasons other than toxicity. 
5.5.1 
MRZ 
Acceptable MRZ dose reductions are as follows: 
 
Dose Level 
Weekly dose 
Concomitant Treatment Schedule 
Adjuvant Treatment Schedule 
Starting dose 
0.8 mg/m2 
Days 1, 8, 15, 29, 36 
Days 1, 8 and 15 (28-day cycle) 
Dose level -1 
0.7 mg/m2 
Days 1, 8, 15, 29, 36 
Days 1, 8 and 15 (28-day cycle) 
Dose level - 2 
0.55 mg/m2 
Days 1, 8, 15, 29, 36 
Days 1, 8 and 15 (28-day cycle) 
Dose level - 3 
0.4 mg/m2 
Days 1, 8, 15, 29, 36 
Days 1, 8 and 15 (28-day cycle) 
 
The minimum permitted dose level for MRZ is 0.4 mg/m2. If toxicity recurs at the minimum permitted dose of MRZ, 
MRZ treatment should be discontinued. Dose re-escalation is not permitted for MRZ.  
Minimum re-treatment criterion prior to the beginning of each new cycle in the adjuvant treatment: creatinine ≤ 
1.5 x ULN, Hgb ≥ 8 g/dL, platelets ≥ 75 x 109/L.  
During adjuvant phase: Marizomib treatment may be held (skipped) a maximum of 3 consecutive doses for 
related toxicity. 
If the 3 consecutive skipped doses are in the same cycle, and the subject is able/unable to resume marizomib on 
the scheduled Day 1 of the subsequent cycle, the Medical Monitor should be contacted to discuss continuation 
or permanent withdrawal of marizomib. 
If the 3 consecutive skipped dose are in 2 consecutive cycles, and the patient is able/not able to resume 
treatment at the next planned visit, the Medical Monitor should be contacted to discuss continuation of 
marizomib or permanent withdrawal.  
MRZ delays: -1day to +3 days: MRZ can be administered 1 day before and up to 3 days after the planned 
administration. The next dose will be administered at the next initially planned visit. 


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Detailed instructions for MRZ dose modifications and actions are provided in the Table below: 
Marizomib-Related Adverse Event 
Severity  
Recommended action regarding MRZ administration 
Central Nervous System 
Common CNS AEs include: 
Hallucinations, ataxia, dizziness, 
gait disturbance, balance 
disorder, fall, dysarthria, 
confusion 
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. 
During concomitant treatment, if AE has not resolved to 
≤ Grade 1 (or baseline) by the next scheduled dose of 
MRZ, skip MRZ and administer TMZ/RT without delay; 
consider dose reduction with the next scheduled dose.  
During adjuvant treatment, if AE has not resolved to ≤ 
Grade 1 (or baseline) by Day 1 of next cycle, administer 
Day 1 TMZ and skip the Day 1 MRZ dose. Resume MRZ 
with the next scheduled dose at reduced level. 
If AE has not resolved to ≤ Grade 1 (or baseline) by Day 1 
of next cycle, administer Day 1 TMZ and skip the Day 1 
MRZ dose. Resume MRZ with the next scheduled dose at 
reduced level. 
If AE has not resolved to ≤ Grade 1 (or baseline) on Days 
8 or 15, skip the MRZ dose and resume with the next 
scheduled dose at reduced level. 
If AE has not resolved to ≤ Grade 1 (or baseline) during 
adjuvant MRZ post-completion of TMZ, delay and reduce 
the MRZ dose. 
In addition, consider other supportive treatment. 
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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Marizomib-Related Adverse Event 
Severity  
Recommended action regarding MRZ administration 
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).  
During concomitant treatment, if AE has not resolved to 
≤ Grade 1 (or baseline) by the next scheduled dose of 
MRZ, skip MRZ and administer TMZ/RT without delay; 
consider dose reduction with the next scheduled dose.  
During adjuvant treatment, if AE has not resolved to ≤ 
Grade 1 (or baseline) by Day 1 of next cycle, administer 
Day 1 TMZ and skip the Day 1 MRZ dose. Resume MRZ 
with the next scheduled dose at reduced level. 
If AE has not resolved to ≤ Grade 1 (or baseline) by Day 1 
of next cycle, administer Day 1 TMZ and skip the Day 1 
MRZ dose. Resume MRZ with the next scheduled dose at 
reduced level. 


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Marizomib-Related Adverse Event 
Severity  
Recommended action regarding MRZ administration 
If AE has not resolved to ≤ Grade 1 (or baseline) on Days 
8 or 15, skip the MRZ dose and resume with the next 
scheduled dose at reduced level. 
If AE has not resolved to ≤ Grade 1 (or baseline) during 
adjuvant MRZ post-completion of TMZ, delay and reduce 
the MRZ dose. 
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. 
When marizomib is administered as single agent (after completion of adjuvant temozolomide treatment) 
Any MRZ-related AE 
Any grade 
If patient is slow to recover from MRZ toxicity, a 
treatment delay can occur for each of the scheduled 
marizomib doses as needed. 
5.5.2 
RT Delays 
RT-related toxicities should be managed as per local practice. RT dose modifications are not allowed per se, but 
information on managing delays is given in the radiotherapy section (see section 5.7.8). In case of any AEs leading 
to RT interruption or delays not considered related to either TMZ or MRZ, both drugs should continue as scheduled 
if medical condition allows it. 
5.5.3 
TMZ 
During concomitant treatment part of the study, TMZ-related toxicities should be managed as per local practice. 
During adjuvant treatment, if the start of treatment cycle needs to be delayed due to TMZ toxicity (not related to 
MRZ), the planned cycle (TMZ + MRZ) may be delayed for a maximum of up to 14 days. If toxicity persists beyond 
14 days, the TMZ treatment will be skipped during this cycle (The start of the cycle begins with the first dose of 
MRZ treatment and will be administered as scheduled) and TMZ treatment will be resumed with the following 
cycle. 
Dose modifications for TMZ are allowed and should follow the standard of care at the institution. In case of any 
AEs leading to TMZ interruption (need to skip a treatment dose) and not considered related to MRZ, MRZ should 
continue as scheduled if medical condition allows it. 
The combined TMZ + RT treatment increases incidence of phototoxicity. Patients should be advised to minimize UV 
light exposure for the duration of the combined treatment and for 1 month after the last RT treatment. 
Prior to start of TMZ treatment, patients should be advised on the risk of potential irreversible infertility and/or 
testicular damage from TMZ and the possibility of sperm conservation.  


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5.6 
Concomitant treatments 
5.6.1 
General 
Concomitant medications to treat comorbid conditions and AEs are permitted. Enzyme-inducing anti-epileptic 
drugs (EIAEDs) are allowed. Steroids are allowed and dosing is at the discretion of the Investigator, with their use 
recorded in the case report form (CRF).  
MRZ appears to have a very low potential for drug-drug interactions as it is neither an inhibitor nor an inducer of 
hepatic cytochrome P450s (CYPs) from different species, it is not influenced by multiple drug resistant/adenosine 
triphosphate (ATP)-binding cassette transporters and is inactive in a broad array of enzyme, ion channel, second 
messenger, and receptor assays. 
Hydrolysis in the systemic circulation and tissues or gastrointestinal (GI) tract appears to be the major metabolic 
route for MRZ and the known metabolites are inactive both as proteasome inhibitors and cytotoxic agents. 
The use of TMZ can reactivate opportunistic infections including CMV, HSV, HZV and PJP. However, PJP prophylaxis 
is not recommended as a standard treatment according to current guidelines (Ref. 52). Therefore, treatment will 
be prescribed as per local standards. If part of local standard of care, prophylaxis against Pneumocystis jirovecii can 
be initiated for patients receiving combined TMZ and RT for the 42-day (maximum 49 days) regimen regardless of 
lymphocyte count. If lymphopenia occurs, they are to continue the prophylaxis until recovery of lymphopenia to 
grade ≤ 1. 
5.6.2 
Supportive care in case of toxicity 
In Phase 1 studies to date, MRZ has caused clinically significant nausea and vomiting requiring the use of anti-
emetics as therapy and also as prophylaxis. In addition, nausea and vomiting are also very commonly associated 
with TMZ. Therefore, both the therapeutic and prophylactic use of anti-emetics is allowed in this study at the 
discretion of the Investigator as necessary (may not be needed at the first dose).  
To date, MRZ has also caused some hallucinations, therefore both the therapeutic and prophylactic use of anti-
psychotics is allowed in this study at the discretion of the Investigator as necessary. 
5.6.3 
Prohibited therapies 
The following treatments are NOT permitted during the study treatment: 
• 
Treatment with other systemic anti-cancer agents before disease progression (chemotherapy, 
immunotherapy, anti-tumor vaccines, targeted agents, or other treatments not part of protocol-specified 
anti-cancer therapy)  
• 
Concurrent investigational agents of any type before disease progression 
• 
Craniotomy, intra-tumoral interstitial therapy, any surgical procedures under investigation or any form of 
radiosurgery 
Any of the above will lead to patient’s discontinuation from study treatment. 
Additional treatment with tumor treating fields in the adjuvant setting is discouraged but will not constitute a 
protocol violation.  
Alternative therapies are discouraged and must be discussed with the local investigator. 
5.6.4 
ECG with use of Marizomib 
To date, there has been no signal of a safety issue with ECG abnormalities including prolonged QTc with 
marizomib. There has been no signal of ECG abnormalities in patient treated with marizomib. However, a thorough 


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analysis of the QT/QTc data has not yet been submitted to the US FDA. Thus additional ECGs will be collected in 
the marizomib arm of the study. 
12-lead ECGs will be collected for all subjects on marizomib at specified timepoints: baseline, Day 1 of concomitant 
treatment, Cycle 2 Day 1 of adjuvant treatment, and as clinically indicated and will be assessed locally.  
ECGs on Day 1 of concomitant treatment and Cycle 2 Day 1 of adjuvant treatment will be collected within 15 
minutes after end of MRZ infusion. The standard 12-lead ECGs (including heart rate, PR-interval, QRS, QT interval, 
and QTc interval) will be performed and recorded. 
For subjects enrolled into the marizomib arm prior to the implementation of protocol version 5, 12-lead ECG on 
Day 1 of the subsequent two cycles of adjuvant treatment within 15 minutes after end of MRZ infusion. 
5.6.5 
Covid-19 vaccines 
As per the European Medicines Agency (EMA): 
If physicians decide to administer SARS-CoV-2 vaccines in patients enrolled in the study, decisions should be 
individualized based on the risk of SARS-CoV-2 complications and potential benefit from the vaccine, general 
condition of the patient and the severity of COVID-19 outbreak in a given area or region and in accordance with the 
vaccine label. Furthermore, the national guidelines and/or institutional guidelines must be followed. 
The available SARS-CoV-2 vaccines, that are not live attenuated vaccines, are not contra-indicated in patients on 
anticancer treatment. 
Treatment schedule should not be altered because of the COVID-19 vaccination. 
The administration of a SARS-CoV-2 vaccine (including brand name) shall be added in the concomitant medication 
form in the eCRF and noted in the patient’s medical file. Any possible vaccine related AE should be captured in the 
AE forms in the eCRFs, specifying the potential relationship to the vaccine. 
5.7 
Radiotherapy 
RT will consist of a conventionally fractionated regimen delivering a total dose of 60 Gy in 30 fractions in 6 weeks, a 
fraction of 2 Gy once daily, 5 days per week. Participating investigators will find the provisions on this chapter 
summarized in the RTQA Guidelines. 
5.7.1 
Facility and Equipment 
Institutions must comply with the Quality Assurance of Radiotherapy requirements and procedures described in 
detail in the Quality Assurance in Radiotherapy section 17.4.1. 
Patients will be treated on megavoltage equipment, i.e. linear accelerator beams with a minimum nominal energy 
of 6 MV. SAD should be at least 100 cm. Electrons, particles and implants are not permitted. The use of Cobalt 
units is not allowed in this trial. 
The volume should be treated by a multiple field technique, with all fields treated at each fraction 
Treatment with a single beam and parallel pair alone are not acceptable. 
Treatment with intensity modulated radiotherapy (IMRT) is recommended. It can be used provided it is i) without 
simultaneous integrated boost, ii) conventional fractionation, and iii) the dose prescription and homogeneity 
criteria are in accordance with ICRU 83 (2010). 
3D treatment planning computers and BEV planning should be used. The use of DVH for planning is mandatory. 
Images, as digital reconstructed radiograph (DRR), should be available for assessment of setup accuracy. 


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5.7.2 
Patient position and data acquisition 
Patients can be planned and treated supine in a custom made immobilization shell (any fixation system with 
relocation accuracy ≤ 3 mm).  
A single phase treatment volume will be used throughout treatment. A cone-down volume or boost volume is not 
allowed. All margins should be added using a 3D growth algorithm where possible. 
The images of the pre-RT MRI, performed with the subject placed in the treatment position (supine), should be 
used to aid definition of the gross tumor volume (GTV) and the clinical target volume (CTV) on the planning CT 
without contrast (≤ 3 mm slice thickness). Wherever possible, an image co-registration should be done. Preferably 
the pre RT MRI should be within 2 weeks of the planning CT otherwise the planning CT should be done with 
contrast.  
5.7.3 
Volume definition 
The definition of volumes will be in accordance with ICRU Reports #50, #62 and #83 [ICRU 1993; ICRU 1999; ICRU 
2010]. 
5.7.3.1 
Gross Target Volume (GTV) 
For subjects whose tumor has been biopsied (open biopsy only; stereotactic biopsy not allowed): the region of 
enhancement (without edema) on planning CT plus pre-RT MRI. 
For subjects whose tumor has been resected: The GTV is the surgical tumor bed plus any residual enhancing tumor 
as seen on the planning scan. Co-registration of planning CT and pre RT MRI should be performed. 
5.7.3.2 
Clinical Target Volume (CTV) 
The GTV plus a margin to account for microscopic spread. This margin will usually be 1.5-2 cm maximum, but can 
be reduced in anatomical regions where spread is unlikely (e.g. bony structures). The exact GTV-CTV margin is left 
to the best estimate of each individual investigator; it may depend on various factors such as the tumor location, 
the previous use of steroids, etc. 
In case of complete or subtotal removal, the position of the tumor bed may have shifted, and the CTV should take 
into account the new position of the abnormality on the planning CT scan and any post-operative imaging. 
5.7.3.3 
Planning Target Volume (PTV) 
The PTV (PTV_6000) will take into account uncertainties of planning and setup. The margin between CTV and PTV 
should be based on known departmental values, but will usually be 0.5-0.7 cm. 
5.7.3.4 
Organs at Risk 
The following Organs at risk (OARs) will be delineated (Ref. 38). Naming of the structures will follow Santanam et 
al. (Ref. 37): 
OAR 
Description 
Eye balls 
The whole of the outside of the globe should be contoured to include sclera and 
cornea. The macula lies opposite the lens. 
Lenses 
Seen at the anterior part of the globe. 
Optic Nerves (if visible) 
From the back of the globe to the optic chiasm passing through the optic canal 
to enter the skull anterior and inferior to the anterior clinoid. Should be 
delineated in continuity with the optic chiasm. 


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OAR 
Description 
Optic Chiasm 
Sits above and behind the anterior clinoids and runs backwards above the sella 
turcica. The anterior and posterior ‘limbs’ should extend 5 mm to include the 
start of the optic nerves anteriorly and optic tracts posteriorly. The chiasm can 
sometimes only be seen on a single slice as it is about 3 mm thick in 
craniocaudal direction. 
Lacrimal Glands 
Situated in the upper lateral region, above the lateral rectus muscle, partly on 
top of the eyeball. 
Internal ear 
Sit just anterior to the lateral aspect of the internal auditory canal. 
Brain Stem 
The foramen magnum to the point where the optic tract passes lateral to the 
midbrain 
Brain** 
Whole brain parenchyma includes all intracranial contents, inclusive of target 
volumes. 
Whole Brain minus PTV 
For ease of DVH calculation. 
Contralateral normal brain 
To be delineated for tumors not crossing the midline. 
Optic Nerve Planning Risk 
Volume (PRV) 
Optic Nerves expanded by volumetric 3 mm 
Optic Chiasm PRV 
Optic Chiasm expanded by volumetric 3 mm 
** Please do not include the brainstem in the contour of the contralateral brain, brain and brain –PTV contours 
5.7.4 
Dose 
Dose prescription and recording should be according to ICRU 83 criteria. This also applies if the treatment is 
delivered by 3D-CRT. 
The PTV should be encompassed by the 95% isodose. However, if the PTV is in close proximity to an OAR the 90% 
isodose is acceptable provided 98% of the PTV receives at least 90% of the prescribed dose. 
The regimen consists of a total dose of 60 Gy in 30 daily fractions, for a total overall time of 6 weeks. The time 
interval between fractions should be at a minimum of 18 hours, with an acceptable variation of ±2 hours on 
weekdays, and a maximum interruption of 72 hours (±2 hours) for weekends or public holidays. The time of day of 
the RT should, if possible, be kept the same each day. This will also facilitate the delivery of TMZ and MRZ. 
5.7.5 
Treatment planning 
The following are mandatory: 
• 
Planning CT scan and pre-RT MRI is required for simulation and planning. 
• 
Three-dimensional treatment planning computers and BEV planning. 
• 
A dose calculation grid of 3 mm or less should be used. 
• 
The use of DVH for planning. 
5.7.5.1 
Dose Limitations to Critical Structures 
Whenever possible, attempts should be made to limit the maximum dose for the OARs as follows: 
• 
Optic Chiasm: ≤55 Gy. to 0.03cc 


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• 
Optic Chiasm PRV ≤55Gy to 0.03cc 
• 
Brainstem: ≤56 Gy. to 0.03cc 
• 
Optic Nerves ≤ 56 Gy to 0.03cc 
• 
Optic Nerves PRV: ≤56 Gy. to 0.03cc 
• 
Eye balls, retina: ≤40 G to Dmax 
• 
Lens: 10 Gy to 0.03cc 
• 
Lacrimal glands: <40 Gy to 0.03cc 
• 
Cochlea: ≤45 Gy if both sides are involved; otherwise ≤60 Gy. (Low priority OaR)to 0.03cc 
• 
The dose to the normal brain minus the PTV should be kept as low as possible. The Dmean is to be ≤ 30 Gy 
Dose to the contra-lateral normal brain should be Dmean ≤ 30Gy, except where the tumor or the PTV margin cross 
midline If required, supplementary shielding of OAR is allowed, even if it lowers the dose to a part of the PTV. 
5.7.6 
Treatment verification and accuracy 
Treatment verification shall be performed at least weekly, preferably using an electronic portal imaging device 
(EPID), according to the standard correction protocol of the participating institute. 
Copies of portal imaging used for verification should be available upon request. 
5.7.7 
Complications 
Expected acute toxicity of conventional RT include headache, fatigue, hair loss, skin reaction, occasionally nausea, 
mucositis (if nasopharynx included), temporary reduced hearing (if ear canal included), and temporary loss of taste 
(if nasopharynx included). 
Depending on the tumor location and the region to be irradiated, several tissues or organs are potentially at risk 
for late damage, such as cortical brain, brain stem, chiasm, ear (mid or internal), lachrymal gland and pituitary 
gland. All efforts should be made during planning to minimize the dose to critical structures. 
Late complications will be recorded according to CTC version 5.0. 
5.7.8 
Treatment interruptions/modifications 
No RT dose adjustments are recommended for treatment interruptions. Maximum overall treatment time should 
be ≤ 49 days. If radiotherapy is delayed, MRZ and/or TMZ should be held until radiotherapy treatment resumes. 
Should radiotherapy be held for longer and if it is believed to be of clinical benefit for the patient to restart RT + 
TMZ ± MRZ, sites should contact the medical monitor. 
Reasons for treatment interruption include major worsening of neurological or mental status or any other medical 
condition that would preclude the continuation of RT. The decision for interruption and resumption of RT after 
interruption will be taken on an individual basis by the local investigator. 
Dose adjustments or transient discontinuations of RT should be avoided as much as possible. In individual cases 
the treating radiation oncologist will discuss with the study coordinator whether lowering of the total tumor dose 
is necessary. 
6 Clinical evaluation, laboratory tests and follow-up 
6.1 
Before treatment start 
The following assessments should be done within 28 days of randomization:  
• 
Signature of informed consent  


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• 
demographics, medical (and cancer) history 
• 
tumor pathology report available  
• 
Availability of FFPE tissue (1 paraffin block or 24 unstained slides minimum) 
• 
fresh frozen tissue from participating centers 
Within 14 days of randomization: 
• 
HBV, HCV and HIV (if allowed by local legislation) serology 
• 
laboratory tests including: 
• 
hematology - Hemoglobin (Hgb), hematocrit (Hct), red blood cell (RBC) count, white blood cell (WBC) 
count, ANC, platelet 
• 
Coagulation:  
• 
Prothrombin time (PT) or International Normalized Ratio (INR) and  
• 
partial thromboplastin time (PTT) or activated PTT (aPTT) 
• 
biochemistry - Sodium, potassium, chloride, calcium, magnesium, glucose, Urea or BUN, serum creatinine, 
uric acid, ALT, AST, alkaline phosphatase, total protein, albumin, and total bilirubin  
• 
urinalysis - protein, blood, glucose, pH; microscopic (RBC, WBC, casts) if abnormal urinalysis  
• 
brain MRI scan with contrast after surgical resection or biopsy. The results of tumor assessments done as part 
of standard of care that are within the 14-day screening period do not have to be repeated if they were done 
at the participating site. All scans are to be uploaded on the EORTC imaging platform. For detailed acquisition 
parameters, see the study specific imaging guidelines. 
• 
MMSE and Quality of life assessment (modified EORTC QLQ C30/BN20) (Appendix E and Appendix H) 
• 
G8 geriatric screening tool (for patients aged 70 years and above) 
• 
For participating centers, tests of objective neurocognitive function: HVLT-R, Trail Making Tests Part A & B and 
COWA and the MOS questionnaire on self-perceived neurocognitive function (Appendix J) 
Within 7 days of randomization: 
• 
physical examination including height, weight  
• 
vital signs (heart rate, temperature, blood pressure) 
• 
Karnofsky Performance Status (KPS) scale (Appendix E) 
• 
12-lead ECG 
• 
baseline adverse event assessment 
• 
ongoing medications  
• 
For WOCBP, urine or serum pregnancy tests  
• 
translational research:  
• 
Mandatory: 10 mL blood draw for plasma and 10 mL blood draw for serum  
• 
Optional: 10 mL blood draw for extracellular vesicles and 20 mL for PBMC; if available, fresh-frozen tissue  
6.2 
During treatment 
Treatment should start within 1 week of randomization. (Delays of 48h due to drug delivery issues will not be 
considered a protocol deviation.) 
6.2.1 
During the 6 weeks of RT and TMZ ± MRZ 
For WOCBP a pregnancy test (serum or urine) within 72 hours before start treatment. 


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The following assessments should be done on a weekly basis. If baseline assessments have been done within 14 
days of start of treatment, they do not have to be repeated for cycle 1 week 1. 
• 
concomitant medications and procedures 
• 
adverse events 
• 
hematology as in section 6.1 
• 
Vital signs (heart rate, temperature, blood pressure) 
At D1 marizomib arm only 
• 
12 -lead ECG within 15 minutes after end of MRZ infusion. 
at 4 weeks (+ 5 days) 
• 
biochemistry and coagulation parameters as in section 6.1 
On the last day of RT (but before start of maintenance treatment):  
• 
Karnofsky Performance Status (KPS) scale 
• 
For WOCBP, urine or serum pregnancy tests 
• 
MMSE and Quality of life assessment (modified EORTC QLQ C30/BN20) 
• 
For participating centers, tests of objective neurocognitive function: HVLT-R, Trail Making Tests Part A & B 
and COWA and the MOS questionnaire on self-perceived neurocognitive function (Appendix J) 
• 
translational research:  
• 
Mandatory: 10 mL blood draw for plasma and 10 mL blood draw for serum  
• 
Optional: 10 mL blood draw for extracellular vesicles and 20 mL for PBMC 
6.2.2 
During TMZ maintenance ± MRZ 
The following assessment should be done before every cycle start (within 3 days before) 
• 
physical examination (including weight) 
• 
Karnofsky Performance Status (KPS) scale (Appendix E) 
• 
vital signs (heart rate, temperature, blood pressure) 
• 
concomitant medications and procedures 
• 
adverse events 
• 
hematology as in section 6.1 
• 
biochemistry as in section 6.1 
• 
For WOCBP, urine or serum pregnancy tests 
At Cycle 1 marizomib arm only, pharmacokinetics. 
   * At Cycle 1 D 1 (first day of the first adjuvant cycle): first blood sample for pharmacokinetics immediately after 
end of MRZ infusion and second sample within 45 minutes after end of MRZ infusion. 
   * At Cycle 1 D 8: sample within 45 minutes after end of MRZ infusion. 
At Cycle 2 Day 1 marizomib arm only 
• 
a 12-lead ECG within 15 minutes after end of MRZ infusion. 
Every 8 weeks (± 7 days) 


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• 
Brain MRI scans. The first scan should occur 4 weeks post end of RT. The 8-week imaging schedule will start 
after this scan. 
All scans are to be uploaded on the EORTC imaging platform. For detailed acquisition parameters, see the 
study specific imaging guidelines. 
Every 12 weeks (± 7 days) after start of maintenance phase 
• 
translational research:  
• 
Mandatory: 10 mL blood draw for plasma and 10 mL blood draw for serum  
• 
Optional: 10 mL blood draw for extracellular vesicles and 20 mL for PBMC 
Every 16 weeks (± 7 days) 
• 
MMSE and Quality of life assessment (modified EORTC QLQ C30/BN20) 
Every 24 weeks (± 7 days) 
• 
For participating centers, tests of objective neurocognitive function: HVLT-R, Trail Making Tests Part A & B and 
COWA and the MOS questionnaire on self-perceived neurocognitive function (Appendix J) 
6.2.3 
During Marizomib maintenance (experimental arm, after stopping TMZ 
maintenance) 
The following assessment should be done before every cycle start (within 3 days): 
• 
physical examination (weight) 
• 
Karnofsky Performance Status (KPS) scale (Appendix E) 
• 
vital signs (heart rate, temperature, blood pressure)  
• 
concomitant medications and procedures 
• 
adverse events 
• 
hematology as in section 6.1 
• 
biochemistry as in section 6.1 
• 
For WOCBP, urine or serum pregnancy tests 
Every 8 weeks (± 7 days), following the imaging schedule defined in section 6.2.2 
• 
Brain MRI scans  
All scans are to be uploaded on the EORTC imaging platform. For detailed acquisition parameters, see the 
study specific imaging guidelines. 
Every 12 weeks (± 7 days) 
• 
translational research:  
• 
Mandatory: 10 mL blood draw for plasma and 10 mL blood draw for serum  
• 
Optional: 10 mL blood draw for extracellular vesicles and 20 mL for PBMC 
Every 16 weeks (± 7 days) 
• 
MMSE and Quality of life assessment (modified EORTC QLQ C30/BN20) 
Every 24 weeks (± 7 days) 
• 
For participating centers, tests of objective neurocognitive function: HVLT-R, Trail Making Tests Part A & B and 
COWA and the MOS questionnaire on self-perceived neurocognitive function (Appendix J) 


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6.3 
After the end of treatment (Follow-up) 
6.3.1 
End-of-Treatment Visit  
The following assessment should be done (28 ±7 days) after the last marizomib or temozolomide dosing (whether 
the patient has progressed or completed the full duration of planned treatment  
• 
physical examination (weight) 
• 
Karnofsky Performance Status (KPS) scale (Appendix E) 
• 
vital signs (heart rate, temperature, blood pressure) 
• 
concomitant medications and procedures 
• 
adverse events 
• 
hematology as in section 6.1 
• 
biochemistry as in section 6.1 
• 
urinalysis as in section 6.1 
• 
For WOCBP, urine or serum pregnancy tests 
• 
brain MRI scan if one has not been done in the previous 4 weeks and no progression as yet been recorded 
If patient has stopped treatment due to progression: 
• 
MMSE 
• 
For participating centers, tests of objective neurocognitive function: HVLT-R, Trail Making Tests Part A & B 
and COWA and the MOS questionnaire on self-perceived neurocognitive function (Appendix J) 
• 
translational research:  
• 
Mandatory: 10 mL blood draw for plasma and 10 mL blood draw for serum  
• 
Optional: 10 mL blood draw for extracellular vesicles and 20 mL for PBMC 
6.3.2 
Post Treatment Follow-up (every 12 weeks ± 7 days) 
6.3.2.1 
Patient has not progressed 
• 
results of MRI scans done as part of standard of care will be collected, or done as per the study schedule of 
every 8 weeks (continuing on initial schedule) until disease progression.  
• 
MMSE, Quality of life assessment (modified EORTC QLQ C30/BN20) every 16 weeks ± 2 weeks 
• 
For participating centers, tests of objective neurocognitive function: HVLT-R, Trail Making Tests Part A & B 
and COWA and the MOS questionnaire on self-perceived neurocognitive function (Appendix J) every 12 
weeks (± 7 days) 
• 
survival status 
• 
subsequent anti-GBM regimens, and treatment outcomes  
6.3.2.2 
Patient has progressed 
To be collected until death. 
• 
survival status 
• 
subsequent anti-GBM regimens, and treatment outcomes 
• 
Quality of life assessment (modified EORTC QLQ C30/BN20) every 16 weeks ± 2 weeks  
At disease progression:  
• 
MMSE 


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• 
For participating centers, tests of objective neurocognitive function: HVLT-R, Trail Making Tests Part A & B 
and COWA and the MOS questionnaire on self-perceived neurocognitive function (Appendix J) 
• 
translational research:  
• 
Mandatory: 10 mL blood draw for plasma and 10 mL blood draw for serum;  
• 
Optional: 10 mL blood draw for extracellular vesicles and 20 mL for PBMC 
• 
optional frozen tissue sample if patient undergoes salvage surgery 


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6.4 Summary table 
 
 
Before 
randomizati
on 
Within 72h of treatment start 
Randomization 
TMZ/RT (± MRZ) 
 
TMZ ± MRZ 
MRZ maintenance 
Follow-up 
(every 12 
weeks ± 7 
days) 
Day 
-28 to -1 
-14 to -1 
-7 to -1 
Day 1k 
Day 1 MRZ only 
weekly 
At 4 weeks (+5d) 
End of RT period 
before cycle start 
Cycle 1 day 1/8 
Cycle 2 day 1 MRZ 
Every 8 weeks 
Every 8 weeks MRZ 
 Every 3 cycles 
Every 16 wks (± 7d) 
 Every 24 wks 
EOT (28d after last 
FU without 
FU after 
Descrip
tion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signed 
inform
ed 
consen
t 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demog
raphics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medica
l and 
cancer 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor 
pathol
ogy 
assess
ment 
from 
archiva
l FFPE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
baselin
e 
advers
e event 
assess
ment 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ongoin
g 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Before 
randomizati
on 
Within 72h of treatment start 
Randomization 
TMZ/RT (± MRZ) 
 
TMZ ± MRZ 
MRZ maintenance 
Follow-up 
(every 12 
weeks ± 7 
days) 
Day 
-28 to -1 
-14 to -1 
-7 to -1 
Day 1k 
Day 1 MRZ only 
weekly 
At 4 weeks (+5d) 
End of RT period 
before cycle start 
Cycle 1 day 1/8 
Cycle 2 day 1 MRZ 
Every 8 weeks 
Every 8 weeks MRZ 
 Every 3 cycles 
Every 16 wks (± 7d) 
 Every 24 wks 
EOT (28d after last 
FU without 
FU after 
medica
tions 
Brain 
MRI 
scans 
 
Xa 
 
 
 
 
 
 
 
 
 
 
 
Xl 
 
 
 
 
Xm Xp 
 
Mini 
Mental 
State 
Examin
ation 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Xn 
Xq 
 
Quality 
of Life 
questio
nnaire 
(modifi
ed 
EORTC 
QLQ 
C30/B
N20) 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Xr 
Xr 
G8 
geriatri
c 
screeni
ng tools 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neuroc
ognitiv
e 
assess
mentsb 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Xn 
Xq 
 
Physica
l 
examin
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 


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Before 
randomizati
on 
Within 72h of treatment start 
Randomization 
TMZ/RT (± MRZ) 
 
TMZ ± MRZ 
MRZ maintenance 
Follow-up 
(every 12 
weeks ± 7 
days) 
Day 
-28 to -1 
-14 to -1 
-7 to -1 
Day 1k 
Day 1 MRZ only 
weekly 
At 4 weeks (+5d) 
End of RT period 
before cycle start 
Cycle 1 day 1/8 
Cycle 2 day 1 MRZ 
Every 8 weeks 
Every 8 weeks MRZ 
 Every 3 cycles 
Every 16 wks (± 7d) 
 Every 24 wks 
EOT (28d after last 
FU without 
FU after 
ation 
includi
ng 
heightc, 
weight 
Heart 
rate, 
temper
ature, 
blood 
pressur
e 
 
 
X 
 
 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
Karnofs
ky 
Perfor
mance 
Status 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
12-lead 
ECGt 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Hemat
ologyd 
 
X 
 
 
 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
Coagul
atione 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Bioche
mistryf 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
Urinaly
sisg  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
FFPE 
tissue 
(1 
paraffi
n block 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Before 
randomizati
on 
Within 72h of treatment start 
Randomization 
TMZ/RT (± MRZ) 
 
TMZ ± MRZ 
MRZ maintenance 
Follow-up 
(every 12 
weeks ± 7 
days) 
Day 
-28 to -1 
-14 to -1 
-7 to -1 
Day 1k 
Day 1 MRZ only 
weekly 
At 4 weeks (+5d) 
End of RT period 
before cycle start 
Cycle 1 day 1/8 
Cycle 2 day 1 MRZ 
Every 8 weeks 
Every 8 weeks MRZ 
 Every 3 cycles 
Every 16 wks (± 7d) 
 Every 24 wks 
EOT (28d after last 
FU without 
FU after 
or 24 
unstain
ed 
slides 
minimu
m) 
Manda
tory: 
20 mL 
blood 
draw 
Option
al: 30 
mL 
blood 
drawh 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Xn 
 
Xn 
Option
al: 
fresh-
frozen 
tissuei 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xᵒ 
Serum 
pregna
ncy 
testj 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
Rando
mizatio
n 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Conco
mitant 
medica
tions & 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 


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Before 
randomizati
on 
Within 72h of treatment start 
Randomization 
TMZ/RT (± MRZ) 
 
TMZ ± MRZ 
MRZ maintenance 
Follow-up 
(every 12 
weeks ± 7 
days) 
Day 
-28 to -1 
-14 to -1 
-7 to -1 
Day 1k 
Day 1 MRZ only 
weekly 
At 4 weeks (+5d) 
End of RT period 
before cycle start 
Cycle 1 day 1/8 
Cycle 2 day 1 MRZ 
Every 8 weeks 
Every 8 weeks MRZ 
 Every 3 cycles 
Every 16 wks (± 7d) 
 Every 24 wks 
EOT (28d after last 
FU without 
FU after 
proced
ures 
Advers
e 
events 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
Surviva
l status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
subseq
uent 
anti-
GBM 
regime
ns, and 
treatm
ent 
outco
mes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
a Brain MRI scan with contrast after surgical resection or biopsy. The results of tumor assessments done as part of 
standard of care that are within the 14-day screening period do not have to be repeated if they were done at the 
participating site. All scans are to be uploaded on the EORTC imaging platform. 
b For participating centers, tests of objective neurocognitive function: HVLT-R, Trail Making Tests Part A & B and 
COWA and the MOS questionnaire on self-perceived neurocognitive function (Appendix J) 
c Height is only to be collected at baseline 
d Hematology consists of hemoglobin (Hgb), hematocrit (Hct), red blood cell (RBC) count, white blood cell (WBC) 
count, ANC, platelet 
e Coagulation consists of prothrombin time (PT) or International Normalized Ratio (INR) and partial thromboplastin 
time (PTT) or activated PTT (aPTT) 
f Biochemistry consists of sodium, potassium, chloride, bicarbonate, calcium, magnesium, glucose, urea or BUN, 
serum creatinine, uric acid, ALT, AST, alkaline phosphatase, total protein, albumin, and total bilirubin 
g Urinalysis consists of protein, blood, glucose, pH; microscopic (RBC, WBC, casts) analysis should be done if 
urinalysis is abnormal 


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h For translational research: Mandatory 10 mL blood draw for plasma and 10 mL blood draw for serum; Optional 10 
mL blood draw for extracellular vesicles and 20 mL for PBMC  
i If site collects fresh frozen tumor tissue, optional collection 
j For WOCBP, urine or serum pregnancy tests are to be done within 7 days of randomization and within 72 hours of 
treatment start 
k If baseline assessments have been done within 14 days of start of treatment, they do not have to be repeated for 
cycle 1 day 1  
l The first MRI scan should occur 4 weeks post end of RT; the 8-week imaging schedule will start after this scan 
m Brain MRI scan if one has not been done in the previous 4 weeks and no progression as yet been recorded 
n At disease progression 
o Frozen tissue sample will be collected at progression if the patient undergoes salvage surgery 
p Results of MRI scans done as part of standard of care will be collected, or done as per the study schedule of every 
8 weeks (continuing on initial schedule) until disease progression 
q For all centers, MMSE every 16 weeks ± 1 week until disease progression;  
 For participating centers, tests of objective neurocognitive function: HVLT-R, Trail Making Tests Part A & B and 
COWA and the MOS questionnaire on self-perceived neurocognitive function every 12 weeks ± 2 weeks, until 
disease progression 
r Quality of life assessment (modified EORTC QLQ C30/BN20) every 16 weeks ± 1 week until death or lost to follow 
up 
s G8 will be measured in all patients aged 70 years and above at baseline.ͭ  
t.For subjects on the marizomib arm, 12-lead ECG to be collected on following days and timepoints ONLY: at 
baseline within 7 days of randomization: on D1 of concomitant treatment within 15 minutes after end of MRZ 
infusion; on Cycle 2 Day 1 of adjuvant treatment after end of MRZ infusion; and as clinically indicated. 
For subjects enrolled prior to the implementation of protocol version 5., 12-lead ECG on Day 1 on the subsequent 
two cycles of afjuvant treatment within 15 minutes after end of MRZ infusion. 
7 Criteria of evaluation 
7.1 
Evaluation of efficacy 
We will use the following criteria to determine the efficacy of Marizomib. 
7.1.1 
General method of response assessment 
Response to treatment is assessed on the basis of a set of target lesion(s) chosen before the first treatment 
administration (the complete list of target lesions must be reported on the initial measurement form before the 
start of treatment). These lesions must initially be measured in their two perpendicular dimensions, and these 
measurements must be repeated at each evaluation of the disease by the same method. Response evaluation is 
based on neuro-radiological imaging (MRI). For this protocol objective response (complete, partial response) and 
progression will be assessed by MRI (see section 7.1.1.4). Objective response will only be assessed in patients with 
measurable disease defined as a clearly enhancing tumor with two perpendicular diameters at entry equal or 
superior to 1 cm.  


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The contrast enhancing area will be considered as the basis for the tumor size assessment. Tumor size is defined as 
the product of the two largest perpendicular diameters. For evaluating partial and complete response, the baseline 
scan must be used for initial comparison. In initially responding (≥ 50% reductions in cross-sectional areas) or 
stabilized (< 50% reduction and < 25% increase in cross-sectional areas) patients, new scans must be compared to 
the nadir, this is the scan showing the maximum response (i.e. minimum tumor size) during or after treatment. In 
assessing response, changes on T2 weighted images must be taken into consideration. 
7.1.1.1 
Definition of target lesions 
Only the following lesions are eligible as target lesions: 
• 
MRI contrast enhancing lesions with two perpendicular diameters of 10 mm or more visible on 2 or more axial 
slices which are 5 mm apart. 
• 
Target lesion(s) must be measurable in two perpendicular diameters 
In most patients, only one lesion will be present. In case of multifocal disease, a minimum of 2 lesions and 
maximum of 3 largest enlarging lesions will be chosen as target lesions and the sum of the products of the 
perpendicular diameters will be determined. All other lesions than target lesions, if applicable, are assessed 
according to the same schedule. They are only taken into account in two situations: 
• 
if one of them clearly progresses, the overall response to therapy will be evaluated as "progression", 
independent of the response of target lesions 
• 
all lesions must have completely disappeared to report a "complete response".  
Adequate investigations must be carried out at each evaluation of the disease to detect eventual new lesions. If 
any new lesion is found, the response will be evaluated as "progression". Regardless of the status of enhancing 
lesions, if progressive lesions are observed on T2 weighted images or FLAIR images, the patient will be considered 
radiologically progressive, but treatment may continue if this is considered to be in the best interest of the patient 
and there are no signs or symptoms of clinical progression.  
By definition, non-target lesions are those that do not meet the criteria for target lesion. 
7.1.1.2 
Evaluation of patient treated after re-operation 
Postoperative changes on contrast enhanced neuro-imaging may interfere with disease evaluation. Within the first 
three days after surgery on MR imaging a thin linear enhancement may develop around the resection cavity, 
thereafter this enhancement may become thick and nodular. Enhancement of dura and meninges may be more 
pronounced, even within the first days. The postoperative linear enhancement may persist for up to 3-6 months, 
dural and meningeal enhancement may last much longer. If MRI made within 48 hours after surgery shows 
enhancing lesions with a nodular or mass like appearance in areas showing tumor on the pre-operative scans this is 
highly suggestive of residual tumor. The use of diffusion-weighted MR imaging in the immediate postoperative MRI 
may help with the identification of ischemic areas around the surgical cavity that may show enhancement with 
further follow-up. 
7.1.1.3 
Schedule of disease evaluation 
The initial assessment of disease (including measurement of all target lesions) must be performed in the two 
weeks preceding randomization. Follow-up assessments will be performed every 8 weeks (or earlier if clinically 
indicated) until disease progression. 
7.1.1.4 
Definition of response  
The primary measure of response and progression will be determined by the local investigator according to the 
RANO criteria. All treatment decisions should be based on the RANO criteria as assessed by the local investigator.  


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Target lesions are measured in their two largest perpendicular diameters. Their area is conventionally calculated as 
the product of these diameters. In case of multifocal disease with more than one target lesion, the total tumor size 
is calculated as the sum of the area of all target lesions. 
Response is defined as follows according to the RANO criteria, which also consider T2 weighted and FLAIR images: 
• 
Complete response (CR) requires all of the following: 1) Complete disappearance of all enhancing measurable 
and non-measurable disease; 2) No new lesions; 3) Stable or improved non-enhancing abnormalities on 
FLAIR/T2 images as compared to baseline; 4) Patients must be off corticosteroids (or on physiologic 
replacement doses only) and stable or improved clinically. 
• 
Partial response (PR) requires all of the following: 1) Only reductions of cross-sectional areas of 50% or more in 
the sum of product of perpendicular diameters of target lesions will be considered a response; when 
calculating the response, the baseline MRI must be used for comparison ; 2) No progression of non-target 
lesions; 3) No new lesions; 4) Stable or improved non-enhancing abnormalities on FLAIR/T2 images as 
compared to baseline; 5) Patients should be on a corticosteroid dose that should not be greater than the dose 
at time of baseline scan, and should be stable or improved clinically. 
• 
Progressive disease (PD): 
• 
Progression is defined by any of the following: 1) 25% increase in sum of the products of perpendicular 
diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of 
corticosteroids; 2) a significant increase in T2/FLAIR non-enhancing lesions on stable or increasing doses of 
corticosteroids compared with baseline scan or best response after initiation of therapy, not due to 
comorbid events; 3) the appearance of any new lesions; 4) clear progression of non-measurable lesions; or 
5) definite clinical deterioration not attributable to other causes apart from the tumor, or to decrease in 
corticosteroid dose. Failure to return for evaluation as a result of death or deteriorating condition should 
also be considered as progression.  
• 
If the evidence of PD is equivocal (target or non-target), treatment may continue until the next 
assessment, but if PD is confirmed at the next follow-up, the earlier date must be used as the date of 
progression 
• 
For patients operated at recurrence and without measurable or non-measurable disease after surgery, any 
new appearance of tumor will qualify for PD. In case non measurable tumor is left after surgery i.e. tumor 
less than 10 mm, unequivocal progression of non-target disease may be accepted as evidence of disease 
progression, where the overall tumor burden has increased sufficiently to merit discontinuation of 
treatment. Modest increase in the size of a non-target lesion is not considered unequivocal progression. If 
the evidence of PD is equivocal (target or non-target), treatment may continue until the next assessment, 
but if confirmed, the earlier date must be used as the date of progression. This implies that in case of gross 
total resection of the enhancing lesion, if at follow up minimal enhancement of unclear significance arises, 
treatment may continue until further follow-up gives unequivocal evidence of tumor progression. 
• 
Stable Disease: This occurs if the patients did not qualify for complete response, partial response, or 
progression (see below) and requires: 1) No meaningful change in the appearance of the FLAIR/T2 images 
compared to baseline or to the nadir (point with the smallest FLAIR/T2 abnormalities) if a decrease occurred. 
2) The patient should be stable clinically. In the event the steroid dosage has been increased for new signs and 
symptoms without confirmation of disease progression on imaging, and further follow-up imaging shows that 
with hindsight this increase in steroids was indeed unequivocally needed due to disease progression, the date 
of progression will be the date steroids were increased. 
• 
In this protocol, although the primary endpoint is OS, in view of the relevance of objective responses, PR, CR, 
and equivocal PD need to be confirmed with an extra MRI made 4 weeks later.  
 


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Criterion 
CR 
PR 
SD 
PD 
T1 gadolinium enhancing disease 
None 
≥ 50% ↓ 
<50% ↓ but 
<25% ↑ 
≥ 25% ↑ 
T2/FLAIR 
Stable or ↓ 
Stable or ↓ 
Stable or ↓ 
↑ 
New lesion 
None 
None 
None 
Present 
Corticosteroids 
None 
Stable or ↓ 
Stable or ↓ 
Not 
applicable* 
Clinical status 
Stable or ↑ 
Stable or ↑ 
Stable or ↑ 
↓ 
Requirements for response 
All 
All 
All 
Any 
*increase in steroids alone does not qualify for PD 
7.1.2 
Overall Survival 
Overall Survival (OS): OS is defined as the number of days from date of randomization to the date of death due to 
any cause. If a patient has not died, the data will be censored at the last date documented to be alive. 
7.1.3 
Progression Free Survival 
Progression Free Survival (PFS): PFS is defined as the number of days from date of randomization to the date of 
earliest disease progression based on Response Assessment in Neuro Oncology (RANO) criteria (as determined by 
the Investigator) or to the date of death due to any cause, if disease progression does not occur. Patients for whom 
neither death nor progression have been documented will be censored on the date of the last radiological 
assessment that the patient was progression-free. If a patient with no post-baseline radiological assessment then 
the data will be censored at the date of randomization. Patients with two or more missing response assessments 
prior to a visit with documented disease progression (or death) will be censored at the last visit where the patient 
was documented to be progression free. Patients who received new anti-cancer therapy or cancer-related surgery 
prior to progression or death will not be censored at the last assessment where the patient was documented as 
progression free prior to the new anti-cancer therapy or cancer-related surgery. Detailed censoring rules will be 
documented in the SAP. 
7.1.4 
Overall Response 
The overall response is evaluated at each assessment of the disease according to RANO criteria.  
7.1.4.1 
Best overall response 
Best overall response is the best response designation recorded from the date of randomization until disease 
progression.  
7.1.4.2 
Objective/complete response 
Objective/complete response includes best overall responses CR and PR/ CR only. All responses must be confirmed 
by repeat MRI 4 weeks later. 
7.1.4.3 
Response duration 
For responders, duration of objective response (CR/PR) and complete response (CR) will be measured similarly to 
PFS (see section 7.1.3) but starting from the time measurement criteria for CR/PR or CR (whichever is recorded 
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7.1.5 
Mini Mental State Examination 
The Mini Mental State Examination (MMSE): is a brief, standardized tool to grade patients’ neurocognitive 
function. It is an 11-question measure that tests five areas of neurocognitive function: orientation, registration, 
attention and calculation, recall, and language. The maximum score is 30 which corresponds to the best 
neurocognitive function. Following Brown et al. (Ref. 6), the patient’s neurocognitive function will be considered 
‘impaired’ if the MMSE score is 26 or less and ‘normal’ if it is 27 or more. Since its creation in 1975 by Folstein et al. 
(Ref. 14), the MMSE has been validated and extensively used in both clinical practice and research. Following 
Tangalos et al. (Ref. 45) and as previously used by Brown et al., a decline of more than 3 points in the MMSE score 
will be considered to represent clinically significant deterioration. See Appendix I. In this study, MMSE will be 
collected up to progression. 
7.2 
Evaluation of safety 
7.2.1 
Adverse events 
All adverse events will be recorded; the investigator will assess whether those events are treatment-related 
(reasonable possibility, no reasonable possibility) and this assessment will be recorded in the database for all 
adverse events. A change in grading will be collected by giving an outcome date to the initial AE. A new adverse 
event needs to be reported to reflect the change in severity. 
The collection period will start at baseline i.e. as from 2 weeks before randomization.  
All adverse events will be followed until resolution while the patient remains on study treatment. When the 
patient discontinues study treatment, suspected adverse reactions (AEs for which there is a reasonable possibility 
that the treatment caused the AE) that started while on study treatment should be followed for 30 days from the 
date of the last dose of study treatment or until considered chronic/ stable (as judged by the Investigator), 
whichever comes first.  
New SAEs and serious suspected adverse reactions that occur during the 30-day period from the date of the last 
dose of study treatment administered should be reported and followed until resolved or considered stable / 
chronic (as judged by the Investigator).  
7.2.2 
General evaluation of adverse events 
This study will use the International Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, for 
adverse event reporting. A copy of the CTCAE can be accessed from the EORTC home page 
https://www.eortc.be/services/doc/ctc/. 
Hematological and biochemistry adverse events will be assessed on the basis of at least monthly blood counts. 
The highest CTCAE grading per cycle and per patient will be computed at the EORTC HQ for analysis.  
Planned safety analysis and tabulations are described in the statistics section. 
7.2.3 
Serious adverse events 
Serious adverse events are defined by the Good Clinical Practice Guideline. 
Serious adverse events should be immediately reported according to the procedure detailed in this protocol (see 
chapter 16 on Reporting Serious Adverse Events) 
7.2.4 
Toxic deaths 
Toxic death is defined as death due to toxicity (defined as adverse events that are not confirmed as unrelated). The 
cause of death must be reported as "toxicity". 


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The evaluation of toxic deaths is independent of the evaluation of response (patients can die from toxicity after a 
complete assessment of the response to therapy). 
7.2.5 
Evaluability for safety 
All patients who have started study treatment will be included in overall safety analyses. 
For hematological events, the medical review team may decide that blood counts have not been performed and/or 
reported according to the protocol and are therefore inadequate for the evaluation of one/several hematological 
parameters in some patients. 
Patients who have discontinued treatment because of toxicity will always be included in the safety analyses. 
7.3 
Evaluation of MGMT status 
Evaluation of MGMT is an integral part of the study design. MGMT status is divided into unmethylated (uMGMT) 
and methylated (mMGMT). Details of the evaluation can be found in chapter 11.  
7.4 
Evaluation of frailty using the G8 geriatric screening tool 
7.4.1 
Background 
Older cancer patients have a much more heterogeneous general health status compared to young cancer patients. 
Some older patients are in perfect general health, while others are vulnerable or frail. Frailty is a well-known 
concept in geriatric medicine (Ref. 9). It is defined as a multi-factorial syndrome, resulting in a reduction of the 
physiological reserve and of the capability to resist stressful events (homeostatic capacity). Frailty is associated 
with an increased risk of unfavorable clinical events: disability, hospitalization, institutionalization, death. In 
oncology, the construct of frailty is as well used to describe patients with increased risk of treatment-associated 
morbidity and mortality. Presence of frailty can be detected by a so-called (Comprehensive) Geriatric Assessment 
(GA). Performance of GA is advised in older cancer patients by the International Society of Geriatric Oncology, SIOG 
(Ref. 55). GA is time consuming (takes about 30 minutes). Therefore, short geriatric screening tools such as the G8 
have been developed as a short and easy to use measurement of general health status. The G8 score has been 
specifically developed in oncology, includes 8 items, takes a few minutes to complete, and can be completed by 
any health care worker (Ref. 2). The score ranges from 1 to 17. A score greater than 14 indicates that there is little 
risk that further GA reveals significant problems in the further assessed GA domains. The G8 was shown to strongly 
predict functional decline and overall survival (Ref. 26). G8 is by far the best studied geriatric screening tool in 
oncological patients, and also has better performance for detection of geriatric problems than other geriatric 
screening tools such as VES-13 (Ref. 11). 
7.4.2 
Assessments 
G8 will be measured in all patients aged 70 years and above at baseline. G8 has to be completed by the clinician, 
the nurse or the trained coder. This screening tool includes 7 items of the Mini Nutritional Assessment and the age 
of the patient. The English version of G8 is included as a protocol appendix.  
7.4.3 
Objective 
The inclusion of the G8 screening tool in EORTC trials will allow a uniform, easy and established approach of frailty 
at baseline. The G8 tool itself has been developed as a screening tool, and not a tool for follow-up. 
The treating physician may decide which actions are needed based on the G8 result (e.g. further geriatric 
assessment in case of a G8 score of less or equal to 14; geriatric interventions if specific problems are detected 
within specific geriatric domains). 


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The assessment of frailty as defined by G8 in all patients aged 70 years and above entered in EORTC trials will allow 
interpretation of whether new treatment strategies have been tested in both fit and less fit patients which has 
importance for the generalizability of the study results.  
8 Statistical considerations 
8.1 
Statistical design 
8.1.1 
Sample size 
For this study, we assumed that in the whole trial population the standard treatment plus marizomib presents with 
a superior OS efficacy compared to the standard treatment alone estimated by a hazard ratio (HR) equal to 0.74 
(26% reduction of the hazard of death). This corresponds to a median OS of 16 months in the standard treatment 
alone compared to 21.6 months for standard treatment plus marizomib (Ref. 8; Ref. 17). We also assume that at 
the time of final analysis, the MGMT methylation status will be distributed 60% unmethylated, 30% methylated 
and 10% undetermined. We also hypothesized that the marizomib effect would be mainly present in the 
unmethylated MGMT subgroup where it would display a HR=0.70 (median OS of 13 months in the control arm and 
compared to 18.6 months for marizomib). The effect in the methylated MGMT subgroup would be HR>0.80 and in 
the undetermined cases which are assumed to be a balanced mixture of unmethylated and methylated MGMT 
cases the effect would be in the line with the overall population, i.e. HR=0.74.  
Based on the network of institution, it should be possible to recruit 400 patients/year (150 patients in the first 
year, and then 400 patients per year).  
For the primary endpoint OS, the formal statistical testing is based on comparisons between two treatment groups 
in both ITT population and unmethylated subgroup. We will use a graphical method (Ref. 5) to control overall Type 
1 error at one-sided 2.5%. We have to recruit 750 patients to show the OS difference with 86% power (taking into 
account the interim analysis for futility) and overall one-sided 1.5% significance in the whole population and with 
80.7% power and one sided 1% significance in the unmethylated MGMT subgroup (uMGMT). We will recruit these 
patients in about 30 months and will follow them up for about 19 months, the time necessary to observe the 
required 488 deaths (320 in uMGMT). We will perform the test in the ITT population and in the uMGMT subgroup 
simultaneously. If one of them is significant, we will attribute the assigned alpha to the other. At the final analysis, 
we will provide treatment effect estimates in the uMGMT and in the methylated MGMT (mMGMT) subgroups.  
In order to avoid exposing too many patients to a possibly ineffective and/or toxic treatment, a non-binding futility 
analysis will be conducted on the whole population when about 88 deaths occur (18% information time). The 
interim analysis will be evaluated by an Independent Data Monitoring Committee (IDMC). The IDMC will 
recommend continuing the study or stopping the study for futility. If the observed hazard ratio (HR) is >1.12, the 
study may be considered to be futile. 
We will analyze other endpoints at exploratory two-sided 5% significance. 
8.1.2 
Randomization and stratifications 
Patients will be centrally randomized (for practical details, see section on registration / randomization procedure). 
A minimization technique will be used for random treatment allocation. Pocock & Simon, 1975; Freedman & 
White, 1976). The minimization algorithm will be detailed in the SAP. 
Stratification factors are:  
• 
Institution,  
• 
Age (≤55, >55 years),  


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• 
Karnofsky performance status (70/80, 90/100),  
• 
Extent of surgery (partial/biopsy, gross total).  
8.2 
Statistical analysis plan 
8.2.1 
Analysis populations 
• 
Intention-to-treat population (ITT): All randomized patients will be analyzed in the arm they were allocated by 
randomization. 
• 
Per protocol population (PP): All randomized patients who are eligible and have started their randomized 
treatment arm. Patients with major protocol deviations as defined in the medical review plan are also excluded 
from the PP population.  
• 
Safety population (SP): All randomized patients who have started any treatment arm i.e. if a patient received 
treatment arm other than the patient’s randomized treatment arm, then the patient will be assigned to the 
treatment arm that the patient actually received during the study in the analysis.  
• 
Patients who did not start any treatment arm are excluded from PP and SP. 
• 
Patients excluded from PP or SP will be reported in separate tables with the reason(s) of exclusion. 
• 
Subgroups: The following subgroups will be defined: MGMT methylation status (uMGMT, mMGMT, 
unknown/missing), age (≤55, >55 years), gender (male, female), Karnofsky performance status (70/80, 90/100), 
baseline steroid use (yes, no), extent of surgery (partial/biopsy, gross total). 
A patient will be considered to be eligible if he/she did not have any deviation from the patient entry criteria listed 
in chapter 3 of the protocol. Potential eligibility problems will be assessed by the Clinical Research Physician at 
time of medical review. 
8.2.2 
Primary and secondary endpoints 
8.2.2.1 
Primary endpoints 
The primary endpoint is OS. 
8.2.2.2 
Secondary endpoints 
Secondary endpoints are:  
PFS based on investigator assessment according to RANO 2010 criteria (Ref. 53). 
ORR based on investigator assessment 
CR/PR rate based on investigator assessment 
DoR based on investigator assessment 
Quality of Life according to the methodology described in chapter 10. 
Mini Mental State Examination (MMSE). 
Incidence of Adverse Event (AEs) in MedDRA terms graded according to NCI CTCAE Version 5.0; Laboratory results 
as measured by CTCAEs Version 5.0 criteria. 
8.2.2.3 
Exploratory endpoints 
Activity of the proteasome in the tumor tissue prior to treatment start and correlation with patient’s outcome to 
assess prognostic and/or predictive value. 


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8.2.3 
Statistical methods 
8.2.3.1 
Efficacy analyses 
We will conduct all primary efficacy analyses in the intent-to-treat population. 
In the primary analyses, differences between the treatment groups in OS will be assessed by a stratified LogRank 
test adjusted for the stratification factors assessed at randomization (except institution), testing the null 
hypothesis (H0): 
• 
H0: HRMRZ arm/control = 1  
Versus the alternative hypothesis (H1) 
• 
H1: HRMRZ arm/control < 1  
We consider this test as confirmatory and will perform it at a 1-sided significance level α=0.015 in the ITT 
population and α=0.01 in the uMGMT subgroup. If one of them is significant, the assigned alpha will be transferred 
to the other and the overall Type 1 error will be controlled at one-sided 2.5% by graphical method. 
Kaplan-Meier survival curves (product-limit estimates) will be presented by treatment group, in the ITT population 
and by MGMT subgroup, together with a summary of associated statistics (median survival time, 6-, 12-, 18-, 24-
month OS rate estimates and estimates for every 6 months thereafter as applicable) including the corresponding 
two-sided 95% confidence intervals (calculated by Greenwood formula’s estimation of the standard deviation 
for rates and by Brookmeyer and Crowley technique for the median).  
The hazard ratio (HR) (including two sided 97% and 95 % confidence interval in the ITT population and two sided 
98% and 95 % confidence interval in the uMGMT subgroup) of the Marizomib group over the control group will be 
calculated by Cox's proportional hazards model stratified by the stratification factors assessed at randomization 
(except institution).  
The primary analysis will take place after 488 deaths (320 uMGMT) deaths have occurred.  
A re-randomization-test analysis will be performed to support the primary analysis in the ITT population and in 
uMGMT.  
The re-randomization test will be performed as follows: 
• 
The procedure will use 50,000 replications.  
• 
Based on the value of their randomization stratification factors, for each replicate, subjects will be (virtually) 
re-assigned to treatments using the Medidata BALANCE minimization randomization algorithm in the order in 
which they were randomized into the trial.  
• 
For each replicate the stratified log-rank test statistic adjusted by randomization stratification factors 
comparing the duration of overall survival will be computed.  
• 
The re-randomization test p-values will be the fraction of replications where the log-rank p-values from the 
replicates are less than or equal to the corresponding p-values from the original analysis. 
Robustness of the results will be established if the re-randomization test p-values are then found to be comparable 
to the corresponding p-values from the original analysis.  
Secondary analyses of efficacy are supportive and will be analyzed in a non-confirmatory sense. Therefore no 
adjustments for multiplicity will be done. The following analyses will be performed: 
The stratified LogRank test will be applied on the PFS time to test for differences between the 2 treatment groups. 
The Cox's proportional hazards model stratified by the stratification factors assessed at randomization (except 


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institution) will provide the hazard ratio (including 95 % confidence interval). Summary of associated statistics for 
each treatment arm (median PFS time, 6-, 12-, 18-, 24-month PFS rate estimates and estimates for every 6 months 
thereafter as applicable) will be displayed with 95 % confidence interval computed using the same methods as for 
OS, and the Kaplan-Meier curve for PFS will be presented. 
For PFS and OS, Kaplan-Meier estimates will be calculated and unstratified Cox’s proportional hazards model will 
be fit for each subgroup as defined in Section 8.2.1, in the ITT population only. Forest Plot will be displayed with a 
subgroup by treatment interaction test. 
The best overall response will be presented in contingency table with frequencies and percentages. The objective 
response (ORR: CR/PR) and complete response rates will be reported with exact (binomial) two-sided 95% CI. The 
medians of objective (PR/CR) and complete (CR) response duration will be estimated from the Kaplan-Meier 
curves. The Brookmeyer and Crowley technique will provide two-sided 95% CI. 
The evolution of MMSE over time will be interpreted taking into account the attrition as a result of patients 
assessed only until progression. All MMSE results will thus be conditional on the patients being otherwise free of 
progression. The distribution of the MMSE at each time point of evaluation will be described on the two treatment 
arms separately using means and their associated standard error (a graphical display will be considered). Median 
and range will also be provided. The proportion of patients with ‘normal’ and ‘impaired’ MMSE score at baseline 
and at key timepoints of evaluation (e.g. Baseline, at end of radiation therapy and then every 16 weeks, see table 
6.4) will also be displayed. Longitudinal analysis might also be performed and detailed in the SAP. 
All secondary analyses will be performed at 2-sided significance level α=0.05 for exploratory purpose. 
8.2.3.2 
Safety analysis 
All analyses will be performed in the safety population:  
The safety and tolerability will be followed from study treatment initiation through up to 30 days after the last 
administration of study treatment.  
The safety analyses will be reported for the whole study time and by treatment period as defined below: 
The chemoradiation period (TMZ/RT or TMZ/RT+MRZ) will start on the day of the first administration of radiation 
therapy and end 27 days after the day of the last administration of radiation therapy. 
The adjuvant TMZ period (adjuvant TMZ +/- MRZ) will start on the day of the first dose of adjuvant TMZ and end-
up 27 days after the first day of administration of the last cycle of adjuvant TMZ. 
The maintenance marizomib period (MRZ) will start 28 days after the first day of administration of the last cycle of 
adjuvant TMZ and end-up 27 days after the first day of administration of the last cycle of maintenance marizomib. 
The follow-up period (FUP) will start 28 days after the first day of administration of the last cycle of maintenance 
marizomib up to 30 days after the last administration of marizomib 
Baseline value will be defined as the last value on or before the first dose of study treatment is administered; if 
multiple values are present for the same date, the average of these values will be used as the baseline. For patients 
who were not treated, the value on or prior to randomization date will be used. Baseline laboratory and AE grades 
will be presented together with other baseline data in the ITT population.  
Hematological and biochemistry parameters 
All laboratory values will be graded. The worst grade of each hematological and biochemistry parameter will be 
calculated for each patient. Frequencies and percentages of grade 1, 2, 3, 4 in each category will be tabulated. A 
column with pooled grade 3/4 frequencies and percentages will also be displayed.  


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In a separate table, the frequencies and percentages of patients with at least one grade (≥1) or one grade 3/4 
hematological or biochemistry toxicity will be presented.  
All adverse events (AE) 
The worst grade of each AE item will be calculated for each patient. Tables with all grades, grades 3/4 and grade 5 
frequencies and percentages will be displayed.  
In a separate table, the frequencies and percentages of patients with at least one grade (≥1) or one grade 3/4 or 
one grade 5 AE of any event will be presented. 
Related AEs 
The worst grade of each likely related AE item will be calculated for each patient. Tables with all grades, grades 3/4 
and grades 5 frequencies and percentages in each AE term will be displayed.  
In a separate table, the frequencies and percentages of patients with at least one grade (≥1) or one grade 3/4 or 
one grade 5 related AE of any event will be presented. 
SAEs and Related SAEs 
After reconciliation with the SAEs listing extracted from the EORTC pharmacovigilance database, the worst grade of 
each (related) serious AE category will be calculated for each patient. Tables with all grades, grades 3/4 and grades 
5 frequencies and percentages in each (related) SAE term will be displayed.  
In a separate table, the frequencies and percentages of patients with at least one grade (≥1) or one grade 3/ 4 or 
one grade 5 (related) SAE of any event will be presented. 
All deaths, as well as deaths within 30 days after last dose of study treatment, will be tabulated. 
8.2.3.3 
Pharmacokinetics analysis 
Pharmacokinetics analysis will be detailed in the statistical analysis plan. 
8.2.4 
Pre-planned sensitivity or exploratory analyses 
If the percentage of patients excluded from PP is superior to 10% in at least one treatment arm, all efficacy 
analyses will be repeated in the PP population.  
For both PFS and OS, the stratified LogRank test and the Cox's proportional hazards model will also be computed 
stratified by the stratification factors assessed at randomization (except institution) and MGMT methylation status. 
Other exploratory analyses may be performed on the basis of subgroups of patients (see section 8.2.1), but results 
of these exploratory analyses may not serve as a basis for drawing conclusions concerning protocol efficacy.  
8.2.5 
Prognostic factor analyses 
Data of this trial will be included into the EORTC newly diagnosed GBM data warehouse for further pooled 
analyses of prognostic factors and exploration of other research questions. 
8.2.6 
Data recording and display 
Frequency tables will be tabulated (by treatment group or otherwise) for all categorical variables by the levels of 
the variables as they appear on the CRF (with %). Categories with a text field specification will be tabulated as 
categories and then supplemented by a listing with the following information for the patients fulfilling the 
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Dates relating to events prior to entry will be presented as the delay in days (or weeks, months, or years) between 
the past event and the date of entry (date of randomization – date of past event + 1) and presented using the 
median and range as well as mean and standard deviation. For example, on the randomization checklist, the date 
of last administration of prior treatment (or the date of first diagnosis of the cancer) will be presented as the time 
elapsed (in days, weeks, months or years, as appropriate) since the day of the last administration and the date of 
entry on study (date of randomization – last administration/diagnosis +1). 
Other delays (e.g. re-treatment delays) are presented as continuous variables using the median and range as well 
as mean and standard deviation. 
Continuous variables for which a coding system exists (such as for laboratory data) will be recoded into categories 
(for adverse events, the grading scale specified in the protocol will be used). Whenever no specific scale exists, lab 
data will be categorized based on the normal range: for example, below the lower normal limit (when 
appropriate), within the normal range, above the upper normal limit (ULN) and the degree to which it is above the 
ULN (for example > 2.5 x ULN, > 5 x ULN, > 10 x ULN). For laboratory data, the nadir is generally displayed. The 
nadir in a given cycle is the lowest laboratory value in that cycle; the overall nadir for a patient is the lowest 
laboratory value among all cycles. 
Other continuous variables (for example age, dose …) are presented using the median range (minimum, 
maximum), mean and standard deviation. 
If appropriate, continuous data may also be presented in categories (for example, age may also be grouped in 
decades). 
8.3 
Interim analyses 
The IDMC will review safety and efficacy data for the study after the randomization of 100 patients with a 
minimum of 3 months of follow-up. The interim review is aimed to assess the study safety and is not designed to 
stop the study early for lack or outstanding efficacy. Nevertheless efficacy data will be reviewed by the IDMC to 
evaluate the risk/benefit profile of each treatment arm.  
One non-binding futility interim analysis will be performed in the ITT population and reviewed by the IDMC when 
about 406 patients are recruited i.e. approximatively 20 months after start of accrual. At that time, 88 deaths 
(information fraction=18%) should already have been observed in the ITT population. The futility boundary is 1.12. 
It was chosen because the probability to stop for futility in absence of effect was about 30%. A percentage which 
was considered appropriate. If the observed HR is larger than (>) 1.12 than futility may be declared. The probability 
to stop for futility in case the targeted effect is true (HR=0.74) is only equal to 2.6%. We will not perform an interim 
analysis in the uMGMT subgroup. Nevertheless, the IDMC might recommend to continue the trial even if futility is 
demonstrated (HR>1.12) for the whole group but an effect in the uMGMT subgroup is suggested. By design, this 
decision will not have an impact on the power of the trial. Further to company's discussions with FDA the following 
change to the initial interim analysis plan was strongly suggested: “A small alpha penalty should be paid for the 
futility analysis, as it will entail a review of the efficacy data.” A small alpha penalty was therefore implemented 
although data was initially planned for futility purpose only.  
A small alpha spending of 0.00001 will be allocated to this interim analysis. The primary efficacy endpoint (OS) will 
be tested at a nominal 1-sided alpha level of 0.01499 in the overall population on the ITT set and unchanged level 
of 0.01 in the uMGMT group as no interim analysis will be performed in this subgroup. 
The alpha spending function used is of the Rho family. The Rho spending function was first published by Kim and 
DeMets (1987) and was generalized by Jennison and Turnbull (2000). It has following functional form: α(t) = αtρ, ρ 
> 0. When ρ = 1, the corresponding stopping boundaries resemble the Pocock stopping boundaries. When ρ = 3, 
the boundaries resemble the O’Brien-Fleming boundaries. Larger value of ρ yield increasingly conservative 


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boundaries. In this study, the small alpha spending of 0.00001 corresponds to rho = 4.26. The associated treatment 
effect boundary is HR=0.40. If a smaller HR would be observed the IDMC could decide to stop the trial for efficacy. 
At the clinical cutoff date (28/04/2020) for the futility analysis presented at the IDMC meeting on 14/09/2020, 106 
death events were observed out of 616 randomized patients (716 registered).  
Although the trial results did not cross the pre-specified futility boundary the IDMC observed that there was as yet 
no evidence that this treatment provided a benefit in survival. The statistical data presented also suggested that it 
was extremely unlikely that a difference would emerge with additional patients or further follow-up. The IDMC 
observed that marizomib in this combination induced severe neurological and neuropsychiatric disorders, as well 
as other treatment-related grade 3-4 side effects, in a substantial proportion of the patients. These observed 
effects were within the known safety profile. As per the previous IDMC reviews for safety, the IDMC 
recommendations allowed the trial to continue under close follow up of the aforementioned side effects.  
Based on the results of the Interim Analysis, the IDMC recommended, that the study be discontinued from further 
recruitment and that results be disclosed to the medical community as soon as possible. Patients still on treatment 
who are tolerating marizomib, may be allowed to continue if so wished by the patient and treating physician.  
8.4 
Follow-up analysis 
Further to the recommendations of the IDMC, the patient recruitment had to be prematurely closed. The final 
number of randomized patients was 749 (750 planned). The results of this study had also to be prematurely 
disclosed. The interim analysis was considered as the final analysis of this study. 
All randomized patients will be followed till the total number of OS events for the initially planned final analysis 
was observed (488 deaths). At that date, a follow-up analysis will be performed in accordance to the updated 
Statistical Analysis Plan for descriptive purpose only, with more mature data for all endpoints.  
 
8.5 
End of study 
End of study occurs when all of the following criteria have been satisfied: 
• 
1. Thirty days after all patients have stopped protocol treatment 
• 
2. The trial is mature for the primary and follow-up analyses as defined in the protocol 
• 
3. The database has been fully cleaned and frozen for this analysis 
EORTC reserves the right to terminate this study prematurely at any time for reasonable medical or administrative 
reasons. Any premature discontinuation will be appropriately documented according to local requirements (e.g., 
IRB/EC, regulatory authorities, etc.). 
9 Trial Governance and Data Monitoring  
9.1 
Study committees 
9.1.1 
Study Management Group (SMG) 
The Study Management Group is set up for this study. It consists of the EORTC Headquarters team in charge of 
running the study (clinical research physician, statistician, clinical scientist, clinical operations manager and data 
managers) and the principal study coordinator.  
The EORTC Headquarter team is responsible for the day -to-day conduct of the trial. The Study Coordinator will 
assist the team in case of problems with patient evaluation (eligibility, treatment compliance, safety).  


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The Study management Group also performs the medical review as indicated below.  
9.1.2 
Study Steering committee (SSC)  
The Study Steering Committee for this study is composed of the study coordinators, the representatives of 
Academic Groups collaborating to the study, at least one representative of the EORTC Headquarters (Study Clinical 
Research Physician or Clinical Scientist).  
This committee provides the general oversight of the study and has the executive power. The SSC monitors study 
progress and conduct and advises on its scientific credibility. The SSC will consider and act, as appropriate, upon 
the recommendations of the independent data monitoring committee.  
9.1.3 
Independent data monitoring committee (IDMC)  
The independent data monitoring committee for EORTC studies (IDMC) is in charge of the independent oversight 
of this study. The composition of the IDMC is described in EORTC Policy "Independent Data Monitoring 
Committees for EORTC studies" (ref. EORTC POL004) and its functioning is ruled by the charter annexed to the 
Policy.  
The study-specific experts on the IDMC performing this review will be selected for their relevant expertise with the 
disease and/or treatments assessed in the study.  
The IDMC reports its recommendations in writing to the Study Management Group through the clinical operations 
manager to the Study Steering Committee and other relevant parties (supporting bodies, collaborative groups…).  
9.2 
Data Monitoring  
9.2.1 
Monitoring during medical review meetings  
The medical review will be performed on a regular basis by the clinical research physician assisted as needed by 
the study management group. The main study coordinator will, in particular, support the Study Clinical Research 
Physician during the medical review process and will assist the team in case of problems with patient evaluation 
(safety, eligibility, treatment compliance). The main study coordinator is also responsible for the review and 
approval of the medical review plan and medical review reports.  
For blinded trials, the medical review is conducted blinded to treatment allocation. 
If at any time during the course of the study, the medical review identifies safety signals or other elements that 
could affect the potential risks and benefits to the study participants. These will be reported to the Study Steering 
Committee and may trigger a review by the EORTC Independent Data Monitoring Committee (IDMC).  
9.2.2 
Monitoring by the IDMC  
The IDMC will be asked to give advice on whether the accumulating data from the trial justifies continuing 
recruitment of further patients or further follow-up. 
The IDMC will review the trial whenever safety problems or other elements are identified during the medical 
review or by the SMG and/or SSC that could affect the potential risks and benefits for study participants.  
The IDMC will also review the intermediate reports of accumulating data according to the study interim monitoring 
plan described in the statistical section of this protocol (see section 8.3). If a decision is made to continue without 
change, the IDMC may advise on the frequency of future reviews of the data on the basis of accrual and event 
rates. 
While the trial is ongoing the accumulating data will generally remain confidential, unless the SSC and IDMC agree 
that the data should be made public. 


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10 Quality of life assessment 
10.1 Rationale 
Health related quality of life (HRQoL) is a multidimensional construct, which can be defined as a state of general 
well-being reflecting physical, psychological, and social well-being and the impact of the disease and/or treatment 
related symptoms on daily-life functioning. The patient’s subjective perspective is an inherent component of 
HRQoL and is therefore best assessed via self-administration. 
Reducing mortality and morbidity is still the most important factor in cancer clinical research. Nevertheless, issues 
such as reducing side effects, symptom relief and improving patients’ satisfaction have also become relevant 
parameters in the evaluation of medical strategies. Cancer treatments may produce adverse effects and diminish a 
patient’s quality of life even when survival is extended. Progress in the acceptance of new cancer therapies is 
sometimes critically dependent on their HRQoL consequences. 
Particularly in GBM patients, who suffer from an incurable disease with a median overall survival of slightly more 
than a year despite intensive treatment, the balance between quantity and quality of survival gain due to 
(experimental) treatment is pivotal. If treatment-related side effects influence the QOL of these patients in a 
negative way, possible gains in terms of progression-free or overall survival will have to be balanced against the 
burden of treatment. It is for this reason that QOL is included as a secondary endpoint in the current study of 
newly-diagnosed GBM patients. 
10.2 Objective 
The main objective of QOL assessment within this trial is to determine the impact of addition of marizomib to 
temozolomide and radiation therapy on five chosen domains being primarily global QOL, with fatigue, physical 
function, neurocognitive function, communication and motor dysfunction as secondary QOL outcomes. It is 
expected that these are likely to be most affected in patients, based on the toxicity profiles and information of 
previous studies.  
The Ho hypothesis will be tested that there is no difference between patients in both arms during and after 
treatment regarding global QOL. A secondary objective is to evaluate the effect of the treatment on the remaining 
symptoms and functioning scales as treatment-related side effects may have a (temporary) negative influence on 
the health-related domains of QOL of these patients. 
10.3 HRQoL instrument 
Quality of life will be assessed with the EORTC Quality of Life Questionnaire (QLQ-C30) version 3. This instrument is 
composed of multi-item and single-item scales. These include five functional scales (physical, role, emotional, 
social, and neurocognitive), three symptom (fatigue, nausea and vomiting and pain) and a global health status/QoL 
scale and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties). All 
scales and single items meet the standards for reliability. The reliability and validity of the questionnaire is highly 
consistent across different language-cultural groups (Ref. 1). The average time to complete the questionnaire is 
approximately 10 minutes. 
While this standard is used in EORTC studies, it lacks some dimensions that pertain to the QL issues in certain brain 
cancer. Therefore, we will also use the EORTC Brain Cancer module (QLQ-BN20), designed for use in brain tumor 
patients undergoing protocol treatment or radiotherapy. It includes 20 items assessing visual disorders, motor 
dysfunction, communication deficit, future uncertainty, as well as other specific symptoms, such as headaches, 
seizures or drowsiness. A retrospective validation study has been performed confirming the psychometric validity 
of this questionnaire. 


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10.4 Study design 
Patients are eligible for the QOL assessment in this study if they fulfill the eligibility criteria (see chapter 3). Should 
the patient refuse to fill out the form, then this should exclude the patient from further participation in the study. 
Patients will be informed in the patient informed consent form that they will have their QOL assessed regularly 
while involved in this trial. In this phase 3 study, OOL will be evaluated in a longitudinal design in all patients 
entered in both arms of the study.  
The QOL questionnaires must be filled out at the hospital when patients come for a scheduled visit according to 
the EORTC “Guidelines for administration of questionnaires” (see Appendix F). The pre-treatment questionnaires 
must be filled within 2 weeks before start of treatment. Subsequent questionnaires are administered after the end 
of combined chemo- and radiotherapy, and subsequently coinciding with the MRI visits and MMSE schedule in 
both treatment arms, also after tumor progression. 
Master copies of the QOL questionnaires will be sent to the participating institutions. The clinical report 
forms will include a question whether the QOL forms have been filled in, and if not, the reason why. The 
questionnaire will be handed out to the patients by the investigator or a study nurse prior to seeing the 
doctor for clinical evaluations. The patient should complete the questionnaires by her/himself in her/his 
own language during the visit as completely and accurately as possible. It is recommended that a key 
person (e.g. research nurse) at each center should be responsible for questionnaire data collection in 
order to optimize the compliance of the patient and to ensure the completeness of the data.  
10.4.1 
HRQoL schedule 
The time windows for eligible HRQoL assessments will be as follows: 
Assessment 
Time window 
Baseline 
No earlier than 14 days before randomization and no 
later than the day of randomization itself. 
At the end of radiation therapy 
No earlier than day of last radiation therapy treatment 
and no later than the first day of TMZ maintenance 
administration 
During TMZ maintenance: every 16 weeks  
Every 16 weeks during TMZ maintenance ± 7 days (at 
MRI scan visit). 
After TMZ maintenance: every 16 weeks until death 
Every 16 weeks ± 7 days. (at MRI scan visit) 
10.5 Statistical considerations 
The primary QOL endpoint that is considered relevant for this study is the Global health/QOL status scale of the 
QLQ-C30 instrument. The secondary QOL endpoints will be the fatigue, physical function, neurocognitive function, 
communication and motor dysfunction scales. Other scales will be analyzed on an exploratory basis. The “financial 
difficulties” scale of the QLQ-C30 will not be analyzed at all. 
The sample size calculation has been performed based on overall survival data. This is the primary endpoint and 
therefore no calculation has been performed based on changes in QOL. The primary QOL endpoints that are 
considered relevant to this trial are detailed above. The QOL data will give information to support or reject the null 
hypothesis that there is no difference between patients in both arms during and after treatment. 


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Data will be scored according to the algorithm described in the EORTC scoring manual (Ref. 13). All scales and 
single items are scored on categorical scales and linearly converted to 0-100 scales. Reporting of data will be 
mainly descriptive, as this is an exploratory analysis. 
10.5.1 
Primary analysis 
The following statistical tests will be done corresponding to the objective listed in section 10.2. 
The following two summary scores will be calculated per subject for each selected scale:  
• 
the average change during treatment (AC-DT) = the average of all post-baseline scale scores up to and 
including the end-of-treatment visit (section 6.3.1) minus the score at baseline. Only scores from valid HRQOL 
forms will be included. 
• 
the average change after treatment (AC-AT): = the average of all post-baseline scale scores during follow-up 
(i.e. after the end-of-treatment visit (section 6.3.1)) minus the score at baseline. Only scores from valid HRQOL 
forms will be included.  
Description of the AC-DT and AC-AT will be presented (mean, standard deviation, median, first and third quartiles, 
minimum, maximum) by treatment group together with mean difference, 95% CI and the non-parametric test p-
value (Wilcoxon).  
10.5.2 
Sensitivity analysis 
The primary analysis will be repeated in the per protocol population. 
The primary analysis will also be repeated taking all received HRQoL forms into account (i.e. including 
invalid/unassigned forms). 
In addition, two new summary statistics will be created: 
• 
Deterioration during treatment (D10-DT) = A binary variable indicating whether the patient experienced a 10 
point decrease from baseline at any post-baseline visit up to and including the end of study treatment visit. 
• 
Deterioration after treatment (D10-AT) = A binary variable indicating whether the patient experienced a 10 
point decrease from baseline at any follow-up visit (i.e. after the end of study treatment visit). 
Description of the D10-DT and D10-AT will be presented (mean, standard deviation, median, first and third 
quartiles, minimum, maximum) by treatment group together with mean difference, 95% CI and the non-parametric 
test p-value (Wilcoxon) to supplement the main analysis.  
10.5.3 
Missing data 
Missing data is a potential major source of bias in HRQoL assessment. 
In order to check the potential impact in the study, the compliance mechanism will be investigated prior to 
initiating the HRQoL analysis. Characteristics of patients with and without valid HRQoL data will be compared and 
trends over time per dropout pattern will be investigated. Model building will be used in order to investigate 
whether the compliance mechanism is linked to selected prognostic variables. 
Once the main analysis is completed, sensitivity analyses will be undertaken to verify the robustness of the results 
vis-à-vis the missing data.  
In case overall compliance is deemed too low (<50%), only an exploratory analysis will be performed in lieu of the 
main analysis. 


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11 Translational research  
11.1 Objective and projects description 
Marizomib is a pan-proteasome inhibitor described in Section 1.1. Prior evidence is showing a trend regarding 
Marizomib therapeutic efficacy and baseline proteasomal activity in tumor cells (see section 1.1). Therefore, in this 
study, we plan to investigate the proteasomal activity in patients with sufficient amount of tissue available for 
these analyses. We have 2 objectives: firstly, we would like to confirm baseline proteasome activity and clinical 
response (PFS and OS), and secondly, we want to see if the proteasome activity is modulated by Marizomib in 
patients with tissue at baseline and at salvage surgery.  
To perform proteasome activity measurement, frozen tumor tissue, at study entry and after salvage surgery should 
it occur, will be collected. Moreover, proteasomal activity will also be measured in the collected buffy coat and 
PBMC samples. The assessment of the proteasomal activity will be done by Eurofins (Breda, The Netherlands). 
Proteasomal activity will be calculated based on the catalytic activity of the proteasome's three subunits and will 
be determined using a spectrofluorometric assay at a laboratory specified at a later date. However, at this stage, 
the exact substrates and precise mechanisms that govern marizomib activity in human tumors is not fully 
understood. So we plan to collect sufficient samples to facilitate exploratory research as our understanding 
improves. These analyses are of exploratory nature. Since the number of samples that are available for analysis 
cannot be predicted exactly, no statistics are provided. 
Extracellular vesicles will be isolated from EDTA blood and stored at IBBL (Luxembourg, LU) for biomarker 
discovery.  
FFPE Tumor tissue will be prospectively collected at IBBL (Integrated BioBank Luxembourg, LU) and send to 
HistoGeneX (Antwerp, BE) for central testing of the MGMT status. Since MGMT status will be used in the primary 
OS analysis to determine if there is a difference in treatment effect which is dependent on this variable, this initial 
tumor tissue is a MANDATORY requirement within this protocol. Subsequently, tissue samples will be stored at an 
EORTC central biobank (IBBL, Luxembourg; Rotterdam, NL or Zurich, CH). To allow for comprehensive 
immunohistochemical assessments of tumor tissue specimens, tissue microarrays (TMA) will be generated. 
Future research might include isolation of ctDNA and gDNA from plasma. Depending on the study results, we may 
look for soluble factors in the serum which may be of interest as potential biomarkers. There is some preliminary 
data to suggest that these methods could give insights into the perturbations taking part at the tumor site without 
need for serial tissue examination (which is almost impossible in CNS tumors in routine practice). The ultimate goal 
of such work would be to define a tumor specific signature in the peripheral blood which could be used to monitor 
and predict response to therapy.  
Exploratory research on tumor tissue or blood may also include evaluation of a multigene or DNA-methylation 
signature to predict benefit from marizomib. We may also investigate other molecular pathways related to the 
development of these specific tumors from a biological point of view; such pathways include, but are not limited 
to, tumor cell proliferation, growth, invasion and metastasis, metabolism, angiogenesis, apoptosis, immune 
response, inflammation, and genomic instability. Multiple molecular and cellular techniques might be used to 
assess those exploratory biomarkers and will be performed by expert laboratories.  
MGMT testing facility: 
HistoGeneX N.V. 
Sample Reception Team 
Sint-Bavostraat 78-80 
2610 Wilrijk 


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Belgium 
Email: info@histogenex.com 
Phone: +32 3 50 20 500 
Storage facility FFPE tissue: 
EORTC Brain Tumor Group Tissue Repository 
Erasmus MC Hospital 
Erasmus MC Josephine Nefkens Institute - Dept of Pathology  
Doctor Molewaterplein 50-60,  
3000DR Rotterdam,  
The Netherlands 
Email: j.m.kros@erasmusmc.nl 
Phone: +31 104087905 
Storage facility blood derivates: Integrated BioBank of Luxembourg (IBBL) Biorepository, Floor 1 
1, Rue Louis Rech, entrée B 
L-3555 Dudelange 
Luxembourg  
Email: eortc@ibbl.lu 
Phone + 352 26 970 520 
Proteasome assessment facility 
Eurofins Central Laboratory, B.V. 
Bergschot 71 
4817 PA  
Breda 
The Netherlands 
Email: MarjoleinKuypers@eurofins.com 
Phone: +31 (0)76 573 73 63 
11.2 Sample Collection 
For more details in collection and shipment of samples, refer to the HBM guidelines, provided as a separate 
document.  
11.2.1 
Tumor samples 
FFPE samples are mandatory for this study. If the patient consents to the TR and frozen tissue is available, 
collection will take place at baseline and at salvage surgery.  
11.2.2 
Blood samples 
Plasma and serum samples will be collected at study entry, after completion of radiotherapy and every 3 cycles 
until progression. Samples will also be collected at the time of tumor progression. All samples will be collected and 
processed as described in the HBM guidelines and stored centrally at IBBL Luxembourg for future research.  
PBMC and extracellular vesicles will also be collected as described in the HBM guidelines. 
All blood derivatives will be centrally collected and stored at IBBL Luxembourg. The collected buffy coat and PBMC 
samples will be shipped to Eurofins (Breda, NL) for the assessment of the proteasome activity. 


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11.2.3 
Sample overview 
Specimen type(s) 
Specimen amount 
Collection time point(s) 
Mandatory 
 
 
Tumor tissue 
1 paraffin block or 24 unstained 
slides minimum 
Study entry 
Plasma and buffy coat  
10mL + buffy coat 
Study entry 
After completion of RT 
Every 3 cycles  
At progression 
Serum 
10mL 
Study entry 
After completion of RT 
Every 3 cycles  
At progression 
Optional 
 
 
Fresh frozen 
1 cc 
Study entry 
After salvage surgery should it 
occur 
plasma samples (vesicles) 
10 mL  
Study entry 
After completion of RT 
Every 3 cycles  
At progression 
PBMCs  
20 mL  
Study entry 
After completion of RT 
Every 3 cycles  
At progression 
 
From the central biobank, HBM and relevant data may be transferred to other research laboratories performing 
molecular analyses or involved in downstream projects, including the incidence of certain molecular markers in a 
given patient population or biomarker discovery. All leftover material remaining after the pre-defined translational 
studies are performed, must always be returned to IBBL or another EORTC central biobank. 
HBM and relevant data can be further used by EORTC alone, in collaboration with other partners or transferred to 
other researchers, including commercial partners, possibly outside of Europe.  
11.3 Data storage, transfer and development of analysis plans 


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The translational projects will be the result of the work of collaborating institutions and EORTC HQ. No hypothesis 
was provided for any project therefore no statistical design or power calculations could be performed. The 
translational projects will be exploratory and descriptive. Project set-up, bio-informatics and statistical analysis 
plan will be jointly developed for each project. These documents will be reviewed and approved by EORTC trial 
statistician, TR scientist, and bioinformatics expert before starting any analysis. They will specify analytical and 
methodological details. Clinical and patient-reported outcome data will be stored in the EORTC clinical database 
and genomic data will be stored at the European Genomic Archive (EGA). Transfer of data will be performed 
according to applicable policies (e.g. EORTC POL008) or according to jointly approved data transfer charters. 
11.4 General principles for human biological material (HBM) 
collection 
Human biological material (HBM) collection involves the collection and storage of biological material, residual 
biological material or derivatives in compliance with ethical and technical requirements.  
Biobanking refers to the chain of procedures that encompass the life cycle of the biological material, e.g. from 
collection, shipping to long term storage and use, and may also be subject to local regulation and/or 
national/international legislation. 
In this study, biological material will be centralized and stored at EORTC Brain Tumor Group Tissue Repository at 
Erasmus MC Hospital, Rotterdam, The Netherlands (FFPE tissue) and Integrated BioBank Luxembourg, Luxembourg 
(blood derivates). From there, the biological material will be used or distributed to the other research laboratories 
involved in the translational research (TR) projects specified in this protocol or defined in the future.  
The following principles apply to storage of HBM: 
• 
The biobank will have a designated manager responsible for collection and will act as a communication point 
with the EORTC. 
• 
The collected HBM should be documented, i.e. the amount remaining and its location. 
• 
The Study Steering Committee (SSC)/Group committee will be responsible for all TR project review and 
prioritization, including the consideration of newly proposed TR projects not specified in the protocol. In the 
absence of a SSC, responsibilities of the SSC are transferred to the Group and/ or EORTC HQ as applicable. 
• 
Final decisions on the use of HBM will be determined by a majority vote of the SSC/Group committee. 
Additional expertise may be sought through advisory non-SSC/Group committee members. 
Access to HBM (see EORTC Biobanking Policy POL020): HBM may be used for another purpose for which it was 
originally collected, subject to meeting ethical principles/and is covered by informed consent/ethics approval. In 
the case of secondary use of HBM, (i.e. for new TR projects that are not specified in the clinical study protocol and 
that were not foreseen at the time of protocol writing) interested parties may apply for the use of HBM and will 
follow the next steps:  
• 
A short description of the new TR projects will be written and submitted to EORTC HQ for coordination with 
the appropriate SSC/Group committee. 
• 
The SSC/Group committee will prioritize the TR projects. Access procedures defined by the SSC/Group 
committee will build on the following key points:  
• 
Project prioritization  
• 
should be strongly based on scientific merit,  
• 
should consider the contribution of the different investigators to the trial and TR project,  


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• 
will take into consideration if the applicant is an EORTC member or not (whilst maintaining the 
principle of access to the wider scientific community and commitments owed to study participants and 
ethical committees). 
• 
Protection of confidentiality must be respected. 
• 
An EORTC HQ feasibility check, including recommendations for regulatory and ethical matters and other 
restrictions on the use of the HBM, will take place. If in the event the HBM collections are still retained at 
individual clinical sites, the TR project leader and the involved EORTC Group are responsible for collecting and 
providing information on availability of HBM for the feasibility assessment. 
• 
Prioritized TR projects will then be reviewed by the Translational Research Advisory Committee (TRAC). 
• 
Once SSC/Group committee prioritization, the EORTC HQ feasibility assessment, and TRAC review are complete 
and when all applicable competent Ethics Committees approvals are in place and ethical principles are met, the 
TR project can be activated and HBM release and analysis can commence. 
• 
The EORTC Board will mediate any disagreements of opinion between TRAC, the EORTC HQ feasibility 
assessment, the SSC/Group committee and the TR project leader(s), as needed. 
 
11.5 Ancillary Radiotherapy related research projects 
11.5.1 
Artificial Intelligence for Automated QUality Assurance in 
RadioTherapy for glioblastoma target volume and organs at risk 
delineation - AQUA RT 
 
11.5.1.1 
Background 
This trial has mandatory RTQA procedures that include the collection and central review of all patients’ radiotherapy 
treatment plans, the individual case review (ICR) (as in Section 17.4.1). This peer review process requires 
considerable effort by physicians and physicists and entails considerable costs. Parts of the process could be 
automated or semi-automated, making it easier and cheaper to run trials with radiotherapy as part of the treatment. 
This ancillary project stems from these observations. The project name is “Artificial Intelligence for Automated 
QUality Assurance in RadioTherapy for glioblastoma target volume and organs at risk delineation - AQUA RT”. 
11.5.1.2 
Description of the project 
The aim of the project is to use autosegmentation algorithms to create alternative segmentations for tumor volume 
and organs at risk, and to use these segmentations as a surrogate for peer review in evaluating protocol compliance 
of the contours submitted by investigators. The final goal is to validate an automated peer review procedure for 
future use in clinical trials. 
11.5.1.3 
Data needed 
The treatment plans submitted and reviewed as part of the RTQA procedures, as well as the review results 
themselves, will be used in the research project. This includes: 
● Complete RT dataset 
○ 
DICOM-IMAGES 
■ Planning CT 


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■ Pre-RT MRI –transaxial images, co-registered with planning CT 
○ 
DICOM-RTSTRUCT (delineations) 
○ 
DICOM-RTDOSE (3D dose matrix for the entire plan) 
○ 
DICOM-RTPLAN 
● Complete Individual Case Review dataset (the outcome of the external RTQA review) 
11.5.1.4 
Involved institutions 
• 
Scientific leader of the project, supervision of autosegmentation and automatic delineation review 
Mauricio Reyes, Prof. Dr. 
ARTORG Center for Biomedical Engineering Research 
Center for AI in Medicine 
University of Bern 
Murtenstrasse 50 
3007 Bern 
Switzerland 
Email: mauricio.reyes@med.unibe.ch 
● Medical leader of the project, supervision of data curation and storage 
Nicolaus Andratschke, Prof. Dr. 
Department for Radiation Oncology 
University Hospital Zurich 
University of Zurich 
Rämistrasse 100 
8091 Zurich  
Switzerland 
Email: nicolaus.andratschke@usz.ch 
● Data curation and storage, medical co-leader  
Jonas Willmann, Dr. 
Department for Radiation Oncology 
University Hospital Zurich 
University of Zurich 
Rämistrasse 100 
8091 Zurich  
Switzerland 
Email: jonas.willmann@usz.ch 
● Deep learning autosegmentation of targets and organs at risk, development of automatic delineation 
review tool 
Amith Kamath, PhD candidate 
ARTORG Center for Biomedical Engineering Research 
Center for AI in Medicine 
University of Bern 
Murtenstrasse 50 
3007 Bern 
Switzerland 
Email: amith.kamath@unibe.ch 


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The project is led by Prof. Mauricio Reyes, Dr. Jonas Willmann, Prof. Nicolaus Andratschke and Mr. Amith Kamath. 
11.5.1.5 
Publication of results 
First and last authorships in all publications stemming from this project will be held by Prof. Mauricio Reyes, Dr. 
Jonas Willmann, Prof. Nicolaus Andratschke and Mr. Amith Kamath. Additional co-authors include the PIs of the trial, 
the RTQA HQ staff, the RTQA Physics Chair, the RTQA reviewers, and one investigator from each of the 5 participating 
centres that provided most datasets. 
 
11.5.2 
Optimizing CTV margins for Radiotherapy in GBM by Machine Learning 
 
11.5.2.1 
Background 
Recurrences in GBM patients after postoperative chemoradiotherapy mostly occur within or at the margin of the 
treatment volume. The standard clinical target volume (CTV) is typically defined as an isotropic 2 cm expansion 
around the surgical cavity and the area of contrast enhancement. This isotropic margin is not patient specific and 
does not take into account the preferential tumor growth along the white matter tracts of the brain. This project 
aims at optimizing the CTV margins using Machine Leaning. 
 
11.5.2.2 
Description of the project 
The project has 4 exploratory objectives: 
• 
Comparison and validation of manual vs automated tumor/target definition. 
• 
Analysis of the pattern of recurrences using deep learning methods. 
• 
Generate anisotropic, personalized CTV margins based on patient, treatment, and imaging parameters via 
deep learning methods. 
• 
Mathematical modeling of tumor growth and assessment of tumor proliferation. 
11.5.2.3 
Methods/analysis plan 
The longitudinal imaging data for each patient will be automatically co-registered. The recurrence volume will be 
automatically segmented. For the first three objectives, the GTV (manual and automated) and recurrence volumes 
will be geometrically analyzed to identify recurrence or growth patterns. The influence of patient and treatment 
parameters (for example age, MGMT-status, type of resection, treatment arm, radiation dose distribution) on the 
recurrence/growth patterns will be investigated. All parameters found to be relevant will be used to generate 
optimized, personalized, probability-based anisotropic CTV margins. The Fisher-Kolmogorov growth model 
assuming uniform proliferation rate and difference in white and grey matter diffusion will be used to assess 
tumour proliferation. 
11.5.2.4 
Data needed 
- 
All pre and post op imaging dataset (according to Imaging guidelines; including 3D T1w pre- contrast, DWI, 
2D FLAIR, GE-EPI perfusion if available, T2w-TSE, 3D T1w post-contrast) 
- 
Complete RT dataset 
o DICOM-IMAGES 
 
Planning CT 
 
Pre-RT MRI –transaxial images, co-registered with planning CT 


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o DICOM-RTSTRUCT (delineations) 
o DICOM-RTDOSE (3D dose matrix for the entire plan) 
o DICOM-RTPLAN 
       - Clinical dataset:  
Patient and treatment characteristics: date of birth (alternatively age at diagnosis), sex, performance 
status before surgery/at diagnosis, performance status before radiotherapy, date of surgery, extent of 
surgery, date of diagnostic MRI, date of postoperative MRI, date of planning-CT and planning-MRI, 
start/end date of RT, total dose and fraction dose, start/end date of concomitant anticancer drugs (for 
each compound), start/end date of adjuvant anticancer drugs (for each compound), pathology incl. 
MGMT and IDH, date of radiological/clinical progression, survival. 
 
11.5.2.5 
Involved institutions 
 
Scientific leader of the project 
Slavka Lukacova, MD, PHD 
Aarhus University Hospital/Arhus University 
Dept. of Oncology/Institute of Clinical Medicine 
P.J.J. Boulevard 99 
8200 Aarhus 
Denmark 
Email: slavka.lukacova@auh.rm.dk, Tel: 0045 40465210 
 
Machine Learning segmentation of targets using RT and MRI datasets & 
Pattern analysis/statistical analysis of treatment parameters vs recurrence 
Anouk Trip, MD, PhD 
Aarhus University Hospital 
Danish Center for Particle Therapy 
P.J.J. Boulevard 99 
8200 Aarhus 
Denmark 
Email: anotri@rm.dk; Tel: 0045 31772510 
 
Mathematical modelling of tumor growth 
Jesper F. Kallehauge, Assoc. prof., Medical Physicist 
Aarhus University Hospital/Aarhus University 


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Danish Center for Particle Therapy 
P.J.J. Boulevard 99 
8200 Aarhus 
Denmark 
Email: jespkall@rm.dk; Tel: 0045 61369794 
 
11.5.2.6 
Publication of results 
Results (planned publications: Recurrence pattern analysis, Individualizing CTV, Growth modelling) will be shared 
on a peer reviewed scientific radio-oncology journal within 2 years of the data release. Anouk Trip, Jesper F. 
Kallehauge, Slavka Lukacova will be first or last authors. The trial PIs will be co-authors. Other co-authors may be 
included from the top recruiting institutions. 
 
12 Results dissemination policy 
12.1 Study disclosure 
12.1.1 
Trial Registration  
This trial will be registered in a public database (https://www.clinicaltrialsregister.eu). As the clinical trial (CT) 
regulation 536/2014 of the European Union (EU) becomes applicable, more information about this trial will be 
uploaded in this public database in compliance with European requirements on transparency. Information posted, 
among others, will allow subjects to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on appropriate trial locations and trial site 
contact information.  
In accordance with applicable EU regulations, a summary of the trial results will be made publicly available within 
one year of the end of study declaration.  
EORTC as Sponsor of this trial will submit the summary of the results based on the final analysis report in 
compliance with the regulations. 
12.1.2 
Final Analysis Report  
A Final Analysis Report that reports summary statistics of all the data collected for the study and presents an 
interpretation of the study results will be issued by the EORTC Headquarters. It will form the basis for the 
manuscript intended for publication. The Final Analysis Report or a summary thereof will be distributed to all 
participating groups, the supporting companies and ethics committees and the results will be posted in relevant 
public databases (as in section 12.1.1).  
12.2 Publication policy 
All publications must comply with the terms specified in the EORTC Policy 009 “Release of Results and Publication 
Policy” version 4.2 dated March 2015 or later. 
In accordance with the Policy 009, results of the present study will be made public once the study data are mature 
for the final analysis of the primary study endpoint (as described in the section “statistics” of the present protocol), 


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irrespective of the findings (positive or negative). Deviations from the results disclosure rules specified in the Policy 
require authorization by the Independent Data Monitoring Committee (IDMC).  
The primary trial publication will be written on the basis of the final analysis report and shall be published in a 
peer-reviewed scientific journal within 1 year of the date of the database lock. 
Prior to submission, all publications (papers, abstracts, presentations…) will be submitted for review to the EORTC 
Headquarters statistician and clinical research physician, to all co-authors and to the designated representative of 
Celgene, if any as per contractual agreement. Approval of the manuscript by EORTC Headquarter representatives is 
required before submission of the manuscript reporting on an EORTC study for publication. 
The authorship rules conform to the recommendations of the International Committee of Medical Journal Editors 
defining the roles of authors and contributors (http://icmje.org/recommendations/browse/roles-and-
responsibilities/defining-the-role-of-authors-and-contributors.html).  
All other investigators and scientific contributors to the study who do not qualify for authorship will be 
acknowledged in the publication.  
Sources of funding or support to the study will be disclosed and acknowledged in the publication. 
The name “EORTC” and of any collaborative Group must be visible in the publication's header of all publications.  
12.3 Data sharing 
EORTC is committed to ensuring that the data generated from its studies be put to good use by the cancer research 
community and, whenever possible, are translated to deliver patient benefit.  
It is therefore EORTC's policy to consider for sharing upon request from qualified scientific and medical researchers 
all data generated from its research whilst safeguarding intellectual property, the privacy of patients and 
confidentiality.  
Considering that ongoing research contributing to the completion of datasets must not be compromised by 
premature or opportunistic sharing and analysis of data, the EORTC will not release the data of its study until the 
primary study results have been published; unless authorization for release has been granted according to the 
terms of EORTC Policy 009. 
Requests for accessing the data of published trials should be filed through the data sharing tab on the EORTC 
website (www.eortc.org). 
13 Investigator authorization procedure 
Investigators will be authorized to register and/or randomize patients in this trial only once they have returned the 
following documents to their Data Center (for the EORTC investigators see chapter 19: Administrative 
responsibilities, for non-EORTC investigators: see your group specific appendix): 
• 
The updated signed and dated Curriculum Vitae of the Principal Investigator in English with a GCP training 
proof. 
• 
The (updated) list of the normal ranges, for their own institution signed and dated by the head of the 
laboratory. Please make sure normal ranges are provided also for those tests required by the protocol but not 
routinely done at the investigator’s institution. 
• 
The Confirmation of interest by Principal Investigator Form (CIF), stating that the investigator will fully comply 
with the protocol. This must include an estimate of yearly accrual and a statement on any conflict of interest 
that may arise due to trial participation. 


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NB: A signed conflict of interest disclosure form will be required only if a possible conflict is declared on 
the CIF.  
• 
The Study Agreement between EORTC and investigator's institution. 
• 
A copy of the favorable opinion of the local or national (whichever is applicable) ethics committee mentioning 
the documents that were reviewed (including the version numbers and version dates of all documents). A list 
of all members of the ethics committee is also requested. 
• 
A copy of the translated and adapted (according to all national requirements) Patient Information / Informed 
Consent sheet. Version numbers and dates must be clearly stated on each page. 
• 
The signature log-list of the staff members with a sample of each authorized signature and the indication of 
the level of delegations. 
• 
The full name, address, phone numbers and e-mail address of the local pharmacist who will be responsible for 
the trial medication (for any trial where the drug will be provided). 
• 
An accreditation, a certification, an established quality control / external quality assessment or another 
validation should be provided for the own laboratory. 
The center specific applicable list of required documents will be included in the protocol activation package, with 
proper instructions as required by this protocol, your group and / or the applicable national law 
The new investigator will be added to the “authorization list”, and will be allowed to register/randomize patients in 
the trial as soon as 
• 
All the above mentioned documents are available at their Data Center. 
• 
All applicable national legal and regulatory requirements are fulfilled. 
Patient registration/randomization from centers not (yet) included on the authorization list will not be accepted. 
14 Patient registration & randomization procedure 
14.1 General procedure 
Patient registration will only be accepted from authorized investigators (see chapter 13 on “Investigator 
authorization procedure"). 
Patients should be registered directly on the Medidata Rave EDC system, accessible 24 hours a day, 7 days a week 
(please consult CRF guidelines for further information). To access Medidata Rave EDC system, the investigator 
needs a username and a password which will be provided by the EORTC Headquarters. 
In case of problems investigators can contact the EORTC Clinical Data Manager (during Brussels business hours). 
As soon as the registration process is started, a Subject ID is allocated to the patient. This number allows the 
identification of the patients in Medidata Rave EDC. 
14.2 Randomization 
Eligibility criteria will be checked at time of randomization. Once eligibility has been verified, treatment will be 
randomly allocated to the patient, together with a sequential patient identification number. This number will allow 
the identification of the patients in the Medidata Rave EDC system that will be used to complete the Case Report 
Forms.  
14.3 Stock management process 
An IVRS system will be used for the drug supply. For more details in, refer to the IMP management guidelines, 
provided as a separate document. 


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15 Forms and procedures for collecting data 
15.1 Case report forms and schedule for completion 
Data will be reported on the electronic CRFs specifically designed by the EORTC Headquarters for this study.  
Data should be electronically sent to the EORTC Headquarters through the Medidata Rave EDC system 
(https://imedidata.com), with the exception of the HRQoL forms, which are paper case report forms (CRFs). 
The paper CRF(s) will be made available to the institution at the time the institution is authorized. 
SERIOUS ADVERSE EVENTS SHOULD BE IMMEDIATELY REPORTED ACCORDING TO THE PROCEDURE DETAILED IN 
THIS PROTOCOL (see chapter 16 on Reporting Serious Adverse Events). 
The electronic CRFs to be completed for a patient and their submission schedule are available on the Medidata 
Rave EDC website immediately after the registration and are also described in the "guidelines for completion of 
case report forms" that are provided to each participating investigator. 
All data must be electronically approved and sent by the responsible investigator or one of his/her authorized 
staff members. 
15.2 Data flow 
The forms must be completed according to the schedule defined in the guidelines for completion of Case Report 
Forms. 
The list of staff members authorized to enter data must be identified on the signature log and sent to the EORTC 
Headquarters by the responsible investigator before the start of the study.  
In all cases, it remains the responsibility of the principal investigator to check that data are entered in the database 
as soon as possible and that the electronic forms are filled out completely and correctly.  
The EORTC Headquarters will perform extensive consistency checks on the received data. Queries will be issued in 
order to resolve other inconsistent data. The queries for the electronic forms will appear in the Rave EDC system 
and must be answered there directly. 
A copy of the questionnaires should be sent to EORTC Headquarters as soon as possible, while the original source 
document should be kept on site.  
When satellite institutions are involved, all contact is made exclusively with the primary institution, for purposes of 
data collection and all other study related issues. 
If an investigator (or an authorized staff member) needs to modify a CRF after the form has been electronically 
sent to the EORTC Headquarters, he/she should edit the concerned data point in the Rave EDC system. The data 
should then be signed again. 
For more information on the data flow, please refer to the study specific guidelines. 
15.3 HBM* sample registration and tracking  
Once the patient is registered, the investigator or his/her authorized staff must register the patient’s samples on 
the EORTC tracking tool. This tool is designed to register, manage and track Human Biological Materials collected in 
the frame of EORTC clinical trials.  
Details about access the tracking tool, register samples and tracking shipments are described on the guidelines of 
HBM* management.  


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(*) Human Biological Material 
16 Reporting of Serious Adverse Events 
ICH GCP and EU Directive 2001/20/EC require that both investigators and sponsors follow specific procedures 
when notifying and reporting adverse events/reactions in clinical trials. These procedures are described in this 
section of the protocol.  
16.1 Definitions 
These definitions reflect the minimal regulatory obligations; specific protocol requirements might apply in addition. 
AE: An Adverse Event is defined as “any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this 
treatment”. An adverse event can therefore be any unfavorable and unintended signs (such as rash or enlarged 
liver), symptoms (such as nausea or chest pain), an abnormal laboratory finding (including results of blood tests, x-
rays or scans) or a disease temporarily associated with the use of the protocol treatment, whether or not 
considered related to the investigational medicinal product. 
AR: An Adverse reaction of an investigational medicinal product is defined as “any noxious and unintended 
response to a medicinal product related to any dose administered”. 
All adverse events judged by either the reporting investigator or the sponsor as having a reasonable causal 
relationship to a medicinal product qualify as adverse reactions. The expression reasonable causal relationship 
means to convey in general that there is evidence or argument to suggest a causal relationship. 
UAR: An Unexpected Adverse Reaction is “any adverse reaction, the nature, or severity of which is not consistent 
with the applicable product information" (e.g. investigator's brochure for an unapproved investigational product or 
summary of product characteristics (SmPC) for a marketed product). 
When the outcome of the adverse reaction is not consistent with the applicable product information this adverse 
reaction should be considered as unexpected. 
Severity: The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate or severe, or as described in CTC grades); the event itself, however, may be of relative minor medical 
significance (such as severe headache). This is not the same as “serious,” which is based on patient/event outcome 
or action criteria usually associated with events that pose a threat to patient’s life or functioning. Seriousness (not 
severity) serves as a guide for defining regulatory reporting obligations.  
SAE: A Serious Adverse Event is defined as any untoward medical occurrence or effect in a patient, whether or not 
considered related to the protocol treatment, that at any dose: 
• 
results in death 
• 
is life-threatening (i.e. an event in which the subject was at risk of death at the time of event; it does not refer 
to an event which hypothetically might have caused death if it was more severe) 
• 
requires inpatient hospitalization or prolongation of existing patient hospitalization 
• 
results in persistent or significant disability or incapacity 
• 
is a congenital anomaly or birth defect 
• 
is a medically important event or reaction. 
Medical and scientific judgment should be exercised in deciding whether other situations should be considered 
serious such as important medical events that might not be immediately life-threatening or result in death or 
hospitalization but might jeopardize the patient or might require intervention to prevent one of the other 
outcomes listed in the definition above. Examples of such events are intensive treatment in an emergency 


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room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. 
SAR: A Serious Adverse Reaction is defined as any SAE which is considered related to the protocol treatment.  
SUSAR: Suspected Unexpected Serious Adverse Reaction.  
SUSARs occurring in clinical investigations qualify for expedited reporting to the appropriate Regulatory Authorities 
within the following timeframes: 
• 
Fatal or life-threatening SUSARs within 7 calendar days 
• 
Non-fatal or non-life-threatening SUSARs within 15 calendar days 
Inpatient hospitalization: a hospital stay equal to, or greater than, 24 hours. 
Second primary malignancy is one unrelated to the treatment of a previous malignancy (and is NOT a metastasis 
from the previous malignancy).  
Secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment with 
investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not considered a 
metastasis of the previous malignancy. 
16.2 Exceptions 
The following situations do not need to be reported as SAEs:  
• 
Elective hospitalization for pre-existing conditions that have not been exacerbated by trial treatment. 
• 
A hospitalization which was planned before the patient consented for study participation and where admission 
did not take longer than anticipated. 
• 
A hospitalization planned for protocol related treatment or protocol related procedure as per institutional 
standard timelines. 
• 
Social and/or convenience admission to a hospital. 
• 
Medical or surgical procedure (e.g. endoscopy, appendectomy); the condition that leads to the procedure is an 
(S)AE. 
• 
Situations where an untoward medical occurrence did not occur (palliative care, rehabilitation, overdose 
without occurrence of an adverse event). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of 
the study that do not worsen. 
16.3 Severity assessment 
The severity of all AEs (serious and non-serious) in this trial should be graded using CTCAE v5.0 
https://www.eortc.be/services/doc/ctc/ 
16.4 Causality assessment 
The investigator is obligated to assess the relationship between protocol treatment and the occurrence of each 
SAE following the definitions in this table: 
Relationship to the protocol treatment 
Description 
Reasonable possibility 
There is a reasonable possibility that the protocol 
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No reasonable possibility 
There is no reasonable possibility that the protocol 
treatment caused the event 
The investigator will use clinical judgment to determine the relationship. Alternative causes, such as natural history 
of the underlying diseases, medical history, concurrent conditions, concomitant therapy, other risk factors, and the 
temporal relationship of the event to the protocol treatment will be considered and investigated. 
The decision will be recorded on the SAE form and, if necessary, the reason for the decision will also be recorded.  
16.5 Expectedness assessment 
The expectedness assessment is the responsibility of the sponsor of the study, unless otherwise specified in the 
Group specific appendix. The expectedness assessment will be performed against the following reference 
documents: 
• 
For Temozolomide: Summary of Product Characteristics (SmPC), the RSI is section 4.8 in the SmPC  
• 
For Marizomib: Investigator's Brochure. The RSI is the IB section entitled “Reference Safety Information”  
16.6 Reporting procedure for investigators 
This procedure applies to all Serious Adverse Events (SAEs) occurring from the time a subject is randomized until 
30 days after last protocol treatment administration and to any SAE that occurs outside of the SAE detection 
period (after the 30-days period), if it is considered to have a reasonable possibility to be related to the protocol 
treatment or study participation. 
Randomization till 30 days after last protocol 
treatment administration: 
All SAEs 
From day 31 after last protocol treatment 
administration: 
Only related SAEs 
Any secondary malignancy should also be reported in expedited way as an SAE with the appropriate seriousness 
criteria! 
All reporting must be done by the principal investigator or authorized staff member (i.e. on the signature list) to 
confirm the accuracy of the report. 
All SAEs must be reported immediately and no later than 24 hours from the time the investigator or staff became 
aware of the event.  
All SAE-related information needs to be provided in English. 
If any relevant additional document in local language is uploaded or forwarded to the Pharmacovigilance Unit 
relevant to an SAE (e.g. autopsy report), this must be accompanied by a translation in English, or the relevant 
information must be summarized in the electronic SAE-form.  
Investigators participating through EORTC must report all SAE-related information to the Medidata Rave EDC 
system (www.imedidata.com). 
If the iMedidata Rave EDC system is out of service, contact the Pharmacovigilance Unit for further instructions to 
report your SAE/Pregnancy:  
EORTC Pharmacovigilance Unit:  


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Email: pharmacovigilance@eortc.org 
Tel No. +32 2 774 1676  
Fax No. +32 2 772 8027 
Investigators participating through non-EORTC groups should consult their group specific appendix for further 
details on the reporting of Serious Adverse Events. 
To enable the sponsor to comply with regulatory reporting requirements, all initial SAE reports should always 
include the following minimal information: an identifiable patient (SeqID), a suspect medicinal product if 
applicable, an identifiable reporting source, the description of the medical event and seriousness criteria, as well as 
the causality assessment by the investigator. Follow-up information of any reported serious adverse event must be 
completed within 7 calendar days of the initial report. If no SAE follow-up information is provided within this 
deadline, the EORTC Pharmacovigilance Unit will make a request to the investigator. 
Queries sent out by the EORTC Pharmacovigilance Unit need to be answered within 7 calendar days. 
16.7 Reporting responsibilities of the Sponsor 
The EORTC Pharmacovigilance Unit will forward all SAE reports to the appropriate persons within the EORTC 
Headquarters and to the pharmacovigilance contact at the pharmaceutical company. 
The EORTC Pharmacovigilance Unit will provide a six-monthly summary which will be added in the Trial Status 
Report and which will be accessible to all participating investigators.  
The EORTC Pharmacovigilance Unit will take in charge the reporting of SUSARs/unexpected events to the all 
Competent Authorities, Ethics committees (of EORTC centers), EudraVigilance Clinical Trial Module (EVCTM), all 
EORTC participating investigators and all central Data Managers of all Cooperating Groups, whenever applicable. 
16.8 Pregnancy reporting 
Pregnancy occurring during a patient’s participation in this trial, although not considered an SAE, must be notified 
to the EORTC Pharmacovigilance Unit within the same timelines as an SAE (within 24 hours) on an electronic 
Pregnancy Notification Form. The outcome of a pregnancy should be followed up carefully and any adverse 
outcome to the mother or the child should be reported. This also applies to pregnancies in female partners of a 
male patient participating in this trial. 
• 
Any pregnancy in a female subject or in a female partner of a male subject diagnosed during the treatment 
period or within 6 months after last protocol treatment administration must be reported to the EORTC 
Pharmacovigilance Unit  
• 
This must be reported within 24 hours of first becoming aware of the event to the Medidata Rave EDC system 
(www.imedidata.com) on an electronic pregnancy form. 
• 
If an SAE occurs in conjunction with the pregnancy, please also report an SAE as explained in the SAE reporting 
section 
17 Quality assurance 
17.1 Control of data consistency 
Data forms will be entered in the EORTC Headquarters database by using the Medidata Rave EDC system. 
Computerized and manual consistency checks will be performed on newly entered forms; queries will be issued in 
case of inconsistencies. Consistent forms will be validated.  


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17.2 On-site monitoring 
The EORTC Headquarters will subcontract Premier Research to perform on-site monitoring visits according to the 
approved study-monitoring plan. 
The first visit in a participating site will be performed within 3 months after the first patient's randomization at this 
site. Frequency and number of subsequent visits will depend on site's accrual and quality observed during the first 
visit.  
The aim of these site visits will be: 
• 
to check informed consent and patient eligibility 
• 
to verify that the site facilities remain adequate for performing the trial 
• 
to verify that the principal investigator and site staff involved in the trial are working in compliance with GCP 
and protocol requirements  
• 
to assess the consistency of data reported on the case report forms with the source data 
• 
to check that Serious Adverse Events have been properly reported and that follow-up information or queries 
are correctly fulfilled 
• 
to check on any protocol deviations and retrain sites when necessary 
• 
to assist the site in resolving any outstanding queries and potential temperature excursion 
• 
to control the drug accountability process 
• 
to check site and pharmacy files 
17.3 Audits 
The EORTC is responsible for the performance of the EORTC investigators. 
The investigator, by accepting to participate in this protocol, agrees that EORTC, any third party (e.g. a CRO) acting 
on behalf of the EORTC, or any domestic or foreign regulatory agency, may come at any time to audit or inspect 
their site and all subsites, if applicable.  
This audit consists of interviews with the principal investigator and study team, review of documentation and 
practices, review of facilities, equipment and source data verification. 
The investigator will grant direct access to paper and/or electronic documentation pertaining to the clinical study 
(e.g. CRFs, source documents such as hospital patient charts and investigator study files) to these authorized 
individuals. All site facilities related to the study conduct could be visited during an audit (e.g. pharmacy, 
laboratory, archives …). The investigator agrees to co-operate and provide assistance at reasonable times and 
places with respect to any auditing activity. 
If applicable, the company(ies) supplying the study drug(s) may have access to anonymized data but will not have 
access to source documents. 
If a regulatory authority inspection is announced, the investigator must inform the EORTC Headquarters 
Compliance and Audits immediately (contact at: Complianceandaudits@eortc.org) In this way EORTC can provide 
support in preparing and/or facilitating the inspection. EORTC representatives/delegates may also attend the 
inspection. 
17.4 Other central review procedures 
17.4.1 
Quality assurance in radiotherapy 
All documents pertaining to RTQA requirements and procedures will be sent to the centers after receipt of the 
signed commitment form at the EORTC Headquarters.  


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The RTQA procedure consists of completing the following prior to institution authorization: 
• 
Level I: Facility Questionnaire (FQ) and Beam Output Audit (BOA) 
• 
Level II: Benchmark Case (BC) 
• 
Level V: Credentialing for the use of IMRT 
During the trial, the following RTQA patient-specific procedure must be performed: 
• 
Level IV: Extensive Individual Case Review (E-ICR) 
The RTQA procedures are summarized here and described in detail in the "RTQA Guidelines" document which will 
be supplied by RTQA team prior to institution authorization. In case of questions or difficulties, please contact the 
trial RTQA team at the following address: rtqa1709@eortc.org. 
17.4.1.1 
Prior to authorization 
17.4.1.1.1 
Facility questionnaire (FQ) and Beam Output Audit (BOA) 
All EORTC centers at authorization must have a valid EORTC FQ and a valid BOA performed by an external auditor. 
Both must be not older than 2 years. This questionnaire must be filled in electronically and submitted on line. The 
web link is on the web page of EORTC under the Study Tools section. 
All centers at authorization must have a valid BOA. Additional information can be found at the EORTC website 
under the Study Tools section. 
To determine if a previously submitted FQ and or BOA is valid please contact rtqa1709@eortc.org and along with 
EORTC institution number. 
17.4.1.1.2 
Benchmark Case 
All EORTC centers prior to authorization will perform a BC procedure if planning on treating patients with IMRT. 
Institutions planning on treating patients with 3D-CRT do not have to complete this procedure. This is a two-step 
procedure that contains a delineation and planning exercise according to the protocol in a provided patient case. 
The benchmark case will be centrally reviewed by the RTQA reviewers of the trial. 
17.4.1.1.3 
Complex Dosimetry check 
All EORTC centers prior to authorization must be credentialed for the use of their IMRT technique via the Virtual 
Phantom Procedure (VPP). This procedure consists of irradiating the site's in-house phantom based on the RT plan 
created for the BC and further details can be found in the "RTQA Guidelines". 
17.4.1.2 
Patient-specific RTQA program 
17.4.1.2.1 
Extensive individual case review (E-ICR) 
For all patients the following must be submitted for central review: all patient digital treatment data, including pre-
operative imaging, and completed Radiotherapy planning eCRF must be submitted prior to the start of RT 
treatment and as soon as possible after randomization. The first 2 patients recruited per institution will be 
prospectively reviewed. All other patients will be reviewed retrospectively. 
Should the review result in an “unacceptable protocol variation”, the institution might be withdrawn from the 
authorization list and no longer be in the position to enter patients in the trial, until a resubmission results in an 
“acceptable per protocol” or "acceptable variation" review. The same rule will apply if case plans are not submitted 
within the requested timelines. 


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All details about the submission procedure, timelines and supplementary forms are described in the RTQA 
Guidelines. 
17.4.1.3 
RTQA report 
The primary RTQA-related research projects include analyses of the Benchmark Case (BC) procedure (site activation) 
and the Individual case review. The analysis of the BC will focus on target volume (TV) and organs at risk (OAR) 
delineation variability and the impact on dose parameters. In the ICR analysis, the variations of Target Volumes and 
OAR delineation will be determined in trial patients and compared with the results from the BC analysis. 
The results of the BC and ICR analyses will be submitted for publication after the first main trial results publication 
or presentation. Submission will be to a peer-reviewed journal focusing on radiation oncology. First authorship will 
be held by the Emmanuel van der Schueren, a fellow who was involved in the analysis of the respective data, last 
authorship by the Clinical Chair of the RTQA group who supervised the work. Additional co-authors will include the 
EORTC HQ staff involved in the work, the RTQA Physics Chair, the RTQA reviewers, the PIs of the trial, and one 
investigator from each of the 5 participating centers that included and uploaded most cases. 
17.4.2 
Scan submission Quality Assurance and Quality Control in imaging 
The EORTC HQ will track all scans of all patients received from the sites and will request/query missing/incomplete 
scans. Furthermore, if the scans arrive in unacceptable quality or in a non-acceptable format, the site will be 
informed to provide substitute scans.  
Scans will be uploaded by the participating centers via the EORTC imaging platform. Please refer to the imaging 
guidelines for more details. 
17.4.3 
Imaging QA/QC level description 
The QA procedure consists of completing the following: 
• 
Prior to site authorization: Imaging Guidelines “read and understood” acknowledgment signature page.  
• 
During the trial, the following imaging procedures will be performed: Prospective scans QC 
17.4.3.1 
Imaging guidelines “read and understood” acknowledgment page 
signature 
Every site participating in an EORTC study with centralized imaging, must comply with the minimum requirements 
established as specified in the imaging guidelines. The first page of the imaging guidelines must be signed and 
returned to the EORTC HQ for every new version of the imaging guidelines. The page must be signed by the 
department head radiologist. This is mandatory from all institutions in this study before activation to participate in  
17.4.3.2 
Prospective scan quality control  
QC will be performed prospectively, on an on-going basis. The EORTC Imaging Officer will be reviewing all scans for 
all patients to check for artifacts and to ensure compliance with the imaging guidelines and study protocol.  
Every subsequent scan on the same patient must be done with the same scanner across all visits. In case of scanner 
breakdown or change of scanners in the department, you need to notify the EORTC HQ.  
17.4.4 
Scan submission 
All scans acquired in the frame of this study should be uploaded to the EORTC imaging platform. Alternatively, 
scans can be sent on disc to the EORTC HQ. For more info, see Imaging guidelines for sites.  


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18 Ethical considerations 
18.1 Patient protection 
The responsible investigator will ensure that this study is conducted in agreement with either the Declaration of 
Helsinki (available on the World Medical Association web site (http://www.wma.net)) and/or the laws and 
regulations of the country, whichever provides the greatest protection of the patient. 
The protocol has been written, and the study will be conducted according to the ICH Harmonized Tripartite 
Guideline on Good Clinical Practice (ICH-GCP, available online at 
https://www.ema.europa.eu/documents/scientific-guideline/ich-e6-r1-guideline-good-clinical-practice_en.pdf). 
The protocol must be approved by the competent ethics committee(s) as required by the applicable national 
legislation.  
18.2 Subject identification 
The name of the patient will neither be asked for nor recorded at the EORTC Headquarters. A sequential 
identification number will be automatically allocated to each patient registered in the trial. This number will 
identify the patient and will be included on all case report forms. In order to avoid identification errors, the 
patient’s code (maximum of 4 alphanumerics) and date of birth or year of birth (as allowed per applicable 
legislation) will also be reported on the case report forms. 
18.3 Informed consent 
All patients will be informed about: 
• 
the aims of the study 
• 
the possible adverse events 
• 
the procedures and possible hazards to which the patient will be exposed 
• 
the mechanism of treatment allocation 
• 
strict confidentiality of any patient data 
• 
medical records possibly being reviewed for trial purposes by authorized individuals other than their treating 
physician 
The template of the patient’s informed consent statement is given as a separate document dated and version 
controlled to this protocol. 
An adapted translation of the PIS/PIC will be provided by EORTC Headquarters and it is the responsibility of the 
Coordinating investigators for this trial (sometimes called National Coordinators) to adapt it to national/local 
requirements where necessary. 
The translated informed consent documents are to be submitted to ethics committees for approval. The 
competent ethics committee for each institution must approve the informed consent documents before the center 
can join the study. It is the responsibility of the competent ethics committee to ensure that the translated 
informed documents comply with ICH-GCP guidelines and all applicable national legislation. 
It is emphasized in the patient information sheet that participation is voluntary and that the patient is free to 
refuse further participation in the protocol whenever he/she wants to. This will not have any impact on the 
patient’s subsequent care. Documented informed consent must be obtained for all patients included in the study 
before they are registered and/or randomized at the EORTC Headquarters. The written informed consent form 
must be signed and personally dated by the patient or by the patient’s legally acceptable representative. 


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All of the above must be done in accordance with the applicable national legislation and local regulatory 
requirements. 
 
 


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Chapters 19 through 21 pertain specifically to the participation of EORTC investigators. Participants from other 
organizations should consult the appendix that is specific to their group to determine if the contents of these 
sections are superseded by procedures specific to their group. 
 
 
 


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19 Administrative responsibilities 
19.1 The study coordinator 
The Study Coordinator works closely with the study team to develop the outline and full protocol and discusses the 
contents of the reports with the study team. The Study coordinator is responsible for publishing the study results. 
He/she will assist the Clinical Research Physician for answering some clinical questions concerning eligibility, 
treatment, and contributes to the medical review of the patients. 
Study coordinator: 
Patrick Roth 
UniversitaetsSpital Zurich 
Raemistrasse 100 
8091 Zurich 
Switzerland 
Phone: +41 44 255 5511 
Fax: +41 44 255 4380 
e-mail: patrick.roth@usz.ch 
19.2 The EORTC Headquarters 
The EORTC Headquarters will be responsible for writing the protocol and PIS/IC, reviewing the protocol, setting up 
the trial, collecting case report forms, controlling the quality of the reported data, organizing the medical review 
and generating reports and analyses in cooperation with the Study Coordinator. All methodological questions 
should be addressed to the EORTC Headquarters. 
EORTC HEADQUARTERS 
Avenue E. Mounierlaan 83/11 
Brussel 1200 Bruxelles 
België – Belgique 
Fax: +32 2 772 3545 
19.3 The EORTC group 
All questions concerning ongoing membership in the group should be addressed to the chairman and/or secretary 
of the group. 
For new membership contact Membership Committee at membership@eortc.org. 
Brain Tumor Group EORTC group 
Chairperson:  
Matthias Preusser 
Address: Medical University of Vienna, Vienna, Austria 
Phone: + 43 (0)1 40400-44450 
Fax: +43 (0)1 40400-44510 
e-mail: matthias.preusser@meduniwien.ac.at 
 


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20 Trial sponsorship and financing 
EORTC is the legal Sponsor for all EORTC participants. 
The contact details of the EORTC are: 
EORTC Headquarters 
Avenue E. Mounierlaan 83/11 
Brussel 1200 Bruxelles 
België – Belgique 
Phone: +32 2 7741611 
Fax: 
+32 2 7723545 
e-mail: eortc@eortc.org 
Financial support is provided by Celgene. 
21 Trial insurance 
A clinical trial insurance has been taken out according to the laws of the countries where the study will be 
conducted. An insurance certificate will be made available to the participating sites at the time of study initiation.  
Clinical trial insurance is only valid in centers authorized by the EORTC Headquarters. For details please refer to the 
section on investigator authorization. 


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Study approach. Durham and London: Duke University Press, 1992: 102 142. 
Ref. 59 
Kim K, DeMets DL (1987). Design and analysis of group sequential tests based on the type I error 
spending rate function. Biometrika 74:149–154. 
Ref. 60 
Jennison, C., & Turnbull, B. W. (2000). Group sequential methods with applications to clinical trials. Boca 
Raton: Chapman & Hall/CRC. 


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Appendix B: Abbreviations 
5-ALA 
5-Aminolevulinic acid  
AE 
Adverse Events  
AlkPhos 
Alkaline phosphatase  
ALT 
Alanine aminotransferase  
ANC 
Absolute neutrophil count  
aPTT 
Activated PTT  
AR 
Adverse reaction  
AST 
Aspartate Aminotransferase 
ATP 
Adenosine triphosphate  
BBB 
Blood brain barrier 
BCNU 
Bis-chloroethylnitrosourea 
BEM 
Beam's eye view 
BOA 
Beam Output Audit  
BSA 
Body surface area  
C1D1 
Cycle 1, Day 1  
CIF 
Principal Investigator Form  
CMV 
Cytomegalovirus 
CNS 
Central nervous system  
COWA 
Controlled Oral Word Association 
CrCl 
Creatinine clearance  
CT 
Computer Tomography 
CTA 
Clinical trial agreement  
CTC 
Common Terminology Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events  
CTV 
Clinical target volume  
CYPs 
Hepatic cytochrome P450s  
d 
Days 
DVH 
Dose volume histogram 
DRR 
Digital reconstructed radiograph  
eCRF 
Electronic case report form  
EGA 
European Genomic Archive  
EGFR 
Epidermal growth factor receptor  
EIAED 
Enzyme-inducing anti-epileptic drug 
E-ICR 
Extensive Individual Case Review  
EOT 
End of treatment 
EORTC 
European Organisation for Research and Treatment of Cancer 
EPID 
Electronic portal imaging device 
EVCTM 
EudraVigilance Clinical Trial Module  
FFPE 
Formalin Fixed Paraffin Embedded 
FQ 
Facility Questionnaire  
GA 
Geriatric Assessment  
GI 
Gastrointestinal  
GTV 
Gross tumor volume 
H0 
Null hypothesis  


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HBM 
Human biological material  
Hct 
Hematocrit 
Hgb 
Hemoglobin  
HQ 
Headquarter 
HRQoL 
Health related quality of life  
HSV 
Herpes simplex virus 
HVLT-R 
Hopkins Verbal Learning Test – Revised 
HZV 
Herpes zoster virus 
HR 
Harzard ratio 
IB 
Investigator's Brochure 
ICH/GCP 
International Conference on Harmonisation /Good Clinical Practice 
ICRU 
International Commission on Radiation Units and Measurements  
IDH 
Isocitrate dehydrogenase  
IDMC 
Independent Data Monitoring Committee  
IIT 
Intention-to-treat 
IMP 
Investigational medicinal product 
IMRT 
Intensity modulated radiotherapy  
INR 
International Normalized Ratio  
IV 
Intravenous  
IVRS 
Interactive Voice Response System  
KPS 
Karnofsky performance score  
LFT 
Liver functions tests  
MGMT 
O-6-Methylguanine-DNA methyltransferase  
mMGMT 
Methylated MGMT  
MMSE 
Mini-Mental State Examination  
MOS 
Medical Outcomes Study 
MRI 
Magnetic resonance imaging  
MRZ 
Marizomib 
NCIC 
National Cancer Institute of Canada  
NYHA 
New York Heart Association  
OAR 
Organs at risk  
ORR 
Overall response rate 
OS9 
Overall survival at 9 months 
PBMC 
Peripheral blood mononuclear cells  
PD 
Progressive disease  
PFS6 
Progression Free Survival Rate at 6 months  
PIS/IC 
Patient Information / Informed Consent sheet 
PJP 
Pneumocystis jiroveci pneumonia 
PK 
Pharmacokinetics 
PO 
per os 
POL 
Policy 
PP 
Protocol population  
PSA 
Prostate-Specific Antigen  
PT 
Prothrombin time  
PTT 
Partial thromboplastin time  
PTV 
Planning Target Volume  


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PWB 
Packed whole blood  
QA&C 
Quality Assurance and Control 
QLQ 
Quality of Life Questionnaire  
QoL 
Quality of Life 
RBC 
Red blood cells 
RP2D 
Recommended phase II dose  
RT 
Radiotherapy 
SAE 
Serious Adverse Event  
SAD 
Source-to-axis distance 
SAR 
Serious Adverse Reaction  
SMG 
Study Management Group 
SmPc 
Summary of product characteristics  
SOC 
Standard of care 
SS 
Safety population  
SSC 
Study Steering committee  
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Event  
TMT A & B 
Trail Making Test Part A & Part B 
TMZ 
Temozolomide 
TR 
Translational research  
TRAC 
Translational Research Advisory Committee  
TTFields 
Tumor-Treating Fields  
UAR 
Unexpected Adverse Reaction  
ULN 
Upper normal limit  
uMGMT 
Unmethylated MGMT  
VPP 
Virtual Phantom Procedure  
WBC 
White blood cells 
WHO 
World Health Organisation  
WOCBP 
Women of child bearing potential  
 
 
 


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Appendix C: New York Heart Association (NYHA) 
classification of heart failure 
Class I 
Patients with cardiac disease but without resulting limitations of physical activity. Ordinary 
physical activity does not cause undue fatigue, palpitation, dyspnoea or anginal pain. 
Class II 
Patients with cardiac disease resulting in slight limitation of physical activity. They are 
comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnoea or 
anginal pain. 
Class III 
Patients with cardiac disease resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnoea or 
anginal pain. 
Class IV 
Patients with cardiac disease resulting in inability to carry on physical activity without 
discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even 
at rest. If any physical activity is undertaken, discomfort is increased. 
 
(The Criteria Committee of the New York Heart Association: Diseases of the Heart and Blood Vessels; 
Nomenclature and Criteria for Diagnosis, 6th ed Boston, Little, Brown 1964). 
 
 


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Appendix D: Common Terminology Criteria for Adverse 
Events 
In the present study, adverse events and/or adverse drug reactions will be recorded according to the  
Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. 
At the time this protocol was issued, the full CTC document was available on the NCI web site, at the following 
address: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm. 
The EORTC Headquarters web site   https://www.eortc.be/services/doc/ctc/   provides a link to the appropriate 
CTC web site. This link will be updated if the CTC address is changed. 


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Appendix E: Karnofsky scale for performance status 
 
Index 
Performance scale 
100 
Normal; no complaints. 
90 
Able to carry on normal activities; minor signs or symptoms of disease. 
80 
Normal activity with effort. 
70 
Cares for one self. Unable to carry on normal activity or to do active work. 
60 
Ambulatory. Requires some assistance in activities of daily living and self-care. 
50 
Requires considerable assistance of frequent medical care. 
40 
Disabled; requires special care and assistance. 
30 
Severely disabled; hospitalization indicated though death not imminent. 
20 
Very sick; hospitalization and active supportive treatment. 
10 
Moribund. 
0 
Dead. 
 
 


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Appendix F: EORTC Quality of Life evaluation: 
guidelines for administration of questionnaires 
 
 
 
 
EORTC Quality of Life evaluation: guidelines for administration of questionnaires 
The instructions given below are intended to provide some general guidelines for collecting quality of life (QOL) 
data in EORTC studies. These instructions apply for all types of questionnaires. 
1. Who is the responsible person (RP) for QOL data collection? 
In each institution, the principal investigator is the responsible for the local organization of QoL data collection. 
This can be delegated to a physician, data manager, (research) nurse or a psychologist. Such a person should have 
the full protocol at his/her disposal as well as the questionnaire(s). This person would also be the intermediate 
contact point in case of any necessary clarification asked by the EORTC Headquarters. 
2. Who should fill out the questionnaire? 
In principle it is the patient who has to complete the QOL forms and preferably without help from others. In the 
case where a patient is too sick to fill out the questionnaire by him/herself or if the patient is not able to complete 
the questionnaire for such reasons as forgetting his/her glasses, another person could read the questions without 
making any suggestions and report the answers on the forms. It is not allowed for another person to fill in the 
questionnaire as if (s)he was the patient (proxy assessment) unless specifically allowed by the protocol. 
3. What instructions should be given to the patient? 
At entry in a study, the RP should give the patient an explanation of the objective of the study and instructions for 
completing the questionnaires. 
The patient should be informed that participation in the QOL protocol is voluntary and that the information 
provided is confidential (identification is only for administrative purposes and includes date of birth and today’s 
date (completion date)). 
The following issues should be explained to the patient: 
• 
The schedule of assessments. 
• 
The questionnaire is a self administered questionnaire that should be completed by the patient him(her)self. 
The patient can ask for aid in reading or writing but should not let another person provide the answers. 
• 
The patient should   circle   the choice that best corresponds to his/her situation. 
• 
There is no right or wrong answer to any of these questions. The answers will not influence any medical 
decision making. 
• 
All questions should be answered.  
• 
The patient will be given a questionnaire in the default language(s) of the hospital. If desired, the patient may 
request another language. The RP will then contact the EORTC Headquarters for the appropriate translation. 
The RP should make sure that the patient understands the instructions. 


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At each subsequent assessment as defined by the protocol, the patient should receive the questionnaire from the 
RP or from other appropriate staff if the RP is unavailable. 
4. Where should the patient complete the questionnaire? 
The patient should complete the questionnaire at the clinic, and, ideally in a quiet, private room. If this is not 
possible, the waiting room is an acceptable alternative. In general it does not take long to complete the 
questionnaire, but patients should be given the time they need to answer all questions. 
5. When should they complete the questionnaire? 
The timing of the planned QoL assessments is detailed in the protocol. When a QOL assessment is planned, the 
questionnaire should be given to the patient preferably before the meeting with the physician, ensuring that the 
patient has enough time to complete the questionnaire. If the patient is to receive a therapy, the questionnaire 
should be filled out before administration of the treatment (unless indicated otherwise in the protocol). The 
questionnaire should not be taken home and/or mailed (unless indicated otherwise in the protocol). 
6. Review of the completed questionnaire 
After the patient has completed the questionnaire, the person handling the questionnaire should: 
• 
Complete the “Hospital Staff” specific data box. 
• 
Check that the completion date is correctly filled in by the patient. 
• 
Screen the questionnaire for omissions. 
If this is the case: 
• 
Please ask the patient the reason for omissions. It may be that patient forgot to flip a page or did not 
understand a question. The patient should not be forced to provide an answer if (s)he does not wish to do so. 
• 
Additional explanation may be provided, but the questions should not be rephrased. 
7. Missing forms 
If for some reason the patient is unable or does not wish to complete a quality of life questionnaire the reason and 
the date of visit should be documented on the corresponding CRF (case report form).  
8. Mailing to EORTC Headquarters 
A copy of the questionnaires should be sent to EORTC Headquarters as soon as possible, while the original source 
document should be kept on site. As it is impossible to retrospectively collect missing quality of life data, please 
make sure the patient completes the questionnaire at the time-point when he/she is supposed to complete it. 
Thank you very much for your cooperation.  
 


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Appendix G: G8 geriatric screening tool 
(Version 1.0 - December 2010) 
 
To be completed by: Clinician, nurse or trained coder. 
Notes: This screening tool includes 7 items of the Mini Nutritional Assessment and the age of the patient. 
Score: Total score by adding up coded answers. 
G8 Screening tool 
 
Items 
Possible answers 
Score 
A 
Has food intake declined over the past 3 months 
due to loss of appetite, digestive problems, chewing 
or swallowing difficulties? 
0: severe reduction in food intake 
1: moderate reduction in food intake 
2: normal food intake 
………... 
B 
Weight loss during the last 3 months? 
0: weight loss >3kg 
1: does not know 
2: weight loss between 1 and 3 kg 
3: no weight loss 
………... 
C 
Mobility 
0: bed or chair bound 
1: able to get out of bed/chair but does 
not go out 
2: goes out 
………... 
E 
Neuropsychological problems 
0: severe dementia or depression 
1: mild dementia or depression 
2: no psychological problems 
………... 
F 
Body Mass Index (weight in kg/height in m2) 
0: BMI less than 19 
1: BMI 19 to less than 21 
2: BMI 21 to less than 23 
3: BMI 23 or greater 
………... 
H 
Takes more than 3 medications per day 
0: yes 
1: no 
………... 
P 
In comparison with other people of the same age, 
how does the patient consider his/her health 
status? 
0: not as good 
0,5: does not know 
1: as good 
2: better 
………... 


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Age 
0: >85 
1: 80-85 
2: <80 
………... 
 
Total score (0-17) 
 
………. 
 
 


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Appendix H: Acceptable birth control methods 
 
Women of childbearing potential (WOCBP) are defined as premenopausal females capable of becoming pregnant 
(i.e. females who have had evidence of menses in the past 12 months, with the exception of those who had prior 
hysterectomy). 
 
A highly effective method of birth control is defined as a method which results in a low failure rate (i.e. less than 
1% per year) when used consistently and correctly. Such methods include: 
• 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulation (oral, intravaginal, transdermal) 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, 
implantable) 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
• 
Sexual abstinence (the reliability of sexual abstinence needs to be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient) 
 
 


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Appendix I: Mini Mental State Examination (MMSE) 
Patient’s Name:  
 
 
 
 
 
Date: 
 
 
 
 
Instructions: Score one point for each correct response within each question or activity. 
Maximum 
Score 
Patient’s 
Score 
Questions 
 
5 
 
“What is the year? Season? Date? Day? Month?” 
5 
 
“Where are we now? State? County? Town/city? Hospital? Floor?” 
3 
 
The examiner names three unrelated objects clearly and slowly, then the 
instructor asks the patient to name all three of them. The patient’s response is 
used for scoring. The examiner repeats them until patient learns all of them, if 
possible. 
5 
 
“I would like you to count backward from 100 by sevens.” (93, 86, 79, 
72, 65, …) 
Alternative: “Spell WORLD backwards.” (D-L-R-O-W) 
3 
 
“Earlier I told you the names of three things. Can you tell me what those 
were?” 
2 
 
Show the patient two simple objects, such as a wristwatch and a pencil, and ask 
the patient to name them. 
1 
 
“Repeat the phrase: ‘No ifs, ands, or buts.’” 
3 
 
“Take the paper in your right hand, fold it in half, and put it on the floor.”(The 
examiner gives the patient a piece of blank paper.) 
1 
 
“Please read this and do what it says.” (Written instruction is “Close your 
eyes.”) 
1 
 
“Make up and write a sentence about anything.” (This sentence must contain a 
noun and a verb.) 
1 
 
“Please copy this picture.” (The examiner gives the patient a blank piece of 
paper and asks him/her to draw the symbol below. All 10 angles must be 
present and two must intersect.) 
 
30 
 
TOTAL 


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Appendix J: Neurocognitive test battery 
 
Certification and Administration procedures for the Neurocognitive Test Battery and collection of Patient 
Reported Outcome (PRO) Questionnaires  
1.1  
General Procedures: Certification for Test Administration  
The healthcare professional (e.g. nurse, psychologist) who is responsible for neurocognitive test administration in 
this study requires pre-certification by M. Klein in order to participate in this protocol. For this pre-certification, the 
test administrator who will be evaluating patients must first obtain, (print) and review the following documents; 
instructions, test scoring forms, a training video and a training video post test. These documents are available on a 
password-protected website at VU University Medical Center Amsterdam. To obtain website and password 
information contact M. Klein, EORTCsupport@vumc.nl.  
The training video of neurocognitive test administration must be reviewed along with the scoring forms and the 
“Test Instructions for the Neurocognitive Test Battery” (see 1.3). The instructions and the training video should be 
retained for review and reference during this study. After viewing the training video, the trainee must complete a 
post test and a “practice” assessment on a non-patient volunteer (e.g. coworker, friend), including completion of 
scoring forms.  
After meeting the requirements of certification for test administration, the Certification Worksheet for test 
administrator (see Appendix K hereunder) must be completed and signed. All materials (the training video post 
test, completed test forms of “practice” assessment and the signed Certification Worksheet) must be scanned and 
emailed to M. Klein, who will score it and review any procedural errors with the trainee. Email: 
EORTCsupport@vumc.nl 
If the trainee demonstrates competency, he/she will be notified of the approval to administer the tests to study 
subjects as part of the EORTC 1709 study and study enrollment may commence. A notification of certification will 
be sent to both the site and to EORTC for their records and to ensure that only the EORTC 1709 study-approved 
examiners are testing subjects on the EORTC 1709 study. 
M. Klein will be available by telephone and e-mail if questions arise about the testing procedures, phone: +31 20 
4448432 / email: EORTCsupport@vumc.nl. If there are administration or procedural errors, M. Klein will discuss 
the test administration and scoring issues over the phone with the test administrator (5-10 min). 
The test forms of each certified examiner will be reviewed by M. Klein for quality control purposes. Procedural 
deviations (if any) will be identified, and sites will be notified of the results of the review. If significant procedural 
variations are noted, re-training (‘re-certification’) of the test administrator will be requested.  
 
1.2 
General Procedures: Neurocognitive Assessment 
The tests that constitute the neurocognitive function (NCF) battery were selected because they are widely used 
standardized psychometric instruments that have been shown to be sensitive to the neurotoxic effects of cancer 
treatment in other clinical trials. NCF has been demonstrated to predict tumor progression and independently 
predict survival for patients with CNS tumors. This battery has also been demonstrated to be practical in terms of 
cost and burden to the patient, with good compliance in multicenter trials. They are widely used, standardized 
psychometric instruments with published normative data that take into account age and, where appropriate, 
education, gender and handedness. The tests were also selected to minimize the effects of repeated 
administration. 


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In addition to objective assessments of neurocognitive functioning, patients' self-reported cognitive function will 
be assessed with a six-item scale developed for use in the Medical Outcomes Study (MOS scale). (Ref. 58) This scale 
assesses day-to-day problems with cognitive function, such as difficulty with reasoning and problem solving, 
slowed reaction time, forgetfulness, and problems with concentration. This questionnaire is included in the scoring 
forms. 
 
Cognitive Domain  
Test  
Time to Administer 
(minutes) 
Memory 
Hopkins Verbal Learning Test – Revised (HVLT-R) 
8  
Visual-motor processing speed 
Trail Making Test (TMT) Part A 
3 
Executive Function 
Trail Making Test (TMT) Part B 
5 
Verbal fluency 
Controlled Oral Word Association (COWA) 
5 
 
Total 
21 
 
The tests are to be administered in one session by a certified examiner. Test instructions (see 1.3 Test instructions 
for the Neurocognitive Test Battery) must be followed verbatim with every patient at every study visit. Results of 
the HLVT-R, TMT and COWA should be recorded on the test forms with a black pen. All test forms must be clearly 
signed by the test administrator. Original patient test forms should be kept at site.  
Administer the tests in the following order to every patient at every visit:  
  
 
 
 
 
1) HVLT-R - Part A Free recall  
  
 
 
 
  
2) TMT - Part A  
  
 
 
 
 
3) TMT - Part B 
  
 
 
 
 
4) COWA 
  
 
 
 
 
5) HVLT-R - Part B Delayed recall  
  
  
 
 
 
6) HVLT-R - Part C Delayed recognition 
  
Sequencing of alternate forms  
Neurocognitive test battery is to be administered at study registration and at various follow-up moments as 
indicated in the summary table of this protocol (section 6.4) and the neurocognitive guidelines. Two of the tests 
to be administered have alternate forms or versions in order to reduce the effects of practice. See the table below 
for the forms to be administered at study registration and subsequent sessions. The forms should continue to be 
alternated in this order for the duration of the study. The packets (version 1-6) available on the website will 
contain the correct alternate forms. Additionally, patients should not be given copies of their tests to avoid 
learning the material between test administrations. 
 


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Test 
Study 
Registration 
2nd visit 
3rd visit 
4th visit 
5th visit 
6th visit 
7th visit 
> > > 
HVLT-R 
Form 1 
Form 2 
Form 3 
Form 4 
Form 5 
Form 6 
Form 1 
COWA 
Form 1 
Form 2 
Form 1 
Form 2 
Form 1 
Form 2 
Form 1 
Dutch 
‘B-D-H’ 
‘P-M-C’ 
‘B-D-H’ 
‘P-M-C’ 
‘B-D-H’ 
‘P-M-C’ 
‘B-D-H’ 
English 
‘C-F-L’ 
‘P-R-W’ 
‘C-F-L’ 
‘P-R-W’ 
‘C-F-L’ 
‘P-R-W’ 
‘C-F-L’ 
French 
‘P-B-G’ 
‘A-T-V’ 
‘P-B-G’ 
‘A-T-V’ 
‘P-B-G’ 
‘A-T-V’ 
‘P-B-G’ 
German 
‘A-M-V’ 
‘K-P-W’ 
‘A-M-V’ 
‘K-P-W’ 
‘A-M-V’ 
‘K-P-W’ 
‘A-M-V’ 
Italian 
‘C-F-G’ 
‘P-D-L’ 
‘C-F-G’ 
‘P-D-L’ 
‘C-F-G’ 
‘P-D-L’ 
‘C-F-G’ 
 
1.3  
Test instructions for the Neurocognitive Test Battery  
 
1)  
HOPKINS VERBAL LEARNING TEST - REVISED (HVLT-R) 
This test has three parts and six alternate forms. Complete the three learning trials, Part A - Free Recall, first. 
Complete Part B - Delayed Recall after a 20-minute delay that includes administration of TMT and COWA. 
Complete Part C - Delayed Recognition immediately after Delayed Recall. 
 
Part A – Free Recall: Trial 1  
Examiner: “I am going to read a list of words to you. Listen carefully, because when I am through, I’d like you to tell 
me as many of the words as you can remember.  
You can tell them to me in any order. Are you ready?” 
Read the words at the rate of one word every 2 seconds.  
Examiner: “OK. Now tell me as many of those words as you can remember.” 
Check off the words the patient recalls on the form. 
If a word is said that is not in the list (for example, “intrusion”), do not write that word on the form and do not say 
anything to the patient about the word not being on the list. 
There is no time limit for each recall trial. However, if the patient does not produce any words for 10-15 seconds, 
ask the patient if he/she can remember any more words. 
If not, move on to trial 2. Later, you can record the number of correct words on the test form. 
 
Part A – Free Recall: Trial 2  
Examiner: “Now we are going to try it again. I am going to read the same list of words to you.  


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Listen carefully, and tell me as many of the words as you can remember, in any order, including the words you told 
me the first time.”  
 
Read the words at the rate of one word every 2 seconds.  
Check off the words the patient recalls on the form. Incorrect/non-list words are not recorded on the test form. 
There is no time limit and patients should be encouraged to do their best. 
If he/she cannot think of any more words move on to trial 3. Later, record the number of correct words. 
 
Part A – Free Recall: Trial 3  
Examiner: “I am going to read the list one more time. As before, I’d like you to tell me as many of the words as you 
can remember, in any order, including all the words you’ve already told me.” 
Read the words at the rate of one word every 2 seconds.  
Check off the words the patient recalls on the form. Incorrect/non-list words are not recorded on the test form. 
There is no time limit and patients should be encouraged to do their best. 
Do not tell the respondent that recall of the words will be tested later! 
Record the time on the clock that you complete Part A – Free Recall (for example, 10:00 A.M.) on the designated 
space ‘Part A Stop Time’ on the HVLT-R form. 
 
2)  
TRAIL MAKING TEST (TMT)  
 
 
 
 
 
* Timed Test * 
This test has two parts (A and B), which both have a sample exercise and a test exercise. 
 
Part A – Sample 
The Sample for Part A must be completed/attempted by each patient at every assessment. Place the Sample A 
worksheet flat on the table, directly in front of the patient (the bottom of the worksheet should be approximately 
six inches from the edge of the table). Give the patient a black pen. 
Examiner: “On this page are some numbers. Begin at number 1 (point to 1) and draw a line from 1 to 2 (point to 2), 
2 to 3 (point to 3), 3 to 4 (point to 4), and so on, in order, until you reach the  
end (point to the circle marked 
END). Draw the lines as fast as you can. Ready, begin.” 
If the patient completes Sample A correctly and in a manner demonstrating that he/she understands what to do, 
proceed immediately to Test A. If the patient makes a mistake on Sample A, point out the error and explain it. The 
following explanations of mistakes serve as illustrations: 
 
“This is where you start (point to number 1).”  
 
“You skipped this circle (point to the circle omitted).” 
 
“You should go from number 1 to 2 (point), 2 to 3 (point), and so on, until you reach the circle marked 
END.” 


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If it is clear that the patient intended to touch a circle but missed it, do not count it as an omission. Remind the 
patient, however, to be sure to touch the circles. If the patient cannot complete Sample A, take his/her hand and 
guide him/her through the trail using the opposite end of the pen, lightly touching the worksheet to avoid making 
marks on the copy.  
Examiner: “Remember, begin at number 1 (point to 1) and draw a line from 1 to 2 (point to 2), 2 to 3 (point to 3), 3 
to 4 (point to 4) and so on, in order, until you reach the circle marked END (point to END). Do not skip around, but 
go from one number to the next in proper order. Remember to work as fast as you can. Ready, begin.” 
If the patient does not succeed, or it becomes evident that he/she cannot do the task, discontinue testing and 
indicate the corresponding reason on the TMT Recording Form. If the patient completes Sample A correctly and 
appears to understand what to do, proceed immediately to Test A. 
 
Part A – Test 
After the patient has completed Sample A, place the Test A worksheet directly in front of the patient. 
Examiner: “Good! Let’s try the next one. On this page are numbers from 1 to 25. Do this the same way. Begin at 
number 1 (point) and draw a line from 1 to 2 (point), 2 to 3 (point), 3 to 4 (point) and so on, in order, until you reach 
the circle marked END (point). Do not skip around, but go from one number to the next in proper order. Remember 
to work as fast as you can. Ready, begin.”  
Start timing as soon as the instruction is given to “begin”. 
Watch closely in order to catch any errors as soon as they are made. If the patient makes an error, call it to his/her 
attention immediately and have him/her proceed from the point the mistake occurred. 
The patient must complete the test in 3 minutes or less. 
Do not stop timing until he/she reaches the circle marked “END”. 
If the patient does not complete the test within 3 minutes terminate the testing. The test can also be discontinued 
if the patient is extremely confused and is unable to perform the task. Collect the worksheet and complete the 
TMT Recording Form indicating the reason the test was terminated and the last correct number reached on the 
test.  
If the patient successfully completes the test collect the worksheet and record the time to completion on the TMT 
Recording Form in minutes and seconds.  
Examiner: “That’s fine. Now we’ll try another one.” 
 
Part B – Sample  
The Sample for Part B must be completed/attempted by each patient at every assessment. Place the  
Sample B worksheet flat on the table, directly in front of the patient. 
Examiner: “On this page (point) are some numbers and letters. Begin at number 1 (point) and draw a line from 1 to 
A (point), A to 2 (point), 2 to B (point), B to 3 (point), 3 to C (point) and so on, in order, until you reach the end 
(point). Remember, first you have a number (point), then a letter (point), then a number (point), then a letter 
(point), and so on. Draw the lines as fast as you can. Ready, begin.” 


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If the patient completes Sample B correctly proceed immediately to Test B. If the patient makes a mistake, point 
out the error and explain it. The following explanations of mistakes serve as illustrations: 
  
“You started with the wrong circle. This is where you start (point to number 1).” 
  
“You skipped this circle (point to the circle omitted).” 
  
“You should go from number 1 (point) to A (point), A to 2 (point), 2 to B (point), B to 3 (point) and so on, 
until you reach the circle marked END (point).” 
If it is clear the patient intended to touch a circle but missed it, do not count it as an omission. Remind the patient, 
however, to be sure to touch the circles. If the patient cannot complete Sample B, take their hand and guide them 
through the trail using the opposite end of the pen.  
Examiner: “Now you try it. Remember, begin at number 1 (point) and draw a line from 1 to A (point), A to 2 (point), 
2 to B (point), B to 3 (point) and so on, in order, until you reach the circle marked END (point). Ready, begin.” 
If the patient does not succeed or it becomes evident that s/he cannot do the task, discontinue testing and indicate 
the corresponding reason on the TMT Recording Form. If the patient completes Sample B correctly and appears to 
understand what to do, proceed immediately to Test B. 
 
Part B – Test 
After the patient has completed Sample B, place the Test B worksheet directly in front of the patient. 
Examiner: “Good! Let’s try the next one. On this page are both numbers and letters. Do this the same way. Begin at 
number 1 (point) and draw a line from 1 to A (point), A to 2 (point), 2 to B (point), B to 3 (point), 3 to C (point) and 
so on, in order, until you reach the circle marked END (point). Remember, first you have a number (point), then a 
letter (point), then a number (point), then a letter (point), and so on. Do not skip around, but go from one circle to 
the next in the proper order. Draw the lines as fast as you can. Ready, begin.”  
Start timing as soon as the instruction is given to “begin”. 
Watch closely in order to catch any errors as soon as they are made. If the patient makes an error, call it to his/her 
attention immediately and have him/her proceed from the point the mistake occurred. 
The patient must complete the test in 5 minutes or less. 
Do not stop timing until he/she reaches the circle marked “END”. 
Collect the worksheet and record the time to completion on the scoring form in minutes and seconds. 
If the patient does not complete the test within 5 minutes terminate the testing. The test can also be discontinued 
if the patient is extremely confused and is unable to perform the task. Collect the worksheet and complete the 
TMT Recording Form indicating the reason the test was terminated and the last correct number or letter reached 
on the test.  
At the top of both Sample forms and Test forms please write: patient code, case number, date of evaluation, 
institution name, name of certified tester, and the certified tester’s phone number.  
 
 
3) CONTROLLED ORAL WORD ASSOCIATION TEST (COWA)  
 
* Timed Test * 
This test has three parts (letters) and two alternate forms. 


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Examiner: “I am going to say a letter of the alphabet, and I want you to say as quickly as you can all of the words 
that you can think of that begin with that letter. You may say any words at all, except proper names such as the 
names of people or places. So you would not say ‘Rochester’ or ‘Robert’. Also, do not use the same word again with 
a different ending, such as ‘Eat,’ and ‘Eating.’ 
For example, if I say ‘S,’ you could say ‘son’, ‘sit,’ ‘shoe,’ or ‘slow.’  
Can you think of other words beginning with the letter ‘S’?” 
Wait for the patient to give a word. If it is a correct response, say “good”, and ask for another word beginning with 
the letter “S”. If the patient gives an inappropriate word on either occasion, correct the patient, and repeat the 
instructions. If the patient then succeeds, proceed to the test. If the patient fails to respond, repeat the 
instructions. If it becomes clear that the patient does not understand the instructions or cannot associate, stop the 
procedure, and indicate the reason(s) on the scoring form. If the patient has succeeded in giving two appropriate 
words beginning with the demonstration letter, proceed to the test. 
Examiner: “That is fine. Now I am going to give you another letter and again you say all of the words beginning 
with that letter that you can think of. Remember, no names of people or places, just ordinary words. Also, if you 
should draw a blank, I want you to keep on trying until the time limit is up and I say STOP. You will have one minute 
for each letter.  
  
 
The first letter is ‘__’. Begin”. 
Start timing immediately, see scoring form. Allow exactly one minute for each letter. 
Record the patient’s responses on the scoring form. 
If the patient discontinues before the end of the time period, encourage him/her to try to think of more words. If 
he/she is silent for 15 seconds, repeat the basic instruction and the letter. 
  
(e.g., “Tell me all the words you can think of that begin with a ‘C’”).  
No extension on the time limit is made in the event that instructions are repeated. 
Continue the evaluation with the remaining two letters, allowing one minute for each. 
Add the total number of correct responses in each column on the COWA scoring form. 
All incorrect and repeated responses must be crossed out with one single line, initialed and dated.  
All duplicate entries that have been verified to have different meanings must be marked “OK”, initialed and dated.  
COWA - Recording and scoring 
The scoring form provides lines on which the patient’s responses can be entered (e.g. write in the word that is said 
by the patient). If his/her speed of word production is too fast to permit verbatim recording, a “+” should be 
entered to indicate a correct response. It can be helpful for the first several patients and for patients known to be 
fast with their word production to tape record the session for transcription at a later time. 
Incorrect responses should be recorded and struck through with a single line followed by your initials and the date 
in the margin next to the error. If the patient provides more responses than there are lines on the scoring form, 
place check marks in the boxes to indicate correct responses only. 
The instructions include a specific prohibition against giving proper names or different forms of the same word. 
Therefore, inflections of the same word (e.g. eat-eating; mouse-mice; loose-loosely; ran-run-runs) are not 


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considered correct responses. Patients often give both a verb and a word derived from the verb or adjective (e.g., 
fun-funny; sad-sadness). These are not considered correct responses.  
On the other hand, if the word refers to a specific object (e.g., foot-footstool; hang-hanger), it would be counted as 
a correct answer. Many words have two or more meanings (e.g. foot; can; catch; hand). A repetition of the word is 
acceptable IF the patient definitely indicates the alternative meaning to you.  
Foreign words (e.g. pasta, passé, lasagna) can be counted as correct if they can be considered part of the lexicon of 
the relevant language, the criterion being listed in a standard dictionary of that language. Slang terms are OK if 
they are in general use. 
Count all the correct responses. The number of correct words should be indicated below each column on the 
scoring form that is sent to M. Klein. If the test is discontinued or omitted, please mark this on the bottom of the 
test form and indicate the reason.  
 
4)  
HOPKINS VERBAL LEARNING TEST - REVISED (HVLT-R)  
Part B – Delayed Recall 
Do not read the list of words again! 
Record the time on the clock that you start Part B – Delayed Recall (for example, 10:20 A.M.) on the designated 
space ‘Part B Start Time’ on the HVLT-R form. 
Administer Part B – Delayed Recall after completing all Trail Making Tests and the COWA. There should be at least 
20 minutes between Part A and Part B of the HVLT-R.  
Examiner: “Do you remember that list of words you tried to learn before? Tell me as many of those words as you 
can remember.” 
Check the box on the corresponding line of the HVLT-R scoring form for each word the patient accurately recalls. 
If a word is said that is not in the list (for example, “intrusion”), do not write that word on the form and don’t say 
anything to the patient about the word not being on the list. 
There is no time limit for each recall trial. However, if the patient does not produce any words for 10-15 seconds, 
ask the patient if he/she can remember any more words. 
Record the number of words that were correctly recalled on the scoring form. 
 
Part C – Delayed Recognition 
Examiner: “Now I’m going to read a longer list of words to you. Some of them are words from the original list, and 
some are not. After I read each word, I’d like you to say “Yes” if it was on the original list or “No” if it was not. Was 
[word] on the list?” 
Read the words from the top of the columns down. 
Check either the “Y” (Yes) or “N” (No) box next to each word to indicate the patient’s response. 
Guessing is allowed. 
If the test is discontinued or omitted, please mark this on the bottom of the test form and indicate the reason. 
The score for this portion of the HVLT-R is the number of list words (i.e. words that in CAPS) correctly identified 
(“yes” response) minus the number of non-list words (i.e. words in lower case) incorrectly identified (“yes” 


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response). Therefore, the actual score can range from –12 (no list words identified and all non-list words identified) 
to +12 (all list words identified and no non-list words identified). 
END NEUROCOGNITIVE TEST BATTERY  
You have now completed the neurocognitive test battery.  
Summary of Requirements for Examiner Approval for the EORTC 1709 study 
Prior to testing a patient, potential examiners must: 
Read “Certification & Administration procedures for the Neurocognitive Test Battery and PRO Questionnaires”  
Contact Martin Klein (EORTCsupport@vumc.nl) to obtain website and password information to get access to a 
password-protected website with all the necessary information 
Obtain instructions and copies of the neurocognitive tests from the password-protected website in Dutch, English, 
French, German or Italian 
Watch the training video available at the password-protected website  
Complete the training video post test available at the password-protected website 
Complete a “practice” assessment (see 1.1) 
Complete the Certification Worksheet (see Appendix K)  
Send ALL completed documents (training video post test, test forms of “practice” assessment and signed 
Certification Worksheet) to the attention of M. Klein. 
 
Scan documents and EMAIL: EORTCsupport@vumc.nl 
Summary of Testing Patients for the EORTC 1709 study  
Certified examiners must: 
Inform the patient of the date for neurocognitive assessment. 
On date of testing, neurocognitive testing should be completed in one session: 
  
Test instructions (see 1.3) must be followed verbatim with every patient at every study visit. 
  
All tests should be completed in black pen. 
  
All test results are recorded on the test forms.  
  
In the event that a patient cannot complete a test, specify the reason(s) on the test form. 
  
All test forms must be signed clearly by test administrator with correct study identifiers. 
Before dismissing the patient, thank the patient for cooperation.  
Remind of next appointment and that these tests will be repeated.  
Patients should not be given copies of their tests to avoid learning the material between test administrations. 
Please keep original test forms at site. In the event of questions, contact M. Klein.  
Send ALL completed documents (neurocognitive scoring forms) as soon as possible to the attention of M. Klein. 
Scan documents and EMAIL: EORTCsupport@vumc.nl 


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Appendix K: Certification Worksheet for test 
administrator 
 
EORTC 1709 study 
This worksheet must be completed and signed by the person requesting certification and submitted to M. Klein 
prior to the registration of any patients to the EORTC 1709 study. Refer to “General Procedures: Certification for 
Test Administration” (Appendix J) for details.  
 
 (Y) 
1. 
Have you reviewed the “Certification & Administration procedures for the Neurocognitive 
Test Battery (Appendix J)? 
 
 (Y) 
2. 
Have you watched the training video of neurocognitive test administration and completed 
the post test? 
 
 (Y) 
3. 
Have you completed a "practice" neurocognitive assessment? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of test administrator  
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed name of test administrator 
 
 
 
 
Institution number/Name 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Telephone number of test administrator 
 
 
 
Email of test administrator 
 
If you have any questions regarding the certification and/or test administration, please contact M. Klein. Once you 
have completed this form, please attach both the “practice” neurocognitive assessment forms and the training 
video post test and submit to: 
M. Klein 
Phone: +31 20 4448432 
Email: EORTCsupport@vumc.nl 
 
For M. Klein’s Use Only  
 
 (Y/N) The above individual has been certified for administering the neurocognitive assessments for this 
study. 
Signature  
 
 
 
 
  
 
Date 
 
 
 
 
 


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Appendix L: Specific protocol instructions during the 
COVID-19 pandemic 
Note: All instructions listed in this Appendix will be solely applicable during the COVID-19 crisis. Furthermore, 
please ensure that any protocol deviations resulting from COVID-19 are: 
• 
Adequately documented in the eCRFs as well as the patient’s medical records or in a NTF to be stored in your 
Study binder (ISF). 
• 
Always begin deviation text with “COVID-19” 
Introduction 
Current information suggests that cancer patients have a higher risk of infection and serious complications from 
infections including COVID-19, than other patients.  
It is strongly recommended that investigators exercise medical/clinical judgement, and decisions regarding each 
patient should be individualized after considering the overall goals of treatment, the patient’s current oncologic 
status and treatment tolerance as well as their general medical condition.  
In addition, investigators should adhere to local and institutional guidelines for SARS-CoV-2 infection and 
suspected COVID-19 infection. 
Risk-benefit assessment 
Introduction to trial 
The EORTC trial 1709 is a randomized phase III trial in which the standard of care for patients with newly diagnosed 
glioblastoma, consisting of temozolomide-based chemoradiotherapy, is compared with the same treatment 
combined with marizomib, a novel proteosome inhibitor. Its purpose is to compare safety and efficacy of the 
experimental therapy with the current standard of care. 
Benefits 
In September 2020, the IDMC committee did recommend stopping the study ‘s recruitment by lack of evidence 
regarding the survival benefit (Refer to Section 1.2.1) 
Risks related to the trial especially during the COVID-19 crisis  
There are potential risks associated with the treatment administered in the trial, and during the COVID-19 crisis, 
these risks may be increased: 
• 
The fact that included patients need to come for regular visits to the hospital, increases their exposure risk 
to persons who are contagious for SARS-CoV-2. General rules like social distancing (1.5 m) and avoidance 
of persons with possible signs or confirmed diagnosis can be applied. However, SARS-CoV-2 can also be 
contagious in persons who do not have symptoms, so every hospital visit increases the risk of attracting 
SARS-CoV-2 infection. 
• 
The treatment regimes in both arms may impair the patients’ immune system. This may lead to an 
increased risk of acquiring a SARS-CoV-2 infection with subsequent occurrence of COVID-19 including 
complications up to death.  
• 
Deviations on the treatment regimen, e.g. delays and interruptions, related to the COVID-19 crisis, can 
negatively influence the efficacy of the drugs and thus the benefit for the patients on trial 
COVID-19 vaccination: 


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As per the European Medicines Agency (EMA): 
If physicians decide to administer SARS-CoV-2 vaccines in patients enrolled in the study, decisions should be 
individualised based on the risk of SARS-CoV-2 complications and potential benefit from the vaccine, general 
condition of the patient and the severity of COVID-19 outbreak in a given area or region and in accordance with the 
vaccine label. Furthermore,  the Country  guidelines and/or institutional guidelines  must be followed. 
 
Treatment schedule should not be altered because of the COVID-19 vaccination. 
 
The administration of a SARS-CoV-2 vaccine stating the name of the vaccine used (e.g. Moderna, Pfizer BioNTech, 
AstraZeneca Oxford, …) shall be added in the concomitant medication form in the eCRF and noted in the patient’s 
medical file. Any possible vaccine related AE should be captured in the AE forms in the eCRFs, specifying the 
potential relationship to the vaccine. 
Proposed measures for patients already enrolled during the COVID-19 crisis and recruitment 
The study coordinators in collaboration with EORTC, propose the following guidelines as long as the current COVID-
19 crisis is ongoing. 
Please ensure that any protocol deviations resulting from COVID-19 are:  
Adequately documented in the eCRFs as well as the patient’s medical records or in a Note to file (NTF) to be stored 
in your Study binder (ISF)  
Always specify the reason of the deviation: “COVID-19” 
All COVID-19 related deviations have to be reported to EORTC HQ via 1709@eortc.org 
 
1. Recruitment of new patients 
 
The trial is closed to recruitment. 
 
2. Guidelines for study assessments 
2.1 With respect to study imaging procedures: 
For the baseline study imaging procedures, the protocol requirements have to be fully met. 
For on-study imaging procedures, it is preferred that the patient have imaging performed at the investigative site 
as directed in the protocol.  
If difficulties are encountered to perform the imaging as per the protocol, there are several possibilities, in order of 
preference: 
Have the imaging performed offsite, locally according to the protocol-specified timing. Guidance should be given 
by the site to the local imaging facility about conducting scans according to all applicable requirements (modality 
etc. as per 1709 Imaging Guidelines).  
Have the imaging performed at the site but delayed to a significant extend (a window of 2 weeks instead of 1 week 
will be allowed) due to travel restriction/safety of the participant. 


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Have the imaging performed offsite but delayed (a window of 2 weeks instead of 1 week will be allowed) due to 
travel restriction/safety of the participant. 
Skip the imaging only if impossible to perform due to travel restriction/safety.  
For all above situations, site needs to report this in the comment fields of the applicable CRFs as well as in the 
Source Data. 
2.2 With respect to study treatments: 
In general, patients with a deadly cancer such as glioblastoma should receive the best possible treatment, also 
during the ongoing pandemic. Withholding or interrupting tumour-specific treatment should therefore be avoided 
whenever possible. For the ongoing EORTC-1709 (MIRAGE) trial, the goal is therefore – taking in account directives 
of local and national authorities - to treat patients as closely to the protocol guidelines as possible, without 
endangering their safety and keeping the risk/benefit ratio for the patient acceptable. 
Patients on treatment will be treated as per protocol, in both arms. Protocol assessments should be performed as 
per protocol as much as possible. Again, taking in account local and/or national directives. 
Assessments should be done at the investigative site if possible. 
In the event it is not possible or not in the best interest of a patient to travel to the treating site because of COVID-
19, the following options are proposed (depending whether IMP administration is required during the visit): 
If assessments are required prior to study treatment administration, as stated in the protocol (chapter 6, “Clinical 
evaluation, laboratory tests and follow-up”) and administration of study treatment cannot be postponed the 
following should be considered: 
Arrange the exact date of the visit (and time) in the centre and perform the assessments in advance 
Provide standard laboratory assessments (as described for the respective visit in chapter 6 “Clinical evaluation, 
laboratory tests and follow-up”) of the subject either by qualified staff of contracted laboratories or contractually 
secured healthcare providers whom employ appropriate safety measures and excludes patients whom are 
quarantined or living with or have been quarantined with a confirmed COVID-19 case 
Treatment related laboratory exams can be done in certified offsite facilities. 
Visits that do not involve administration of study treatment, and that cannot be met because of the COVID-19 
crisis, can be replaced by a telephone consultation. 
These deviations will not to be considered as protocol violations and must be documented clearly both in the 
eCRFs as well as in the patients' medical file on site as a COVID-19-related deviation (please specify every deviation 
in the eCRF with “COVID-19”). All other COVID-19-related deviations to the protocol will be documented equally. In 
case of doubt, the 1709 medical monitor can always be contacted to discuss (1709medmon@eortc.org). COVID-19-
related deviations will not be considered protocol violations as long as they do not endanger the safety of the 
patient. 
With respect to Marizomib (MRZ): 
It is advised to follow protocol treatment as closely as possible under the present circumstances for both 
treatment arms, in the best interest of the patient. Skipping or interrupting treatment will also follow the protocol 
guidelines, the same as for toxicities or non-toxicities (see chapter 5 of the protocol “Therapeutic regimens, 
expected toxicity, dose modifications”). Interruptions exceeding the described period (e.g., 3 consecutive 
marizomib administrations or a full cycle in both arms) must be discussed with the medical monitor 


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(1709medmon@eortc.org) to decide if it is still in the best interest of the patient to restart the treatment or 
further delay.  
Marizomib (MRZ), seen the parenteral administration (IV) and the tight timelines between start of reconstitution 
and start of administration, must be administered at your institution. Delays and skipping of administration are 
allowed as described in the protocol (chapter 5 “Therapeutic regimens, expected toxicity, dose modifications”). 
With respect to Temozolomide (TMZ) 
TMZ will continue to be distributed to the patient as per the sites local practice. 
2.3 With respect to patient physical visits:  
Patient physical visits which do not require study treatment administration or are not crucial for the safety of the 
patient can be changed in phone visits where needed. 
2.4 With respect to patient reported data: 
Quality of Life (QoL) questionnaires can be collected through phone or a video conference. Voice scripts are 
available on the study web documentation. 
If phone assessment cannot be arranged, the QoL questionnaires can be collected by providing the questionnaires 
to the patients. Patients should be instructed to complete the questionnaires within the intended timepoint 
(according to protocol). Patients should also complete the date on the form with the date they completed the 
questionnaire. Sites are requested to make their own guidelines to patients in their own language. 
MMSE and neurocognitive testings cannot be collected through phone or video conference. If impossible to 
perform due to travel restriction/safety, a protocol deviation should be documented as this is not according to 
protocol. 
2.5 With respect to collection of biomaterial: 
If the collection of a sample is part of the inclusion criteria (FFPE tumor tissue block or 24 unstained slides) and if 
impossible to collect the sample(s) due to travel restriction and/or safety concerns, the patient cannot be enrolled 
in the trial. 
The collection of sample(s) can be skipped only if all following (2) criteria are met 
• 
The HBM samples are not part of the inclusion criteria and 
• 
The collection of the HBM samples is impossible to perform due to travel restrictions and/or safety 
concerns. 
If these 2 criteria are fulfilled, the sample collection can be skipped and a deviation must be entered, as this was 
not according to the protocol. 
2.6 With respect to collection of RTQA 
Concerning the mandatory central review of the treatment plan for the first two patients per site, we acknowledge 
that timely submission of the data by investigators and review by our reviewers may not be feasible during this 
pandemic with reduced personnel. We ask that you continue to send the data for all patients (those for 
prospective or retrospective review) as soon as possible and we will continue to send the cases to our reviewers 
asking also for their evaluation as soon as possible. Despite this, as a temporary measure, please do not hold up a 
patient’s treatment waiting for review and proceed as planned. We will inform you when processes should be 
returned to timely reviewing. 
2.7 With respect to on-site monitoring visits 


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All on-site monitoring visits are currently suspended. CRAs will contact your staff to schedule the next monitoring 
visit, when the situation will evolve positively and in compliance with the Governments and sites 
recommendations. In the meantime, EORTC 1709 study team will keep in touch with your staff to provide any 
support deemed necessary. 
 
3. Serious adverse event reporting: 
• 
Sites should follow the SAE reporting as described in the protocol e.g. the sites should continue to report SAEs 
immediately and no later than 24 hours from the time the investigator or site staff became aware of the event, 
as described in the protocol. There are no specific adaptations to the protocol defined SAE reporting procedure 
due to COVID-19. 
• 
Should sites have any SAE reporting related questions, please contact us at pharmacovigilance@eortc.org  
• 
Should there be a suspected or confirmed serious case of COVID-19 infection, report it as SAE: 
• 
Please remember to provide the mandatory SAE information as per protocol and as per the CRF 
completion guidelines.  
• 
Please indicate if the COVID-19 infection was confirmed by a test.  
• 
Please provide as much information as available. 
 
4. Informed consent 
In all participating countries, except Germany, if an amendment is currently ongoing requiring re-consent of 
already enrolled patients and/or additional consent is necessary for the implementation of new urgent changes in 
trial conduct (mainly expected for reasons related to COVID-19), alternative ways of obtaining such re-consents 
should be considered during the pandemic e.g. contacting the trial participants via phone or video-calls and 
obtaining oral consents supplemented with email confirmation. Any consent obtained this way should be 
documented and confirmed by way of normal consent procedures at the earliest opportunity when the trial 
participants will be back at the regular sites. 
 

SAP_001.pdf: 
Marizomib (NPI-0052) 
 
Statistical Analysis Plan v2.0. Protocol 1709-BTG 
 
EORTC 
Confidential and Proprietary 
1 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
A phase III trial of marizomib in combination with standard temozolomide-based radio 
chemotherapy versus standard temozolomide-based radio chemotherapy alone in patients with 
newly diagnosed glioblastoma 
 
STUDY DRUG: 
 Marizomib (NPI-0052) 
PROTOCOL NUMBER: 
 Intergroup Study (EORTC-1709-BTG)  
DATE FINAL: 
 18/03/2021  
 
Prepared by: 
Thierry Gorlia, EORTC lead statistician 
Avenue E. Mounierlaan 83/11 
 Brussel 1200 Bruxelles  
België – Belgique 
 
 
CONFIDENTIAL 
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. 


Marizomib (NPI-0052) 
 
Statistical Analysis Plan v2.0. Protocol 1709-BTG 
 
EORTC 
Confidential and Proprietary 
2 
 
TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS.......................................................................................6 
2. 
INTRODUCTION ........................................................................................................9 
3. 
USE OF THE STATISTICAL ANALYSIS PLAN ...................................................11 
4. 
STUDY OBJECTIVES ..............................................................................................12 
4.1. 
Primary Objective .......................................................................................................12 
4.2. 
Secondary Objectives .................................................................................................12 
5. 
INVESTIGATIONAL PLAN .....................................................................................13 
5.1. 
Overall Study Design and Plan ...................................................................................13 
5.2. 
Study Endpoints ..........................................................................................................21 
5.2.1. 
Primary Efficacy Endpoint(s) .....................................................................................21 
5.2.2. 
Secondary Efficacy Endpoint(s) .................................................................................21 
5.2.3. 
Key Exploratory Endpoint ..........................................................................................21 
5.2.4. 
Safety Endpoints .........................................................................................................21 
5.3. 
Stratification, Randomization, and Blinding ..............................................................22 
5.4. 
Sample Size Determination ........................................................................................22 
6. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................24 
6.1. 
Analysis Conventions .................................................................................................24 
6.2. 
Analysis Sets ...............................................................................................................26 
6.2.1. 
Intent-to-Treat Population/Full Analysis Set ..............................................................26 
6.2.2. 
Safety Population ........................................................................................................26 
6.2.3. 
Per-Protocol Population ..............................................................................................27 
7. 
SUBJECT DISPOSITION ..........................................................................................28 
8. 
PROTOCOL VIOLATIONS ......................................................................................30 
9. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................31 
9.1. 
Demographics and Baseline Characteristics ...............................................................31 
9.2. 
Disease Characteristics ...............................................................................................32 
9.3. 
Medical History ..........................................................................................................33 
9.4. 
Prior and Concomitant Medications ...........................................................................33 
9.4.1. 
Prior Medications ........................................................................................................34 
9.4.2. 
Concomitant Medications ...........................................................................................34 
10. 
STUDY TREATMENTS AND EXTENT OF EXPOSURE......................................35 


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10.1. 
Treatment Duration .....................................................................................................35 
10.2. 
Cumulative Dose ........................................................................................................36 
10.3. 
Dose Intensity .............................................................................................................36 
10.4. 
Relative Dose Intensity ...............................................................................................37 
10.5. 
Dose Reduction/Interruption/Delay ............................................................................38 
11. 
EFFICACY ANALYSIS ............................................................................................39 
11.1. 
Multiplicity .................................................................................................................39 
11.2. 
Analysis of Primary Efficacy Endpoint ......................................................................40 
11.3. 
Analyses of Secondary Efficacy Endpoints ................................................................41 
11.3.1. 
Progression-free Survival ...........................................................................................41 
11.3.2. 
Response .....................................................................................................................42 
11.3.3. 
Mini Mental State Examination (MMSE) ..................................................................44 
11.4. 
Pre-planned sensitivity analyses .................................................................................44 
11.5. 
Subgroup Analyses .....................................................................................................44 
12. 
SAFETY ANALYSIS ................................................................................................46 
12.1. 
Adverse Events ...........................................................................................................46 
12.1.1. 
Treatment-emergent adverse events (TEAEs) ............................................................46 
12.1.2. 
Deaths .........................................................................................................................48 
12.1.3. 
Adverse Events of Special Interest .............................................................................48 
12.2. 
Clinical Laboratory Evaluations .................................................................................49 
12.2.1. 
Hematology .................................................................................................................49 
12.2.2. 
Biochemistry ...............................................................................................................49 
12.3. 
Vital Sign/Physical Examination Measurements........................................................50 
12.4. 
Electrocardiograms .....................................................................................................50 
12.5. 
Pharmacokinetic Endpoints ........................................................................................50 
12.6. 
Health Economic Endpoints .......................................................................................51 
13. 
HEALTH-RELATED QUALITY OF LIFE ANALYSIS ..........................................52 
13.1. 
Rationale .....................................................................................................................52 
13.2. 
Objective .....................................................................................................................52 
13.3. 
HRQoL Instrument .....................................................................................................52 
13.4. 
Study Design ...............................................................................................................53 
13.5. 
HRQoL Schedule ........................................................................................................54 
13.6. 
Statistical Considerations ............................................................................................54 


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13.6.1. 
Primary Analysis ........................................................................................................54 
13.6.2. 
Sensitivity Analysis ....................................................................................................55 
13.6.3. 
Missing Data ...............................................................................................................55 
14. 
REFERENCES ...........................................................................................................56 
15. 
APPENDICES ............................................................................................................57 
15.1. 
Handling of Dates .......................................................................................................57 
15.1.1. 
Calculation Using Dates .............................................................................................58 
15.2. 
Censoring Rules for PFS ............................................................................................59 
 
 
 


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LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms ............................................................................ 6 
 


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1. 
List Of Abbreviations 
 
Table 1: Abbreviations and Specialist Terms 
AC-AT 
Average change after treatment 
AC-DT 
Average change during treatment 
AE 
Adverse event 
 
Akaike Information Criteria 
 
American Joint Committee on Cancer 
ALT 
Alanine aminotransferase (SGPT) 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase (SGOT) 
BMI 
Body mass index 
BSA 
Body surface area 
BTG 
Brain Tumor Group 
CI 
Confidence interval 
CID 
Clinically important difference 
CIR 
Clinically important response  
CrCl 
Creatinine clearance 
CSR  
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
D10-AT 
Deterioration after treatment 
D10-DT 
Deterioration during treatment 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EORTC 
European Organisation for the Research and Treatment of Cancer 
EOS 
End of study 
EOSR 
End-of-study report 
FAR 
Final analysis report 


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FUP 
Follow-up 
GBM 
Glioblastoma multiforme 
Hgb 
Hemoglobin 
HLT 
High-level term 
HLGT 
High-level group term 
HR 
Hazard ratio 
HRQoL 
Health-related quality of life 
IDH 
Isocitrate dehydrogenase 
IDMC 
Independent Data Monitoring Committee 
IHC 
Immunohistochemistry 
IQR 
Interquartile range 
ITT 
Intent-to-treat 
IV 
Intravenous (-ly) 
LLT 
Lowest level term 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
mMGMT 
Methylated O-6-methylguanine-DNA methyltransferase 
MGMT 
O-6-methylguanine-DNA methyltransferase 
MMSE 
Mini-Mental State Examination 
MRI 
Magnetic resonance imaging 
MRZ 
Marizomib 
NA 
Not applicable 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PO 
Orally (per os) 
PP 
Per Protocol Population 
PT 
Preferred term 


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QLQ-BN20 
Quality of Life Questionnaire Brain Cancer Module 
QLQ-C30 
Quality of Life Questionnaire C30 
QoL 
Quality of life 
RANO 
Response Assessment in Neuro-Oncology 
RT 
Radiotherapy 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SE 
Standard error  
SGOT 
Serum glutamic oxaloacetic transaminase (AST) 
SGPT 
Serum glutamic pyruvic transaminase (ALT) 
SP 
Safety population  
SSC 
Study Steering Committee 
TMZ 
Temozolomide 
TR 
Translational Research 
TTE 
Time to event 
TTF 
Tumor treating fields 
uMGMT 
Unmethylated MGMT 
ULN 
Upper limit of normal 
US 
United States 
UV 
Ultraviolet 
WHO 
World Health Organization 
 


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2. 
Introduction 
The intergroup Study (EORTC-1709-BTG) protocol v7.0 which was issued on 22 OCT 2019 
planned a review of study data by the Independent Data Monitoring Committee (IDMC) for futility 
and safety. The clinical cutoff date for this analysis was 28 APR 2020 when 88 deaths were initially 
observed as requested by study design. After data update and cleaning, the database was locked 
on 07 AUG 2020. The IDMC performed the study review on 14 SEP 2020. At the cutoff date, 616 
patients were randomized and 106 deaths were reported. Although the trial results did not cross 
the pre-specified futility boundary, the IDMC observed that there was as yet no evidence that 
marizomib provides a benefit in survival. The statistical data presented also suggested that it was 
extremely unlikely that a difference would emerge with additional patients or further follow-up. 
The IDMC observed that marizomib in this combination induced severe neurological and 
neuropsychiatric disorders, as well as other treatment-related Grade 3-4 side effects, in a 
substantial proportion of the patients. The IDMC therefore recommended that the study be 
discontinued from further recruitment and that results be disclosed to the medical community as 
soon as possible. However, if patients still on treatment were tolerating marizomib, they were 
allowed to continue, if so wished by the patient and treating physician. The IDMC did not request 
that a further interim analysis be implemented.  
Following the IDMC recommendation, the patient recruitment was prematurely closed. The total 
number of randomized patients was 749 (750 planned). The results of the study were prematurely 
disclosed to the study investigators and to Celgene, a BMS company, and Bristol Myers Squibb 
(BMS). An amended study protocol v8.0 was released on 30 SEP 2020 to reflect that the interim 
OS analysis performed is considered as the primary OS analysis of the study.  
For the publication of the primary analysis results, a new database lock will be performed in mid 
2021 at the same cut-off date (28 APR 2020) as for the IDMC review but with cleaner data for, 
primary endpoint, study treatment exposure, safety and other secondary endpoints.  
All randomized patients will be followed till the total number of overall survival (OS) events for 
the initially planned final analysis is observed (488 deaths in the intent-to-treat [ITT] population 
and 320 in the unmethylated O-6-methylguanine-DNA methyltransferase [MGMT] subgroup). 
The cutoff date of the long term follow-up analysis is expected Q2 2022. The number of deaths 
will be closely monitored, ie, every three months. More frequent monitoring might be decided 
when number of deaths in the ITT population gets closer to 488. At that date, a long term follow-
up analysis will be performed with more mature data for all endpoints. As the primary results will 
have been already released, the intent of this long term follow-up analysis is for descriptive 
purposes only.  
The original signed statistical analysis plan (SAP) should be amended and signed to describe the 
analyses and data presentations for the current primary analysis and the long-term follow-up 
analysis. 
The purpose of SAP v2.0 is to ensure the credibility of the study findings by pre-specifying the 
statistical approaches to the analysis of study data prior to database lock. The SAP was prepared 
by European Organisation for the Research and Treatment of Cancer (EORTC) and reviewed by 
BMS. It contains definitions of analysis populations, derived variables and statistical methods for 
the analysis of efficacy and safety. It describes analysis conventions to guide the statistical 
programming work. Throughout this SAP, the treatment arms are referred to as control and MRZ. 


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This SAP was finalized and signed prior to the clinical database lock for the primary analysis. All 
statistical analyses detailed in this SAP will be conducted using SAS® Version 9.4 or higher.  
 
Compared to SAP v1.0 main changes in the SAP v2.0 are the following: 
 Interim OS analysis becomes the primary OS analysis. The multiplicity strategy will be 
applied during this analysis. 
 The long term follow-up analysis will be performed at 5% significance.  
 The re-randomization test will not be performed because of lack of marizomib benefit 
following the review of the analysis of OS by the IDMC. 


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3. 
Use of the Statistical Analysis Plan 
 
The primary analysis report will present the following sections of the SAP: 
Section 
Presented 
7. Subject Disposition 
All 
8. Protocol Deviations/Violations 
All 
9. Demographics and Baseline Characteristics 
All 
10. Study Treatments and Extent of Exposure 
All 
11. Efficacy Analysis 
All  
12. Safety Analysis 
All 
13. Quality of Life Analysis 
All 
 
The long term follow-up analysis report will present the following sections of the SAP: 
Section 
Presented 
7. Subject Disposition 
All 
8. Protocol Deviations/Violations 
All 
9. Demographics and Baseline Characteristics 
All 
10. Study Treatments and Extent of Exposure 
All 
11. Efficacy Analysis 
All  
12. Safety Analysis 
All 
13. Quality of Life Analysis 
All 
Important note: Further to the IDMC recommendations, marizomib will be discontinued 
per physician/patient decision with the consequence of a decreased exposure to marizomib 
compared to exposure planned in the protocol. All analyses will be performed in the 
populations planned in the protocol.  


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4. 
Study Objectives 
To compare the overall survival of glioblastoma patients treated with standard temozolomide 
(TMZ)-based chemo radiotherapy alone or TMZ-based chemo radiotherapy in combination with 
marizomib. 
4.1. 
Primary Objective 
The primary objective of this study is to compare overall survival in subjects receiving marizomib 
(MRZ) in combination with control treatment (ie, TMZ with concomitant radiotherapy [RT], 
followed by TMZ maintenance therapy) (MRZ/TMZ/RT→MRZ/TMZ) with subjects receiving 
control treatment only (TMZ/RT→TMZ). The testing strategy is defined to assess this objective 
in both the ITT population and the uMGMT stratum with adequate statistical power.  
4.2. 
Secondary Objectives 
Secondary objective is to compare progression-free survival (PFS) between the two treatment 
arms in the ITT population and in the uMGMT stratum.  
Further secondary objectives are: 
To assess the response to MRZ combined with TMZ/RT→TMZ in comparison of 
TMZ/RT→TMZ in the ITT population and in the uMGMT stratum. 
To assess the safety and tolerability of MRZ combined with TMZ/RT→TMZ in comparison to 
TMZ/RT→TMZ in the safety population (SP). 
To assess objective and self-perceived neurocognitive function and health-related quality of life 
(HRQoL) of subjects treated with this approach in the ITT population and in the uMGMT 
stratum. 
 


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5. 
Investigational Plan 
5.1. 
Overall Study Design and Plan 
This is a multicenter, randomized, controlled, open-label Phase 3 superiority trial with a safety 
monitoring plan and an early stopping rule for futility.  
After signing the informed consent form and upon confirmation of the subject eligibility, 
subjects were randomized 1:1 to the experimental arm, referred to as 
(MRZ/TMZ/RT)→MRZ/TMZ, or to the control arm (TMZ/RT→TMZ). The total targeted 
number of subjects to be randomized is 750 (approximately 375 in each arm). 
Experimental arm: Standard radiotherapy (60 Gy in 30 fractions over 6 weeks) + TMZ 75 mg/m2 
orally (PO) daily for 6 weeks (during RT) and MRZ dose 0.8 mg/m2 intravenously (IV) at days 
1, 8, 15, 29 and 36. 
This is followed, after 4-week break, by up to 6 cycles of maintenance TMZ 150-200 mg/m2 PO 
on days 1-5 of a 28-day cycle and up to 18 cycles of maintenance MRZ treatment (0.8 mg/m2 
IV) at days 1, 8, 15 of a 28-day cycle until disease progression, unacceptable toxicity or 
withdrawal of consent. 
Continuation of maintenance TMZ beyond 6 cycles is not encouraged but will not constitute a 
protocol violation as long as it does not exceed 12 cycles in total. 
Control arm: Standard RT (60 Gy in 30 fractions over 6 weeks) + TMZ 75 mg/m2 PO daily for 6 
weeks (during RT) then (after 4-week break) up to 6 cycles of maintenance TMZ 150-200 mg/m2 
PO on days 1-5 of a 28-day cycle. 
Continuation of maintenance TMZ beyond 6 cycles is not encouraged but will not constitute a 
protocol violation as long as it does not exceed 12 cycles in total. 
Subjects who at the start of the study are planning to get tumor-treating-fields (TTF) treatment 
are excluded from study entry, however those who decide after completing the concomitant part 
of the treatment to get TTF as part of their adjuvant treatment will not be discontinued, nor will 
they be considered protocol violators.  
  
 


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Study treatment was discontinued for a subject in the event of: 
 Progressive disease 
 Unacceptable overall toxicity for all drugs. 
 Protocol violation  
 Loss to follow-up  
 Patient significant non-compliance 
 Pregnancy 
 Physician/Patient decision 
 Death 
An end-of-treatment visit had to be performed, and follow-up for survival, subsequent therapy 
and date of progressive disease (PD) were collected, whenever feasible. 
Subjects had the right to withdraw from the study at any time for any reason.  
In the case that the subject decides to prematurely discontinue study treatment, the subject must 
be followed for disease assessments and survival follow-up, unless the subject decides to 
withdraw consent for the collection of these data. In the case that the subject withdraws consent, 
the subject must be asked if they can still be contacted for survival follow-up only. The outcome 
of these discussions should be documented in both the medical records and in the electronic case 
report form (eCRF).  
 
 
 
 


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Study activities 
 
Before 
randomization 
Within 72h of treatment start 
Randomization 
TMZ/RT (± MRZ) 
 
TMZ ± MRZ 
MRZ maintenance 
Follow-up 
(every 
12 weeks ± 
7 days) 
Day 
-28 to -1 
-14 to -1 
-7 to -1 
Day 1k 
Day 1 MRZ only 
weekly 
At 4 weeks (+5d) 
End of RT period 
  before cycle start  
  (within3d of) 
Cycle 1 Day 1/8 MRZ 
only 
Cycle 2 Day 1 MRZ 
only  
Every 8 weeks (± 7d) 
Every 8 weeks MRZ 
only (± 7d) 
 Every 3 cycles (± 7d) 
Every 16 wks (± 7d) 
 Every 24 wks (± 7d) 
EOT (28d after last 
TMZ/MRZ) 
FU without progression 
FU after progression 
Descrip-
tion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signed 
informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demogra-
phics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and 
cancer history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor 
pathology 
assessment 
from archival 
FFPE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
adverse event 
assessment 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ongoing 
medications 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brain MRI 
scans 
 
Xa 
 
 
 
 
 
 
 
 
 
 
 
Xl 
 
 
 
 
Xm 
Xp 
 


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Before 
randomization 
Within 72h of treatment start 
Randomization 
TMZ/RT (± MRZ) 
 
TMZ ± MRZ 
MRZ maintenance 
Follow-up 
(every 
12 weeks ± 
7 days) 
Day 
-28 to -1 
-14 to -1 
-7 to -1 
Day 1k 
Day 1 MRZ only 
weekly 
At 4 weeks (+5d) 
End of RT period 
  before cycle start  
  (within3d of) 
Cycle 1 Day 1/8 MRZ 
only 
Cycle 2 Day 1 MRZ 
only  
Every 8 weeks (± 7d) 
Every 8 weeks MRZ 
only (± 7d) 
 Every 3 cycles (± 7d) 
Every 16 wks (± 7d) 
 Every 24 wks (± 7d) 
EOT (28d after last 
TMZ/MRZ) 
FU without progression 
FU after progression 
Mini Mental 
State 
Examina-tion 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Xn 
Xq 
 
Quality of 
Life question-
naire 
(modified 
EORTC QLQ 
C30/BN20) 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Xr 
Xr 
G8 geriatric 
screening 
tools 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurocogniti
ve assess-
mentsb 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Xn 
Xq 
 
Physical 
examina-tion 
including 
heightc, 
weight 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Heart rate, 
tempera-ture, 
blood 
pressure 
 
 
X 
 
 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 


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Before 
randomization 
Within 72h of treatment start 
Randomization 
TMZ/RT (± MRZ) 
 
TMZ ± MRZ 
MRZ maintenance 
Follow-up 
(every 
12 weeks ± 
7 days) 
Day 
-28 to -1 
-14 to -1 
-7 to -1 
Day 1k 
Day 1 MRZ only 
weekly 
At 4 weeks (+5d) 
End of RT period 
  before cycle start  
  (within3d of) 
Cycle 1 Day 1/8 MRZ 
only 
Cycle 2 Day 1 MRZ 
only  
Every 8 weeks (± 7d) 
Every 8 weeks MRZ 
only (± 7d) 
 Every 3 cycles (± 7d) 
Every 16 wks (± 7d) 
 Every 24 wks (± 7d) 
EOT (28d after last 
TMZ/MRZ) 
FU without progression 
FU after progression 
Karnofsky 
Perfor-mance 
Status 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
12-lead 
ECGt,u 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Hemato-logyd 
 
X 
 
 
 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
Coagula-tione 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Biochemis-
tryf 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
Urinalysisg  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
FFPE tissue 
(1 paraffin 
block or 24 
unstained 
slides 
minimum) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mandatory: 
20 mL blood 
draw 
Optional: 30 
mL blood 
drawh 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Xn 
 
Xn 


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Before 
randomization 
Within 72h of treatment start 
Randomization 
TMZ/RT (± MRZ) 
 
TMZ ± MRZ 
MRZ maintenance 
Follow-up 
(every 
12 weeks ± 
7 days) 
Day 
-28 to -1 
-14 to -1 
-7 to -1 
Day 1k 
Day 1 MRZ only 
weekly 
At 4 weeks (+5d) 
End of RT period 
  before cycle start  
  (within3d of) 
Cycle 1 Day 1/8 MRZ 
only 
Cycle 2 Day 1 MRZ 
only  
Every 8 weeks (± 7d) 
Every 8 weeks MRZ 
only (± 7d) 
 Every 3 cycles (± 7d) 
Every 16 wks (± 7d) 
 Every 24 wks (± 7d) 
EOT (28d after last 
TMZ/MRZ) 
FU without progression 
FU after progression 
Optional: 
fresh-frozen 
tissuei 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xᵒ 
Serum 
pregnancy 
testj 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
Randomi-
zation 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomi-tant 
medications 
& procedures 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
Adverse 
events 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
Survival 
status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Subsequent 
anti-GBM 
regimens, and 
treatment 
outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
PK study in 
MRZ arm 
only 
 
 
 
 
 
 
 
 
 
 
 
Xv 
 
 
 
 
 
 
 
 
 


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a Brain MRI scan with contrast after surgical resection or biopsy. The results of tumor assessments done as part of standard of care that are within the 14-day 
screening period do not have to be repeated if they were done at the participating site. All scans are to be uploaded on the EORTC imaging platform. 
b For participating centers, tests of objective neurocognitive function: HVLT-R, Trail Making Tests Part A & B and COWA and the MOS questionnaire on self-
perceived neurocognitive function (Error! Reference source not found. of the protocol) 
c Height is only to be collected at baseline 
d Hematology consists of hemoglobin (Hgb), hematocrit (Hct), red blood cell (RBC) count, white blood cell (WBC) count, ANC, platelet 
e Coagulation consists of prothrombin time (PT) or International Normalized Ratio (INR) and partial thromboplastin time (PTT) or activated PTT (aPTT) 
f Biochemistry consists of sodium, potassium, chloride, bicarbonate, calcium, magnesium, glucose, urea or BUN, serum creatinine, uric acid, ALT, AST, alkaline 
phosphatase, total protein, albumin, and total bilirubin 
g Urinalysis consists of protein, blood, glucose, pH; microscopic (RBC, WBC, casts) analysis should be done if urinalysis is abnormal 
h For translational research: Mandatory 10 mL blood draw for plasma and 10 mL blood draw for serum; Optional 10 mL blood draw for extracellular vesicles and 
20 mL for PBMC  
i If site collects fresh frozen tumor tissue, optional collection 
j For WOCBP, urine or serum pregnancy tests are to be done within 7 days of randomization and within 72 hours of treatment start 
k If baseline assessments have been done within 14 days of start of treatment, they do not have to be repeated for cycle 1 day 1  
l The first MRI scan should occur 4 weeks post end of RT; the 8-week imaging schedule will start after this scan 
m Brain MRI scan if one has not been done in the previous 4 weeks and no progression as yet been recorded 
n At disease progression 
o Frozen tissue sample will be collected at progression if the patient undergoes salvage surgery 
p Results of MRI scans done as part of standard of care will be collected, or done as per the study schedule of every 8 weeks (continuing on initial schedule) until 
disease progression 
q For all centers, MMSE every 16 weeks ± 1 week until disease progression;  
 For participating centers, tests of objective neurocognitive function: HVLT-R, Trail Making Tests Part A & B and COWA and the MOS questionnaire on self-
perceived neurocognitive function every 12 weeks ± 2 weeks, until disease progression 
r Quality of life assessment (modified EORTC QLQ C30/BN20) every 16 weeks ± 1 week until death or lost to follow up 
s G8 will be measured in all patients aged 70 years and above at baseline.ͭ 
t For subjects on the marizomib arm, 12-lead ECG to be collected on following days and timepoints ONLY: at baseline within 7 days of randomization: on D1 of 
concomitant treatment within 15 minutes after end of MRZ infusion; on Cycle 2 Day 1 of adjuvant treatment after end of MRZ infusion; and as clinically 
indicated. 


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u For subjects enrolled prior to the implementation of protocol version 5., 12-lead ECG on Day 1 on the subsequent two cycles of adjuvant treatment within 15 
minutes after end of MRZ infusion. 
 v In marizomib arm only : C1D1 ( first day of first adjuvant cycle) 2 mL within 10 minutes after end of infusion and 2 mL at 45 minutes following end of 
infusion. C1D8 2mL at 45 minutes following end of infusion. 
 


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5.2. 
Study Endpoints 
5.2.1. 
Primary Efficacy Endpoint(s) 
Primary endpoint is overall survival (OS). 
5.2.2. 
Secondary Efficacy Endpoint(s) 
The following are secondary endpoints:  
Key secondary endpoints: 
 Progression-free survival (PFS)  
Other secondary endpoints: 
 Best overall response, objective response, complete response, duration of response  
 Quality of Life (EORTC QLQ C30 version 3/BN20 version 1.0) 
 Neurocognitive assessment (HVLT-R, Trail Making Tests Part A & B and COWA and 
the MOS questionnaire on self-perceived neurocognitive function) 
 Mini Mental State Examination (MMSE) 
5.2.3. 
Key Exploratory Endpoint 
The following is the key translational research (TR) endpoint: 
 Activity of the proteasome in the tumor tissue prior to treatment start and correlation with 
subject’s outcome. 
5.2.4. 
Safety Endpoints 
The following are the safety endpoints: 
 Frequencies and percentages of worst AEs or laboratory event grades 
 
 


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5.3. 
Stratification, Randomization, and Blinding 
 
Subjects were centrally randomized in a 1:1 ratio using the multidimensional dynamic allocation 
algorithm from Medidata BALANCE module.  
Medidata Balance uses a multidimensional Dynamic Allocation algorithm that minimizes 
imbalances across multiple dimensions including overall study, sites, factors and cross-factor 
strata.  Like other dynamic allocation methods, it contains: 
 An imbalance measure expressing the distance between the target treatment allocation and 
an allocation of treatments within a subgroup of subjects.  
 A scoring system to summarize and prioritize the treatment imbalances over all subgroups 
of subjects (e.g. over sites, randomization factors, strata, etc.).  
 A selection method to assign a treatment to the next subject which will minimize the total 
imbalance score. 
Subjects who are eligible were randomized according to the following stratification factors: 
 Institution,  
 Age (≤55, >55 years),  
 Karnofsky performance status (70/80, 90/100),  
 Extent of surgery (partial/biopsy, gross total).  
 
5.4. 
Sample Size Determination 
For this study, we assumed that in the ITT population the standard treatment plus MRZ presents 
with a superior OS efficacy compared to the standard treatment alone, estimated by a hazard ratio 
(HR) equal to 0.74 (26% reduction of the hazard of death). This corresponds to a median OS of 16 
months in the standard treatment alone compared to 21.6 months for standard treatment plus MRZ 
(Chinot OL, 2014) (Gilbert MR, 2014). We also assume that at the time of final analysis, the 
MGMT methylation status will be distributed to 60% unmethylated, 30% methylated and 10% 
undetermined. We also hypothesized that the MRZ effect would be mainly present in the uMGMT 
stratum where it would display a HR of 0.70 (median OS of 13 months in the control arm compared 
to 18.6 months for MRZ) (Chinot OL, 2014) (Gilbert MR, 2014). The effect in the mMGMT 
stratum would be HR > 0.80 and in the undetermined cases, which are assumed to be a balanced 
mixture of uMGMT and mMGMT cases, the effect would be in line with the overall population, 
ie,  HR = 0.74. 
Based on the network of the institution, it should be possible to recruit 400 subjects/year 
(150 subjects in the first year, and then 400 subjects per year).  
For the primary endpoint of OS, the formal statistical testing is based on comparisons between two 
treatment groups in both ITT population and uMGMT stratum. We will use a graphical method to 
control overall Type 1 error at one-sided 2.5% (Bretz F, 2009). We have to recruit 750 subjects to 
show the OS difference with 86% power (taking into account the interim analysis for futility) and 
overall one-sided 1.5% significance in the ITT population and with 80.7% power and one sided 
1% significance in the uMGMT stratum. We will recruit these subjects in about 30 months and 
will follow them up for about 19 months, the time necessary to observe the required 488 deaths 


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(320 in uMGMT) for the primary analysis. We will perform the test in the ITT population and in 
the uMGMT stratum simultaneously. If one of them is significant, we will attribute the assigned 
alpha to the other. At the final analysis, we will provide treatment effect estimates in the uMGMT 
stratum, in the mMGMT stratum and in the undefined MGMT stratum. 
In order to avoid exposing too many subjects to a possibly ineffective and/or toxic treatment, a 
non-binding futility analysis will be conducted in the ITT population when about 88 deaths occur 
(18% of the number of deaths needed for the final analysis). The interim analysis will be evaluated 
by an IDMC. The IDMC will recommend continuing the study or stopping the study for futility. 
If the observed HR is >1.12, the study may be considered to be futile. 
We will analyse other endpoints at exploratory two-sided 5% significance.  
 


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6. 
General Statistical Considerations 
6.1. 
Analysis Conventions 
This section provides general considerations for data handling, summary, and analysis. This also 
includes general definitions of certain kinds of endpoints. More details about specific endpoints 
and additional analysis methods, as needed, will be specified within the description of analysis of 
data in this SAP.  
 Data from all study centers will be combined for analysis; 
 All stratified primary efficacy analyses in the ITT population and in the PP 
population will use the stratification factors (see section 5.3). All stratified sensitivity 
efficacy analyses in the ITT population will use the stratification factors and the 
MGMT methylation status;   
 Frequency tables will be tabulated (by treatment group or otherwise) for all 
categorical variables by the levels of the variables as they appear on the CRF (with 
%). Categories with a text field specification will be tabulated as categories and then 
supplemented by a listing with the following information for the subjects fulfilling the 
condition for the specification (subject identification, treatment group, value of the 
item and text field contents); 
 Dates relating to events prior to entry will be presented as the delay in days (or 
weeks, months, or years) between the past event and the date of entry (date of first 
date of dosing of study drug – date of past event + 1) and presented using the median, 
range, interquartile range (IQR) as well as mean and standard deviation. For example, 
on the randomization checklist, the date of last administration of prior treatment (or 
the date of first diagnosis of the cancer) will be presented as the time elapsed (in days, 
weeks, months or years, as appropriate) since the day of the last administration and 
the date of entry on study (date of randomization – last administration/diagnosis +1); 
 Other delays (eg, re-treatment delays) are presented as continuous variables using the 
median, range and IQR as well as mean and standard deviation; 
 Continuous variables for which a coding system exists (such as for laboratory data) 
will be recoded into categories (for adverse events, the grading scale specified in the 
protocol will be used). Whenever no specific scale exists, lab data will be categorized 
based on the normal range: for example, below the lower normal limit (when 
appropriate), within the normal range, above the upper limit of normal (ULN) and the 
degree to which it is above the ULN (for example > 2.5 x ULN, > 5 x ULN, > 10 x 
ULN). For laboratory data, the nadir is generally displayed. The nadir in a given cycle 
is the lowest laboratory value in that cycle; the overall nadir for a subject is the lowest 
laboratory value among all cycles; 
 Other continuous variables (for example age, dose …) are presented using the median 
range (minimum, maximum), IQR, mean and standard deviation; 
 If appropriate, continuous data may also be presented in categories (for example, age 
may also be grouped in decades); 


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 P-values will be rounded to 3 decimal places. P-values that round to 0.000 will be 
presented as ‘<0.001’ and p-values that round to 1.000 will be presented as ‘>0.999’;  
 Confidence intervals (CIs) will be presented as 2-sided 95% CIs unless specified 
differently in specific analysis; 
 All mean and median values will be formatted to one more decimal place than the 
measured value. Standard deviation values will be formatted to two more decimal 
places than the measured value; 
 All percentages will be rounded to whole numbers and one decimal. The number and 
percentage of responses will be presented in the form xx (xx.y%), where the 
percentage is in the parentheses; 
 All listings will be sorted for presentation in order of treatment arm, subject, and date 
of procedure or event; 
 All analysis and summary tables will have the analysis population sample size (ie, 
number of subjects); 
 The day of the first dose of any study drug will be defined as Day 1.  
 
Dealing with Multiple Values on the Same Day for Lab and Vital Signs Parameters 
In cases where multiple values for the same variable are collected on the same visit (including 
baseline visit and post-baseline visits), the arithmetic average will be calculated and used as the 
value for that day for mean changes in laboratory and vital signs parameters.  
Definition of Baseline Observation 
Unless otherwise specified, the baseline observation is defined as the last non-missing 
measurement collected prior to or on randomization. If no measurement collected prior to or on 
randomization, then the last non-missing observation prior to or on the first dose date of study drug 
(TMZ/MRZ) is considered. 
Definition of Final Observation 
For lab and vital sign parameters, the final observation is defined as the last non-missing post-
baseline measurement collected during the study. 
 
Time-to-Event Endpoints  
All time-to-event (TTE) endpoints are defined using a time variable and an event indicator. The 
time variable represents the time from a pre-defined time origin to the onset of a predefined event 
of interest or the last time when adequate assessments have been made to rule out the onset of the 
event. The latter case indicates that the endpoint has been right-censored. In this study, a time 
variable is defined as the date of event or censoring - date of randomization + 1.The event indicator 
is set to 0 if the event has been observed during the course of the study and 1 if it is censored. 
When multiple assessments are needed to ascertain the occurrence of an event, the earliest date 
among all of these assessments is taken to be date of the event or censoring. The time variable will 
be computed in days and converted into months (1 month = 30.4375 days) for analysis of TTE 


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endpoints. When no post-randomization observations are available for a subject for any given 
endpoint, then the endpoint is taken to be censored on the date of randomization. All TTE 
endpoints defined in this study are concerned with only the first incidence of an event of interest, 
and recurrence of the same event is not considered. An event, however, may be defined in a 
composite fashion, i.e. as the occurrence of one among several different outcomes. An example of 
such an endpoint is PFS where the event is either disease progression or death. The composite 
event is observed when at least one of the component events occurs, and the time to the earliest 
among the occurring component events is considered to be the TTE for the composite event. 
 
End of Study  
End of study occurs when all of the following criteria have been satisfied: 
 1. Thirty days after all subjects have stopped protocol treatment 
 2. The trial is mature for the analysis of the primary endpoint as defined in the protocol 
 3. The database has been fully cleaned and frozen for this analysis 
EORTC reserves the right to terminate this study prematurely at any time for reasonable medical 
or administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (e.g. Institutional Review Board [IRB]/Ethics Committee [EC], 
regulatory authorities, etc.). 
6.2. 
Analysis Sets 
The primary efficacy analyses will be performed on the ITT population for the primary and 
secondary endpoints. Sensitivity analyses will be conducted for the primary and secondary 
endpoints based on the per protocol Set (PP) population and the additional populations defined in 
this section. 
The safety analyses will be conducted only in the Safety population (SP). 
Subjects excluded from PP or SP will be reported in separate tables with the reason(s) of 
exclusion. 
 
6.2.1. 
Intent-to-Treat Population/Full Analysis Set 
The ITT population includes all subjects in the arm they were allocated by randomization, i.e. 
regardless of whether they started any study treatment or received the wrong treatment. The ITT 
will be the primary analysis set for efficacy endpoints. 
6.2.2. 
Safety Population 
The SP includes all randomized subjects who have started any treatment arm (at least one dose of 
TMZ or MRZ), i.e. if a subject received a treatment arm other than the subject’s randomized 
treatment arm, then the subject will be assigned to the treatment arm that the subject actually 
received during the study in the analysis. Thus, a subject randomized to the MRZ arm who received 
TMZ but did not receive MRZ will be included in the control arm. Subjects allocated to the control 


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arm who received at least one dose of MRZ will be included in the MRZ arm. The SP will be the 
primary analysis set for analysis of safety endpoints. 
6.2.3. 
Per-Protocol Population 
The PP includes all randomized subjects who are eligible and have started their randomized 
treatment arm. Subjects with major protocol deviations as defined in the medical review plan are 
also excluded from the PP population. 
Subjects who did not receive MRZ or TMZ, with or without RT are excluded from PP and SP. 
Patients excluded from PP or SP will be reported in separate tables with the reason(s) of 
exclusion. 
 
 


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7. 
Subject Disposition 
Subject disposition summary (number and percentage of subjects) will be presented on all 
subjects who are enrolled. The number of subjects will be summarized by investigator site and 
overall.  
 Subjects who were enrolled  
 Subjects who were screen failures 
 Subjects who were randomized  
 Subjects who took at least 1 dose of study drug (MRZ/TMZ) 
 Subjects who discontinued the study drugs 
 
Listing for screen failure reasons/ineligibility will be provided. 
A summary of subject disposition will be presented by treatment arm for the following analysis 
populations: 
 ITT  
 SP 
 PP 
 
The number of subjects completing the study according to the protocol will be also displayed.  
Reasons for treatment discontinuation will be summarized for all ITT subjects with the 
following categories: 
 Completed 
 Progressive disease (PD)/relapse/death due to PD 
 Adverse events (AEs) 
 Withdrawal by subject 
 Physician's decision 
 Protocol deviation 
 Death  
 Other malignancy 
 Lost to follow-up 
 Pregnancy 
 Other (specify, including discontinuation of study drugs further to IDMC decision) 
 


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Reasons for completing the study follow-up/study (i.e. no more follow up visit and no longer 
participating in the study) will be collected on the eCRF and will be summarized for ITT subjects 
with the following categories: 
 Death 
 Lost to follow-up 
 Withdrawal by subject 
 Other (specify, including discontinuation of study drugs further to IDMC decision) 
 
Listings will be provided for ITT subjects randomized but not treated, and for treated subjects 
who discontinued treatment with reason for treatment discontinuation highlighting 
discontinuation of study drugs further to IDMC decision. 
 


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8. 
Protocol Violations 
 
The protocol violations were identified and assessed by clinical research physician or designee 
following EORTC standard operational procedure. The protocol violations will be summarized 
overall and by treatment arm in the ITT population and for the unmethylated MGMT stratum.  
A listing of subjects with protocol violations will be provided.  
 


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9. 
Demographics And Baseline Characteristics 
Summaries for the demographics and baseline characteristics will be summarized for the ITT 
population and by MGMT stratum (unmethylated, methylated and undetermined). Baseline 
clinical characteristics are defined as the latest data collected on or before Day 1 (or randomization 
day in case Day 1 is missing). When there are retested values, the retest values will be used for the 
analysis. Individual subject listings will be provided to support the tables. 
 
9.1. 
Demographics and Baseline Characteristics 
Demographic characteristics will be summarized using the following information from the 
Screening/Baseline Visit eCRF pages. 
There will be no statistical comparison of demographic and baseline measurements between 
treatment arms. 
At a minimum, the following continuous demographics and baseline characteristics will be 
summarized 
 Age expressed in years ( age = year of randomization – year of birth); 
 Height expressed in cm; 
 Weight expressed in kg; Body Mass Index (BMI) expressed in kg/m2 (calculated via 
weight / [height2] where weight is expressed in kg and height in m); (BMI less than 
19;  BMI of 19 to less than 21;  BMI of 21 to less than 23; BMI of 23 or greater); 
 Body surface area (BSA), expressed in m2 (set to BSA captured in the eCRF, 
otherwise calculated based on Dubois’ methods, ie, 0.007184 * height0.725 * 
weight0.42, where height is expressed in cm and weight in kg if BSA missing in the 
eCRF); 
 Clearance, calculated based on the Cockcroft Gault formula, where creatinine 
clearance (CrCl) (mL/min) = (140 – age) (weight [kg]) / 72 (serum creatinine 
[mg/dL]; for females, the formula is multiplied by 0.85) (Cockcroft, 1976); 
 Relevant vital signs, i.e. systolic blood pressure, diastolic blood pressure and pulse 
rate; 
 Mini mental state examination (MMSE) total raw score; 
 
 


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At a minimum, the following categorical demographics and baseline characteristics will be 
summarized: 
 Age categories expressed in years (≤55, >55) and  (≤65 , >65); 
 Sex (Female, Male); 
 Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not reported); 
 Race (American Indian or Alaska native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Multiple, Other, Not reported);  
 Baseline Eastern Cooperative Oncology Group (ECOG) Karnofsky Performance Status 
(70/80, 90/100);  
 Electrocardiogram (ECG): Normal, Abnormal Not Clinically Significant, Abnormal 
Clinically Significant or Missing). 
 Mini mental state examination (MMSE) total raw score  (<=27,>27);  
 Baseline steroid use (yes, no),  
 Hematology & Biochemistry values,  
 Adverse Events (Common Terminology Criteria for Adverse Events [CTCAE] grade) 
before start of treatment; 
9.2. 
Disease Characteristics 
At a minimum, the following categorical baseline disease characteristics will be summarized: 
 Primary disease (MedDRA); 
 MGMT methylation status (methylated, unmethylated, undetermined/invalid);  
 World Health Organization (WHO) classification of tumor (GBM, isocitrate 
dehydrogenase [IDH] wildtype, GBM, IDH mutant, Giant Cell GBM, Epithelioid 
glioblastoma, GBM, not otherwise specified [NOS], Other, Unknown); 
 Extent of surgical resection (Biopsy, Partial or subtotal resection, Gross total resection, 
Unknown);  
 IDH 1/2 mutation (Absent, Present, Cannot be determined, Not done); 
 IDH 1 R132H immune histochemistry (IHC) (Negative, Positive, Cannot be determined, 
Not done); 
 1p/19q deletion (1p/19q co-deletion, 1p only deleted, 19q only deleted, None detected, 
Cannot be determined, Not done); 
 Tumor hemisphere (Left, Right, Both, Midline); 
 Tumor localization (Frontal, Temporal, Parietal, Occipital, Multilobal, Central). 
 KI-67/MIB1 percentage of positive nuclei 


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 Number of lesions observed 
At a minimum, the following continuous baseline disease characteristics will be summarized: 
 Time (weeks) from first pathological diagnosis to randomization 
 Target lesions maximum diameter (cm) 
 Time (weeks) from tumor resection to randomization 
 Time between first pathological diagnosis or tumor resection which ever occur first and 
date of randomization (weeks) 
There will be no statistical comparison of disease characteristics between treatment arms. 
 
9.3. 
Medical History 
Based on variables extracted from the medical history eCRFs the number and percentage of 
subjects in each of the following categories will be presented by treatment arm: Note that the 
conditions/diagnosis will be presented by Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class (SOC) and preferred term (PT) by descending order of frequency 
and graded by CTCAE. Subjects reporting more than one condition/diagnosis will be counted 
only once for that condition/diagnosis.   
 Non-malignant medical condition will be presented by SOC and PT. A similar summary 
will be generated for the currently active abnormalities only, by SOC and PT. 
 Type of primary malignancy: will be presented using the American Joint Committee on 
Cancer (AJCC) classification instead of the MedDRA SOC; 
For each medical condition, a listing with subject ID numbers will be provided.  
There will be no statistical comparison of medical history between treatment arms. 
 
9.4. 
Prior and Concomitant Medications 
A prior medication is defined as any medication with an end date prior to the date of randomization 
and collected on the eCRFs. A concomitant medication is defined as any drug that started on the 
day of or after randomization, but not later than 35 days after the last protocol drug administration. 
Medications with a start date prior to the date of randomization and continuing after randomization 
are also classified as concomitant medications. A medication will also be considered a concomitant 
medication if one of the following three cases occur: (1) the start date is missing and the end date 
is either after or on the day of randomization; (2) the start date is not missing but not 35 days after 
the last protocol drug administration and the end date is missing; (3) both the start date and the end 
date are missing. 
Subjects reporting the same medication generic name two or more times will be counted only 
once for that generic name.   
For each prior or concomitant medication, a listing with subject ID numbers will be provided.  


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There will be no statistical comparison for the prior and concomitant medications between 
treatment arms. 
 
9.4.1. 
Prior Medications 
A summary showing the number and percentage of subjects who took prior medications will be 
presented by WHO therapeutic drug class and generic drug name and by treatment arm. 
 
9.4.2. 
Concomitant Medications 
A summary showing the number and percentage of subjects who took concomitant medications 
will be presented by WHO therapeutic drug class and generic drug name and by treatment arm.  
 


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10. 
Study Treatments And Extent Of Exposure 
Study treatment and extent of exposure summaries will be provided for each drug based on the 
SP. Descriptive statistics will be provided for treatment duration, number of cycles, cumulative 
dose, dose intensity, and relative dose intensity by treatment arm.  
10.1. 
Treatment Duration 
Radiotherapy 
Radiotherapy consists of a conventionally fractionated regimen delivering a total dose of 60 Gy 
in 30 fractions in 6 weeks, a fraction of 2 Gy once daily, 5 days per week. The RT duration (in 
weeks) is defined as last RT dose date – first RT dose date+1)/7.  
 
Chemotherapy 
The treatment start date is the date of the first dose of study drugs (MRZ or TMZ). The treatment 
end date is the date on which the decision was made by investigator to discontinue subject’s 
treatment. Whenever the treatment is given in cycles and the last planned day of treatment is not 
the last day of the cycle, the total duration of the treatment must account for this by adding the 
appropriate number of days to complete the last cycle.  
Temozolomide is given on a daily basis for 6 weeks during RT (concomitant phase) and after a 
4-week interval, TMZ is given on days 1-5 of a 28-day cycle (maintenance phase).  
 The concomitant TMZ duration (in weeks) is defined as (last concomitant TMZ dose date 
– first concomitant TMZ dose date+1)/7. 
 The maintenance TMZ duration (in weeks) is defined as ([maintenance TMZ end date – 
maintenance TMZ start date] +1+ (28-n))/7 where n is the last day of administration of the 
last cycle, ie, Day 1, 2, 3, 4, or 5.  
Marizomib is given on Days 1, 8, 15, 29, 36 for one cycle of 6 weeks during radiotherapy 
(concomitant phase) and after a 4-week interval, MRZ is given on days 1,8,15 of a 28-day cycle 
(maintenance phase). 
 The concomitant MRZ duration (in weeks) is defined as ([last concomitant MRZ end date 
– first concomitant MRZ start date] +1+ (42-n))/7. 
 The maintenance MRZ duration (in weeks) is defined as ([maintenance MRZ end date – 
maintenance MRZ start date] +1+ (28-n))/7, where n is the last day of administration of the 
last cycle, ie, Day 1, 8, or 15. 
For subjects who are still on treatment at the time of study closure or clinical cutoff, the planned 
cycle length will be used to calculate the end date and for both drugs the treatment duration ( in 
weeks) is defined as: [the study treatment end date – the first study drug start date + 1]/7.  
Descriptive statistics will be provided for treatment duration and total number of cycles by 
treatment arm. 


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10.2. 
Cumulative Dose  
For RT, cumulative dose is defined as the dose given across the treatment period in Gy.  
Radiotherapy consists of a conventionally fractionated regimen delivering a total dose of 60 Gy 
in 30 fractions in 6 weeks, a fraction of 2 Gy once daily, 5 days per week.  
For chemotherapy, cumulative dose is defined as the sum of all doses taken across the treatment 
period in mg or mg/m2.  
Doses for TMZ 
Dose modifications for TMZ follow the standard of care at the institution.  
 
Doses for MRZ 
Acceptable MRZ dose reductions are as follows: 
 
Dose Level 
Weekly dose 
Concomitant Treatment 
Schedule 
Adjuvant Treatment Schedule 
Starting dose 
0.8 mg/m2 
Days 1, 8, 15, 29, 36 
Days 1, 8 and 15 (28-day cycle) 
Dose level – 1 
0.7 mg/m2 
Days 1, 8, 15, 29, 36 
Days 1, 8 and 15 (28-day cycle) 
Dose level – 2 
0.55 mg/m2 
Days 1, 8, 15, 29, 36 
Days 1, 8 and 15 (28-day cycle) 
Dose level – 3 
0.4 mg/m2 
Days 1, 8, 15, 29, 36 
Days 1, 8 and 15 (28-day cycle) 
10.3. 
Dose Intensity  
Dose intensity during the treatment is defined as the cumulative dose divided by the treatment 
duration. Dose intensity will be calculated separately for TMZ and MRZ.   
The dose intensities of TMZ and MRZ per subject are defined separately for the concomitant and 
the maintenance phase. The dose intensities will be calculated as: 
𝐷𝑜𝑠𝑒 𝐼𝑛𝑡𝑒𝑛𝑠𝑖𝑡𝑦𝐶𝑜𝑛𝑐
=
𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑑𝑜𝑠𝑒 𝑜𝑓 𝐶𝑜𝑛𝑐 𝑇𝑀𝑍/𝑀𝑅𝑍 𝑓𝑟𝑜𝑚 1𝑠𝑡 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑢𝑛𝑡𝑖𝑙 𝑒𝑛𝑑 𝑜𝑓 𝑅𝑇𝑋 (𝑚𝑔
𝑚2)
𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 (𝑤𝑒𝑒𝑘𝑠)
 
 
𝐷𝑜𝑠𝑒 𝑖𝑛𝑡𝑒𝑛𝑠𝑖𝑡𝑦𝑀𝑎𝑖𝑛
=
𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑑𝑜𝑠𝑒 𝑜𝑓 𝑀𝑎𝑖𝑛 𝑇𝑀𝑍/𝑀𝑅𝑍 𝑠𝑖𝑛𝑐𝑒 𝑠𝑡𝑎𝑟𝑡 𝑜𝑓 1𝑠𝑡 𝑚𝑎𝑖𝑛𝑡𝑒𝑛𝑎𝑛𝑐𝑒 𝑇𝑀𝑍 𝑐𝑦𝑐𝑙𝑒 (𝑚𝑔
𝑚2)
𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 (𝑤𝑒𝑒𝑘𝑠)
 
 


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10.4. 
Relative Dose Intensity  
Relative dose intensity is the dose intensity divided by the planned dose intensity.  
The planned dose intensity is  
𝑃𝑙𝑎𝑛𝑛𝑒𝑑 𝑑𝑜𝑠𝑒 𝑖𝑛𝑡𝑒𝑛𝑠𝑖𝑡𝑦𝐶𝑜𝑛𝑐 𝑇𝑀𝑍 𝑜𝑟 𝑀𝑅𝑍
=
42 ∗75 𝑚𝑔
𝑚2  𝑜𝑓 𝑇𝑀𝑍 𝑜𝑟 5 ∗0.8 𝑚𝑔
𝑚2  𝑜𝑓 𝑀𝑅𝑍
𝑇ℎ𝑒𝑜𝑟𝑒𝑡𝑖𝑐𝑎𝑙 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑜𝑛𝑒 𝑐𝑦𝑐𝑙𝑒 (𝑤𝑒𝑒𝑘𝑠) = 6 𝑤𝑒𝑒𝑘𝑠 
 
𝑃𝑙𝑎𝑛𝑛𝑒𝑑 𝑑𝑜𝑠𝑒 𝑖𝑛𝑡𝑒𝑛𝑠𝑖𝑡𝑦𝑀𝑎𝑖𝑛 𝑇𝑀𝑍
=
(150 𝑚𝑔
𝑚2 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 1 + ∑(𝑛−1) ∗200 𝑚𝑔
𝑚2
𝑁
1
) 𝑁
⁄
  𝑜𝑓 𝑇𝑀𝑍  
𝑇ℎ𝑒𝑜𝑟𝑒𝑡𝑖𝑐𝑎𝑙 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑜𝑛𝑒 𝑐𝑦𝑐𝑙𝑒 (𝑤𝑒𝑒𝑘𝑠) = 4 𝑤𝑒𝑒𝑘𝑠 
 
𝑃𝑙𝑎𝑛𝑛𝑒𝑑 𝑑𝑜𝑠𝑒 𝑖𝑛𝑡𝑒𝑛𝑠𝑖𝑡𝑦𝑀𝑎𝑖𝑛 𝑀𝑅𝑍
=
3 ∗0.8 𝑚𝑔
𝑚2  𝑜𝑓 𝑀𝑅𝑍
𝑇ℎ𝑒𝑜𝑟𝑒𝑡𝑖𝑐𝑎𝑙 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑜𝑛𝑒 𝑐𝑦𝑐𝑙𝑒 (𝑤𝑒𝑒𝑘𝑠) = 4 𝑤𝑒𝑒𝑘𝑠 
 
Relative dose intensities will be categorized into < 60%, 60% to <80%, 80% to <90%, 90% to 
<110%, and ≥ 110%, and frequency counts will be provided by treatment arm. 
 
For RT, the (relative) dose intensity is not meaningful. The number of subjects with cumulative 
dose >90%, <=90% of the planned total dose (60 Gy) will be summarized by treatment arm.  
 
 


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10.5. 
Dose Reduction/Interruption/Delay  
For RT, temporary treatment interruption and/or premature discontinuation will be summarized by 
treatment. The number of subjects who have at least one day of temporary interruption and/or who 
prematurely discontinued, the number of days of temporary interruption and the reason for 
temporary interruption and/or premature discontinuation will be summarized by treatment arm.   
For chemotherapy, dose reduction/interruption/delay will be summarized by treatment arm.  The 
number of subjects who have at least one dose reduction/interruption/delay, number of dose 
reductions/interruptions/delays per subject, cycle of the first dose reduction/interruption/delay and 
reason for dose reduction/interruption/delay will be summarized by treatment arm. 
 
 
 
 


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11. 
Efficacy Analysis 
All efficacy evaluations will be conducted using the ITT population. If the percentage of subjects 
excluded from PP is larger than 10% in at least one treatment arm, supportive analyses of OS and 
PFS using the PP population will be conducted.   
Statistical comparisons will be made between the MRZ and control arms. Efficacy results that will 
be considered statistically significant after consideration of the strategy for controlling the family-
wise Type 1 error rate are described in Section 11.1, Multiplicity. All statistical tests will be one-
sided at the significance levels defined below, and the corresponding p-values and two-sided Cis 
for intended point estimates will be reported. 
The clinical database stratification variables will not be used to perform the stratified statistical 
test, the one recorded by the randomization system will be used instead. 
 
11.1. 
Multiplicity 
For the primary endpoint OS, the formal statistical testing is based on comparisons between the 
MRZ and control arms in both ITT population and the uMGMT stratum. We will use a graphical 
method to control overall Type 1 error at one-sided 2.5%, 1.5% significance in the ITT population 
and 1% significance in uMGMT. If one of them is significant, we will attribute the assigned alpha 
to the other. We will analyze other endpoints at exploratory two-sided 5% significance. 
 
Figure 1: Type One Error Rate Control Strategy 
 
 
* The alpha for testing will be dynamically determined based on the alpha propagation strategy as illustrated by the 
graph above.  
 
 


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11.2. 
Analysis of Primary Efficacy Endpoint 
 
Overall survival is the primary efficacy endpoint defined as the number of days from date of 
randomization to the date of death due to any cause (the date of death or censoring - date of 
randomization + 1). If a subject has not died, the data will be censored at the last date documented 
to be alive. 
 
In the primary analyses, differences in OS between the treatment groups will be assessed by a 
stratified LogRank test adjusted for the stratification factors assessed at randomization (except 
institution), testing the null hypothesis (H0): 
 
 H0: HRMRZ arm/control arm = 1 
 
Versus the alternative hypothesis (H1) 
 
 H1: HRMRZ arm/control  arm< 1 
 
The IDMC declared that there was no evidence that marizomib provides a benefit in OS 
In the primary analysis of OS, the above Type One Error Rate Control Strategy (section 11.1) 
will be applied.  
In the long-term follow-up analysis of OS, the comparison will be performed at 2-sided 
significance level α=0.05 in the ITT and in each MGMT methylation status.  
The primary analysis will be performed with the number of deaths in the ITT population at the 
time of the new database lock.   
The long-term follow-up analysis will take place after 488 deaths in the ITT population and 320 
uMGMT deaths have occurred.  
The HR (including two-sided 95 % CI) of the MRZ group over the control group will be calculated 
by Cox's proportional hazards model stratified by the stratification factors assessed at 
randomization (except institution) in the ITT population.  Assumptions underlying the Cox 
Proportional Hazard regression model will be checked using the ASSESS statement of PROC 
PHREG, based on the graphical and numerical methods (Lin D., 1993). If a severe deviation from 
proportional treatment hazards is detected (e.g., crossing hazards) this will be taken into account 
in the clinical interpretation of the treatment effect but no other measure of effect (e.g, restricted 
mean) or significance test will be computed.  
Kaplan-Meier survival curves (product-limit estimates) will be presented by treatment group, in 
the ITT population and by MGMT methylation status, together with a summary of associated 
statistics (median survival time, 6-, 12-, 18-, 24-month OS rate estimates and estimates for every 
6 months thereafter as applicable) including the corresponding two-sided 95% confidence 


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intervals (calculated by Greenwood formula’s estimation of the standard deviation for rates and 
by Brookmeyer and Crowley technique for the median). 
Unstratified Cox’s proportional hazards model will be fitted for each subgroup defined in section 
11.5 in the ITT population only. Forest Plot will be displayed with a subgroup by treatment 
interaction test. 
All secondary analyses will be performed at 2-sided significance level α=0.05 for exploratory 
purpose. 
The originally planned re-randomization test will not be performed as further to the review by 
the IDMC, there was no evidence that marizomib provides a benefit in overall survival and by 
consequence no significant result had to be validated with a re-randomization test.     
 
11.3. 
Analyses of Secondary Efficacy Endpoints 
The secondary efficacy endpoints will be analyzed based on ITT population and by MGMT 
methylation status.  
11.3.1. 
Progression-free Survival 
Progression-free survival will be defined as the number of days from date of randomization to the 
date of earliest disease progression based on Response Assessment in Neuro-Oncology (RANO) 
criteria (as determined by the Investigator) or to the date of death due to any cause, if disease 
progression did not occur (the date of progression or death or censoring - date of randomization + 
1). Subjects for whom neither death nor progression have been documented will be censored at the 
date of the last radiological assessment that the subject was progression-free. If a subject has no 
post-baseline radiological assessment, then the data will be censored at the date of randomization. 
Subjects with two or more missing assessments prior to a visit with documented disease 
progression (or death) will be censored at the last assessment where the subject was documented 
to be progression free. Subjects who received new anti-cancer therapy or cancer-related surgery 
prior to progression or death will not be censored at the last assessment where the patient was 
documented as progression free prior to the new anti-cancer therapy or cancer-related surgery. 
Censoring rules are documented in section 15.2. 
The following PFS analyses will be performed at 2-sided significance level α=0.05 for exploratory 
purpose. The stratified LogRank test will be applied on the PFS time to test for differences between 
the 2 treatment groups. The Cox's proportional hazards model stratified by the stratification factors 
assessed at randomization (except institution) will provide the HR (including 95% CI). Summary 
of associated statistics for each treatment arm (median PFS time, 6-, 12-, 18-, 24-month PFS rate 
estimates and estimates for every 6 months thereafter as applicable) will be displayed with 95% 
CI computed using the same methods as for OS, and the Kaplan-Meier curve for PFS will be 
presented. 
Progression-free survival Kaplan-Meier estimates will be calculated and unstratified Cox’s 
proportional hazards model will be fitted for each subgroup defined in Section 11.5 in the ITT 
population only. Forest Plot will be displayed with a subgroup by treatment interaction test. 


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11.3.2. 
Response 
The measure of response and progression will be determined by the local investigator according 
to the RANO criteria (Wen, 2010). All treatment decisions should be based on the RANO 
criteria as assessed by the local investigator.  
Target lesions are measured in their two largest perpendicular diameters. Their area is 
conventionally calculated as the product of these diameters. In case of multifocal disease with 
more than one target lesion, the total tumor size is calculated as the sum of the area of all target 
lesions. 
Response is defined as follows according to the RANO criteria, which also consider T2 weighted 
and FLAIR images: 
 Complete response (CR) requires all of the following: 1) Complete disappearance of all 
enhancing measurable and non-measurable disease; 2) No new lesions; 3) Stable or improved 
non-enhancing abnormalities on FLAIR/T2 images as compared to baseline; 4) Patients must 
be off corticosteroids (or on physiologic replacement doses only) and stable or improved 
clinically. 
 Partial response (PR) requires all of the following: 1) Only reductions of cross-sectional 
areas of 50% or more in the sum of product of perpendicular diameters of target lesions will 
be considered a response; when calculating the response, the baseline magnetic resonance 
imaging (MRI) must be used for comparison ; 2) No progression of non-target lesions; 3) No 
new lesions; 4) Stable or improved non-enhancing abnormalities on FLAIR/T2 images as 
compared to baseline; 5) Patients should be on a corticosteroid dose that should not be 
greater than the dose at time of baseline scan, and should be stable or improved clinically. 
 Progressive disease (PD): 
 Progression is defined by any of the following: 1) 25% increase in sum of the products of 
perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on 
stable or increasing doses of corticosteroids; 2) a significant increase in T2/FLAIR non-
enhancing lesions on stable or increasing doses of corticosteroids compared with baseline 
scan or best response after initiation of therapy, not due to comorbid events; 3) the 
appearance of any new lesions; 4) clear progression of non-measurable lesions; or 5) 
definite clinical deterioration not attributable to other causes apart from the tumor, or to 
decrease in corticosteroid dose. Failure to return for evaluation as a result of death or 
deteriorating condition should also be considered as progression.  
 If the evidence of PD is equivocal (target or non-target), treatment may continue until the 
next assessment, but if PD is confirmed at the next follow-up, the earlier date must be 
used as the date of progression 
 For patients operated at recurrence and without measurable or non-measurable disease 
after surgery, any new appearance of tumor will qualify for PD. In case non-measurable 
tumor is left after surgery, i.e. tumor less than 10 mm, unequivocal progression of non-
target disease may be accepted as evidence of disease progression, where the overall 
tumor burden has increased sufficiently to merit discontinuation of treatment. Modest 
increase in the size of a non-target lesion is not considered unequivocal progression. If 
the evidence of PD is equivocal (target or non-target), treatment may continue until the 


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next assessment, but if confirmed, the earlier date must be used as the date of 
progression. This implies that in case of gross total resection of the enhancing lesion, if at 
follow up minimal enhancement of unclear significance arises, treatment may continue 
until further follow-up gives unequivocal evidence of tumor progression. 
 Stable Disease: This occurs if the patients did not qualify for CR, PR, or progression (see 
above) and requires: 1) No meaningful change in the appearance of the FLAIR/T2 images 
compared to baseline or to the nadir (point with the smallest FLAIR/T2 abnormalities) if a 
decrease occurred. 2) The patient should be stable clinically. In the event the steroid dosage 
has been increased for new signs and symptoms without confirmation of disease progression 
on imaging, and further follow-up imaging shows that with hindsight this increase in steroids 
was indeed unequivocally needed due to disease progression, the date of progression will be 
the date steroids were increased. 
 In this protocol, although the primary endpoint is OS, in view of the relevance of objective 
responses, PR, CR, and equivocal PD need to be confirmed with an extra MRI made 4 weeks 
later.  
Criterion 
CR 
PR 
SD 
PD 
T1 gadolinium enhancing 
disease 
None 
≥ 50%  
<50%  but 
<25%  
≥ 25%  
T2/FLAIR 
Stable or  
Stable or  
Stable or  
 
New lesion 
None 
None 
None 
Present 
Corticosteroids 
None 
Stable or  
Stable or  
Not 
applicable* 
Clinical status 
Stable or  
Stable or  
Stable or  
 
Requirements for response 
All 
All 
All 
Any 
 CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease 
*increase in steroids alone does not qualify for PD 
The overall response is evaluated at each assessment of the disease according to RANO criteria. 
Best overall response is the best response designation recorded from the date of randomization 
until disease progression.  Objective/complete response includes best overall responses CR and 
PR/ CR only.  For responders, duration of objective response (CR/PR) and CR will be measured 
similarly to PFS (see section 11.3.1) but starting from the time measurement criteria for CR/PR 
or CR (whichever is recorded first) is met. The best overall response will be presented in 
contingency table with frequencies and percentages. The objective response (ORR: CR/PR) and 
CR rates will be reported with exact (binomial) two-sided 95% CI and compared between the 
treatment arm over the control arm using a one-sided Cochran-Mantel-Haenszel (CMH) test, 
stratified by stratification factors assessed at randomization (except institution). Odds ratios will 
be presented with 95% CIs. 
The medians of objective response (PR/CR) and CR duration will be estimated from the Kaplan-
Meier curves. The Reflected Method will provide two-sided 95% CI. 
 


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11.3.3. 
Mini Mental State Examination (MMSE) 
The Mini Mental State Examination (MMSE) is a brief, standardized tool to grade subjects’ 
neurocognitive function. It is an 11-question measure that tests five areas of neurocognitive 
function: orientation, registration, attention and calculation, recall, and language. The maximum 
score is 30 which corresponds to the best neurocognitive function. Following Brown et al. (Brown 
PD, 2003), the subject’s neurocognitive function will be considered ‘impaired’ if the MMSE score 
is 26 or less and ‘normal’ if it is 27 or more. Since its creation in 1975 by Folstein et al. (Folstein 
MF, 1975), the MMSE has been validated and extensively used in both clinical practice and 
research. Following Tangalos et al. (Tagalos EG, 1996) and as previously used by Brown et al., a 
decline of more than 3 points in the MMSE score will be considered to represent clinically 
significant deterioration. In this study, MMSE will be collected up to progression. 
 
The evolution of MMSE over time will be interpreted at 2-sided significance level α=0.05 for 
exploratory purpose taking into account the attrition as a result of subjects assessed only until 
progression. All MMSE results will thus be conditional on the subjects being otherwise free of 
progression. The distribution of the MMSE at each time point of evaluation will be described on 
the two treatment arms separately using means and their associated standard error (a graphical 
display will be considered). Median and range will also be provided. The proportion of subjects 
with ‘normal’ and ‘impaired’ MMSE score at baseline and at key timepoints of evaluation (e.g., 
baseline, at end of radiation therapy and then every 16 weeks) will also be displayed.  
Linear mixed models with treatment, a (linear) time effect, a time-treatment interaction as fixed 
effects and subject specific random effect is fitted. The covariance structure which minimizes 
Akaike Information Criteria (AIC) will be used.  
Longitudinal plots of mean MMSE score and 95% confidence interval based on Least Square 
Means from the linear mixed model will be presented over all assessment times by treatment group. 
11.4. 
Pre-planned sensitivity analyses 
If the percentage of patients excluded from PP is superior to 10% in at least one treatment arm, 
all efficacy analyses will be repeated in the PP population. 
At both final and long term follow-up analyses and for both PFS and OS, the stratified LogRank 
test and the Cox's proportional hazards model will also be computed stratified by the 
stratification factors assessed at randomization (except institution) and MGMT methylation 
status in the ITT population.     
Other exploratory analyses may be performed on the basis of subgroups of patients (see section 
11.5), but results of these exploratory analyses may not serve as a basis for drawing conclusions 
concerning protocol efficacy. 
11.5. 
Subgroup Analyses 
Overall survival and PFS will also be analyzed within the following subgroups: 
 MGMT 
 Age (≤55, >55 years),  


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 Sex (male, female),  
 Karnofsky performance status (70/80, 90/100),  
 MMSE (≤27,>27), 
 Baseline steroid use (yes, no),  
 Extent of surgery (partial/biopsy, gross total). 
Additional subgroup analyses based on other baseline disease characteristics might be performed 
as appropriate. 


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12. 
Safety Analysis 
All safety analyses will be conducted using the SP.  
The safety and tolerability will be followed from study treatment initiation through up to 30 days 
after the last administration of study treatment. The safety analyses will be reported for the whole 
study time and by treatment period for the safety analysis as defined below: 
The concomitant period (TMZ/RT or TMZ/RT+MRZ) will start on the day of the first 
administration of radiation therapy and end 27 days after the day of the last administration of 
radiation therapy and before the start of adjuvant TMZ period whichever occurred first. 
The adjuvant TMZ period (ie, when TMZ is administered alone or with MRZ) will start on the day 
of the first dose of adjuvant TMZ and end up to 27 days after the first day of administration of the 
last cycle of adjuvant TMZ  
The maintenance MRZ period (ie, when MRZ is administered alone after discontinuation of TMZ) 
will start 28 days after the first day of administration of the last cycle of adjuvant TMZ and end up 
to 27 days after the first day of administration of the last cycle of maintenance MRZ. 
The follow-up period (ie, when all treatments are discontinued) will start 28 days after the first day 
of administration of the last cycle of maintenance MRZ or adjuvant TMZ up to 30 days after the 
last treatment administration (MRZ or TMZ) 
12.1. 
Adverse Events 
This study will use CTCAE, version 5.0, for AE reporting. The highest CTCAE grading per cycle 
and per subject will be computed. 
All treatment-emergent adverse events (TEAEs) will be coded using the MedDRA version 21.0 or 
higher. System organ class, high-level group term (HLGT), high-level term (HLT), preferred term 
(PT), and lowest level term (LLT) will be provided. 
For all other TEAEs not described in the CTCAE criteria, the intensity will be assessed by the 
investigator as mild (Grade 1), moderate (Grade 2), severe (Grade 3), life-threatening (Grade 4), 
or death (Grade 5). TEAE with missing grade will be reported under the category “Missing”. 
12.1.1. 
Treatment-emergent adverse events (TEAEs) 
Adverse events will be analyzed in terms of TEAEs which are defined as AEs occurring or 
worsening on or after the date of start of treatment and within 30 days after the last treatment 
administration. AEs present at baseline which resolve during treatment and occurred again (at any 
grade) are considered TEAEs. AEs present at baseline which did not resolve within 30 days of the 
last treatment or which resolved but did not occur again are excluded from TEAEs. 
 
Unless otherwise specified, summary of TEAEs will be provided for the whole study time and per 
period, overall and per treatment arm. 
 
 
 


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An overall summary of TEAEs will be provided for: 
 subjects with at least one TEAE; 
 subjects with at least one TEAE related to any study drug; 
 subjects with at least one treatment-emergent serious AE (SAE) 
 subjects with at least one treatment-emergent serious AE (SAE) related to any study drug; 
 subjects with at least one CTCAE Grade 3 or 4 TEAE; 
 subjects with at least one CTCAE Grade 3 or 4 TEAE related to any study drug; 
 subjects with at least one TEAE leading to death (Grade 5); 
 subjects with at least one TEAE leading to death (Grade 5) related to any study drug; 
 subjects with at least one TEAE leading to dose reduction; 
 subjects with at least one TEAE leading to dose interruption; 
 subjects with at least one TEAE leading to study drug withdrawal; 
In addition, TEAEs will be summarized per SOC and per PT for the following: 
 all TEAEs; 
 TEAEs, occurring for more than 10% of subjects in any treatment group; 
 TEAEs related to any study drug (TMZ, MRZ);  
 CTCAE Grade 3 or 4 TEAE; 
 CTCAE Grade 3 or 4 TEAE related to any study drug; 
 TEAEs by age group, for the whole study time only; 
 TEAEs by sex, for the whole study time only; 
 TEAEs by race, for the whole study time only; 
 Treatment-emergent serious AEs (SAEs); 
 Treatment-emergent serious AEs (SAEs) related to any study drug; 
 TEAEs leading to death; 
 TEAEs related to any study drug leading to death; 
 TEAEs leading to dose reduction; 
 TEAEs leading to dose interruption; 
 TEAEs leading to study drug withdrawal. 
 
Subjects with multiple occurrences of the same event will be counted only once per subject for 
each summary. Results will be reported in descending order of overall subject frequency in the 
overall column (unless otherwise specified) by SOC and by PT within the SOC. For summaries 


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by severity grade, the highest grade out of the same TEAEs underwent by a subject will be 
reported. 
Listings for the corresponding summary tables will be presented separately. 
 
12.1.2. 
Deaths 
All deaths, as well as deaths within 30 days after last dose of study treatment, will be tabulated. 
 
12.1.3. 
Adverse Events of Special Interest 
BMS provided EORTC with a list of adverse events of special interest (AESIs). The categories 
for AESIs are as followed which are defined by MedDRA SMQs, HLTs, and PTs 
1) Ataxia including Fall, Gait Disturbances, and Balance Disorders/Dizziness 
2) Dysarthria 
3) Hallucination/Delirium 
Unless otherwise specified, summaries of treatment-emergent AESIs will be provided for the 
whole study time and per period, overall and per treatment arm. 
Overall summaries of AESIs will be provided for: 
 subjects with at least one AESI; 
 subjects with at least one AESI related to any study drug; 
 subjects with at least one serious AESI (SAE); 
 subjects with at least one serious AESI (SAE) related to any study drug; 
 subjects with at least one CTCAE Grade 3 or 4 AESI; 
 subjects with at least one CTCAE Grade 3 or 4 AESI related to any study drug; 
 subjects with at least one AESI leading to death; 
 subjects with at least one AESI related to any study drug leading to death; 
 subjects with at least one AESI leading to dose reduction, 
 subjects with at least one AESI leading to dose interruption 
 subjects with at least one AESI leading to study drug withdrawal; 
In addition, treatment-emergent AESIs will be summarized per AESI category and per PT for the 
followings: 
 all AESIs; 
 AESIs related to any study drug; 
 CTCAE Grade 3 or 4 AESIs; 


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 CTCAE Grade 3 or 4 AESIs related to any study drug; 
 AESIs by age group , for the whole study and overall; 
 AESIs by sex, for the whole study and overall; 
 AESIs by race, for the whole study and overall; 
 Serious AESIs (SAEs); 
 Serious AESIs (SAEs) related to any study drug; 
 AESIs leading to death; 
 AESIs leading to death related to any study drug;  
 AESIs leading to dose reduction; 
 AESIs leading to dose interruption; 
 AESIs leading to study drug withdrawal. 
 
12.2. 
Clinical Laboratory Evaluations 
This study will use the International CTCAE, version 5.0 for grading of applicable laboratory tests. 
Normal ranges will be used to determine the categories of below and above normal ranges for lab 
tests that have no severity grade. Hematological and biochemistry adverse events will be assessed 
on the basis of at least monthly blood counts. The worst grades during the treatment period will be 
summarized by treatment arm. Listings of clinical laboratory data from central laboratory with 
abnormal flags will be provided by subjects and tests. Listings will also be provided for the local 
laboratory data. The nadir and overall nadir will be presented with median, range (minimum, 
maximum), IQR, mean and standard deviation. 
 
12.2.1. 
Hematology 
In order to investigate the maximal degree of myelosuppression, absolute neutrophil counts 
(ANC), white blood cell counts (WBC), platelet counts, and hemoglobin will be summarized by 
worst grade overall for each subject. Frequencies and percentages of Grade 1, 2, 3, 4 in each 
category will be tabulated. A column with pooled Grade 3/4 frequencies and percentages will also 
be displayed. In a separate table, the frequencies and percentages of subjects with at least one 
Grade ≥1 or one Grade 3 or 4 hematological toxicity will be presented. 
For erythrocytes and hematocrit normal ranges will be used to determine the categories of below 
and above normal ranges. 
12.2.2. 
Biochemistry 
Creatinine, creatinine clearance, protein, albumin, total bilirubin, alkaline phosphatase, alanine 
aminotransferase (SGPT), aspartate aminotransferase (SGOT), glucose, sodium, potassium, 
chloride, total calcium, calcium, ionized, total magnesium, magnesium, ionized will be 


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summarized by the worst grade in each treatment cycle and by the worst grade overall. The worst 
grade of each biochemistry parameter will be calculated for each subject. Frequencies and 
percentages of Grade 1, 2, 3, 4 in each category will be tabulated. A column with pooled Grade 3 
or 4 frequencies and percentages will also be displayed. In a separate table, the frequencies and 
percentages of subjects with at least one Grade ≥1 or one Grade 3 or 4 hematological or 
biochemistry toxicity will be presented. 
For urea, urea nitrogen, uric acid, bicarbonate normal ranges will be used to determine the 
categories of below and above normal ranges. 
12.3. 
Vital Sign/Physical Examination Measurements 
For vital signs, the shift from baseline to worst during the treatment in below, within, and above 
the normal ranges will be displayed in cross–tabulations for each treatment. Summary statistics 
(N, Mean, Standard Deviation, Median, Minimum, and Maximum) of observed values and change 
from baseline values will be presented. 
  
12.4. 
Electrocardiograms 
The overall ECG interpretation will be summarized by presenting the number and percentage of 
subjects with ‘Normal’, ‘Abnormal, not clinically significant’, and ‘Abnormal, clinically 
significant’ by treatment. The shift from baseline to worst during the treatment in the overall ECG 
interpretation will be displayed in cross–tabulations for each treatment. 
 
QT analysis 
Descriptive analysis by sex of the length of the QT intervals among the subjects will be provided. 
The QTc-interval at baseline, Day 1 of concomitant treatment, Cycle 2 Day 1 of adjuvant treatment 
will be summarized, including change from baseline. The average of the readings at each visit will 
be used for the summary.   
 
12.5. 
Pharmacokinetic Endpoints 
The plasma concentration of MRZ will be described by the nominal time of collection using 
summary statistics based on the pharmacokinetics (PK) population.  The PK population is defined 
as a collection of subjects who had at least one quantifiable plasma concentration of MRZ.  As 
appropriate, the plasma concentrations may be used for exploratory exposure-response analyses of 
efficacy and safety endpoints. The analyses might be described in a separate analysis plan and 
reported separately. 
If the number of samples collected is not sufficient only patient listings with PK data will be 
presented. 
  


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12.6. 
Health Economic Endpoints 
The health economic data might be collected locally to support local regulatory requirements. The 
analyses, if conducted, will be described in a separate analysis plan and reported separately. 


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13. 
Health-related Quality Of Life Analysis 
 
13.1. 
Rationale 
Health-related quality of life is a multidimensional construct, which can be defined as a state of 
general well-being reflecting physical, psychological, and social well-being and the impact of the 
disease and/or treatment related symptoms on daily-life functioning. The subject’s subjective 
perspective is an inherent component of HRQoL and is therefore best assessed via self-
administration. 
Reducing mortality and morbidity is still the most important factor in cancer clinical research. 
Nevertheless, issues such as reducing side effects, symptom relief and improving subjects’ 
satisfaction have also become relevant parameters in the evaluation of medical strategies. Cancer 
treatments may produce adverse effects and diminish a subject’s quality of life even when survival 
is extended. Progress in the acceptance of new cancer therapies is sometimes critically dependent 
on their HRQoL consequences. 
Particularly in glioblastoma multiforme (GBM) subjects, who suffer from an incurable disease 
with a median OS of slightly more than a year despite intensive treatment, the balance between 
quantity and quality of survival gain due to (experimental) treatment is pivotal. If treatment-related 
side effects influence the HRQoL of these subjects in a negative way, possible gains in terms of 
progression-free or overall survival will have to be balanced against the burden of treatment. It is 
for this reason that HRQoL is included as a secondary endpoint in the current study of newly-
diagnosed GBM subjects. 
13.2. 
Objective 
The main objective of HRQoL assessment within this trial is to determine the impact of addition 
of MRZ to TMZ and RT therapy on five chosen domains being primarily global HRQoL, with 
fatigue, physical function, neurocognitive function, communication and motor dysfunction as 
secondary HRQoL outcomes. It is expected that these are likely to be most affected in subjects, 
based on the toxicity profiles and information of previous studies. The Ho hypothesis will be tested 
that there is no difference between subjects in both arms during and after treatment regarding 
global HRQoL. A secondary objective is to evaluate the effect of the treatment on the remaining 
symptoms and functioning scales as treatment-related side effects may have a (temporary) negative 
influence on the health-related domains of HRQoL of these subjects. 
 
13.3. 
HRQoL Instrument 
Health-related quality of life will be assessed with the EORTC Quality of Life Questionnaire 
(QLQ-C30) version 3. This instrument is composed of multi-item and single-item scales. These 
include five functional scales (physical, role, emotional, social, and neurocognitive), three 
symptom (fatigue, nausea and vomiting and pain) and a global health status/QoL scale and six 
single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties). 


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All scales and single items meet the standards for reliability. The reliability and validity of the 
questionnaire is highly consistent across different language-cultural groups. The average time to 
complete the questionnaire is approximately 10 minutes. While this standard is used in EORTC 
studies, it lacks some dimensions that pertain to the QL issues in certain brain cancer. Therefore, 
we will also use the EORTC Brain Cancer module (QLQ-BN20), designed for use in brain tumor 
subjects undergoing protocol treatment or radiotherapy. It includes 20 items assessing visual 
disorders, motor dysfunction, communication deficit, future uncertainty, as well as other specific 
symptoms, such as headaches, seizures or drowsiness. A retrospective validation study has been 
performed confirming the psychometric validity of this questionnaire (Cocks K, 2012).The 
threshold for minimal clinically important difference will be used as recommended in the 
published literature for EORTC QLQ-C30 and QLQ-BN20 (Maringwa J, 2011).    
 
13.4. 
Study Design  
Subjects are eligible for the HRQoL assessment in this study if they fulfill the eligibility criteria 
(see chapter 3 of the protocol). Should the subject refuse to fill out the form, then this should 
exclude the subject from further participation in the study. Subjects will be informed in the subject 
informed consent form that they will have their HRQoL assessed regularly while involved in this 
trial. In this Phase 3 study, HRQoL will be evaluated in a longitudinal design in all subjects entered 
in both arms of the study. The HRQoL questionnaires must be filled out at the hospital when 
subjects come for a scheduled visit according to the EORTC “Guidelines for administration of 
questionnaires” (see appendix F of the study protocol). The pretreatment questionnaires must be 
filled within 2 weeks before start of treatment. Subsequent questionnaires are administered after 
the end of combined chemo- and radiotherapy, and subsequently coinciding with the MRI visits 
and MMSE schedule in both treatment arms, also after tumor progression. Master copies of the 
HRQoL questionnaires will be sent to the participating institutions. The clinical report forms will 
include a question whether the HRQoL forms have been filled in, and if not, the reason why. The 
questionnaire will be handed out to the subjects by the investigator or a study nurse prior to seeing 
the doctor for clinical evaluations. The subject should complete the questionnaires by her/himself 
in her/his own language during the visit as completely and accurately as possible. It is 
recommended that a key person (e.g. research nurse) at each center should be responsible for 
questionnaire data collection in order to optimize the compliance of the subject and to ensure the 
completeness of the data. 
 
 


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13.5. 
HRQoL Schedule 
The time windows for eligible HRQoL assessments will be as follows: 
 
Assessment 
Time window 
Baseline 
No earlier than 14 days before randomization 
and no later than the day of randomization 
itself. 
At the end of radiation therapy 
No earlier than day of last radiation therapy 
treatment and no later than the first day of 
TMZ maintenance administration 
During TMZ/MRZ maintenance: every 
16 weeks  
Every 16 weeks during TMZ maintenance ± 
7 days (at MRI scan visit). 
After TMZ/MRZ maintenance: every 
16 weeks until death 
Every 16 weeks ± 7 days. (at MRI scan visit) 
13.6. 
Statistical Considerations 
The primary HRQoL endpoint that is considered relevant for this study is the Global health/QoL 
status scale of the QLQ-C30 instrument. The secondary HRQoL endpoints will be the fatigue, 
physical function, neurocognitive function, communication and motor dysfunction scales. Other 
scales from QLQ-C30 and QLQ-BN20 will be analyzed on an exploratory basis. The “financial 
difficulties” scale of the QLQ-C30 will not be analyzed at all. 
The sample size calculation has been performed based on OS data. This is the primary endpoint 
and therefore no calculation has been performed based on changes in HRQoL. The primary 
HRQoL endpoints that are considered relevant to this trial are detailed above. The HRQoL data 
will give information to support or reject the null hypothesis that there is no difference between 
patients in both arms during and after treatment. 
Data will be scored according to the algorithm described in the EORTC scoring manuals for the 
corresponding instruments. All scales and single items are scored on categorical scales and linearly 
converted to 0-100 scales.  
Primary and sensitivity analyses will be performed in the ITT population and in the uMGMT 
stratum. 
 
13.6.1. 
Primary Analysis 
The following statistical tests will be done corresponding to the objective listed in section 13.2. 
The following two summary scores will be calculated per subject for each selected scale:  
 the mean changes from baseline during treatment (AC-DT) = the average of all post-
baseline scale scores up to and including the end-of-treatment visit minus the score at 
baseline. Only scores from valid HRQoL forms will be included.  


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 the mean changes from baseline after treatment (AC-AT): = the average of all post-
baseline scale scores during follow-up (ie, after the end-of-treatment visit) minus the 
score at baseline. Only scores from valid HRQoL forms will be included. 
Description of the AC-DT and AC-AT will be presented (mean, standard deviation, median, first 
and third quartiles, minimum, maximum) by treatment group. The mean difference between the 
two treatment arms for AC-DT and for AC-AT with corresponding 2-sided 95% CI will be 
derived and contrasted with the 0 (no treatment arm difference) and the clinically important 
difference (CID) threshold, as defined in a recently published paper of Cocks et al, 2012. The 
status change (improved/no change/deteriorated) for the proportion of patients analysis will be 
defined based on the pre-defined clinically important response (CIR) threshold as recommended 
by Cocks and Buchanan (2015).  
13.6.2. 
Sensitivity Analysis 
The primary analysis will be repeated in the PP and the uMGMT stratum.  
The primary analysis will also be repeated taking all received HRQoL forms into account (ie, 
including invalid/unassigned forms). In addition, two new summary statistics will be created: 
 Deterioration during treatment (D10-DT) = A binary variable indicating whether the 
subject experienced a 10-point decrease from baseline at any post-baseline visit up to and 
including the end of study treatment visit.  
 Deterioration after treatment (D10-AT) = A binary variable indicating whether the subject 
experienced a 10-point decrease from baseline at any follow-up visit (ie, after the end of 
study treatment visit). 
Description of the D10-DT and D10-AT will be presented (mean, standard deviation, median, first 
and third quartiles, minimum, maximum) by treatment group together with mean difference, 
95% CI to supplement the main analysis. 
13.6.3. 
Missing Data 
Missing data are a potential major source of bias in HRQoL assessment. In order to check the 
potential impact in the study, the compliance mechanism will be investigated prior to initiating the 
HRQoL analysis. Characteristics of subjects with and without valid HRQoL data will be compared 
and trends over time per dropout pattern will be investigated. Model building will be used in order 
to investigate whether the compliance mechanism is linked to selected prognostic variables.  
Once the main analysis is completed, sensitivity analyses will be undertaken if warranted by the 
proportion and pattern of missing data to verify the robustness of the results related to the missing 
data. The sensitivity analysis will not be performed if the proportion of missing data is < 20%.  
In case overall compliance is deemed too low (< 70%), only an exploratory analysis will be 
performed instead of the main analysis. 
 


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14. 
References 
 
Bretz F, M. W. (2009). A graphical approach to sequentially rejective multiple test procedures. 
Stat Med, 28(4):586-604. 
Brown PD, B. J. (2003). Effects of radiotherapy on cognitive function in subjects with low grade 
glioma measured by the Folstein Mini-Mental State Examination. J Clin Oncol, 21(13): 
2519-24. 
Chinot OL, W. W. (2014). Bevacizumab plus radiotherapy-temozolomide for newly diagnosed 
glioblastoma. N Engl J Med, 370(8): 709-22. 
Cocks K, K. M.-J. (2012). Evidence-based guidelines for interpreting change scores for the 
European Organisation for the Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30. Eur J Cancer, Jul;48(11):1713-21. 
Folstein MF, F. S. (1975). Mini-mental state: A practical method for grading the cognitive state 
of subjects for the clinician. J Psychiatr Res, 12(3): 189-98. 
Gilbert MR, D. J. (2014). A randomized trial of bevacizumab for newly diagnosed glioblastoma. 
N Engl J Med, 370(8): 699-708. 
Lin D., W. L. (1993). Checking the Cox Model with Cumulative Sums of Martingale-Based 
Residuals. Biometrika, 80, 557–572. 
Maringwa J, Q. C.-V. (2011). Minimal clinically meaningful differences for the EORTC QLQ-
C30 and EORTC QLQ-BN20 scales in brain cancer patients. Ann Oncol, Sep;22(9):2107-
12. 
Tagalos EG, S. G. (1996). The Mini-Mental State Examination in general medical practice: 
clinical utility and acceptance. Mayo Clin Proc, 71: 829-37. 
Cocks K, Buchanan J.(2015). Defining responders on the European Organization for Research  
 
 
and Treatment of Cancer (EORTC) Quality of Life Questionnaire (30-item core module)  
 
 
(QLQ-C30) subscales. [abstract]. Presented at: The 22nd Annual Conference for the   
 
 
International Society for Quality of Life Research (ISOQOL). 2015; Vancouver, British  
 
 
 
Columbia, Canada: Abstract 2063. 
 
 


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15. 
Appendices  
15.1. 
Handling of Dates 
Dates will be stored as numeric variables in the SAS analysis files and reported in 
DDMMMYYYY format (i.e. the Date9. datetime format in SAS). Dates in the clinical database 
are classified into the categories of procedure dates, log dates, milestone dates, outcome dates, and 
special dates. 
 Procedure Dates are the dates on which given protocol-specified procedure are performed.  
They include the dates of laboratory testing, physical examinations, tumor scans, etc.  They 
should be present whenever data for a protocol-specified procedure are present and should 
only be missing when a procedure are marked as NOT DONE in the database.  Procedure 
dates will not be imputed. 
 Log Dates are dates recorded in CRF data logs.  Specifically, they are the start and end 
dates for adverse events and concomitant medications/procedures.  They should not be 
missing unless an event or medication is marked as ongoing in the database. Otherwise, 
incomplete log dates will be imputed according to the following rules (e.g. for duration or 
cycle assignment, etc.): 
o If the day component is missing from a date, an interpolated date will be generated 
with day = 1. 
o If the month component is missing from a date, an interpolated date will be 
generated with month = July. 
o If the day and month component are missing from a date, an interpolated date will 
be generated with day = 1 and month = July. 
o If the year component is missing from a date, no interpolated date will be generated 
and the date will remain unknown. 
 Milestone Dates are dates of protocol milestones such as randomization, study drug start 
date, study drug termination date, study closure date, etc.  They should not be missing if 
the milestone occurs for a subject. They will not be imputed. 
 Outcome Dates are dates corresponding to study endpoints such as survival, progression, 
etc.  In most cases they are derived either from a milestone (e.g. the survival date is derived 
from the death date), or a procedure date (e.g. the progression date is derived from the date 
of the tumor scan that was used to determine progression). They may be subject to 
endpoint-specific censoring rules if the outcome did not occur, but they are not otherwise 
subject to imputation.  
 Special Dates cannot be classified in any of the above categories.  They may be subject to 
variable-specific censoring and imputation rules.  
Dates recorded in comment fields will not be imputed or reported in any specific format. 
 


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15.1.1. 
Calculation Using Dates 
Calculations using dates (e.g., subject’s age or relative day after the first dose of study drug) will 
adhere to the following conventions:  
 Study days after the start day of study drug will be calculated as the difference between 
the date of interest and the first date of dosing of study drug plus 1 day. The generalized 
calculation algorithm for relative day is the following:  
o If TARGET DATE >= DSTART then STUDY DAY = (TARGET DATE – 
DSTART) + 1;  
o Else use STUDY DAY = TARGET DATE – DSTART. 
Note that Study Day 1 is the first day of treatment of study drug. Negative study days are reflective 
of observations obtained during the baseline/screening period.  Note: Partial dates for the first 
study drug are not imputed in general. All effort should be made to avoid incomplete study drug 
start dates.  
Subject’s date of birth will not be collected in this trial. Age at registration, age at randomization 
(expressed in years) are extracted from study eCRFs. 
 
 


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15.2. 
Censoring Rules for PFS 
Situation 
Date of Progression or 
Censoring  
Situation/Outcome 
No baseline assessments and 
alive after 2 scheduled 
assessments 
Randomization 
Censored 
 
Death within the first two 
scheduled assessments 
without any adequate 
assessment 
Date of death 
Event 
Death between adequate 
assessments 
Date of death 
Event 
No progression 
Date of last adequate 
assessment with evidence of 
no progression 
Censored 
Study discontinuation for 
reasons other than disease 
progression or death 
Date of last adequate 
assessment with evidence of 
no progression 
Censored 
New anti-cancer therapy or 
cancer-related surgery prior 
to progression or death 
Date of last adequate 
assessment after start of new 
anti-cancer therapy or 
cancer-related surgery with 
evidence of progression prior  
Date of last adequate 
assessment after start of new 
anti-cancer therapy or 
cancer-related surgery with 
evidence of no progression  
Event 
 
 
 
Censored 
Death or progression after an 
extended lost-to-follow-up 
time (two or more missed 
scheduled assessments) 
Date of last adequate 
assessment with evidence of 
no progression 
Censored