Clinical trial NCT02858895
Conditions: Glioblastoma Grade IV Astrocytoma Glioblastoma Multiforme Grade IV Glioma
Keywords: High grade glioma malignant glioma recurrent glioblastoma recurrent GBM recurrent GB glioblastoma (GB) glioblastoma multiforme (GBM) progressive glioblastoma Brain tumor Brain cancer immunotherapy targeted IL4R
Sponsor: Medicenna Therapeutics, Inc.
Start date: 2017-04-11; Completion date: 2019-10-31
Enrollment: 47 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single-arm, open-label, multicenter study in approximately 52 adults with primary (de novo) GB that has recurred or progressed (first or second recurrence, including this recurrence) after treatment(s) including surgery and radiotherapy with or without chemotherapy and following discontinuation of any previous standard or investigational lines of therapy.

Detailed description:
The study drug, MDNA55, is a fusion protein comprising a genetically engineered Interleukin-4 (IL-4) linked to a modified version of the Pseudomonas aeruginosa exotoxin A (PE). MDNA55 binds to the IL-4 receptor (IL4R), over-expressed by cancer cells and non-malignant immunosuppressive cells of the tumor microenvironment (TME), and delivers a potent cell-killing agent, PE.

The study will be conducted at up to 10 clinical sites following institutional review board approval and completed informed consent.

Subjects that meet the study eligibility criteria will undergo surgery associated with study drug administration. MDNA55 will be administered locally by convection-enhanced delivery (CED).

Post-treatment follow-up assessment of safety and efficacy will be performed monthly for the first 6 months and bimonthly thereafter for approximately 1 year after study drug administrations. Subjects will continued to be followed for survival and post-study treatment(s) of GB after study completion or withdrawal.

Arms: arm 1: Single infusion of MDNA55 via convection enhanced delivery (CED).\*

\*Subjects may be eligible to receive a second administration of MDNA55.
Interventions: intervention 1: MDNA55
Intervention descriptions: intervention 1: MDNA55 is an engineered circularly permuted interleukin-4 (cpIL-4) genetically fused to the catalytic domain of the pseudomonas exotoxin A (PE).

Protocol documents:
Prot_002.pdf: 
Protocol # MDNA55-05 
Version v.6.1   
 
 
CONFIDENTIAL   
 
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Clinical Protocol Number: MDNA55-05 
An Open-Label Non-Randomized, Multi-Center Phase-2 Study of 
Convection-Enhanced Delivery (CED) of MDNA55 in Adults with 
Recurrent or Progressive Glioblastoma  
 
 
Product Name: 
MDNA55 
Indication: 
Recurrent or Progressive Glioblastoma  
 
 
Version Number:  
Version 6.1; 19 JUL 2019 
 
IND Number: 
BB IND 007004 
 
 
Sponsor: 
Medicenna Therapeutics Inc.  
2 Bloor Street West, Suite 700 
Toronto, ON M4W 3E2  
Canada 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This protocol contains proprietary information and is provided for confidential use by the 
Investigator for the conduct of this clinical trial and for corresponding application to Institutional 
Review Boards (IRBs)/Independent Ethics Committees (IECs) in support of this trial. It may 
not be reproduced or distributed without written consent of the Sponsor (Medicenna 
Therapeutics Inc.). 




Protocol # MDNA55-05 
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PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT 
PAGE 
Protocol MDNA55-05 
(Original: Version 6.1; 19 JUL 2019) 
An Open-Label Non-Randomized, Multi-Center Phase-2 Study of 
Convection-Enhanced Delivery (CED) of MDNA55 in Adults with 
Recurrent or Progressive Glioblastoma  
I agree to conduct this study as described in this protocol (MDNA55-05), including all future 
protocol amendments and in accordance with all the Sponsor's guidelines provided to me. 
The study will be conducted in compliance with 21 CFR Parts 50, 56, and 312 and EU Clinical 
Trials Directive (EUCTD); the International Council on Harmonization guidelines on Good 
Clinical Practice [ICH E6 (R2)], and all applicable local regulatory requirements.  
I agree to provide all information requested in the Protocol, Work Sheets and the Electronic 
Document Capture (EDC) system provided to me by the Sponsor in a manner to assure 
legibility and accuracy, and to this end, I agree to follow all instructions for completing the 
Work Sheets and EDC within 5 business days of recording the corresponding data.  
I also agree that all information provided to me by the Sponsor, including non-clinical data, 
Investigator’s Brochure, Protocol, guidelines, manuals, EDC system, and verbal and written 
information, will be kept strictly confidential and confined only to personnel involved in 
conducting this study. It is recognized that this information may be given in confidence to the 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) to obtain written and 
dated approval for the protocol, written informed consent, consent-form updates, subject-
recruitment procedures (e.g., advertisements), and any other written information to be 
provided to the subjects, before initiating this study. 
In addition, no reports or information (verbal and written) regarding this study, its progress or 
results, will be provided to anyone not involved in the study other than to regulatory agencies 
or other competent authorities as required by law, the Sponsor, or in confidence to the 
IRB/IEC, without written and authorized permission of the Sponsor.  
I agree not to implement any changes to, or deviations from the protocol without prior 
agreement in writing from the Sponsor and after review and documented approval from the 


Protocol # MDNA55-05 
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IRB/IEC, except to eliminate an immediate health hazard to the study subjects or to provide 
prompt and necessary medical care. 
Audits and inspections may be performed at the Investigator site before, during, and after the 
study by competent authorities and authorized persons of the Sponsor. Informed consent and 
IRB/IEC approval will assure that competent authorities have access to individual identified 
patient records as may be required by law. 
I acknowledge that the Sponsor of the study, Medicenna Therapeutics Inc., has the right to 
discontinue the study at any time.  
* NOTE: The MDNA55 Investigator’s Brochure, Pharmacy Manual, Study Reference Guide 
and Image Acquisition Guide are cited in this protocol and provide pertinent information 
regarding the investigational drug and the procedures to be conducted in this study. By signing 
below, you acknowledge that you have received and read these referenced study documents 
and will follow all procedures described in this protocol.  
 
 
 
 
 
Principal Investigator  
(Print Name) 
 
 
Signature 
 
Date (dd/mm/yyyy) 
 




Protocol # MDNA55-05 
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PROTOCOL SYNOPSIS 
TITLE: 
An Open-Label Non-Randomized, Multi-Center Phase-2 Study of Convection-
Enhanced Delivery (CED) of MDNA55 in Adults with Recurrent or Progressive 
Glioblastoma  
RATIONALE: 
MDNA55 is a fusion toxin comprising a genetically engineered circularly 
permuted interleukin-4 (cpIL-4) fused to a modified version of the Pseudomonas 
aeruginosa exotoxin A (PE). MDNA55 binds to the IL-4 receptor (IL4R), over-
expressed by cancer cells and non-malignant immunosuppressive cells of the 
tumor micro-environment (TME), and delivers a potent cell-killing agent, PE. A 
large percentage of glioblastomas (GBs) and their TME express IL4R in 
relatively high amounts, making it a relevant target for MDNA55. Intra- and 
peritumoral infusion minimizes systemic exposure to the fusion toxin, while the 
image-guided CED technique enhances exposure of active drug throughout the 
target region. 
MDNA55 shares many properties with immunotherapies, such as immune 
checkpoint inhibitors, including the possibility of response following a prolonged 
(> 3 months) period of pseudo-progression. Given acknowledged difficulties in 
determination of true progression in patients treated with immunotherapies, the 
determination of progressive disease (PD) will be informed by use of 
multimodality MRI and/or biopsy prior to subject withdrawal.   
STUDY 
OBJECTIVES:  
Primary 
To assess overall survival (OS)  
Secondary 
To assess the effect of IL4-R status on overall survival (OS) 
To assess the safety of MDNA55 following CED  
To determine the objective response rate (ORR) per Response Assessment in 
Neuro-Oncology 
(RANO)-based 
criteria 
incorporating 
advanced 
imaging 
modalities. 
To assess progression-free survival (PFS)  
Exploratory 
To assess the pharmacokinetics (PK) of MDNA55 in peripheral plasma  
To assess serum anti-MDNA55 antibody titers and, if elevated, determine 
neutralizing antibody titers  
To determine the relationship between clinical outcomes and response 
assessment status by different sets of imaging-based response criteria 
To perform additional ad hoc efficacy and safety analyses as needed based on 
the data acquired in this study 
To assess the performance of the Brainlab catheter during infusion in terms of 
distribution and convection of the infusate using real time MRI monitoring 
KEY ENROLLMENT 
CRITERIA: 
In order to be eligible to participate in this study, male and female subjects 
≥ 18 years of age must have primary (de novo) GB that has recurred or 
progressed (per standard RANO criteria), a life expectancy > 12 weeks and a 
Karnofsky performance status (KPS) ≥ 70. Subjects must have tumor diameter 
of ≥ 1 cm x ≥ 1 cm (minimum) to 4 cm in any direction by pre-interventional 
magnetic resonance imaging (MRI) within 14 days of planned treatment and not 
have features which make the tumor a poor target for CED (e.g. significant 
liquefaction or geometric features not conducive to CED). IL4-R status of tumor 
will be determined based on archived biopsy from the time of initial diagnosis. 






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Other 
Duration of response (DOR), defined as the time from first response until 
disease progression or death among those subjects achieving a complete 
response (CR) or partial response (PR) to treatment.   
Duration of clinical benefit (DOCB), defined as the time from first response or 
disease stabilization until disease progression or death among those subjects 
achieving a complete response (CR), partial response (PR), or stable disease 
(SD) 
Additional, exploratory, efficacy analyses may include ORR and PFS based on 
the Investigator’s assessment of response, other time-to-event endpoints (e.g., 
time to post-study treatment of GB) and exploration of response according to 
biomarker status. 
SAFETY 
ENDPOINTS: 
Serious adverse events (SAEs) and treatment emergent adverse events (AEs) 
Clinical laboratory results 
Physical and neurological examinations 
KPS 
Electrocardiogram (ECG)  
Additional, exploratory, safety analyses may include specific AEs of interest and 
the relationship of safety to plasma MDNA55 pharmacokinetic (PK) parameters 
and/or evaluation of immune parameters.   
OTHER 
ENDPOINTS: 
MDNA55 PK parameters in peripheral plasma  
Anti-MDNA55 antibody titer in serum 
Neutralizing antibody titer (if anti-MDNA55 titer observed)  
STATISTICAL 
ANALYSES, 
POWER AND 
ANALYSIS 
POPULATIONS: 
Subject Populations 
Following quality review of study images mid-way through recruitment, local 
tissue reactions, inflammation, immune cell infiltration, edema and/or necrosis, 
subsequent to MDNA55 administration, was observed in some subjects and has 
been seen to be indistinguishable from possible tumor growth using the imaging 
techniques adopted from the outset of this study. Therefore, obtaining reliable 
imaging data for the primary efficacy analysis has been shown to be 
confounded. Consequently, under protocol version 6.0, the surrogate endpoint 
Objective Response Rate (ORR) will be assessed as a secondary outcome 
measure with the median Overall Survival (mOS) becoming the primary variable.  
Intent to Treat (mITT) 
An ITT population will comprise all subjects who receive any amount of study 
drug will be used for the primary efficacy analyses.  
A modified ITT population for secondary response analyses (mITT, see below) 
will comprise all subjects who receive any amount of study drug and have 
adequate imaging or clinical data for the ORR analysis. 
NOTE: Patients who expire or progress clinically prior to the first MRI 
examination will not be evaluable for any of the response assessments.   
Per Protocol (PP) Population 
The PP population will comprise all subjects in the mITT population who also 
have no major protocol violations during the study. This population will be 
finalized prior to the final database lock and primary analysis of the study data. 
Efficacy analyses will be conducted on this population in support of the primary 
efficacy results. 


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IL4R Analysis Population 
The IL4R analysis population will be the same as the ITT Population, excluding 
patients who do not have archived tissue or adequate tissue available for 
analysis, and will be used for efficacy analyses in subgroups according to IL4R 
expression status.  
Safety Population 
The Safety population will comprise all subjects treated on study. Safety 
analyses will be presented on this population. 
Analyses 
The primary efficacy analysis of OS will be assessed according to a single-arm, 
single-stage design on the ITT population. OS will be determined via Kaplan-
Meier estimation, with medians, quartiles, and 95% confidence intervals (CIs) 
reported. mOS will tested using a single sample one sided log-rank test on a 
10% significance level against historical control with null hypothesis of mOS of 
8 months and alternative hypothesis of OS > 8 months. 
With at least 46 evaluable ITT subjects there will be over 80% power for the 
primary analysis. 
A secondary analysis of the primary variable will be conducted in the IL4-R 
population according to IL4-R status.  
Details of the planned analyses and methods will be published in the SAP 
(statistical analysis plan) prior to database lock. 
PFS will be determined via Kaplan-Meier estimation, with medians, quartiles, 
and 95% confidence intervals (CIs) reported. mPFS will be tested with a single 
sample one sided log-rank test on a 10% significance level against historical 
control with null hypothesis of mPFS 4 months and alternative hypothesis of OS 
> 4 months.  
Descriptive analysis of the OS and PFS at 6, 9, and 12 months after treatment 
will be based on the raw proportions of subjects surviving (and progression-free) 
at those time points as well as Kaplan-Meier estimation. Further analyses will 
also be conducted by IL4R stratum, including examination of the treatment effect 
by IL4R level. 
Efficacy analyses may also explore subject subsets (e.g. IL4R level, tumor size, 
KPS, gender, age, steroid use,) and response by other applicable criteria.  
Descriptive statistics will be provided for subject demographics and disposition, 
safety, and exposure data and will include the number of observations, mean, 
standard deviation, median, and range for continuous variables and number and 
percent for categorical variables; 95% CIs will be presented where appropriate. 
 
 
 




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TABLE OF CONTENTS 
SIGNATURE PAGE ................................................................................................................. 2 
PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE .......................................... 3 
PERSONNEL RESPONSIBLE FOR CONDUCTING STUDY ................................................. 5 
PROTOCOL SYNOPSIS ......................................................................................................... 6 
MODIFIED FOR PROTOCOL VERSION 6.0 ........................................................................ 11 
TABLE OF CONTENTS ........................................................................................................ 12 
LIST OF ABBREVIATIONS ................................................................................................... 15 
1 
INTRODUCTION ........................................................................................................... 17 
1.1 
Treatment of Recurrent or Progressive GB ................................................................. 20 
1.2 
Targeted Intratumoral Therapy .................................................................................... 21 
1.2.1 
Fusion Toxins ........................................................................................................ 21 
1.2.2 
Interleukin-4 Receptors as a Drug Target for GB .................................................. 21 
1.2.3 
Convection Enhanced Delivery .............................................................................. 22 
1.2.4 
Real-time Imaging of Convective Delivery ............................................................. 22 
1.3 
Experience with the Investigational Drug (MDNA55) ................................................... 23 
1.3.1 
Nonclinical Experience with MDNA55 ................................................................... 23 
1.3.2 
Clinical Experience with MDNA55 ......................................................................... 24 
1.4 
Study Rationale ............................................................................................................ 24 
1.4.1 
Rationale for Endpoint Methods ............................................................................ 24 
1.4.2 
Rationale for Dose ................................................................................................. 25 
1.4.3 
Rationale for Selection of Catheters to be used for Administration of MDNA55 .... 27 
1.4.4 
Rationale for Infusion Planning / Catheter Placement Planning ............................ 28 
1.4.5 
Rationale for Infusate Flow Rate ........................................................................... 29 
1.4.6 
Rationale for Real-Time Imaging of Infusate Distribution ...................................... 30 
1.4.7 
Rationale for No Resection Following CED Infusion ............................................. 31 
2 
STUDY OBJECTIVES ................................................................................................... 32 
2.1 
Primary Objective ......................................................................................................... 32 
2.2 
Secondary Objectives .................................................................................................. 32 
2.3 
Exploratory Objectives ................................................................................................. 32 
3 
STUDY DESIGN ............................................................................................................ 32 
4 
STUDY POPULATION .................................................................................................. 34 
4.1 
Number of Subjects ...................................................................................................... 34 
4.2 
Eligibility Criteria ........................................................................................................... 35 
4.2.1 
Inclusion Criteria .................................................................................................... 35 
4.2.2 
Exclusion Criteria ................................................................................................... 37 
4.3 
Study Duration ............................................................................................................. 39 
4.4 
Subject Withdrawal Criteria .......................................................................................... 40 
5 
STUDY DRUG ............................................................................................................... 41 
5.1 
Investigational Agent: MDNA55 ................................................................................... 41 
6 
TREATMENT PLAN ...................................................................................................... 42 


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6.1 
Dose ............................................................................................................................. 43 
6.2 
Dose Administration ..................................................................................................... 43 
6.3 
Instructions for MDNA55 Infusate Administration ........................................................ 45 
6.4 
Image Acquisition - Schedule and Requirements ........................................................ 50 
7 
STUDY PROCEDURES AND OBSERVATIONS .......................................................... 54 
7.1 
Efficacy Evaluation ....................................................................................................... 54 
7.1.1 
Survival .................................................................................................................. 54 
7.1.2 
Tumor Response Assessment ............................................................................... 54 
7.2 
Safety Evaluation ......................................................................................................... 54 
7.2.1 
Laboratory Evaluations .......................................................................................... 55 
7.2.2 
Safety Considerations ............................................................................................ 55 
7.2.3 
Pharmacokinetic and Immune Parameter Evaluations .......................................... 56 
7.3 
Tumor Tissue Analysis ................................................................................................. 56 
7.3.1 
Biomarker Analysis including IL4R Expression ..................................................... 57 
7.3.2 
O6-Methylguanine-Methyltransferase Analysis ..................................................... 57 
7.4 
Evaluation of Progression versus Pseudo-progression ............................................... 57 
7.5 
Study Visit Schedule .................................................................................................... 58 
7.5.1 
Pretreatment Period ............................................................................................... 63 
7.5.2 
Treatment Period ................................................................................................... 65 
7.5.3 
Post-Treatment Follow-up Assessments ............................................................... 68 
7.5.4 
Early Termination Visit ........................................................................................... 70 
7.5.5 
Post-Study Follow-Up ............................................................................................ 70 
7.6 
Usage of Concomitant Medications ............................................................................. 71 
7.6.1 
Antiemetic Medications .......................................................................................... 71 
7.6.2 
Colony Stimulating Factors .................................................................................... 71 
7.7 
Dietary Restrictions ...................................................................................................... 71 
7.8 
Prohibited Medications ................................................................................................. 71 
8 
REPORTING AND DOCUMENTATION OF RESULTS ................................................ 72 
8.1 
Evaluation of Efficacy ................................................................................................... 72 
8.1.1 
Overall Survival ...................................................................................................... 72 
8.1.2 
Objective Response Rate ...................................................................................... 72 
8.1.3 
Other Time-to-Event Endpoints ............................................................................. 73 
8.2 
Evaluation of Safety ..................................................................................................... 74 
8.2.1 
Definitions .............................................................................................................. 75 
8.2.2 
Evaluating and Recording of Adverse Events ....................................................... 76 
9 
STATISTICAL METHODS ............................................................................................. 80 
9.1 
Determination of Sample Size ..................................................................................... 81 
9.2 
Statistical and Analytical Plans .................................................................................... 81 
9.2.1 
Randomization ....................................................................................................... 81 
9.2.2 
Analysis Populations .............................................................................................. 82 
9.2.3 
Missing Data .......................................................................................................... 83 


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9.2.4 
Baseline and Demographic Characteristics ........................................................... 83 
9.2.5 
Analysis of Efficacy ................................................................................................ 83 
9.2.6 
Analysis of Safety Variables .................................................................................. 84 
9.2.7 
Interim Analysis ..................................................................................................... 85 
9.2.8 
MRI Analysis .......................................................................................................... 85 
9.2.9 
Tumor Tissue Analysis .......................................................................................... 85 
9.3 
Data Quality Assurance ............................................................................................... 86 
9.4 
Multiplicity control ......................................................................................................... 86 
10 
INVESTIGATOR REQUIREMENTS AND STUDY MANAGEMENT ............................. 86 
10.1 Study Initiation ............................................................................................................. 87 
10.2 Informed Consent ........................................................................................................ 88 
10.3 Protocol Adherence ..................................................................................................... 88 
10.4 Monitoring Procedures ................................................................................................. 88 
10.4.1 
Routine Monitoring ................................................................................................. 88 
10.4.2 
Inspection and Auditing Procedures ...................................................................... 89 
10.5 Data Recording and Retention of Study Data .............................................................. 89 
10.6 Confidentiality of Data .................................................................................................. 90 
10.7 Study Drug Accountability ............................................................................................ 90 
10.8 Study Completion ......................................................................................................... 91 
10.9 Study Discontinuation .................................................................................................. 92 
10.10 Clinical Study Report .................................................................................................... 92 
10.11 Ethical Conduct of the Clinical Investigation ................................................................ 92 
10.12 Compliance with Financial Disclosure Requirements .................................................. 92 
10.13 Contractual and Financial Details ................................................................................ 92 
10.14 Insurance, Indemnity, and Compensation ................................................................... 93 
11 
REFERENCES .............................................................................................................. 94 
 
LIST OF TABLES 
Table 1: Example Antibiotic and H-2 Antagonist Therapy* ................................................. 44 
Table 2: Example Dexamethasone Protocol* ..................................................................... 44 
Table 3: Example Mannitol Protocol* .................................................................................. 44 
Table 4: Example Low-Dose Bevacizumab* ....................................................................... 45 
Table 5: Procedure using VarioGuide™ Neuro-navigation for Biopsy and Catheter Placement, 
Followed by CED Infusion ..................................................................................... 47 
Table 6: Imaging Schedule* ................................................................................................ 51 
Table 7: Schedule of Evaluations and Procedures* ............................................................ 59 
Table 8: Efficacy Endpoints ................................................................................................ 74 
 
LIST OF FIGURES 
Figure 1: Schematic of MDNA55 Mechanism of Action ....................................................... 17 
 


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LIST OF ABBREVIATIONS 
ADP 
adenosine diphosphate 
AE 
adverse event 
ALT (SGPT) 
alanine transaminase (serum glutamate pyruvate transaminase)  
AST (SGOT) 
aspartate transaminase (serum glutamic-oxaloacetic transaminase) 
BUN 
blood urea nitrogen  
CED 
convection-enhanced delivery 
CI 
confidence interval 
CNS 
central nervous system 
cp 
circular permutation/permuted 
cpIL-4 
circularly permuted version of IL-4 (see also MDNA55)  
CR 
complete response 
CSC 
cancer stem cell 
CSF 
cerebral spinal fluid 
CTCAE 
Common Terminology Criteria for Adverse Events  
CTEP 
Cancer Therapy Evaluation Program  
DOCB 
duration of clinical benefit  
DOR 
duration of response 
DWI  
diffusion weighted imaging  
ECG 
Electrocardiogram 
EDC 
electronic data capture  
FDA 
Food and Drug Administration 
FLAIR 
fluid-attenuated inversion recovery 
Gd-DTPA 
gadolinium-diethylenetriamine pentaacetic acid (Magnevist®) 
GB 
glioblastoma  
GCP 
Good Clinical Practice  
HIPAA 
Health Insurance Portability and Accountability Act  
HSA 
human serum albumin  
IHC 
Immunohistochemistry 
ICH 
International Council on Harmonization 
IEC 
Independent Ethics Committee  
IL-4 
interleukin-4  
IL-4PE 
IL-4 fused to a portion of Pseudomonas Exotoxin A (code name: MDNA55) 
IL4R 
IL-4 receptor 
INR 
International normalized ratio 
IRB 
Institutional Review Board  
IV 
intravenous(ly) 
KPS 
Karnofsky performance status  
LDH 
lactate dehydrogenase  
MDNA55 
Study drug; IL-4PE; previously called NBI 3001, PRX321 
MDSC 
myeloid derived suppressor cell 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGMT 
O6-methylguanine-methyltransferase 
MRI 
magnetic resonance imaging  
MTD 
maximum tolerated dose 


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NCI 
National Cancer Institute 
NBF 
Neutral Buffered Formalin 
NIH 
National Institutes of Health 
OR 
objective response 
ORR 
objective response rate  
OS 
overall survival  
PBS 
phosphate buffered saline  
PD 
progressive disease 
PE 
Pseudomonas exotoxin  
PFS 
progression-free survival 
P-gp 
p-glycoprotein  
PK 
pharmacokinetic  
PR 
partial response 
PsR 
pseudo-response 
PsP 
pseudo-progression 
PT 
prothrombin time  
RANO 
Response Assessment in Neuro-Oncology (criteria) 
mRANO 
modified RANO 
RNA 
ribonucleic acid 
rCBV 
relative cerebral blood volume 
RCD 
real-time convective delivery 
SAE 
Serious adverse event 
SD 
stable disease 
SOC 
System Organ Class  
SRC 
Safety Review Committee 
TAM 
tumor associated macrophages  
Th2 
T-helper cell type-2  
TME 
tumor microenvironment  
TRAM 
Tumor Response Assessment Map 
US 
United States 
USP 
United States Pharmacopoeia 
Vd 
volume of distribution  
Vd/Vi 
volume of distribution: Volume of infusion ratio  
VEGF 
vascular-endothelial growth factor  
Vi 
volume of infusion 
WBC 
white blood cell (count) 
WHO 
World Health Organization  
 
 


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1 
Introduction 
The study drug, MDNA55, is a fusion protein consisting of a targeting domain linked to a pro-
apoptotic cell-killing payload. It was discovered and developed by Drs. Raj Puri (United States 
[US] Food and Drug Administration [FDA]) and Ira Pastan (National Cancer Institute “NCI”) and 
has been described by various researchers in over 50 publications. It is a therapeutic agent that 
selectively targets cancer cells that over-express the interleukin-4 receptor (IL4R).  
The targeting domain is an engineered circularly permuted version of interleukin-4 (cpIL-4) which 
is genetically fused to potent payload comprised of a truncated version of the bacterial toxin, 
Pseudomonas aeruginosa exotoxin (PE) A (Kreitman et al., 1994). It was developed for the 
treatment of glioblastoma (GB) and other adult and pediatric central nervous system (CNS) 
cancers including immunosuppressive cells of the glioblastoma tumor microenvironment (TME) 
that frequently over-express the IL-4 receptor (IL4R; Puri et al., 1994; Kohanbash et al., 2013).  
The mechanism of action of MDNA55 is well documented (Kreitman et al., 1994; Rand et al., 
2000; Puri et al., 2009) and is depicted in Figure 1. MDNA55 binds to IL4R overexpressed on the 
surface of tumor cells and the entire complex is endocytosed. Following cleavage and activation 
by furin-like proteases found in high concentrations in the endosome of cancer cells, the catalytic 
domain of the truncated PE is released into the cytosol where it induces cell death via adenosine 
diphosphate (ADP)-ribosylation of the Elongation Factor-2 and induction of apoptosis through 
caspase activation (Shapira and Benhar, 2010). 
Figure 1: Schematic of MDNA55 Mechanism of Action 
 
 


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Many features of MDNA55 make it a rational choice for the treatment of GB and other primary 
and metastatic tumors in the CNS: 
1. The majority of cancer biopsy and autopsy samples from adult and pediatric CNS tumors, 
including recurrent GB biopsies, have been shown to over-express the IL4R with little or 
no IL4R expression in normal adult and pediatric brain tissue (Puri et al., 1996; Kawakami 
et al., 2002; Joshi, et al., 2001; Konanbash et al., 2013). Cells that do not express the 
IL4R target do not bind to MDNA55 and are, therefore, not subject to PE-mediated effects 
(Kawakami et al., 2002; Puri et al., 2005).  
2. Unlike chemotherapeutic agents and radiation, MDNA55’s cell-killing ability is not growth-
rate dependent (Li and Hall, 2010). Due to its mechanism of action, quiescent cancer stem 
cells and slower growing non-malignant cells of the TME may be as sensitive to MDNA55 
as rapidly dividing tumor cells. 
3. O6-methylguanine-methyltransferase 
(MGMT) 
positive 
cancer 
cells 
(harboring 
unmethylated MGMT promoters and therefore resistant to temozolomide) are sensitive to 
MDNA55. CNS and non-CNS cancer cell lines such as T98G (glioblastoma), HT-29 (colon 
cancer), and Mia-Paca-2 (pancreatic cancer) are known to over-express MGMT and are 
resistant to alkylating agents such as temozolomide (Huang et al., 2012; Kuo et al., 2007; 
Kokkinakis et al., 2003). However, these IL4R-expressing cell lines show picomolar 
sensitivity to MDNA55 (Puri et al., 1996; Kreitman et al., 1995; Shimamura et al., 2007), 
indicating that MDNA55 could provide a treatment option for MGMT positive GB patients.  
4. Furin-like proteases are required for cleavage of MDNA55 and activation of the PE toxin 
(Chironi et al., 1997; Shapira and Benhar, 2010). High expression levels of furin in targeted 
glioma cells as opposed to normal cells (Mercapide, et al., 2002; Wick et al., 2004) 
provides additional tumor specificity and is also a contributory factor to the exceptional 
picomolar sensitivity of cancer cells to MDNA55. 
5. The pro-apoptotic domain of MDNA55 (i.e., PE) is far more potent than chemotherapeutic 
agents (Li and Hall, 2010). It kills cancer cells by arresting protein synthesis (Shapira and 
Benhar, 2010), a mechanism not employed by other anti-cancer agents. 
6. Internalization of MDNA55 into the target cell occurs via a mechanism that is independent 
of p-glycoprotein (P-gp), a membrane associated protein that is commonly used to 
transport chemotherapeutic drugs. Mutations in P-gp often lead to cancer cells becoming 
resistant to traditional chemotherapeutic drugs, a problem not expected with MDNA55 


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since it does not rely on P-gp for entry into the cell (Strome et al., 2002; de Jong et al., 
2003).  
7. GB has a robust immunosuppressive TME and may comprise up to 40% of the tumor 
mass (Kennedy et al., 2013). Recently, it has been shown that malignant gliomas have a 
T-helper cell type-2 (Th2) bias and are heavily infiltrated by myeloid derived suppressor 
cells (MDSCs) and tumor associated macrophages (TAMs) and that the IL4/IL4R bias 
mediates their immunosuppressive functions (Harshyne, et al., 2016). Furthermore, IL4R 
is up-regulated on glioma-infiltrating myeloid cells but not in the periphery or in normal 
brain (Kohanbash et al., 2013). Thus, purging Th2 cells, MDSCs, and TAMs using 
MDNA55 may alleviate the immune block associated with cancer (in a manner similar to 
immunomodulators such as ipilumimab, pembrolizumab or nivolumab), thereby promoting 
anti-tumor immunity and aid in long-term disease control.  
Safety of MDNA55 has been adequately characterized in non-clinical studies. In addition, safety 
and efficacy of MDNA55, administered as a single dose by local intra- and peritumoral infusion 
via convection-enhanced delivery (CED) has been evaluated in a total of 72 adults with high grade 
recurrent gliomas (including 66 adults with recurrent GB) in three prior clinical studies. All 
nonclinical and clinical studies conducted to date are summarized in the current Investigator’s 
Brochure. 
Although not designed for efficacy, the Phase 1/2 clinical studies in adults with recurrent GB 
treated with MDNA55 generated sufficient data during and post-study to warrant supplemental 
analysis of tumor response, survival and the effect of tumor response on survival outcomes. 
Analysis of efficacy is provided in the current Investigator’s Brochure.  
Results from prior studies show promising anti-tumor effects when MDNA55 is administered via 
CED. Thus, by implementing recent advances in CED, a multi-center, single-arm, open-label 
study will be carried out in approximately 52 (at least 46 evaluable) patients with GB at recurrence 
or progression who will receive MDNA55 via intra- and peritumoral infusion using CED. The 
efficacy of MDNA55 will be investigated with subjects having tumor diameter of ≥ 1 cm x ≥ 1 cm 
(minimum) to 4 cm in any direction, no more than 2 relapses, and a Karnofsky score of ≥ 70 which 
are consistent with the inclusion criteria used in recent clinical trials for recurrent GB. Of note, the 
IL4R tumor expression profile, of subjects treated with MDNA55 in prior clinical studies was not 
determined. In this study, a retrospective analysis of IL4R expression of the archived tissue 
obtained at first diagnosis of GB will be conducted to determine the role of the IL4R biomarker on 
treatment response and patient outcomes. In addition, the IL4R biomarker and other 


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immunotherapy markers may be retrospectively tested if pre-treatment and/or post-treatment 
biopsy samples are available.  
Planning software will be utilized to optimize catheter placement (Rosenbluth et al., 2012) and 
small diameter catheters with a stepped design will be used to significantly reduce reflux along 
the catheter tract (Jahangiri et al., 2016; Krauze et al., 2005b) in order to improve distribution of 
MDNA55. 
Furthermore, 
co-infusion 
of 
a 
surrogate 
tracer 
(gadolinium-diethylenetriamine 
pentaacetic acid [Magnevist®] [Gd-DTPA]) during CED will enable effective real-time monitoring 
of drug distribution thereby ensuring adequate coverage of the tumor and the peritumoral 
infiltrating margin with MDNA55 (Chittiboina et al., 2014; Jahangiri et al., 2016).  Use of the latest 
CED technologies and real-time imaging has the potential to improve MDNA55 distribution, its 
safety as well as patient outcomes.  
1.1 Treatment of Recurrent or Progressive GB 
Standard first-line treatment for primary GB includes surgical resection of the bulk tumor to the 
maximal extent possible consistent with neurological preservation, followed by radiotherapy, often 
in combination with temozolomide (Stupp protocol; Stupp et al., 2005). When relapse or 
progression occurs in patients who have undergone the Stupp protocol, therapeutic options are 
unfortunately limited and generally not effective.  
Surgery may be indicated in a minority of relapsed patients with disease that is symptomatic from 
mass effect, but it results in only limited prolongation of survival (Keles et al., 2004). Survival may 
be improved by combining surgery with the Gliadel® (carmustine) implant. However, the majority 
of patients with relapsed disease are not candidates for additional surgery (Weller et al., 2013). 
The use of Gliadel is thereby limited as surgery is required for Gliadel administration.  
Avastin® (bevacizumab) has been seen to improve 6-month progression free survival (PFS) to 
42.6% and increase in median overall survival to 9.3 months in patients with recurrent GB. 
Genentech received accelerated approval from the US FDA for Avastin, in patients with 
recurrent GB patients who had failed first-line chemotherapy, based on an overall response rate 
of 28% (Friedman et al., 2009).  
Despite these agents, there is an urgent need for more effective targeted therapies for the 
treatment of recurrent GB. Intra- and peritumoral infusion via CED of targeted fusion toxin, such 
as MDNA55, is a promising novel tumor-specific therapeutic for the treatment of this disease. 


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1.2 
Targeted Intratumoral Therapy 
1.2.1 Fusion Toxins  
Fusion toxins fall into the category of targeted therapy and generally consist of highly potent 
bacterial or plant toxin moieties (payloads) fused to tumor-specific ligands (targeting domains). 
They represent a novel anti-cancer modality that may offer several advantages over conventional 
therapies. One such novel fusion toxin in development is MDNA55. Fusion toxins such as 
MDNA55 take advantage of the selective expression of receptors (e.g., IL4R) on tumor cells, 
cancer stem cells (CSCs) and tumor microenvironment (TME) (safety and tolerability) with the 
effectiveness of potent toxins (anti-tumor efficacy). The function of the targeting domain of 
MDNA55 (i.e., IL-4) is “to guide” the toxin specifically to the tumor cells while sparing normal cells. 
Fusion toxins such as MDNA55, directed at tumor specific targets therefore, exhibit a relatively 
wide therapeutic index when compared to conventional chemotherapeutic agents.  
MDNA55 has the following unique characteristics: 
• 
Induces tumor shrinkage independent of growth rate. Quiescent CSCs, slow growing cells 
of the TME and rapidly dividing cancer cells are equally sensitive at the picomolar range 
(Hall et al., 1992) 
• 
Uses a multi-pronged approach to cancer therapy. MDNA55 is able to simultaneously 
target bulk tumor, deplete CSCs (Merchant et al., 2015) and may also purge TAMs and 
MDSCs, key components of the TME (Bankaitis and Fingleton, 2015) 
New understanding of the role played by the TME in protecting cancer indicates that targeting 
cancer cells alone will not significantly alter survival outcomes. With a multi-pronged approach, 
MDNA55 may therefore provide an overall meaningful and durable long-term response in CNS 
tumors that over-express the IL4R. 
1.2.2 Interleukin-4 Receptors as a Drug Target for GB 
The study drug, MDNA55, was developed for the treatment of recurrent GB, as various types of 
CNS tumors have been known to frequently over-express the IL4R and available data 
demonstrate that a large percentage of GBs express the IL4R at relatively high levels (Puri et al., 
1994; Puri et al., 1996; Joshi et al., 2001; Joshi et al., 2002). Detailed information on IL4R as a 
drug target for GB including recent studies evaluating IL4R expression in matched biopsy samples 
of newly diagnosed and recurrent GB obtained from the same patient are provided in the current 


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Investigator’s Brochure. These data indicate that GB patients continue to express the IL4R at 
recurrence and in some cases, at much higher levels. 
1.2.3 Convection Enhanced Delivery 
MDNA55 is a large fusion protein (53 kDa) and as such is not able to cross the blood brain barrier 
(BBB). In order to by-pass the BBB, localized delivery techniques such as convection enhanced 
delivery (CED) are being widely developed for CNS diseases. CED improves drug delivery to 
brain tumors intraparenchymally by utilizing bulk flow, or fluid convection, established as a result 
of a pressure gradient, rather than a concentration gradient (Yin et al., 2011). As such, CED offers 
markedly improved distribution of infused therapeutics within the CNS compared to direct injection 
or via drug eluting polymers, both of which depend on diffusion for parenchymal distribution. 
Additionally, CED obviates the challenges of systemic agents crossing the BBB while minimizing 
systemic exposure and toxicity. (Fiandaca et al., 2008; Yin et al., 2011; Vogelbaum and Aghi, 
2015). Advantages of CED over diffusion-based delivery include:  
• 
Expanded volume of distribution (Vd); volume of distribution being greater than the volume 
of infusion (Vi);  
• 
Uniform concentration of the infused therapeutic within the target volume;  
• 
Delivery of the vast majority of the infused therapeutic within the target volume.  
CED distribution is enhanced by the arterial pulsations within the brain’s perivascular spaces 
(Hadaczek et al., 2006). Additionally, better understanding of the complexities of the extracellular 
matrix and its effects on convection has led to improved distribution (Hamilton et al., 2001; Neeves 
et al., 2007; Nguyen et al., 2001). For example, technical CED infusion parameters, such as 
cannula size and shape, infusion rate, infusate concentration, and tissue sealing time, have been 
defined and refined to improve distribution of study agents while limiting potential toxicities and 
morbidities (Morrison et al., 1999; Chen et al., 1999; Wein et al., 2002; Krauze et al., 2005b; Healy 
and Vogelbaum, 2015; Lewis et al., 2016). 
1.2.4 Real-time Imaging of Convective Delivery  
A major advance in the safe and potentially efficacious use of CED in neurosurgery has been the 
development of real-time imaging of convective delivery (RCD), which utilizes magnetic 
resonance imaging (MRI) to visualize the CED process with the aid of co-convected contrast 
agent (Krauze et al., 2005a; Fiandaca et al., 2009; Nguyen et al., 2003; Krauze et al., 2005b; 
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allows physicians to directly monitor distribution of therapeutics within the brain. Thus, reflux along 
the CED catheter or leakage outside the target area, especially at higher flow rates, can be 
monitored and corrective steps taken, such as retargeting the catheter or altering the rate of 
infusion (Fiandaca et al., 2008; Varenika et al., 2008).  
The RCD technique will be used in this study and represents an important advancement in drug 
delivery and distribution in the brain. Earlier clinical trials that did not utilize RCD did not achieve 
adequate distribution of the study drug, which may have caused the studies to not meet their 
clinical endpoints (Gill et al., 2003; Marks et al., 2010; Sampson et al., 2010). Use of RCD in this 
trial will enable direct visualization of the study drug distribution, permit uniform tumor coverage 
and enhanced contact between target cells (GB and TME) and MDNA55.  
In many studies using RCD, the surrogate tracer of choice has been gadolinium. Gd-DTPA 
(Magnevist®) is a contrast agent manufactured by Bayer Healthcare Pharmaceuticals, Inc., and 
has been used clinically for many years.  
Prior in vitro and in vivo studies (Mardor, et al., 2009; Ding et al., 2010) have shown that Gd-
DTPA is biocompatible and safe when co-administered with the MDNA55 (see current 
Investigator’s Brochure). Gd-DTPA, in combination with fusion toxins, has also been safely 
administered intracerebrally to patients in multiple clinical studies using CED (Lonser et al., 2007; 
Weber et al., 2003a; Weber et al., 2003b; Sampson, et al., 2011; Chittiboina, et al., 2014). 
Although gadolinium-based contrast agents are not approved for intracerebral administration, 
these studies support that Gd-DTPA can be safely administered via CED infusion in combination 
with locally administered therapeutics, such as MDNA55.  
In 2017 the EMA (EMA/457616/2017) and FDA (FDA Drug Safety Communication [5-22-2017]) 
both conducted reviews of gadolinium safety following some evidence of low levels of gadolinium 
deposition in brain tissues following intravenous administration in animals. No evidence of harm 
to humans has been described, nevertheless minimizing gadolinium exposure is recommended 
as a precautionary measure. 
1.3 
Experience with the Investigational Drug (MDNA55) 
1.3.1 Nonclinical Experience with MDNA55 
All non-clinical studies of MDNA55 alone or in combination with Gd-DTPA are summarized in the 
current Investigator’s Brochure.   


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1.3.2 Clinical Experience with MDNA55 
To date, a total of 86 adults have received MDNA55, including 72 adults with high grade glioma. 
All prior clinical studies conducted with MDNA55 are summarized in the current Investigator’s 
Brochure.  
Multiple doses of MDNA55 have been intratumorally administered to study subjects in an 
investigator initiated study; Rand et al., 2000) where 9 subjects with histologically confirmed 
recurrent GB were infused with MDNA55. MDNA55 concentration and infusion volumes ranged 
from 0.2 to 6.0 µg/mL and 30 to 185 mL, respectively. Two of the 9 subjects in this study received 
more than one infusion.  
MDNA55 has been granted orphan drug status by the US FDA and the European Medicines 
Agency for the treatment of gliomas and Fast Track designation for the treatment of recurrent GB 
and AA by the US FDA. 
1.4 
Study Rationale 
This study is designed to test the hypothesis that mOS is improved to a clinically significant extent 
with MDNA55 administered via CED, as compared to current available treatments for 
recurrent/progressive GB. The assumptions regarding response to current treatment are based 
on aggregated mOS data from previous clinical trials in patients with recurrent/progressive 
glioblastoma weighted according to consistency with the subject inclusion criteria in this trial. The 
current design is based on a null hypothesis that mOS is 8.0 months versus the alternative 
hypothesis that mOS is 11.5 months following treatment with MDNA55.  
1.4.1 Rationale for Endpoint Methods 
Overall Survival is the chosen primary endpoint for this trial as an unequivocal, objective, direct 
measure of clinical outcome.   
In this study ORR will be assessed as a secondary endpoint because MDNA55 shares many 
properties with immunotherapies, including the possibility of pseudo-progression seen on post-
treatment imaging and the possibility of response following prolonged (> 3 months) pseudo-
progression (Weber et al., 2003a; 2003b; Okada et al., 2015), both of which can confound the 
assessment of ORR (Ellingson et al., 2017b). The mode of action of MDNA55 includes initial 
inflammatory response and necrosis in areas of macroscopic and microscopic infiltrative tumor 
whereby localized inﬂammatory responses mimic radiological features of tumor progression with 
increased enhancement and edema (Weber et al., 2003a; 2003b). 


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Pseudo-progression is an increase in contrast enhancement on MRI without true underlying tumor 
progression and may be due to tumor necrosis associated with MDNA55’s known mechanism or 
local tissue reaction due to the CED procedure. Subjects with pseudo-progression may develop 
brain edema, mass effect and other symptoms that are clinically indistinct from typical disease 
progression. Failure to recognize this phenomenon may result in premature subject withdrawals 
from the study, prior to establishing evidence of clinical benefit. To minimize these confounding 
effects, the application of the RANO criteria in this study will include the use of multi-modality 
imaging assessments for response analysis and allowing of the designation of non-progression 
status to patients who have no subsequent signs of disease progression on imaging after initially 
being considered to have progressive disease (PD). Multi-modality assessments include contrast-
enhanced MRI, diffusion MRI, perfusion MRI, spectroscopic MRI, TRAMs, clinical evaluation and 
tumor tissue biopsy to aid identification of pseudo-progression during early progressive 
enhancement on T1 images with contrast. Furthermore, in determining PD, there will be less 
weight on T2-FLAIR images associated with edema. Worsening of clinical symptoms attributed 
to edema or increased use of steroids to control edema will not automatically be registered as 
PD. 
For the same reason, sites will be strongly recommended that subjects remain in the study for at 
least 120 days post treatment unless unequivocal evidence of confirmed disease progression is 
agreed. 
1.4.2 Rationale for Dose 
 
 
 
  
 
 
 
  
 
 
 
 


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The total dose will not exceed 240 µg (the established MTD for the compound).  
1.4.3 Rationale for Selection of Catheters to be used for Administration of 
MDNA55  
In earlier clinical studies conducted with MDNA55 and other therapeutic agents, catheters were 
not designed for effective CED and demonstrated that they were prone to reflux and leakage of 
the therapeutic agent away from the region of interest. In recent years, smaller diameter MRI-
compatible catheters with a stepped design have been introduced which have been shown to 
dramatically reduce reflux along the catheter tract when compared to the large diameter flexible 
ventricular catheters used in previous GB studies (Krauze et al., 2005b; Rosenbluth et al., 2011; 
White et al., 2011; Gill et al., 2013; Jahangiri et al., 2016). This has allowed for improved flow 
rates (see Section 1.4.5). 
In the US, there are essentially 2 step design catheter options and both are being and/or have 
been used in CED studies; the Brainlab Flexible Catheter [510(k) K123605] and the MRI 
Interventions SmartFlow® Cannula [510(k) K102101]. The Brainlab catheter is an MRI-
compatible flexible catheter that has a rigid stylet design for accurate positioning. This catheter 
can be left in-place post-surgery and will therefore be employed in this study as it allows continued 
post-surgical infusion. On the other hand, the SmartFlow® cannula is rigid and can only be used 


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intra-operatively. Like the Brainlab catheter, it is also MRI compatible, has an identical tip design 
and is amenable for accurate placement. Both catheters are intended for single use only and not 
intended for implantation. MDNA55 infusate (prepared in Elliotts B® solution together with 0.02% 
HSA and 7mM of Gd-DTPA) has been tested and shown to be bio-compatible with the Brainlab 
catheter and other tubing components comprising the infusion assembly and will therefore be 
used in this study.  
1.4.4 Rationale for Infusion Planning / Catheter Placement Planning  
The efficiency of CED in distributing a drug into a tumor depends on correct placement of 
catheters within the tumor, catheter diameter, flow rate, infusate characteristics, and tissue 
consistency of the treated area (Wein et al., 2002; Sampson et al., 2007; Jahangiri et al., 2016). 
An incorrectly placed catheter can lead to the infused drug exiting the tumor through sulci or taking 
a path of least resistance into the cerebrospinal fluid (CSF), resulting in limited drug exposure of 
the tumor, and lack of efficacy and potential toxicity.  
To ensure optimal placement for maximal tumor coverage, Brainlab iPlan® Flow software will be 
used as the primary tool for generating a pre-treatment plan for placement of catheters (Sampson 
et al., 2007) prior to infusion. Using MRI of the tumor obtained prior to infusion, the software will 
be used to predict the optimal trajectory for placement of each catheter, making sure to avoid 
fissures, sulci, and other elements that can contribute to inadequate distribution. iPlan® software 
helps to predict the placement of the catheter tip according to the catheter placement guidelines 
(see Section 6.3), to optimize convection of the infusate as well as assist in ensuring safe 
placement of catheters by avoiding blood vessels, etc.  
For this study, the iPlan®Flow software and MRI imaging will be employed for pre-treatment 
catheter trajectory planning. Pre-treatment catheter trajectory planning will be performed with aim 
to place up to 4 catheters but a minimum of 2, depending upon the tumor size. Planning for 
catheter placement will only target the enhancing region of the tumor on MRI.  MRI perfusion 
imaging and other advanced imaging modalities may be used to inform on optimal placement of 
the catheter tips in the active tumor and to support trajectory planning to avoid significant 
vasculature.  
All investigational sites selected for this study have prior CED experience; nevertheless, all sites 
will be thoroughly trained in the correct use of the catheter, infusion planning, catheter placement 
and CED infusion with peer-to-peer support of early cases to ensure consistency across study 
sites. 


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1.4.5 Rationale for Infusate Flow Rate 
Infusion parameters, such as catheter size and shape, infusion flow rate and infusate 
concentration, have been defined as factors that have an effect on the efficiency of CED. In 
previous clinical studies with MDNA55, the infusion flow rate of 10 µL/min/catheter was evaluated 
(using large diameter ventricular catheters that were not designed for CED) to administer large 
volumes of infusate over several days.  
As discussed above (Section 1.4.3) smaller diameter catheters designed specifically for CED of 
therapeutics into the brain tumor have been developed, which permit higher flow rates with 
minimal back flow due to their step design Krauze et al. (2005b) and Richardson et al. (2011) as 
well as recent studies at UCSF (Butowski et al., 2015), showed that 50 µL/min is a safe flow rate 
without reflux and affords better manipulation of the dynamics of infusion, allowing for better tumor 
coverage, especially with larger volumes. Further, Butowski et al. (2015) reported that for efficient 
CED in brain tumors, the maximum volume of drug should be infused in the shortest possible 
time. In this study, flow rates will be individualized as use of real-time MRI infusion monitoring will 
enable the Investigator to determine the optimal flow rate of infusate for each subject.  
Although the MDNA55 infusate has shown to be bio-compatible with the Brainlab catheters at 
flow rates of up to 50 µL/min, optimal flow rate for effective intra- and peritumoral distribution of 
MDNA55 in vivo via the Brainlab flexible catheter is not established and may vary from patient to 
patient due to tumor heterogeneity. Therefore, the rate of infusion will be conservatively assessed 
with flow rate initiated at 3 µL/min/catheter and gradually increased in a stepwise manner to a 
maximum of 10 µL/min/catheter (see Section 6.3). The infusion flow rate can be adjusted at the 
discretion of the Investigator during the real time monitoring period to check leakage, reflux and 
functioning of all implanted catheters (with subject maintained under anesthesia). The flow rate 
should be established such that the duration of infusion is at least 24 hours to a maximum of 
approximately 48 hours. In the event only one catheter is functioning the flow rate may be 
increased to complete infusion in 48 hours or less but greater than 24 hours. After the real-time 
MRI infusion monitoring period is completed, the remainder of the infusion will continue with the 
subject awake. MRI will be performed upon completion of infusion as a final evaluation of 
MDNA55 infusate distribution. 
The rate of infusion may be reduced by 50% or the infusion stopped and restarted at the discretion 
of the Investigator if the subject shows signs of intolerance. Section 7.5.2.3 provides information 
relating to interruption or discontinuation of infusion. Reduction to the maximum permitted rate of 
administration to see drug delivery sustained for up to 48 hours may be considered, guided by 


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ongoing evaluation of potential toxicities by the SRC and advised to the investigators by the 
sponsor’s medical representative accordingly and recorded in the Study Reference Guide. 
1.4.6 Rationale for Real-Time Imaging of Infusate Distribution  
NeoPharm conducted a study from 2004 to 2006 using an IL-13-PE fusion protein (cintredekin 
besudotox, CB), to target the IL-13 decoy receptor, IL-13Ralpha2, known to be over-expressed 
in GB. This was a randomized Phase 3 trial of GB patients at first recurrence in which CED was 
used to locally administer CB following surgical resection of the tumor. The study drug did not 
show survival advantage when compared to Gliadel (Kunwar et al., 2010).  
Several reasons have been proposed to explain the lack of efficacy of CB (Chandramohan et al., 
2012; Jarboe et al., 2007; Sampson et al., 2010). 
• 
The trial did not include real-time imaging to ascertain if the required amount of drug was 
delivered to the tumor site (Sampson et al., 2010).  
• 
The estimated coverage of relevant target volumes was low, so that only 20.1% of the 
penumbra surrounding the resection cavity was covered (Chandramohan et al., 2012).  
• 
Post-trial analysis on catheter positioning revealed only 49.8% of catheters met all 
positioning criteria (Chandramohan et al., 2012).  
Thus, even where IL-13Ralpha2 was present in the tumor (Jarboe et al., 2007), delivery of the 
drug to the tumor target was suboptimal. These results highlight the need for real-time imaging to 
assess catheter placement and drug distribution.  
The objective in this study will be to achieve maximal coverage of the tumor and peritumoral 
margin. Therefore, real-time imaging of drug distribution, through co-infusion of a tracer will be 
employed as a means of assessing infusate distribution.  
Preclinical studies using MDNA55 were carried out to evaluate the effect of the imaging agent 
Gd-DTPA in combination with various concentrations of MDNA55 (Ding et al., 2010) and human 
serum albumin (HSA) administered by direct infusion into rat brains via CED. Results showed that 
the addition of Gd-DTPA (7 µmol/mL) was well tolerated and that Gd-DTPA did not affect the 
potency of MDNA55. Feasibility of safely co-infusing Gd-DTPA as a surrogate tracer has been 
demonstrated in a number of clinical studies (Chittiboina et al., 2014; Lonser et al., 2007; 
Souweidane 2014; Weber et al., 2003a; Weber et al., 2003b). Therefore, in this study, co-infusion 
of Gd-DTPA (commercially available Magnevist®) will allow for depiction of overall drug 
distribution without significant safety concern. Notably, co-infusion of Gd-DTPA will enable 


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continuous real-time monitoring of MDNA55 distribution and permit real-time adjustment of 
infusate delivery by either shutting down a non-convecting catheter, repositioning the catheter or 
adjusting the infusate flow rate).  
Under protocol versions 1.0, 2.0 and 3.0 Gd-DTPA was administered at a concentration of 7 mmol 
for real-time imaging, with the chosen concentration confirmed by the SRC after the treatment of 
the first 6 study subjects. However, following concerns regarding a possible increase in frequency 
and intensity of neurotoxicity AEs following adoption of protocol version 3.0, as described in 
section 1.4.1, and in light of emergent concerns regarding Gd-DTPA, detailed in section 1.2.4, it 
was decided to lower the concentration of gadolinium as a risk minimization measure. 
Subsequently, the 2 mmol concentration of Gd-DTPA necessary for adequate imaging will be 
used for the remainder of the study.   
Following a review of infusate-distribution data for subjects enrolled in protocol versions 1.0 to 4.0 
inclusive, it was determined that continuous real-time MRI monitoring of MDNA55 for at least the 
first 3 hours was not necessary. Sites should therefore confirm convection in all catheters as 
desired and adjust infusion flow rate as required and remove the subject from the MRI scanner 
once these objectives are met in order to limit subject exposure to anesthesia. 
1.4.7 Rationale for No Resection Following CED Infusion 
In previous clinical studies carried out with MDNA55 in subjects with recurrent GB, the objective 
was to target the bulk tumor in situ by delivering increasing intra- and peritumoral doses of 
MDNA55. In the first study (Phase 1) resection was only performed in response to uncontrolled 
edema. In the second study (Phase 2), the objective was to resect the tumor three weeks post-
infusion irrespective of the edema response.  
Tumor resection post-treatment neither affected disease outcome nor improved patient survival 
(see current Investigator’s Brochure for more detail). Histological examination of resected tumors 
showed that by the time they were removed 3 weeks post infusion most tumors consisted mainly 
of necrotic tissue.  
Resection post treatment did not appear to provide a better treatment outcome compared to non-
resected subjects while exposing them to the additional risks associated with CNS surgery. Thus, 
the treatment strategy for this study will consist of intra- and peritumoral administration of 
MDNA55 without tumor resection.   


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2 
Study Objectives 
2.1 
Primary Objective 
• 
To assess overall survival (OS)  
2.2 
Secondary Objectives  
Including: 
• 
To assess the effect of IL4-R status on overall survival (OS) 
• 
To assess the safety of MDNA55 following CED  
• 
To determine the objective response rate (ORR) per Response Assessment in Neuro-
Oncology (RANO)-based criteria incorporating advanced imaging modalities  
• 
To assess progression-free survival (PFS)  
2.3 
Exploratory Objectives 
Including: 
• 
To assess the pharmacokinetics (PK) of MDNA55 in peripheral plasma  
• 
To assess serum anti-MDNA55 antibody titers and, if elevated determine neutralizing 
antibody titers  
• 
To perform additional ad hoc efficacy and safety analysis as needed based on the data 
acquired in this study  
• 
To determine the relationship between clinical outcomes and response assessment status 
by different sets of imaging-based response criteria 
• 
To assess the performance of the Brainlab catheter during infusion in terms of distribution 
and convection of the infusate using real time MRI monitoring 
3 
Study Design 
This is a single-arm, open-label, multicenter study in approximately 52 (at least 46 evaluable) 
adults with primary (de novo) GB that has recurred or progressed (according to RANO criteria). 
The study will be conducted at up to 12 clinical sites following institutional review board approval 
and completed informed consent.  


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The concentration and volume of MDNA55 will be adjusted based on tumor size such that total 
dose will not exceed the established maximum tolerated dose (MTD) of 240 µg. Doses up to 180 
µg have been used in this study to-date, with no evidence of dose dependency for safety. 
Eligible subjects will undergo surgery associated with catheter placement at which time a tissue 
biopsy will also be performed. MDNA55 infusate will be infused with the objective of achieving 
coverage of the tumor and peritumoral margin to the maximum extent possible as indicated by 
distribution of a co-infused gadolinium tracer observed by MRI. Pre-treatment catheter trajectory 
planning will be performed with aim to place up to 4 catheters but a minimum of 2, depending 
upon the tumor size. Planning for catheter placement will only target the enhancing region of the 
tumor on MRI. 
Infusion via each catheter will be initiated at the rate of 3 µL/min/catheter and gradually increased 
in a stepwise manner. The infusion flow rate can be adjusted at the discretion of the Investigator 
during real time MRI (with subject maintained under anesthesia) provided that the flow rate per 
catheter does not exceed 10 µL/min. All functioning catheters should be convecting at similar flow 
rates. The flow rate should be established such that the duration of infusion is at least 24 hours 
to a maximum of approximately 48 hours. In the event only one catheter is functioning the flow 
rate may be increased to complete infusion in 48 hours or less but greater than 24 hours. After 
the real-time MRI infusion monitoring period is completed, the remainder of the infusion will 
continue with the subject awake. MRI will be performed upon completion of infusion as a final 
evaluation of MDNA55 infusate distribution. 
 
 
  
 
 
 
 
 
 
 
 
 


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Post-treatment follow-up assessment of safety will be performed 14 days after CED infusion. 
Thereafter, efficacy and safety assessments will be performed at 30, 60, 90 and 120 days after 
CED infusion and every 8 weeks thereafter until 360 days of active follow up have been 
completed. Subjects who discontinue before the Day 360 visit will undergo all the procedures 
scheduled for the Day 360 visit at the time of discontinuation (see section 7.5.4 for specific details 
concerning early termination visit).  
Subjects who complete the Day 360 assessment without disease progression or who discontinue 
early without disease progression will continue to be followed for disease status until progression. 
After progression (on study or during post-study follow-up), subjects will continue to be followed 
for survival and post-study treatment(s) for GB and imaging for GB until death (or termination of 
data collection by the Sponsor or withdrawal of consent by the subject). 
4 
Study Population  
The population for this study will consist of subjects with histologically proven primary (de novo) 
GB that has recurred or progressed (per RANO criteria) after treatment(s) including surgery and 
radiotherapy with or without chemotherapy (according to local practice; Stupp protocol, Stupp et 
al., 2005) and following discontinuation of any previous standard or investigational lines of therapy 
(up to 2 prior lines of therapy).    
4.1 
Number of Subjects 
Approximately 52 subjects with recurrent or progressive GB will be enrolled in order to achieve 
46 evaluable subjects for the primary survival analyses.  


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4.2 
Eligibility Criteria 
Prospective subjects must have baseline evaluations performed prior to treatment with study drug 
and must meet all inclusion and exclusion criteria. In addition, the subject must be thoroughly 
informed about all aspects of the study, including the study visit schedule and required evaluations 
and all regulatory requirements for informed consent. Written informed consent must be obtained 
from the subject before conducting any study-specific procedures.  
The following criteria apply to all prospective subjects considered for enrollment into the study 
unless otherwise specified. 
4.2.1 Inclusion Criteria  
Prospective subjects will be eligible for participation if they meet all of the following criteria: 
1) Subjects must be ≥ 18 years old and have a life expectancy ≥ 12 weeks  
2) Histologically proven, primary (de novo) GB that has recurred or progressed (first or 
second recurrence, including this recurrence) after treatment(s) including surgery and 
radiotherapy with or without chemotherapy (according to local practice; Stupp protocol, 
Stupp et al., 2005) and following discontinuation of any previous standard or 
investigational lines of therapy 
3) Confirmation that archived tissue is available from first diagnosis of GB for biomarker 
analysis  
4) Subjects must have evidence of tumor recurrence/progression as determined by standard 
RANO criteria following standard therapy: 
a) Includes primary GB 
b) Screening MRI must be performed within 14 days prior to planned infusion, and 
subjects receiving steroids must be on a stable, or decreasing dose for at least 5 days 
prior to imaging 
c) 
More than 12 weeks must have elapsed since the completion of radiation therapy at the 
time of study entry, unless the majority of the new enhancement is outside of the radiation 
field (for example, beyond the high-dose region or 80% isodose line) 
5) Recurrent tumor must be supratentorial, contrast-enhancing GB no smaller than 1 cm x 1 
cm (largest perpendicular dimensions) and no larger than 4 cm maximum in a single 
direction based on MRI taken within 14 days prior to catheter placement 


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6) Karnofsky Performance Score (KPS) ≥ 70 
7) Women 
of 
child-bearing 
potential 
must 
have 
a 
negative 
beta-human 
chorionic 
gonadotropin pregnancy test documented within 14 days prior to treatment 
8) Women and men of child-bearing potential must agree to use adequate contraception: 
hormonal or barrier method of birth control; abstinence, etc. for the duration of study 
participation and for 6 months post drug administration. Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this study, 
she should inform her treating physician immediately 
9) Requirements for organ and marrow function as follows: 
• 
adequate bone marrow function: 
o 
leukocytes > 2,000/µL 
o 
absolute neutrophil count > 1,000/µL 
o 
platelets 
> 100,000/μL 
• 
adequate hepatic function: 
o 
total bilirubin < 1.5 X institutional upper limit of normal (ULN)  
o 
aspartate transaminase (AST) < 2.5 X institutional upper limit of normal (ULN) 
o 
alanine transaminase (ALT) < 2.5 X institutional ULN 
• 
adequate renal function: 
o 
creatinine not to exceed 1.5 X institutional ULN 
OR  
o 
creatinine clearance: ≥ 60 mL/min/1.73 m2 for subjects with creatinine levels above 
institutional ULN 
• 
lymphocytes > 500/μL 
• 
adequate coagulation function 
o 
international normalized ratio (INR) < 1.4 
o 
partial thromboplastin time (PTT) ≤ institutional ULN, unless receiving therapeutic 
low molecular weight heparin (corrected, if necessary, to exclude potential 
antibody effects) 


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10) Able to read, understand, and sign the informed consent document before undergoing any 
study-specific procedures or have a legal representative willing to do so; subjects must be 
registered prior to treatment with study drug 
11) Subjects must be able and willing to undergo multiple brain MRI examinations 
12) Subjects must be able and willing to comply with all study procedures 
13) Any related toxicities following discontinuation of prior GB therapies must have resolved 
to CTCAE Grade 1 or lower prior to inclusion in this study 
4.2.2 Exclusion Criteria 
Subjects will be ineligible for participation if they meet any of the following criteria: 
1 
Prior treatment with cytotoxic chemotherapy 
• 
Temozolomide (standard induction and / or maintenance dosing) within the past 4 weeks 
prior to planned infusion 
• 
“Metronomic” Temozolomide (low-dose, continuous administration) within the past 7 
days prior to planned infusion 
• 
Nitrosoureas within the past 6 weeks prior to planned infusion 
• 
Treatment with any other cytotoxic agent within the past 4 weeks prior to planned 
infusion 
2 
Prior investigational treatment within the past 4 weeks or prior immunotherapy or antibody 
therapy within the past 4 weeks prior to planned infusion; Subjects with prior immunotherapy 
within 
6 
months 
of 
planned 
infusion 
must 
have 
confirmed 
evidence 
of 
tumor 
recurrence/progression as determined by iRANO or mRANO criteria.   
3 
Prior treatment with bevacizumab (Avastin) or other vascular-endothelial growth factor 
(VEGF) inhibitors or VEGF-receptor signaling inhibitors within the past 4 weeks prior to 
planned infusion 
4 
Prior therapy that included interstitial brachytherapy or Gliadel® Wafers (carmustine implants) 
within the past 12 weeks prior to planned infusion   
5 
Prior surgery (including stereotactic radiosurgery and biopsy procedures) within the past 4 
weeks prior to planned infusion 
6 
Ongoing Optune© therapy within 5 days of planned initiation of infusion  
7 
Secondary GB (i.e., GB that progressed from low-grade diffuse astrocytoma or AA)  


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8 
Known mutation in either the isocitrate dehydrogenase 1 (IDH1) or the IDH2 gene.  
9 
Tumor in the brainstem (not including fluid-attenuated inversion recovery [FLAIR] changes), 
an infratentorial tumor, diagnosis of gliomatosis cerebri (highly infiltrative T2 hyperintense 
tumor with ill-defined margins encompassing at least three lobes of the brain. 
10 Multifocal or multicentric satellite tumors with enhancement observed outside a 4cm x 4cm 
area on a single plane (maximum area covered by drug infusion). Multifocal lesions are 
defined by >1 measurable enhancing lesion (1cm x 1cm perpendicular dimensions) 
separated by at least 1cm with confluent T2 hyperintensity between the lesions. Multicentric 
lesions are defined by >1 measurable enhancing lesion (1cm x 1cm perpendicular 
dimensions) separated by at least 1cm with normal brain between the lesions). Measurable 
enhancing tumors separated by at least 1cm with any enhancing components >4cm apart 
are excluded from the current study, as these regions will not be covered by the infusion.  
11 Tumor with a mass effect (e.g. 1-2 cm midline shift)  
12 Subjects with tumors for which the preponderance of tissue is not of the type in which 
convection would be possible (e.g. preponderance of cystic component) 
13 Tumor with geometric features that make them difficult to adequately cover the tumor volume 
with infusate using CED catheters according to expert review (e.g. on grounds of consistency, 
location, geometry, relationship to surrounding structures, presence of cyst, etc.); such 
tumors are likely to include the following: 
• 
tumors that appear to wrap around ventricular structures (such as an “elbow” or “L- 
shape”) where convection is likely to be compromised  
• 
tumors in which post-surgical enhancement in T1 images in the margins around a 
resection cavity may be confused with recurring tumor; subjects in whom this 
enhancement is below 1 cm thickness are excluded  
• 
superficial tumors where direct infiltration of tumor into the cortical surface is apparent 
on MRI unless the distal margin of the enhancing tumor is ≥ 3cm from the cortical 
surface (Subjects with superficial tumors where separation of the tumor from the sub-
dural space by a continuous layer of intact cortex is apparent on MRI remain eligible) 
14 Clinical symptoms that are thought by the Investigator to be caused by uncontrolled increased 
intracranial pressure, hemorrhage, or edema of the brain 
15 Any condition that precludes the administration of anesthesia 


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16 Known to be human immunodeficiency virus positive 
17 On-going treatment with cytotoxic therapy; no additional antineoplastic therapies (including 
surgical modalities) are planned until there is confirmed evidence of tumor progression (as 
per modified RANO criteria) after administration of the study drug 
18 Concurrent or a history of any significant medical illnesses that in the Investigator’s opinion 
cannot be adequately controlled with appropriate therapy or would compromise the subject’s 
ability to tolerate the study drug therapy and/or put the subject at additional risk or interfere 
with the interpretation of the results of this trial 
19 Known history of allergy to gadolinium contrast agents 
20 Presence of another type of malignancy requiring treatment within < 3 years prior to the 
screening visit, except for adequately treated carcinoma in-situ of the cervix, prostate cancer 
not actively treated, and basal or squamous cell carcinoma of the skin 
21 Unwilling or unable to comply with the requirements of this protocol, including the presence 
of any condition (physical, mental, or social or geographical) that is likely to affect the 
subject’s returning to the investigational site for follow-up visits including for imaging or other 
unspecified reasons that, in the opinion of the Investigator or Sponsor, make the subject’s 
enrollment incompatible with study objectives 
4.3 
Study Duration  
Study duration is 12 months for each subject with the day of catheter placement/ start of infusion 
being designated as Day 0.  
Post-treatment follow-up assessment of safety will be performed 14 days after CED infusion. 
Thereafter, efficacy and safety assessments will be performed at 30, 60, 90 and 120 days after 
CED infusion and every 8 weeks thereafter until 360 days of active follow up have been 
completed. Subjects who discontinue before the Day 360 visit will undergo all the procedures 
scheduled for the Day 360 visit at the time of discontinuation.  
Subjects who complete the Day 360 assessment without confirmed disease progression or 
discontinue early without confirmed disease progression will continue to be followed for disease 
status until progression where possible. After confirmed progression (on study or during post-
study follow-up), subjects will continue to be followed, where possible, for survival, post-study 
treatment(s) for GB and imaging for GB until death (or termination of data collection by the 
Sponsor or withdrawal of consent by the subject). 


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4.4 
Subject Withdrawal Criteria  
All subjects who receive MDNA55 treatment should be followed for safety and efficacy. Subjects 
are free to withdraw their consent and discontinue the study at any time without giving a reason 
and without any disadvantage to future treatment.  
The Investigator will withdraw a subject whenever continued participation is no longer in the 
subject’s best interests. Reasons for withdrawing a subject include, but are not limited to the 
following: 
• 
Confirmed disease progression; before withdrawing a subject for disease progression, 
Investigators are encouraged to: 
o 
Ensure confirmatory imaging is obtained following a suitable interval once 
radiological disease progression is suspected (i.e. PD is not confirmed if a 
subsequent scan shows disease control) 
o 
Use all available diagnostic imaging modalities (e.g. perfusion MRI, PET scan, 
spectroscopic MRI) to exclude the possibility of pseudo-progression 
o 
Within the first 120 days of the study  
§ 
Perform diagnostic biopsy to determine disease status (Vogelbaum et al., 
2012; Weller et al., 2016) 
§ 
Discuss all potential subject withdrawals for disease progression with the 
study’s medical monitor 
• 
Occurrence of an AE or a concurrent illness,  
• 
Start of any recurrent GB treatment [excluding low dose bevacizumab (Avastin) (see 
section 6.2)] 
• 
Subject’s non-compliance or  
• 
Significant uncertainty on the part of the Investigator that continued participation is prudent 
Subjects requiring surgical resection for control of physical symptoms should NOT be 
discontinued from the study if examination of excised tissue finds evidence of tumor necrosis but 
no residual tumor. Likewise, if low-dose bevacizumab (doses typically used to control radiation 
induced necrosis) is needed for symptom control and/or steroid sparing (see section 6.2), the 


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subject need not be withdrawn however subsequent assessments of objective response must be 
confirmed by repeat imaging at the appropriate interval.  
The reason for discontinuation (e.g., withdrawal of consent, lost to follow-up, unable or unwilling 
to undergo imaging procedures) must be documented fully in the electronic data capture (EDC) 
form and in the subject’s medical records. Subjects who discontinue the study for any reason 
should undergo the assessments scheduled for the Day 360 visit at the time of discontinuation 
(see section 7.5.4 for specific details concerning early termination visit).  
Subjects who complete the Day 360 assessment without disease progression or who discontinue 
early without disease progression will continue to be followed for disease status until progression. 
After progression (on study or during post-study follow-up), subjects will continue to be followed 
for survival and post-study treatment(s) for GB and imaging for GB until death (or termination of 
data collection by the Sponsor or withdrawal of consent by the subject). 
5 
Study Drug 
5.1 
Investigational Agent: MDNA55 
Classification  
MDNA55 (IL-4[38-37]-PE38KDEL) is a recombinant fusion toxin, of approximately 53 kDa, 
consisting of an engineered circularly permuted (cp) version of interleukin-4 (cpIL-4) which is 
genetically fused to potent payload comprised of a truncated version of the bacterial toxin, 
Pseudomonas aeruginosa exotoxin (PE) A (Kreitman et al., 1994).  
Mechanism of Action 
The mechanism of action of MDNA55 is well documented (Rand et al., 2000; Kreitman et al., 
1994, Puri et al., 2009) and is depicted in Figure 1. MDNA55 binds to IL4R overexpressed on the 
surface of tumor cells and the entire complex is endocytosed. Following cleavage and activation 
by furin-like proteases found in high concentrations in the endosome of cancer cells, the catalytic 
domain of the truncated PE is released into the cytosol where it induces cell death via ADP-
ribosylation of the Elongation Factor-2 and induction of apoptosis through caspase activation 
(Shapira and Benhar, 2010). 
MDNA55 is produced by a fed batch fermentation process using recombinant Escherichia coli. It 
is expressed intracellularly in the form of inclusion bodies. Following cell lysis and solubilization 
of the inclusion bodies, crude protein is purified using multiple chromatographic purification steps.  


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MDNA55 is supplied as a sterile frozen solution at a concentration of 
 
 
 
 
and labeled according to country-specific regulatory requirements.  
Storage and Handling  
Vials will be stored at -70°C (± 10°C); MDNA55 is known to be stable for at least 3 years.  
Composition of Infusate for CED  
MDNA55 drug product will be diluted in Elliotts B® Solution to produce an infusate with a final 
concentration adjusted to ensure the delivery of a total dose of MDNA55 of up to 240 µg based 
on tumor size, with 
 HSA and 
 Gd-DTPA (commercially available Magnevist®; 469.1 
mg/mL; 
 Details on the preparation of MDNA55 infusate are provided in the 
Pharmacy Manual. 
Side Effects 
Complete and updated AE information is available in the current version of the Investigator’s 
Brochure. 
6 
TREATMENT PLAN  
MDNA55 will be administered at a fixed concentration. For patients treated under protocol version 
5.0, this will be 6.0 µg/mL, unless advised otherwise by the sponsor’s medical representative on 
behalf of the SRC (see section 5.1) and detailed in an updated pharmacy manual. The study is 
designed to utilize a volume of infusion (Vi) to achieve maximal coverage of the tumor and 
peritumoral margin. Use of a surrogate tracer (Gd-DTPA) during infusion of MDNA55 will aim to 
monitor the pattern of coverage of the tumor and peritumoral margin and estimate the volume of 
distribution (Vd). 
 
 
 
 
 
 


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6.1 
Dose  
 
 
 The total dose will not exceed 240 µg (the established MTD).  
The study is designed to utilize a volume of infusion (Vi) individualized for each subject based on 
tumor size in order to achieve maximal coverage of the tumor and peritumoral margin. Use of a 
surrogate tracer (Gd-DTPA) during infusion of MDNA55 will aim to monitor the pattern of coverage 
of the tumor and peritumoral margin and estimate the volume of distribution (Vd). The duration of 
infusion will be at least 24 hours; however, infusion may continue to approximately 48 hours if 
required.   
In the event of any concerns by the SRC regarding the possibility of related adverse events, 
reductions to the concentration, volume or rate of administration may be advised via the Sponsor’s 
medical representative and detailed in an updated pharmacy manual. Likewise, the SRC may 
permit usage of concentrations up to 12 µg/mL (provided total dose does not exceed 240 µg 
(MTD) if ongoing data review suggests a positive benefit-risk. 
 
 
 
 
 
 
 
6.2 
Dose Administration 
Total volume of infusion (see section 6.1) will be administered via up to 4 catheters surgically 
placed according to catheter placement guidelines (see Section 6.3).  
The infusate will consist of MDNA55, HSA and Gd-DTPA (commercially available Magnevist®) in 
Elliotts B® Solution.  
Customary antibiotic prophylaxis for such a procedure is required and shall be administered in 
accordance with institutional policy; an example antibiotic protocol is outlined in Table 1.  


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Table 1: Example Antibiotic and H-2 Antagonist Therapy* 
Drug 
Dose 
Route 
Duration 
Ceftriaxone 
1 to 2 g/day 
IV 
Beginning the day of catheter 
implantation and continuing until the 
completion of the MDNA55 infusion  
Cefazolin 
3 g/day 
IV 
Vancomycin 
1 g/day 
IV 
Cimetidine 
300 mg/QID 
Oral 
Beginning the day that 
dexamethasone is started until it is 
stopped 
Ranitidine 
150 mg/BID 
Oral 
Famotidine 
20 mg/BID 
Oral 
*To be administered in accordance with institutional policy; Abbreviation: BID = twice daily; IV = 
intravenous; QID = 4 times daily 
 
Example dexamethasone protocol is outlined in Table 2. Dexamethasone may be used during 
the study for prophylaxis or treatment of inflammatory tissue responses to MDNA55, with or 
without evidence of peritumoral edema and / or signs and symptoms suggestive of raised 
intracranial pressure. For the prevention and / or treatment of Grade ≥3 neurotoxicities mannitol 
may be used in addition. Example mannitol protocol is outlined in Table 3, if required.  
Routine prophylactic use steroids +/- mannitol may be advised by the study SRC if required to 
manage acute toxicities.  
Table 2: Example Dexamethasone Protocol* 
Time point  
Dexamethasone Dose  
Day of catheter placement and postoperative  
    Days 0 and 1:  
6 mg every 6 hours 
Postoperative Days 2 and 3:  
4 mg every 6 hours 
Postoperative Days 4 and 5:  
3 mg every 6 hours 
Postoperative Days 6 and 7:  
2 mg every 6 hours 
Postoperative Days 8 and 9:  
1 mg every 6 hours 
Thereafter  
taper to off in 8 to 28 days based on neurological 
exam 
*As an example only. To be administered in accordance with institutional policy. If a lower dose regime or 
more rapid taper is considered effective, these should be used preferentially. 
 
Table 3: Example Mannitol Protocol* 
Time point  
Mannitol Dose  
At any time during the duration of the infusion if 
subject develops symptoms of increased 
intracranial pressure 
Day 0, 1, or 2 depending on duration of planned 
infusion  
25 g every 6 hours for 24 hours; or per institutional 
practice usually 0.25 to 2 g/kg IV over at least 30 
min administered not more frequently than every 6 
to 8 hours. 
+ dexamethasone up to maximum of 16 mg daily 
*To be administered in accordance with institutional policy 


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Low-dose bevacizumab (Avastin), at doses typically used to control radiation induced necrosis 
(Delishaj et al., 2017) Table 4, may be used for symptom control and/or steroid sparing.  Use of 
low-dose bevacizumab for more than 3 cycles is not recommended due to its potential to confound 
efficacy results in this study. 
Table 4: Example Low-Dose Bevacizumab* 
Time point 
Bevacizumab Dose** 
Not before Day 30 follow up visit 
5 mg/kg q2w x 3 cycles (i.e. 6 weeks)  
OR 
7.5 mg/kg q3w x 3 cycles (i.e. 9 weeks) 
* To be administered in accordance with standard of care / institutional policy and only under circumstances
described above in this section
** May be repeated as required
6.3 
Instructions for MDNA55 Infusate Administration 
Pre-treatment catheter trajectory planning using screening/planning MRI and CT scan (registered 
with iPlan®Flow Infusion planning software) will be performed within 14 days of catheter 
placement following approval of subject for enrollment. Catheter trajectories will be planned using 
the following guidelines: 
a. The planning processes is designed to ensure all catheter tips are placed within the
enhancing tumor; Aim is to place up to 4 catheters but a minimum of 2, depending upon
the tumor size.
b. The catheter tip must not be located within necrotic, cystic, or CSF regions including the
ventricular system, sulci, or any resection cavity or blood vessel
c.
The catheter tip should be placed approximately 1 cm from the ventricular system or sulci
in areas where ependyma / pia mater remains intact and ≥ 1 cm away from such areas
and previous resection cavities where there is no intact margin
d. Catheter(s) should not cross sulci or blood vessels
e. Suitability of the skull surface (bone condition and prosthetic material from previous
surgery) should be considered in planning the locations for the catheter anchor screw
points (per reference CT scan)


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The approved neuro-navigation system VarioGuide™ by Brainlab will be utilized for the surgical 
elements of MDNA55 administration (i.e. surgical placement of catheters) on Day 0.  
The workflow for study drug administration employing VarioGuide™ is described in Table 4. Table 
5 also outlines the required materials for catheter placement and infusion.  
 
 








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6.4 
Image Acquisition - Schedule and Requirements 
MRI will be used in this study to evaluate eligibility, to plan and confirm catheter placement, to 
assess infusate distribution, and to follow the subject for response, progression or pseudo-
progression.  
An independent central image review will be performed, for purposes of this protocol, and 
interpretation of medical images according to a study specific Imaging Charter.  
Table 6 summarizes the images which must be acquired for this study. All scans must be obtained 
using pre-defined imaging protocols to ensure reproducibility at different time points and in a 
manner consistent with the Consensus Guidelines (Ellingson et al., 2015). All image data will be 
sent to the imaging database via electronic transfer. Training will be provided to the relevant site 
staff (radiologists, radiology technicians) to ensure that the required MRI scanning parameters 
are used for the indicated time points. 
A study-specific Image Acquisition Guide details the imaging protocol and minimum requirements 
for the successful acquisition and transfer of image data.  


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Table 6: Imaging Schedule*  
SCAN 
PURPOSE 
Screening MRI 
Within 14 days prior to catheter 
placement  
Assess radiologic eligibility criteria  
Independent central assessment of objective tumor characteristics   
Catheter trajectory planning using iPlan® Flow Infusion planning software 
Image acquisition for perfusion and diffusion assessment 
Electronic image data transfer immediately following acquisition (< 4 hours) 
Screening CT Scan a 
Within 14 days prior to catheter 
placement  
Assessed during screening to ensure no prior skull defects or hardware that would preclude catheter 
placement 
Catheter trajectory planning to ensure no prior skull defects or hardware in the way of planned entry points 
for any of the planned catheter trajectories 
Electronic image data transfer immediately following acquisition (< 4 hours) 
Pre-operative Planning MRI b,c  
Within 24 hours prior to catheter 
placement  
Scan for tumor dimensions and volume estimations, using same MRI scanner that will be used for all 
follow-up MRIs 
Image acquisition for perfusion and diffusion assessment  
Finalization of catheter trajectory planning using iPlan® Flow Infusion planning software 
Pre-operative scan with in situ scalp fiducials to assure optimal catheter placement (within 24 hours of 
catheter placement), where possible, or other validated patient registration tools 
Electronic image data transfer immediately following acquisition (< 4 hours) 
Catheter Placement Confirmation b  
Day 0 - Following surgical placement 
of catheters 
Confirmation of catheters placed by MRI prior to starting infusion 
Electronic image data transfer following acquisition (< 2 days) 
REAL-TIME INFUSION 
MONITORING b  
Day 0 –  initial period of CED Infusion 
MRI will be performed for approximately one hour to monitor the distribution of the infusate in real time 
while subject is maintained under anesthesia (see section 6.3).  
Repeat MRIs will be collected continuously (at approximately 10-15 minute scanning intervals). 
Electronic image data transfer following acquisition (< 2 days) 
End of Infusion MRI 
Within 4 hours (ideally within 2 hours) 
following infusion end time 
MRI will be performed after completion of the infusion to allow for a final evaluation of drug distribution and 
confirmation of final catheter positions  
Electronic image data transfer following acquisition (< 2 days) 
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Screening MRIs will be assessed for determination of disease status, subject eligibility and 
convectibility. These images will be evaluated at the site and transmitted to the central reviewer  
to provide independent central assessment of objective tumor characteristics. All image reviews 
concerning study endpoints will be conducted in a blinded manner by an independent reviewer, 
without knowledge of the clinical condition or identity of the subject or the local site assessment. 
 
 
The following criteria will be utilized for independent evaluation of objective tumor characteristics 
for consideration in determination of eligibility as follows:  
• 
Tumor diameter of ≥ 1 cm x ≥ 1 cm (perpendicular dimensions), minimum, and a maximum 
size in any single dimension of 4 cm  
• 
Tumor location not infratentorial or involving brainstem 
• 
Exclude regions in the eloquent areas or close to eloquent areas of the brain. 
• 
Diagnosis of gliomatosis cerebri (highly infiltrative T2 hyperintense tumor with ill-defined 
margins encompassing at least three lobes of the brain) 
• 
Multifocal lesions and multicentric lesions are discouraged, but allowable so long as all 
boundaries of any multifocal, measurable enhancing lesions are within a 4cm x 4cm area 
(maximum area covered by drug infusion). Multifocal lesions are defined by >1 
measurable enhancing lesion (1cm x 1cm perpendicular dimensions) separated by at least 
1cm with confluent T2 hyperintensity between the lesions. Multicentric lesions are defined 
by >1 measurable enhancing lesion (1cm x 1cm perpendicular dimensions) separated by 
at least 1cm with normal brain between the lesions.  
Independent central review of screening MRIs will be expedited. No subject will be enrolled in the 
study without this central imaging assessment being performed and reviewed by the Medical 
Monitor with further advice based on imaging reviews from CED experts, as required, especially 
in regard to tumors considered not to be good candidates for CED (see Section 4.2.2; exclusion 
criterion #13). All subjects will be approved for enrollment by the Medical Monitor following 
comprehensive review of a screening eligibility package comprising the independent central 
imaging assessment as well as documentation substantiating screening assessments.   


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Follow up MRIs will be subject to local site review for lesion assessment including tumor 
measurements in order to ensure consistency in all local tumor assessments (see Image 
Acquisition Guide). 
Follow up MRIs will also be subject to independent central image review for determination of 
response/progression including tumor volume and perfusion criteria at each follow up time point.  
7 
Study Procedures and Observations  
7.1 
Efficacy Evaluation 
7.1.1 
Survival 
After progression (on study or during follow-up), subjects will continue to be followed for survival 
and post-study treatment(s) for GB and imaging for GB, where possible, until death (or termination 
of data collection by the Sponsor or withdrawal of consent by the subject). 
7.1.2 
Tumor Response Assessment  
MDNA55 shares many properties with immunotherapies, such as immune checkpoint inhibitors, 
including the possibility of response following a prolonged (> 3 months) period of pseudo-
progression. Given acknowledged difficulties in determination of true progression in patients 
treated with immunotherapies, the determination of progressive disease (PD) will be informed by 
use of multimodality MRI and/or biopsy prior to subject withdrawal.   
Tumor response will be determined using RANO-based criteria (section 8.1.1) incorporating 
advanced imaging modalities.  
ORR, PFS, duration of response (DOR), and duration of clinical benefit (DOCB) will be assessed 
based on the independent assessment.  
See section 8.1 for information on efficacy endpoints. 
7.2 
Safety Evaluation 
Safety will be evaluated through AE monitoring, clinical evaluations (i.e., vital signs, physical 
examinations, electrocardiogram [ECG]), laboratory tests (i.e., hematology, serum chemistries, 
and urinalysis), antibody (serum anti-MDNA55 antibody and neutralizing antibody where 
applicable) assessments, and plasma drug levels on PK samples from the signing of informed 
consent until the last study visit (360 days post-CED infusion or termination). 


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7.2.1 
Laboratory Evaluations  
All study sites will conduct their own hematology, serum chemistry, and urinalysis tests (within 
their respective local certified laboratories) at various time points for each subject (see Table 7). 
Required clinical laboratory tests for each panel will be as follows: 
• 
Hematology: hemoglobin, hematocrit, platelet count, white blood cell (WBC) count, and 
WBC differential; 
• 
Coagulation: prothrombin time (PT)/PTT/INR (PTT, corrected, if necessary);   
• 
Serum chemistry: AST, ALT, lactate dehydrogenase (LDH), total bilirubin, indirect 
bilirubin, alkaline phosphatase, total protein, albumin, sodium, potassium, chloride, 
carbon dioxide, calcium, phosphorus, blood urea nitrogen (BUN), creatinine, uric acid, 
and glucose; 
• 
Urinalysis: pH, specific gravity, protein, glucose, ketones, blood, leukocyte esterase, and 
nitrite. Microscopy required only to follow-up clinically significant abnormal findings; and 
• 
Pregnancy: Serum pregnancy tests will be performed at screening and at 30 and 
180 days post CED infusion for all women of childbearing potential. 
The Investigator or a designated associate will review all clinical laboratory results, and clinically 
significant findings will be reported as AEs (see Section 8.2.2) and followed or treated according 
to institutional guidelines or the treating physician’s medical judgment.  
7.2.2 
 Safety Considerations  
Physical examinations will be performed at screening, within 24 hours prior to catheter placement 
and following CED infusion on Days 1 or 2 (according to infusion duration), 14, 30, 60, 90, 120, 
180, 240, and 360 (or early termination). The screening and Day 360 (or early termination) 
examinations will be complete physical examinations; other examinations should be focused, at 
the discretion of the Investigator, to assess changes from the previous examination. Clinically 
significant changes in physical examination findings during or after treatment, including transient 
neurological symptoms, will be reported as AEs. 
Other safety assessments will include vital signs. The Investigator or a designated associate will 
review all vital sign results, and clinically significant findings will be reported as AEs (see Section 
8.2.2) and followed or treated according to institutional guidelines or the treating physician’s 
medical judgment. Triplicate twelve-lead ECGs are taken during screening and within 2 hours 


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following completion of infusion, and clinically significant abnormal findings must be followed by 
the Investigator.  
7.2.3 
Pharmacokinetic and Immune Parameter Evaluations  
Systemic exposure to MDNA55 is not expected following intra- and peritumoral infusion and 
circulating MDNA55 has not been detected in previous clinical studies. To continue to evaluate 
the potential of systemic exposure, blood samples will be collected for analysis at the times 
indicated in Table 7.   
Blood samples will also be collected for testing for the presence of antibodies against MDNA55 
(Table 7). If serum anti-MDNA55 antibodies are present, further immunogenicity assessments will 
be carried out for determination of antibody neutralization potential. Other immune parameters 
may also be assessed. 
All collected blood samples will be processed according to a laboratory manual and samples will 
be stored at -70°C until instructions are provided to the site to ship the samples to the central 
testing laboratory (MicroConstants Inc., San Diego, CA). 
7.3 
Tumor Tissue Analysis 
During screening, subject eligibility assessment requires confirmation that archived tumor tissue 
from initial GB diagnosis is available for the patient. At the time of study treatment, prior to catheter 
insertion, biopsy samples will be collected, if the neurosurgeon determines it is possible to harvest 
viable tumor tissue from along the planned trajectory of the CED catheter(s).  
Tissue sample archived from initial GB diagnosis and/or tissue sample archived following 
recurrence 
will 
be 
utilized 
for 
retrospective 
analysis 
of 
IL4R 
expression 
using 
immunohistochemistry (IHC). The tissue sample may also be subject to retrospective analysis of 
other biomarkers, including but not be limited to methylation status of the MGMT gene (Section 
7.3.2).  
Biomarker analyses will be conducted to determine if there is a correlation between IL4R 
expression and/or MGMT status and treatment response to MDNA55.  
Tissue samples from biopsies taken at the time of MDNA55 infusion will be evaluated for disease 
status, including assessment of the immunological state of the tumor. 
Analyses on other tumor tissue samples obtained during other surgical procedures or local 
evaluations of disease status (e.g. samples from repeat resections or biopsies taken to establish 


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tissue response status) should be recorded and may be used in sensitivity, sub-group and other 
exploratory analyses.  
7.3.1 
Biomarker Analysis including IL4R Expression  
Archived tumor tissue specimens from subjects entering the study will be processed by IHC at a 
CLIA certified laboratory (QualTek Molecular Laboratories, Goleta, CA) for retrospective analysis 
of IL4R expression to determine if there is a correlation between IL4R expression and tumor 
response following MDNA55 treatment. Instructions for processing and submitting archived tissue 
are provided in the Study Reference Guide.  
Tissue sections will be graded for IL4R expression by examining staining intensity in a blinded 
fashion for each specimen using a semi-quantitative scale of 0, 1+, 2+, and 3+ (as well as H-
Score). Further quantitative assessment of IL4R staining may include standardized image 
analysis. Efficacy endpoints (such as PFS, ORR, OS, DOR, DOCB) will be evaluated versus 
intensity of IL4R expression.  
In addition, pre-anesthesia blood sample as well as pre-treatment tumor tissue specimens (from 
subjects where viable tissue can be harvested at the time of catheter placement) will be processed 
by 
Mitra 
Biotech 
(Woburn, 
MA) 
for 
exploratory 
retrospective 
analysis 
of 
the 
tumor 
microenvironment by conducting an RNA (ribonucleic acid) based immune profile. Instructions for 
processing and submitting the blood and biopsy samples are provided in the Study Reference 
Guide. 
7.3.2 
O6-Methylguanine-Methyltransferase Analysis 
MGMT-expressing cancer cells (harboring unmethylated MGMT promoters and therefore 
resistant to temozolomide) are sensitive to MDNA55.  
Thus, tumor tissue specimens from subjects will be processed at a CLIA certified laboratory for 
MGMT DNA methylation analysis using a quantitative methylation-specific PCR technique. 
Primary and secondary endpoints will be analyzed against the MGMT methylation status.  
7.4 
Evaluation of Progression versus Pseudo-progression   
For malignant gliomas, conventional MRI with contrast is currently used to determine radiologic 
response. While this method has been used to determine overall tumor response, it is known that 
image interpretation can be confounded by pseudo-progression due to the fact that conventional 
MRI is unable to differentiate tumor/non-tumor enhancing tissues (Verma et al., 2013; Ellingson 
et al., 2017b). Therefore, determination of true response may take several months post-treatment 


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(Floeth et al., 2002; Vogelbaum et al., 2012). Increasingly, evidence supports the designation of 
non-progression status to patients who have no subsequent signs of disease progression on 
imaging despite initially being considered to have PD, following treatment with immune-based 
therapies (Hodi et al., 2018). To address this issue, advanced imaging techniques such as 
perfusion MRI, PET imaging and spectroscopic MRI have been evaluated for the ability to 
distinguish between true and pseudo-progression and confirm response in GB patients at earlier 
time points (Ion-Mărgineanu et al., 2017; Thomas et al., 2015; Boxerman et al, 2014).  
7.5 
Study Visit Schedule 
All clinical study evaluations and procedures will be performed according to the schedule of 
assessments (Table 7) and the instructions listed in the sections following. 
All on-study visit procedures are allowed a window of time unless otherwise noted. *Treatment 
or visit delays for weekends, public holidays or weather conditions do not constitute a protocol 
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* 
Treatment or visit delays for weekends, public holidays or weather conditions do not constitute a protocol violation 
a 
Safety assessed after initiation of infusion (during and following CED infusion throughout entire hospitalization period) and safety follow-up to 
be performed on Days 14 and 30 (± 3 days), and 60, 90, 120, 180, 240, 300 and 360 (± 7 days)  
b 
Scheduled follow-up to be performed with MRI up to 12 months after CED infusion on Day 30 (± 3 days) and Days 60, 90 and 120, then q8w 
until Day 360 (± 7 days) NOTE: at the Day 300 visit only MRI, physical exam/neurological exam/KPS need be performed 
c 
Subjects who discontinue before the Day 360 visit will undergo all the procedures scheduled for the Day 360 visit if early termination is 
between follow-up visit time points with the specific provision that MRI will not be required if last MRI performed was within 2 weeks prior to 
the early termination date. When early termination is in line with a study follow up visit time point that visit will be considered the early 
termination time point and no other assessments apart from the respective visit date assessments will be required. 
d 
ICF can be signed in advanced of the 14 day screening period 
e 
Operative report to be accessioned  
f 
Archived tissue from the resection of the initial GB diagnosis required for biomarker analysis including IL4R IHC, MGMT DNA methylation, 
and other translational biomarkers 
g 
All MRIs acquired throughout entire study schedule will follow will be performed according to imaging protocols outlined in the study specific 
Image Acquisition Guide 
g1 
Screening MRI to be subject to independent assessment to verify objective radiologic tumor characteristics [e.g. tumor size; subjects must 
have tumor diameter of ≥ 1 cm x ≥ 1 cm (minimum) to 4 cm in any direction, etc.]; additional image reviews of screening MRI pertaining to 
evaluation of suitability of subjects for convection may be performed by CED experts; if subject approved for enrollment, screening MRI will 
also be used for catheter placement planning using iPlan® Flow 
g2 
Pre-operative planning MRI can be performed in one or two MRI exams as required, based on local capabilities; Timing of planning images to 
support catheter trajectory planning is described in Table 6; Planning MRI images will be registered with iPlan® Flow Infusion planning 
software to support finalization of catheter trajectory plan. 
g3 
On Day 0 MRI performed following catheter placement prior to the start of CED infusion as well as during infusion for real-time MRI infusion 
monitoring (for approximately 1 hour while subject is maintained under anesthesia) (see Section 6.3 for CED infusion procedure)  
g4 
On Day 1 or Day 2 (depending on duration of infusion) MRI performed within 4 hours (ideally within 2 hours) after completion of infusion 
relative to infusion end date/time; another MRI performed within 18-30 hours after completion of infusion prior to subject being discharged 
from the hospital  
g5 
MRI performed as part of the scheduled follow-up visits on Days 30, 60, 90, 120 and then q8w thereafter until Day 360 / early termination. For 
patients who are progression free, MRIs will continue as per the institution’s standard of care schedule until confirmed disease progression.  
g6 
CT scan acquisition only required when no CT scan is available within 3 months of planned infusion 
h1 
Females of child bearing potential only at Screening, Days 30 and Day 180 
h2 
Hematology: hemoglobin, hematocrit, platelet count, white blood cell (WBC) count, and WBC differential; 
 
Serum chemistry: AST, ALT, lactate dehydrogenase (LDH), total bilirubin, indirect bilirubin, alkaline phosphatase, total protein, albumin, 
sodium, potassium, chloride, carbon dioxide, calcium, phosphorus, blood urea nitrogen (BUN), creatinine, uric acid, and glucose 
h3 
Coagulation: prothrombin time (PT)/PTT/INR (PTT, corrected, if necessary)   




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u 
Blood samples for hematology, serum chemistry, and coagulation (Section 7.2.1) shall be taken in parallel with either the PK blood collection 
that is performed within 1 hour following completion of infusion or the PK blood collection that is performed ~3 hours following completion of 
infusion 
  
 


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7.5.1 
Pretreatment Period  
7.5.1.1 
Informed Consent  
Each subject will provide signed informed consent and Health Insurance Portability and 
Accountability Act (HIPAA) authorization as per institutional and/or Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) guidelines and in accordance with the requirements 
of the International Council on Harmonization guidelines on Good Clinical Practice (ICH E6 GCP) 
and the principles of the Declaration of Helsinki. Major deviations may not be made from the 
informed consent provided by the Sponsor unless requested by the IRB/IEC. If translation of 
informed consent form (ICF) is required, the Sponsor will review a certified back-translation to 
ensure all elements are present. The IRB/IEC-approval document must be provided to the 
Sponsor or their representative for regulatory purposes. 
Before a subject undergoes any study-related procedures or examinations, the Investigator or 
approved delegate will explain to each subject (or legal guardian) the nature of the study, its 
purpose, procedures, expected duration including the necessity to collect information about the 
subject's treatment and disease after completion of the scheduled last follow-up visit, and the 
potential benefits and risks of participation.  
Subjects will be informed of their right to refuse to consent to the study or to withdraw from the 
study at any time without any change in the quality of their health care. Subjects will be provided 
with a copy of the IRB/IEC approved ICF and they will have sufficient time to consider the study 
information and ask any questions.  
If a subject (or legal guardian) agrees to participate in the study, he/she (or legal guardian) will 
sign and date a statement indicating their informed consent. The statement will also be signed by 
the Investigator or approved delegate to indicate that he/she fully informed the subject and 
witnessed the freely provided consent. A copy of the signed ICF will be given to the subject, and 
a copy will be filed in the medical record. The original signed ICF will be kept on file with the 
Investigator’s study records.  
7.5.1.2 
Screening Assessments (within 14 Days of Infusion) 
Before a subject can be considered for entry into the study, the Investigator must receive the 
subject's clinical history, general laboratory results, specific radiological evaluations and 
diagnoses, and a chronology of all previous therapies for the treatment of GB, including outcomes, 


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from the referring physician. Subjects should have results from a previous histological diagnosis 
of initial primary (de novo) GB and a pre-study MRI scan providing radiological evidence of 
recurrence or progression. 
A written and signed ICF and HIPAA authorization must be obtained before any study-specific 
assessments are initiated (See Section 7.5.1.1). The ICF can be signed in advanced of the 14 
day screening period. 
The following assessments must be carried out within 14 days before catheter placement:  
• 
Screening MRI to assess radiologic eligibility criteria and catheter trajectory planning 
using iPlan® Flow Infusion planning software 
o 
Electronic image data transfer immediately following acquisition (< 4 hours) 
• 
CT scan assessed during screening to ensure no prior skull defects or hardware that would 
preclude catheter placement (CT scan acquisition only required when no CT scan is 
available within 3 months of planned infusion) 
o 
Electronic image data transfer (should be concomitant with transfer of screening 
MRI) 
• 
Verification that archived tumor tissue (from initial GB diagnosis) is available for 
retrospective biomarker analysis 
• 
Complete medical and oncologic history, including history of prior surgical procedures 
and prior treatments, prior conditions, signs and symptoms and any residual/ongoing 
toxicity relating to prior treatment(s) 
• 
Complete physical and neurological examinations, including height, weight, mental 
status, cranial nerves, motor and sensory examinations, and KPS 
• 
Baseline signs and symptoms 
• 
Vital signs (pulse, respiratory rate, weight and blood pressure) 
• 
Standard 12-lead ECG (triplicate assessment) 
• 
Hematology, serum chemistry, and coagulation (Section 7.2.1) 
o 
If the coagulation values are clinically significant, they must be repeated until within 
normal limits, unless subject is receiving therapeutic low molecular weight heparin 


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NOTE: Any test results outside of the reference ranges may be repeated at the 
discretion of the Investigator 
• 
Collection of blood sample for Immunogenicity analysis (baseline) 
• 
Collection of blood sample for PK analysis (baseline) 
Concomitant medications and treatments will be recorded from 14 days before infusion (Day 0) 
until the Day 360 (or early termination) visit, and AEs will be recorded from the time of signing the 
informed consent document until the Day 360 (or early termination) visit. 
In addition, a serum pregnancy test must be performed within 14 days before infusion (Day 0) for 
all female subjects of childbearing potential. 
While the above assessments are being carried out, screening MRI will be subject to review by 
CED experts pertaining to evaluation of suitability of tumor for convection. The screening MRI will 
also be sent to an independent central assessment of objective radiologic tumor characteristics.  
Subjects will be approved for enrollment by the Medical Monitor following comprehensive review 
all screening results.  
Following approval of subject for enrollment, Investigator/site will be notified and preliminary pre-
treatment catheter trajectory planning using CT scan and screening MRI (registered with iPlan® 
Flow Infusion planning software) can ensue (see Section 6.3 for catheter placement guidelines).  
NOTE: use of iPlan® Flow software is required for catheter trajectory planning. 
7.5.2 
Treatment Period 
7.5.2.1 
Pre-operative study Procedures within 24 hours of catheter placement  
Within 24 hours prior to catheter placement, subjects will undergo the following procedures and 
assessments: 
• 
Pre-operative Planning MRI  
o 
Pre-operative planning MRI can be performed in one or two MRI exams as 
required, based on local capabilities; Timing of planning images to support catheter 
trajectory planning is described in Table 6. 
o 
Planning MRI images will be registered with iPlan® Flow Infusion planning 
software to support finalization of catheter trajectory plan.  


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• 
NOTE: use of iPlan® Flow software is required for catheter trajectory planning. 
• 
Brief medical history and physical and neurological examinations including KPS, 
noting/recording any changes since screening;  
• 
Vital Signs (pulse, respiratory rate, weight and blood pressure) 
• 
Review of Baseline Signs and Symptoms noting/recording any changes or new 
signs/symptoms since screening in medical history; Any changes to concomitant 
medications will also be recorded;  
• 
Treatment Plan (study specific source worksheet) will be completed and reported to 
hospital pharmacy for dispensing infusate at the time required on Day 0. 
7.5.2.2 
Study Drug Administration (Day 0)  
On Day 0 subjects will undergo the following procedures and assessments:  
• 
Pre-anesthesia blood draw  
o 
Blood sample collection and processing will use a study specific sample collection 
kit and require immediate shipment to the central laboratory  
• 
Just prior to catheter insertion, core tumor biopsy samples (at least 3 cores) will be 
collected, if the neurosurgeon determines it is possible to harvest viable tumor tissue from 
along the planned trajectory of the CED catheter(s) 
o 
Biopsy sample tissue collection and processing will use a study specific sample 
collection kit and require immediate shipment to the central laboratory 
• 
Catheter placement and infusion (see Section 6.3 for outline of surgical procedures and 
instructions for study drug administration via CED with real-time imaging) 
o 
See Table 1 for example of mandatory antibiotic / H-2 antagonist therapy and 
Table 2 and Table 3 for optional dexamethasone and mannitol therapy for 
management of raised intra-cranial pressure (ICP). 
o 
Throughout entire surgical workflow for catheter placement and infusion vital signs 
(pulse, respiratory rate and blood pressure) will be performed according to 
institutional best practice; study specific vital signs check points during the surgical 
workflow are as follows: 


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§ 
Vital signs taken prior to initiation of anesthesia 
§ 
Vitals signs taken following placement of all catheters but prior to patient 
being loaded into MRI machine for the real-time infusion monitoring 
segment  
§ 
Vital signs taken approximately 1 hour post initiation of infusion  
§ 
Site will record any abnormal vitals observed at any time during surgical 
vital signs monitoring as unscheduled findings 
• 
Any AEs experienced or concomitant medications received during the catheter placement 
procedure or during the infusion will be recorded in the subjects’ medical records and EDC 
system 
NOTE: Subjects will likely be admitted to hospital for 2 nights.  
7.5.2.3 
Interruption or Discontinuation of Infusion  
If a subject experiences a clinically significant Grade 3 or 4 AE considered by the Investigator to 
be related to the study drug or due to infusion procedure, the infusion will be stopped. Infusion 
may be restarted at the Investigator’s discretion if the AE responds to medical management; 
otherwise, the infusion should be discontinued permanently. 
Should an interruption of the infusion be due to observed mass effect / increased intracranial 
pressure (ICP), treatment with mannitol is suggested (see Table 3) with infusion resuming after 
recovery (if possible), such that it can be completed within the maximum infusion duration window 
of approximately 48 hours.  
Treatment may be discontinued at the discretion of the Investigator. In the unlikely event that all 
catheters are placed erroneously (not in line with placement guidelines in section 6.3) or cannot 
be used (e.g. catheters do not function/convect), the procedure will be halted and no infusion 
given to the subject. 
7.5.2.4 
End of CED Infusion (Day 1 - 2) 
These procedures must be completed at the end of the CED infusion (see Section 6.3): 
• 
A standard 12 Lead ECG (triplicate assessment) will be performed immediately following 
completion of the infusion (within 2 hours) 


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• 
MRI for final evaluation of drug distribution (with catheters maintained in place) will be 
performed within 4 hours (ideally within 2 hours) following completion of infusion 
o 
Removal of catheters and closure of incisions in accordance with institutional 
practice at bedside.  NOTE: catheters are only removed after the end of infusion 
MRI is performed.   
• 
Collection of blood samples for PK analysis as soon as possible but not more than 1 hour 
following infusion end time, approximately 3 hours following completion of infusion and 
then (after the ~3 hour sample collection) every 6 hours ± 2 hours until 24 hours or until 
subject is discharged from the hospital (whichever occurs first)  
• 
Blood samples for hematology, serum chemistry, and coagulation (Section 7.2.1) shall be 
taken in parallel with either the PK blood collection that is performed within 1 hour following 
completion of infusion or the PK blood collection that is performed ~3 hours following 
completion of infusion.  
• 
MRI performed within 18-30 hours after infusion end time to assess non-specific 
enhancement following the infusion   
• 
Brief medical history and physical and neurological examinations including KPS, noting 
any changes since prior to study drug administration shall be performed when the subject 
is ambulatory prior to hospital discharge.  
• 
Vital signs (pulse, respiratory rate, blood pressure and weight) taken when the subject is 
ambulatory prior to hospital discharge.  
• 
Any AEs and new concomitant medications and/or changes to concomitant medications 
will be recorded throughout entire hospitalization period.   
7.5.3 
Post-Treatment Follow-up Assessments  
Assessment of safety will be performed on Day 14 (± 3 days) after infusion. Both efficacy and 
safety assessments will be performed on Days 30 (± 3), 60 (± 7), 90 (± 7) and 120 (± 7) and every 
8 weeks (± 7) thereafter until at least 360 days of active follow up have been completed after start 
of infusion. Unscheduled MRI exams may be required for confirmation of overall response status 
when preliminary CR or PR or PD by repeat assessment 4 weeks (or at appropriate interval for 
post bevacizumab (Avastin®) therapy) after it is observed (required if preliminary response or 
preliminary progression is observed at Day 120, 180, 240, 300 or 360). Subjects who undergo 


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post-treatment surgery to de-bulk the tumor, and if the tumor is shown to be largely necrotic with 
no viable tumor, will continue to be followed for tumor recurrence by MRI at the scheduled visits 
in order to establish PFS. 
Subjects who complete the Day 360 assessment without disease progression or discontinue early 
without disease progression will continue to be followed for disease status until progression where 
possible. After progression (on study or during post-study follow-up), subjects will continue to be 
followed (by access of available medical records or via periodic telephone contact to the 
subject/caregiver), where possible, for survival, post-study treatment(s) for GB and imaging for 
GB until death (or termination of data collection by the Sponsor or withdrawal of consent by the 
subject). 
7.5.3.1 
14 Days (± 3 days) After Infusion 
Subjects will return 14 (± 3) days after infusion.  
Concomitant medications/therapies and AEs will be assessed by asking non-leading questions, 
and the following procedures will also be performed: 
• 
Vital signs (pulse, respiratory rate, weight and blood pressure) 
• 
Physical and neurological examinations including KPS 
• 
Hematology, serum chemistry, and coagulation (Section 7.2.1) 
• 
Collection of a blood sample for immunogenicity;  
• 
Collection of a blood sample for PK  
7.5.3.2 
Follow up (for period of 12 months After Infusion) 
Following completion of infusion, subjects will return on Days 30 (± 3), 60 (± 7), 90 (± 7) and 120 
(± 7), and every 8 weeks (± 7) thereafter until Day 360 to undergo follow-up MRI. For sites that 
may use TRAMs, delayed contrast extravasation MRI can be performed on Days 30, 60, 90, 120 
and 180 for calculation of TRAMs image map to be used for exploratory analyses of tissue 
response (calculation of TRAMs may be performed at the other follow up visits as or if requested 
by the Investigator).  
At all of the above-named visits concomitant medications/therapies and AEs will be assessed by 
asking non-leading questions, and the following procedures will also be performed: 
• 
Physical and neurological examinations including KPS 


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• 
Vital signs (pulse, respiratory rate, weight and blood pressure) 
• 
Hematology, serum chemistry, and coagulation (Section 7.2.1) 
• 
Serum pregnancy test (female subjects; Day 30 and Day 180 visits only) 
• 
Collection of blood samples for immunogenicity (Day 30, Day 120, Day 240 and Day 360 
or early termination)  
At any time-point during the follow-up period, should analyses on tumor tissue sample material 
occur at the discretion of the Investigator (e.g. biopsies to establish tissue response status), result 
should be recorded and material retained for biomarker analysis, where possible. 
Other assessments will be performed at the Investigator’s discretion and as necessary to follow 
up any AEs previously recorded.  
The Day 360 visit will be equivalent to the early termination visit and will end the subject’s safety 
reporting.  
7.5.4 
Early Termination Visit  
Subjects who discontinue before the Day 360 visit will undergo all the procedures scheduled for 
the Day 360 visit if early termination is between follow-up visit time points. A new / repeat MRI will 
not be required if the last MRI performed was within 2 weeks prior to the early termination date, 
results from this prior MRI will be carried forward for the early termination assessment. When 
early termination is within 2 weeks following study follow up visit time point (i.e. Day 30, 60, 90, 
120, 180 or 240) that visit will be considered the early termination time point and no additional 
assessments beyond the respective visit date assessments will be required. In the event that a 
subject is withdrawn from the study prior to the Day 360 visit, post-study follow-up should ensue 
(see Section 7.5.5 below). 
7.5.5 
Post-Study Follow-Up 
Subjects who complete the Day 360 assessment without disease progression or discontinue early 
without disease progression will continue to be followed for disease status until progression where 
possible. After progression (on study or during post-study follow-up), subjects will continue to be 
followed (by access of available medical records or via periodic telephone contact to the 
subject/caregiver), where possible, for survival, post-study treatment(s) for GB and imaging for 
GB until death (or termination of data collection by the Sponsor or withdrawal of consent by the 
subject). 


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7.6 
Usage of Concomitant Medications  
All concurrent medical conditions and complications of the underlying malignancy will be treated 
at the discretion of the Investigator according to acceptable local standards of medical care. 
Subjects should receive analgesics, antiemetics, antibiotics, anti-pyretics, and blood products as 
necessary. Although warfarin-type anticoagulant therapies are permitted, careful monitoring of 
coagulation parameters is imperative to avoid complications of any possible drug interactions. All 
concomitant medications, including transfusions of blood products, will be recorded in the EDC 
system.  
Guidelines for treating certain medical conditions are discussed below; however, institutional 
guidelines for the treatment of these conditions may also be used. The concomitant therapies that 
warrant special attention are discussed below. 
7.6.1 
Antiemetic Medications  
Dexamethasone and a 5-HT3 blocker (e.g., ondansetron or granisetron) may be administered to 
subjects as pre-medications unless contraindicated for the individual subject. Antiemetics will also 
be prescribed as clinically indicated during the study period. 
7.6.2 
Colony Stimulating Factors  
Though unlikely to be needed, the use of granulocyte colony-stimulating factors is permitted to 
treat subjects with neutropenia or neutropenic fever but not to allow for study eligibility.  
7.7 
Dietary Restrictions 
None. 
7.8 
Prohibited Medications 
The following therapies are not permitted during a subject’s participation in the study:  
• 
Other anti-neoplastic therapy, including cytotoxics, targeted agents, endocrine therapy, or 
other antibodies, including Avastin® (bevacizumab) with any treatment intent. NOTE: 
Low-dose bevacizumab (Avastin®) (doses typically used to control radiation induced 
necrosis, see section 6.2) use is permitted 
• 
Radiotherapy 
• 
Any other investigational therapy 


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Should such therapies be administered if a subject is withdrawn from the study due to progressive 
disease, relevant disease related treatment data will continue to be collected until death or 
termination of data collection by the Sponsor or withdrawal of consent by the subject. 
8 
REPORTING AND DOCUMENTATION OF RESULTS 
8.1 
Evaluation of Efficacy 
8.1.1 
Overall Survival 
The time from start of treatment to the date of death from any cause. For subjects who are not 
known to have died as of the data-inclusion cut-off date, OS time will be censored at the date of 
the last contact confirming the subject was alive.  
8.1.2 
Progression-free survival 
The time from start of treatment to the date of confirmed objective progression or death from any 
cause, whichever occurs first. For subjects who are not known to have died or progressed as of 
the data-inclusion cut-off date, PFS time will be censored at the date of the last objective 
progression-free disease assessment prior to the date of any subsequent recurrent GB treatment.  
PFS will be determined by RANO-based assessments, adopting the general approaches 
described for the modified RANO (mRANO) assessment with the response rubric of iRANO (for 
immunotherapy agents). Additional response assessments will incorporate the use of advanced 
imaging modalities (e.g. MRI perfusion / diffusion assessments) in the m/iRANO approach, to 
support differentiation of true vs. pseudo progression / response. 
8.1.3 
Objective Response Rate 
Objective Response Rate (ORR) is the proportion of subjects who achieved a complete response 
(CR) or partial response (PR) out of all treated subjects. 
According to the modified RANO criteria, a responder is defined by radiographic and clinical 
criteria (Ellingson et al., 2017a). CR and PR together with Stable Disease (SD) and initial and 
confirmed Progressive Disease (PD) will be first assessed by radiographic changes in tumor size 
as determined by conventional MRI and further assessed by use of advanced imaging [e.g.  
diffusion weighted imaging, perfusion using dynamic susceptibility contrast and/or Tumor 
Response Assessment Maps (TRAMs), etc.] where available. In addition, deterioration of 


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neurologic function and increase in steroid use will be used to determine PD provided it is 
confirmed by advanced imaging and/or biopsy since extended duration of pseudo-progression is 
frequently observed following immunotherapies such as MDNA55 (Weber et al., 2003a; 2003b; 
Okada et al., 2015).  
For the purpose of study endpoints, Objective Response (OR) status should be confirmed by 
repeat examination after at least 4 weeks.  Patients who receive low-dose bevacizumab 
(Avastin) treatment to control edema, a preliminary OR observed at least 4 weeks post-
bevacizumab treatment will require a confirmatory OR after at least 4 additional weeks. 
Subjects who remain on study following surgical resection / de-bulking with no histological 
evidence of recurrent tumor will have a best OR of SD following surgery and will continue to be 
followed by MRI as scheduled until new recurrence or confirmed PD to determine PFS. 
Imaging assessment will be carried out using comprehensive imaging guidelines to help identify 
pseudo-progression where possible.  
A blinded central review will be employed to provide independent assessment of response or 
progression following treatment with MDNA55 according to RANO-based criteria (Wen et al., 
2010; Ellingson et al., 2017a) incorporating advanced imaging modalities. To rule out pseudo-
progression, advanced imaging modalities and/or biopsy will be utilized. 
8.1.4 
Other Time-to-Event Endpoints 
The time-to-event endpoints are defined in Table 8.  




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8.2.1 
Definitions  
8.2.1.1 
Adverse Event  
An AE (also known as an adverse experience) is defined as any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered drug related. More 
specifically, an AE can be any unfavorable and unintended sign (e.g., an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a drug, without any judgment 
about causality. An AE can arise from any use of the drug (e.g., off-label use, use in combination 
with another drug) and from any route of administration, formulation, or dose, including an 
overdose.  
Any condition present before the catheter placement, including pre-existing conditions and pre-
study AEs, will be considered medical history and will not be reported as a treatment-emergent 
AE unless the condition worsens during or after catheter placement.  Any worsening (i.e., any 
clinically significant adverse change in frequency and/or intensity) of a preexisting condition, 
which is temporally associated with the use of the Sponsor’s product, is also an AE. 
8.2.1.2 
Adverse Reaction 
An adverse reaction is defined as any AE caused by the use of a drug. Adverse reactions are a 
subset of all suspected adverse reactions for which there is reason to conclude that the drug 
caused the event.  
8.2.1.3 
Suspected 
A suspected adverse reaction is defined as any AE for which there is a reasonable possibility that 
the drug caused the AE. For the purposes of IND safety reporting, “reasonable possibility” 
indicates that there is evidence to suggest a causal relationship between the drug and the AE. A 
suspected adverse reaction implies a lesser degree of certainty about causality than an adverse 
reaction. 
8.2.1.4 
Serious 
An AE or suspected adverse reaction is considered serious if, in the view of either the Investigator 
or Sponsor, it results in any of the following outcomes:  
Death 
Life-threatening AE 


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o 
an AE or suspected adverse reaction is considered life-threatening if, in the view of 
either the Investigator or Sponsor, its occurrence places the subject at immediate risk 
of death. It does not include an AE or suspected adverse reaction that, had it occurred 
in a more severe form, might have caused death.  
Inpatient hospitalization or prolongation of existing hospitalization 
o 
applies if the reported AE requires at least a 24-hour in-patient hospitalization or, if in 
the opinion of the Investigator, prolongs an existing hospitalization. A hospitalization 
for an elective procedure or a routinely scheduled treatment is not an SAE by this 
criterion because a “procedure” or a “treatment” is not an untoward medical 
occurrence. An emergency room visit of less than 24 hours by itself does not constitute 
a SAE. 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life function 
Congenital anomaly/birth defect 
o 
applies if a subject exposed to a medicinal (investigational) product gives birth to a 
child with congenital anomaly or birth defect. 
Medical and scientific judgment should be exercised in determining seriousness in other 
situations, such as important medical events that may not be immediately life-threatening, result 
in death, or hospitalization, but may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed in the definition above. These events should be considered 
serious and subject to reporting procedures specified below in Section 8.2.2.4. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization. 
8.2.2 
Evaluating and Recording of Adverse Events   
At each visit, all AEs that are observed, elicited by the Investigator, or reported by the subject will 
be recorded in the appropriate section of the EDC System and evaluated by the Investigator and 
the Medical Monitor. 
Minimum information required for each AE includes description of the event, duration (start and 
end dates), severity, assessment of seriousness, and causal relationship to study drug and 
delivery/infusion procedure.  


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If discernible at the time of completing the AE section in the EDC System, a specific disease or 
syndrome rather than individual associated signs and symptoms should be identified by the 
Investigator and recorded in the appropriate AE section in the EDC System. However, if an 
observed or reported sign, symptom, or clinically significant laboratory anomaly is not considered 
by the Investigator to be a component of a specific disease or syndrome, then it should be 
recorded as a separate AE in the appropriate AE section in the EDC System (clinically significant 
laboratory abnormalities are those that are identified as such by the Investigator and/or those that 
require intervention). 
8.2.2.1 
Relatedness of Adverse Events   
The Investigator will assign attribution of the possible association of the event with use of the 
investigational drug and, separately, for the surgical/infusion procedure (i.e. AEs that occur during 
catheter placement prior to start of infusion of study treatment versus AEs with onset after start 
of infusion). Relationship will be determined for each as follows: 
• 
Related:  There is evidence to suggest a causal relationship between the drug and the 
AE, such as: 
o 
An event that is uncommon and known to be strongly associated with drug 
exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome) 
o 
An event that is not commonly associated with drug exposure, but is otherwise 
uncommon in the population exposed to the drug (e.g., tendon rupture) 
• 
Unrelated:  Another cause of the AE is more plausible (e.g., due to underlying disease or 
occurs commonly in the study population), or a temporal sequence cannot be established 
with the onset of the AE and administration of the study treatment, or a causal relationship 
is considered biologically implausible. 
In general, AEs that are worsening of baseline or pre-existing conditions are considered 
unrelated, unless there is reason to believe that the worsening was attributable to the 
investigational drug. Further, if death occurs due to progressive disease it is not considered 
attributable to MDNA55. 
8.2.2.2 
Severity of Adverse Events  
The severity of AEs will be graded and recorded by the Investigator using the National Cancer 
Institute CTCAE version 4.0 guidelines. When specific AEs are not listed in the CTCAE 4.0 they 


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will be graded by the Investigator as none, mild, moderate or severe according to the following 
grades and definitions:  
Grade 
Definition  
Grade 0 
No AE (or within normal limits) 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2 
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL) 
Grade 3: 
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL 
Grade 4: 
Life-threatening consequences; urgent intervention indicated 
Grade 5: 
Death related to AE 
 
8.2.2.3 
Follow-up of Adverse Events  
All AEs will be followed with appropriate medical management until resolved. Subjects withdrawn 
from study for unacceptable AEs will be followed until resolution or stabilization of the AE. For 
selected AE for which administration of the investigational drug was stopped, a re-challenge of 
the subject with the investigational drug may be conducted if considered both safe and ethical by 
the Investigator. 
8.2.2.4 
Serious Adverse Event Reporting   
Within 24 hours of becoming aware of any SAE (regardless of its relationship to investigational 
product) that occurs during the course of the clinical study up until 12 months from start of infusion, 
the study personnel at the site must notify the pharmacovigilance vendor, ProPharma, within 24 
hours of discovery using a written report (SAE Report Form) via Fax or Email as outlined in table 
below (the SAE Report Form must be submitted by the site within 24 hours even if it is 
incomplete). This ensures timely reporting of applicable reports to the applicable Health 
Authorities. The form must be signed by the Principal Investigator or designee, and if not available, 
the unsigned report should be faxed/emailed for initial processing and resubmitted after the 
Investigator’s signature has been obtained. 




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Serious Unexpected Serious Adverse Reaction (SUSAR) Reporting to Sites:  
ProPharma will provide a SUSAR safety packet to all study Investigators at which point site must 
submit the SUSAR safety packet to their IRB/IEC according to their local requirements.  
Site must also observe the statutory reporting time frame for expedited reporting of all SUSARs 
to FDA: 
Fatal or life threatening SUSARs:  
Not later than 7 calendar days after the sponsor has information that the case reported fulfils the 
criteria for a fatal or life-threatening SUSAR, with any follow up information to be reported within 
a further 8 calendar days.  
All other SUSARs: 
Not later than 15 calendar days after the sponsor has information that the case fulfilled the criteria 
for a SUSAR.     
8.2.2.5 
Pregnancy Reporting  
Although pregnancy is not considered an AE, the Investigator (or his or her designee) is 
responsible for recording in the subject’s source document any pregnancy during or within 6 
months after completing infusion. All subjects who become pregnant must be followed by the 
Investigator until the end of the pregnancy to determine the outcome. The outcome of the birth 
(health of infant) must be reported to the Medical Monitor. 
9 
Statistical Methods 
The primary efficacy analysis of OS will be assessed according to a single-arm, single-stage 
design on the ITT population. OS will be determined via Kaplan-Meier estimation, with medians, 
quartiles, and 95% confidence intervals (CIs) reported. mOS will tested using a single sample one 
sided log-rank test on a 10% significance level against historical control. 
A secondary analysis of the primary variable will be conducted in the IL4-R population according 
to IL4-R status.  
PFS will be assessed and summarized as OS.  


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Descriptive analysis of the OS and PFS at 6, 9, and 12 months after treatment will be based on 
the raw proportions of subjects surviving (and progression-free) at those time points as well as 
Kaplan-Meier estimation. Further analyses will also be conducted by IL4R stratum, including 
examination of the treatment effect by IL4R level. 
Efficacy analyses may also explore subject subsets (e.g. IL4R level, tumor size, KPS, gender, 
age, steroid use,) and response by other applicable criteria.  
Descriptive statistics will be provided for subject demographics and disposition, safety, and 
exposure data and will include the number of observations, mean, standard deviation, median, 
and range for continuous variables and number and percent for categorical variables; 95% CIs 
will be presented where appropriate. 
9.1 
Determination of Sample Size 
The sample size is calculated for the primary analysis and based on the following assumptions: 
uniform accrual over time, no loss to follow-up, exponentially distributed death times, use of the 
exponential MLE test, follow-up time 12 months and a one-sided test on a 10% significance level. 
With a null hypothesis of a median OS of 8 months and an alternative hypothesis of 11.5 months 
the power for the primary test will be over 80% with 46 evaluable subjects.  
9.2 
Statistical and Analytical Plans 
The primary analysis will occur when median survival is reached (> 50% of all subjects have died) 
or all subjects have completed the Day 360 visit or discontinued prior to completing the Day 360 
visit whichever happens last. Collection of follow-up data will continue until all patients have 
withdrawn from follow-up. Supplementary reports, presenting updated time-to-event data, will be 
prepared after completion of the 2-year survival follow-up period and beyond, if required. 
Descriptive statistics will be presented including the number and percent for categorical variables 
and the number of observations, mean, standard deviation, median, and range for continuous 
variables; 95% confidence intervals (CIs) will be presented as appropriate. 
9.2.1 
Randomization 
This study is a single-arm design. All subjects will receive active treatment. No randomization will 
be performed. 


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9.2.2 
Analysis Populations 
Following quality review of study images mid-way through recruitment, local tissue reactions, 
inflammation, immune cell infiltration, edema and/or necrosis, subsequent to MDNA55 
administration, was observed in some subjects and has been seen to be indistinguishable from 
possible tumor growth using the imaging techniques adopted from the outset of this study. 
Therefore, obtaining reliable imaging data for the primary efficacy analysis has been shown to be 
confounded. Consequently, under protocol version 6.0, the surrogate endpoint Objective 
Response Rate (ORR) will be assessed as a secondary outcome measure with the median 
Overall Survival (mOS) becoming the primary variable. 
9.2.2.1 Intent to Treat (ITT) 
An ITT population will comprise all subjects who receive any amount of study drug will be used 
for the primary efficacy analyses, other purely survival-based endpoints and all safety analyses.  
A modified ITT population for secondary imaging-based analyses, including PFS, (mITT, see 
below) will comprise all subjects who receive any amount of study drug and have adequate 
imaging or clinical data for the ORR analysis. NOTE: Patients who expire or progress clinically 
prior to the first MRI examination will not be evaluable for any of the response assessments.   
9.2.2.2 Per Protocol (PP) Population 
The PP population will comprise all patients in the ITT population (or mITT for imaging-based 
endpoints) who also have no major protocol violations during the study. This population will be 
finalized prior to the final lock and primary analysis of the study data. Efficacy analyses will be 
conducted on this population in support of the primary efficacy results. 
9.2.2.3 IL4R Analysis Population 
The IL4R Analysis Population will be the same as the ITT Population, excluding patients who do 
not have archived tissue or adequate tissue available for analysis,  and will be used for efficacy 
analyses in subgroups according to IL4R expression status (Section 9.2.9). 
9.2.2.4 Safety Population 
The Safety population will comprise all patients treated on study. Safety analyses will be 
presented on this population. 


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9.2.3 
Missing Data 
All available data will be used, and no efficacy data will be imputed. Procedures for handling 
missing dates will be described in the statistical analysis plan. For the analyses of response, 
subjects with baseline assessments but no post-treatment assessments will be counted as non-
responders. For time to event variables, patients not known to have experienced an event at the 
time of analysis will be censored as specified in Section 9.2.5.2. 
9.2.4 
Baseline and Demographic Characteristics 
Baseline and demographic characteristics will be summarized and presented descriptively. 
9.2.5 
Analysis of Efficacy 
Details of all planned efficacy analyses and methods will be published in the SAP (statistical 
analysis plan) prior to database lock. 
9.2.5.1 
Primary Efficacy Variable 
OS will be defined as the time (in weeks) from start of the CED infusion until death from any 
cause. Subjects not know to have died at the time of the analysis will be censored at the time of 
last contact. 
OS and will be summarized using the Kaplan-Meier method and tested using a single sample one 
sided log-rank test on a 10% significance level with null hypothesis of OS 8 months and alternative 
hypothesis of OS > 8 months. 
9.2.5.2 
Secondary Efficacy Variables 
Secondary efficacy variables will include OS variants, ORR and PFS. 
ORR will be presented as the percentage of subjects with CRs or PRs by the RANO-based 
criteria, including those incorporating advanced imaging modalities; only confirmed responses will 
be presented (i.e., those observed on 2 consecutive MRI scans not less than 4 weeks apart and 
at appropriate interval following discontinuation of bevacizumab if response was not observed 
prior to use of bevacizumab).  
PFS will be summarized using the Kaplan-Meier method. PFS will be assessed using a single 
sample log-rank test (against historical control) at 10% significance level with null hypothesis of 
mPFS 4 months and alternative hypothesis of mPFS > 4 months. PFS will be defined as the time 


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(in weeks) from start of the CED infusion until radiologic or neurologic disease progression or 
death from any cause. Subjects not know to have died or experienced disease progression at the 
time of the analysis will be censored at the time of the last radiologic assessment demonstrating 
lack of progression or, if during the follow-up period, the time of last contact indicating lack of 
progression. 
Graphical displays and incidence estimates will show PFS and OS at 6, 9, and 12 months. 
9.2.5.3 
Other Efficacy Variables and Analyses  
DOR will be summarized using the Kaplan-Meier method, including graphical displays. DOR will 
be calculated only for the subset of subjects with a response (CR or PR), and it will be defined as 
the time (in weeks) from first response until radiologic disease progression or death from any 
cause. Responders alive and progression-free at the time of the analysis will be censored at the 
time of the last radiologic assessment demonstrating lack of progression or, if during the follow-
up period, the time of last contact indicating lack of progression. 
DOCB will be summarized using the Kaplan-Meier method, similar to DOR. DOCB will be 
calculated only for the subset of subjects with a stable disease or better (CR, PR, or SD), and it 
will be defined as the time (in weeks) from first response until radiologic disease progression or 
death from any cause. Censoring will be performed in a fashion similar to DOR. 
Additional, exploratory, efficacy variables may include ORR and PFS based on the Investigator’s 
assessment of response and other time-to-event endpoints (e.g., time to post-study treatment of 
GB). Analyses will also be conducted by IL4R stratum, including examination of the treatment 
effect by IL4R level.  
Efficacy analyses will also explore subject subsets (procedural success, IL4R level, sequence 
number by site [learning], tumor size, tumor coverage, time of infusion, maximum flow rate, 
number of catheters, percentage of planned infusate administered, KPS, gender, age, steroid 
use, immune status) and response by other applicable criteria. Subgroup and sensitivity analyses 
comparing subjects included before and after protocol version 3.0 may be explored. 
9.2.6 
Analysis of Safety Variables 
Safety variables, including AEs, laboratory results, vital signs, ECGs, antibody assessments, and 
serum drug levels on PK samples, will be summarized and presented, by study time where 
appropriate. 


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AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Cancer 
Therapy Evaluation Program (CTEP) Common Terminology Criteria for Adverse Events NCI 
CTCAE v4.0 will be used to grade the severity of AEs. Treatment emergent AEs will be 
summarized by system organ class (SOC) and by preferred terms for all treated subjects and 
subset of subjects of interest. Certain summaries of the treatment-emergent AEs will also be 
generated by severity, relationship to study drug, relationship to infusion, catheter placement, 
volume of infusate, and prior therapies. Proportion of patients experiencing Grade 3 and 4 
laboratory test results will be summarized. 
9.2.7 
Interim Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
No formal interim analyses for efficacy have been conducted or are planned.  
9.2.8 
MRI Analysis  
Exploratory analyses will be performed to assess the relationships between planned tissue 
coverage, actual tissue coverage, tissue toxicity, tissue response (perfusion MRI-derived relative 
cerebral volume and tracer kinetic (permeability, intravascular and extravascular volumes maps) 
and clinical results and IL4R expression. These analyses will be descriptive in nature. 
9.2.9 
Tumor Tissue Analysis  
Exploratory analyses will be performed to assess the relationship of IL4R expression levels in 
tumor tissue with treatment response, tissue response and survival. This analysis will be 
descriptive in nature.  


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9.3 
Data Quality Assurance 
Steps to be taken to assure accuracy and reliability of data include selection of qualified 
Investigators who have experience with intracranial administration of therapeutic agents and 
appropriate research centers, and review of protocol procedures with the Investigator and 
associated personnel before the start of the study. There will be periodic monitoring by a Sponsor 
representative(s). 100% of data entered into the EDC System and database will be reviewed for 
accuracy and completeness by a Sponsor representative(s) during on-site monitoring visits, and 
any discrepancies will be resolved with the Investigator or designees, as appropriate. Data in the 
clinical trial database will be further checked for accuracy and consistency by a series of 
computerized and manual procedures.  
9.4 
Multiplicity control 
Multiplicity is controlled by hierarchical testing of the endpoints. First the primary endpoint (OS) 
will be tested at a 10% one sided significance level. The PFS and the secondary endpoints are 
then tested in a hierarchical manner (all at a 10% one-sided significance level), first PFS and then 
secondary endpoints. Testing will only continue if the prior null hypothesis is rejected – thereby 
controlling the familywise type-I error. Further details will be specified in the SAP. 
10 Investigator Requirements and Study Management 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with ICH E6 GCP and all 
applicable regulatory requirements. 
Before initiating this trial, the Investigator will have written and dated approval from the Institutional 
Review Board for the protocol, written informed consent form, subject recruitment materials, and 
any other written information to be provided to subjects before any protocol related procedures 
are performed on any subjects.  
The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 
requirements. The IRB must comply with the regulations in 21 CFR §56 and applicable regulatory 
requirements. 


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10.1 Study Initiation  
The following documentation must be received by the Sponsor or their representative prior to 
initiation of the trial: 
• 
The names of Principal Investigators and any Sub-Investigators must appear on the 
appropriate form complying with local regulations (e.g., US FDA Form 1572) and signed 
by 
all 
Principal 
Investigators. 
Investigators 
must 
also 
complete 
all 
regulatory 
documentation as required by ICH E6 GCP and by local or national regulations 
• 
Current (within 2 years) curricula vitae of the Principal Investigator and all Sub-
Investigators 
• 
IRB/IEC membership list 
• 
Written documentation of IRB/IEC approval of protocol (identified by protocol number 
and/or title and date of approval) and informed consent document (identified by protocol 
number and/or title and date of approval) 
• 
A copy of the IRB/IEC-approved informed consent document 
• 
Written documentation of IRB/IEC review and approval of any advertising materials to be 
used for study recruitment must be received by the Sponsor or their representative. 
Informed consent forms and any advertising materials must also be reviewed and 
approved by the Sponsor or their representative prior to seeking approval of IRB/IEC and 
regulatory agencies 
• 
Current laboratory certification of laboratory performing the hematology, coagulation, and 
serum chemistry analyses (issuing agency and expiration date), as well as current normal 
laboratory ranges for all laboratory tests 
• 
A signed Clinical Research (Protocol) Agreement (see page 3 of this protocol) 
• 
Certified translations of IRB/IEC approval letters, pertinent correspondence, and approved 
informed consent document (when applicable) 
• 
Financial disclosure form for Principal Investigator and all Sub-Investigators, their spouses 
and dependent children 
• 
Clinical Trial Agreement  


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10.2 Informed Consent  
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation. Participants must 
sign the IRB/IEC-approved informed consent form prior to participation in any study specific 
procedure. The participant must receive a copy of the signed and dated consent document. The 
original signed copy of the consent document must be retained in the medical record or 
Investigator file.  
10.3 Protocol Adherence 
Once the protocol has been approved, any substantive changes to the protocol made by the 
Sponsor must be documented in the form of a major amendment. The major amendment must 
be signed by the Investigator and approved by IRB/IEC and submitted to the FDA prior to 
implementation. Changes of an administrative nature (no likely impact on patient safety or data 
integrity) may be instituted as minor amendments. 
Each Investigator must adhere to the protocol as detailed in this document, will be responsible for 
enrolling only those subjects who have met protocol eligibility criteria, and must agree that no 
changes to the protocol are made, except to eliminate an immediate hazard to the study subjects. 
If it becomes necessary to alter the protocol to eliminate an immediate hazard to subjects, the 
Investigator must then notify the Sponsor and IRB in writing within five (5) working days after 
implementation. The Sponsor will be responsible for updating any participating sites. 
10.4 Monitoring Procedures  
The Investigator is responsible for the validity of all data collected at his/her site. The purpose of 
monitoring is to verify that the rights and well-being of human subjects are protected, that trial 
data are accurate (complete and verifiable to source data), and that the trial is conducted in 
compliance with the protocol, ICH E6 GCP, and regulatory requirements. 
10.4.1 
Routine Monitoring 
Monitors assigned by the Sponsor or their representative will conduct regular visits to the 
investigational sites to monitor various aspects of the study. The Investigator must agree to allow 
Sponsor-authorized personnel direct access to the clinical (or associated) files and clinical trial 
supplies for all potential and enrolled study subjects to verify EDC System entries. The 
Investigator should make adequate time and space available for monitoring visits. 


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The site must complete pages in the EDC System in a timely manner and on an ongoing basis to 
allow regular review by the study monitor.  
Whenever a subject’s name is revealed on a document that is to be given to the Sponsor, the 
name must be blacked out permanently by the site personnel, leaving the initials visible, and 
annotated with the subject study number as identification. 
10.4.2 
Inspection and Auditing Procedures 
Authorized personnel from external regulatory authorities and quality assurance personnel 
authorized by the Sponsor may carry out inspections and audits. The purpose of an audit is to 
ensure that ethical, regulatory, and quality requirements are fulfilled in all studies performed by 
the Sponsor. 
Auditors and inspectors must have direct access to study files, subject’s clinical files, and 
associated study records as well as to clinical supply dispensing and storage areas and any other 
locations used for the study. In the event that the site is notified directly of a regulatory inspection, 
the Investigator should notify the Sponsor representative as soon as possible, so that the Sponsor 
representative can assist with preparations for the inspection. 
10.5 Data Recording and Retention of Study Data  
The Principal Investigator and/or his/her designee, will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study and will be 
responsible for recording all data with respect to protocol procedures, drug administration, 
laboratory data, safety data, and efficacy ratings in the EDC system. The Investigator may 
formally designate authority to appropriately qualified staff to complete pages in the EDC system, 
by authorizing and completing the signature log.  
The information entered into the EDC system shall be identical to that appearing in original source 
documents. Source documents will be found in the subject’s medical records maintained by 
institutional personnel. All source documentation must be available for review/monitoring by 
monitors appointed by the Sponsor or their representative and/or regulatory agencies. 
All corrections on source documents must be made in a way that follows the Standard Operating 
Procedures of the site, does not obscure the original entry. The correct data must be inserted, 
dated, and initialed by study site personnel. If it is not obvious why a change has been made, a 
reason must be provided. DO NOT ERASE, OVERWRITE, OR USE CORRECTION FLUID.  


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In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered in the EDC system. The Investigator will 
approve all completed CRFs to attest that the information contained on the CRFs is true and 
accurate.  
The Investigator must sign the final EDC System “End of study” pages (Principal Investigator 
signature page) to attest for the accuracy and completeness of all data. These pages must not be 
signed until after the EDC files have been reviewed 1 final time.  
If the Investigator relocates or retires, or otherwise withdraws responsibility for maintenance and 
retention of study files, the Sponsor must be notified in writing, so that adequate provision can be 
made with regard to the trial documents. 
Trial documents should be retained at least 2 years after the last approval of a marketing 
application until there are no pending or planned marketing applications, or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the product. These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with the Sponsor. The Investigator should take measures to 
prevent accidental or premature destruction of these documents. The archiving arrangements will 
be addressed by the monitor when closing out the site. The Sponsor will inform the Investigator, 
in writing, as to when these documents no longer need to be retained. 
10.6 Confidentiality of Data 
Subjects’ medical information obtained by this study is confidential, and disclosure to third parties 
other than those noted below is prohibited. 
Upon the subject’s permission, medical information may be given to his or her personal physician 
or other appropriate medical personnel responsible for his or her welfare. 
Data generated by this study must be available for inspection by representatives of the US FDA 
or other Health Regulatory Authorities, national and local health authorities, the Sponsor or their 
representative, and the IRB/IEC.  
10.7 Study Drug Accountability 
All investigational drug required for completion of this study will be provided by the Sponsor. Each 
site will acknowledge receipt of the drug indicating shipment content and condition. Damaged 
supplies will be replaced. 


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The Principal Investigator shall not make the investigational drug available to any individuals other 
than to qualified study subjects. Furthermore, the Principal Investigator will not allow the 
investigational drug to be used in any manner other than that specified in this protocol. 
Accurate records of all study drug received/inventoried, dispensed from the study site Pharmacy 
will be maintained. 
During the study and at the end of the study, the monitor will verify all inventory and accountability 
records maintained by the hospital pharmacy. All used drug vials are disposed of at the study site 
according to the institution’s standard operating procedure. Any unused drug vials will be 
inspected to ensure proper drug dispensing and accuracy of supply. Return unused study drug 
as directed by the Sponsor or their representative. 
All other study materials supplied by the Sponsor, such as catheters and infusion pumps, must 
be accurately accounted for as well. Unopened, expired, or unused materials as well as infusion 
pumps will be returned as directed by the Sponsor or their representative. 
10.8 Study Completion 
The following data and materials are required by the Sponsor or their representative before the 
study can be considered complete or terminated: 
• 
All test results from screening through the end of the study (e.g., clinical data, all special 
test results) 
• 
EDC System properly completed by appropriate study personnel 
• 
Study personnel signature and responsibility log 
• 
Completed drug accountability records 
• 
Copies of protocol amendments and IRB/IEC approval/notification, if appropriate 
• 
Documentation of a close letter to the site IRB/IEC by the Principal Investigator 
• 
Completion of all SAE and supplemental follow-up reports in addition to all data queries 
• 
Undertaking by the Investigator to retain/archive study documents as per applicable 
regulatory requirements 


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10.9 Study Discontinuation 
The Sponsor has the right to terminate this study at any time. Reasons for terminating the study 
may include (but are not limited to) the following: 
• 
The incidence or severity of AEs in this or other studies indicates a potential health hazard 
to subjects 
• 
Subject enrollment is unsatisfactory; and/or 
• 
Data recording is inaccurate or incomplete 
If appropriate, reimbursement for reasonable expenses will be made. 
10.10 
Clinical Study Report 
The results of this trial will be documented in an integrated statistical and clinical study report that 
will include a discussion of the study objectives, methodology, clinical observations, and 
conclusions in relation to the study objectives.  
10.11 
Ethical Conduct of the Clinical Investigation 
The Investigator will ensure that this study is conducted in full conformance with the principles of 
the "Declaration of Helsinki” and its amendments, or with the laws and regulations of the locality 
in which the research is conducted, whichever affords the greater protection to the individual. 
10.12 
Compliance with Financial Disclosure Requirements 
By participating in this protocol, the Investigator agrees to provide to the Sponsor accurate 
financial information to allow the Sponsor to submit complete and accurate certification and 
disclosure statements as required by local and international guidelines.  
10.13 
Contractual and Financial Details 
The Investigator (and/or, as appropriate, the hospital administrative representative) and/their 
representative will sign a clinical study agreement prior to the start of the study, outlining overall 
Sponsor (and/or, as appropriate, the Sponsor representative) and Investigator responsibilities in 
relation to the study. Financial remuneration will cover the cost per included subject, based on 
the calculated costs of performing the study assessments in accordance with the protocol, and 
the specified terms of payment will be described in the contract. The contract should describe 


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whether costs for pharmacy, laboratory, and other protocol-required services are being paid 
directly or indirectly. 
10.14 
Insurance, Indemnity, and Compensation 
The Sponsor will provide Product Liability insurance for all subjects included in the clinical study. 
Where required, a hospital-specific indemnity agreement will be used. 


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76. 
Verma N, Cowperthwaite MC, Burnett MG and  Markey MK. Differentiating tumor recurrence from 
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necrosis: 
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imaging 
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Neuro 
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May;15(5):515-34.  
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Vogelbaum MA, Jost S, Aghi MK, Heimberger AB, Sampson JH, et al. Application of novel 
response/progression 
measures 
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surgically 
delivered 
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Assessment in Neuro-Oncology (RANO) Working Group. Neurosurgery. 2012 Jan; 70(1):234-43. 
78. 
Michael A. Vogelbaum and Manish K. Aghi. Convection-enhanced delivery for the treatment of 
glioblastoma. Neuro Oncol. 2015 Mar; 17 (Suppl 2): ii3–ii8. Published online 2015 Mar 5. 
79. 
Weber F, Asher A, Bucholz R, et al. Safety, tolerability, and tumor response of IL4-Pseudomonas 
exotoxin (NBI-3001) in patients with recurrent malignant glioma. Journal of Neuro-Oncology 
2003a;64:125-37. 
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Weber FW, et al. Local convection enhanced delivery of IL4-Pseudomonas exotoxin (NBI-3001) for 
treatment of patients with recurrent malignant glioma. Acta Neurochir Suppl 2003b; 88:93-103. 
81. 
Wein LM, Wu JT, Lanculescu AG, et al. A mathematical model of the impact of infused targeted 
cytotoxic agents on brain tumors: implications for detection, design and delivery. Cell Prolif 2002; 
35:343-61.  
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Weller M, Seystahl K, Wick W. Therapeutic options in recurrent glioblastoma-An update. Crit Rev 
Oncol Hematol. 2016 Mar;99:389-408. Epub 2016 Jan 21. 
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Weller M, Coughesy T, Perry J, Wick W. Standards of care for treatment of recurrent glioblastoma--
are we there yet? Neuro Oncol 2013 Jan; 15(1):4-27. 
84. 
Wen PY, et al. Response assessment challenges in clinical trials of gliomas. Curr Oncol Rep 2010; 
12(1):68-75. 
85. 
Wen PY, et al. Updated response assessment criteria for high-grade gliomas: response assessment 
in neuro-oncology working group. J Clin Oncol 2010; 28(11):1963-72. 
86. 
White E, Bienemann A, Malone J, et al. An evaluation of the relationships between catheter design 
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2011 Jul 15;199(1):87-97. 
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Wick W, Wild-Bode C, Frank B, Weller M. BCL-2-induced glioma cell invasiveness depends on furin-
proteases. J Neurochem. 2004 Decl 91(6): 1275-83. 
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Yin D, Valles FE, Fiandaca MS, et al. Optimal region of the putamen for image-guided convection-
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SAP_001.pdf: 
S T A TI S TI C A L  A N A L Y SI S  P L A N  
 
 
TI T L E  P A G E  
 
 
 
 
 
 
A N  O P E N- L A B E L N O N - R A N D O MI Z E D, M U L TI- C E N T E R P H A S E - 2 S T U D Y O F 
C O N V E C TI O N- E N H A N C E D D E LI V E R Y ( C E D) O F  M D N A 5 5 I N A D U L T S WI T H 
R E C U R R E N T O R P R O G R E S SI V E G LI O B L A S T O M A 
 
 
 
 
 
 
 
 
 
Fi n al Versi o n 2. 0: O C T  2 3, 2 0 1 9  
 
 
C o nfi de ntialit y State me nt  
 
T he i nf or mati o n c o ntai ne d i n t his d oc u me nt is pri vile ge d a n d c o nfi de ntial. 
D o  n ot c o p y, circ ulate, or ot her wise distri b ute wit h o ut writte n a ut h orizati o n fr o m 
Me dice n na T hera pe utics, I nc. 


Pa ge 2 of 3 1  
 
T A B L E  O F  C O N T E N T S  
P A G E  
 
 
T A B L E O F  C O N T E N T S  ........................................................................................................... 2 
D E C L A R A TI O N  .................................................................................................................... 4  
R E VI SI O N HI S T O R Y  ............................................................................................................. 5 
LI S T O F  A B B R E VI A TI O N  ..................................................................................................... 6 
1.  
I N T R O D U C TI O N .................................................................................................... 8 
2.  
O BJ E C TI V E S  .......................................................................................................... 9 
3.  
S T U D Y  D E SI G N  ................................................................................................... 1 0  
3. 1  Ge neral St u d y Desi g n  ....................................................................................................... 1 0  
3. 2  Ra n d o mizati o n a n d Bli n di n g  ............................................................................................ 1 0  
3. 3  St u d y Treat me nt  ................................................................................................................ 1 0  
4.  
S T U D Y  E N D P OI N T S  ........................................................................................... 1 4  
4. 1  Pri mar y Efficac y E n d p oi nt  ............................................................................................... 1 4  
4. 2  Sec o n dar y Efficac y E n d p oi nts  .......................................................................................... 1 4  
4. 3  Ot her Efficac y E n d p oi nts  .................................................................................................. 1 4  
4. 4  E x pl orat or y E n d p oi nts  ...................................................................................................... 1 4  
4. 5  Safet y E n d p oi nts  ............................................................................................................... 1 5  
4. 6  Ot her E n d p oi nts  ................................................................................................................. 1 5  
5.  
S T U D Y  P O P U L A TI O N S  ........................................................................................ 1 6  
5. 1  I nte nt t o Treat P o p ulati o n (I T T)/ Safet y ............................................................................ 1 6  
5. 2  M o difie d I nte nt t o Treat P o p ulati o n ( mI T T) .................................................................... 1 6  
5. 3  Per  Pr ot oc ol P o p ulati o n ( P P) ............................................................................................ 1 6  
5. 4  I L 4 R P o p ulati o n  ................................................................................................................ 1 6  
5. 5  P K  P o p ulati o n  .................................................................................................................... 1 6  
5. 6  A nti- Dr u g- A nti b o d y P o p ulati o n  ....................................................................................... 1 6  
6.  
S T A TI S TI C A L A N A L Y SI S C O N SI D E R A TI O N S  ............................................... 1 6  
6. 1  Ha n dli n g of Missi n g Data  a n d Dr o p o ut  ............................................................................ 1 6  
6. 2  Ha n dli n g of Missi n g or I nc o m plete Date  .......................................................................... 1 7  
6. 3  Visit  Wi n d o wi n g  ............................................................................................................... 1 7  
6. 4  Baseli ne Defi niti o n  ........................................................................................................... 1 7  
6. 5  Deri ve d Varia bles  ............................................................................................................. 1 7  


Pa ge 3 of 3 1  
 
7.  
S T A TI S TI C A L M E T H O D O L O GI E S A N D  A N A L Y S E S  .................................... 1 8  
7. 1  Ge neral Statistical  C o n ve nti o ns  ......................................................................................... 1 8  
7. 2  S u bject Dis p ositi o n  ........................................................................................................... 1 9  
7. 3  Pr ot oc ol De viati o ns  ........................................................................................................... 1 9  
7. 4  De m o gra p hics a n d Baseli ne C haracteristics  ..................................................................... 1 9  
7. 4. 1  De m o gra p hics  ................................................................................................................ 2 0  
7. 4. 2  Baseli ne a n d Disease  C haracteristics  ............................................................................. 2 0  
7. 5  Me dical Hist or y  ................................................................................................................ 2 1  
7. 6  Pri or a n d C o nc o mita nt Me dicati o ns/ C ortic oster oi ds  ........................................................ 2 1  
7. 7  Efficac y A nal yses  ............................................................................................................. 2 1  
7. 7. 1  Pri mar y Efficac y A nal yses  ............................................................................................ 2 1  
7. 7. 1. 1  S u b gr o u p A nal yses  ..................................................................................................... 2 2  
7. 7. 2  Sec o n dar y Efficac y A nal yses  ......................................................................................... 2 2  
7. 7. 3  E x pl orat or y E n d p oi nts A nal yses  ................................................................................... 2 3  
7. 7. 4  Ot her Efficac y E n d p oi nts A nal yses  ............................................................................... 2 5  
7. 8  Safet y A nal yses  ................................................................................................................. 2 6  
7. 8. 1  A d verse E ve nts  .............................................................................................................. 2 7  
7. 8. 2  Vital  Si g ns  ...................................................................................................................... 2 8  
7. 8. 3  P h ysical e xa mi nati o n ..................................................................................................... 2 8  
7. 8. 4  Electr ocar di o gra m ( E C G) .............................................................................................. 2 8  
7. 8. 5  Cli nical La b orat or y Res ults  ............................................................................................ 2 8  
7. 8. 6  Ne ur ol o gical e xa mi nati o ns  ............................................................................................ 2 9  
7. 8. 7  Kar n ofs k y Perf or ma nce Sc ore ( K P S) ............................................................................ 3 0  
7. 8. 8  A nti b o d y / I m m u n o ge nicit y ........................................................................................... 3 0  
7. 9  P har mac o ki netic Listi n g  ................................................................................................... 3 0  
8.  
I N T E RI M A N A L Y SI S  .......................................................................................... 3 0  
9.  
C H A N G E S T O  P L A N N E D  A N A L Y SI S F R O M S T U D Y  P R O T O C O L  .............. 3 0  
1 0.  
R E F E R E N C E S  ....................................................................................................... 3 1  
1 1.  
A P P E N DI C E S  ........................................................................................................ 3 1  






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LI S T  O F  A B B R E VI A TI O N  
 
A b bre vi ati o n or 
s peci al ter m 
E x pl a n ati o n  
A E  
A d verse E ve nt  
C E D  
C o n vecti o n- E n ha nce d Deli ver y  
CI  
C o nfi de nce I nter val 
C N S  
Ce ntral Ner v o us S yste m  
c pI L- 4 
circ ularl y per m ute d versi o n of I L- 4 
C R  
C o m plete Res p o nse  
C S R  
Cli nical St u d y Re p ort  
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts  
D O C B  
D urati o n of Cli nical Be nefit  
D O R  
D urati o n of Res p o nse  
E C G  
Electr ocar di o gra m  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G B  
Gli o blast o ma  
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n  
I H C 
I m m u n o hist oc he mistr y 
I L 4 R 
I L- 4 rece pt or 
I N R 
I nter nati o nal N or malize d Rati o  
I T T 
I nte nt t o Treat  
I V 
I ntra ve n o us(l y) 
K M  
Ka pla n -Meier  
K P S  
Kar n ofs k y Perf or ma nce Stat us  
L D H  
Lactate  De h y dr o ge nase  
M D N A 5 5  
St u d y dr u g; I L- 4 P E; pre vi o usl y calle d N BI 3 0 0 1, P R X 3 2 1  
M G M T  
O 6-met h yl g ua ni ne -met h yltra nsferase  
mI T T  
M o difie d I nte nt t o Treat  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
m R A N O  
M o difie d R A N O  
M RI  
Ma g netic Res o na nce I ma gi n g 
M T D  
Ma xi m u m T olerate d D ose  
N CI  
Nati o nal Ca ncer I nstit ute 
O R  
O bjecti ve Res p o nse  
O R R  
O bjecti ve Res p o nse Rate  
O S  
O verall S ur vi val  
P D  
Pr o gressi ve Disease  
P E  
Pse u d o m o nas e x ot o xi n 
P F S  
Pr o gressi o n Free S ur vi val  


Me dice n na  T hera pe utics  I nc 
Statistical A nal ysis Pla n 
Versi o n Fi nal 2. 0  
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Date: Oct 2 3, 2 0 1 9  
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A b bre vi ati o n or 
s peci al ter m 
E x pl a n ati o n  
P K  
P har mac o ki netics  
P P  
Per  Pr ot oc ol  
P R  
Partial Res p o nse  
P T  
Pr ot hr o m bi n Ti me  
P T T  
Partial T hr o m b o plasti n Ti me  
R A N O  
Res p o nse Assess me nt i n Ne ur o- O nc ol o g y (criteria) 
S A E  
Seri o us A d verse E ve nts  
S A P  
Statistical  A nal ysis Pla n  
S D  
Sta ble Disease  
S O C  
S yste m Or ga n Class  
S R C  
Safet y Re vie w C o m mittee  
T E A E  
Treat me nt-e mer ge nt A d verse E ve nt  
T M E  
T u m or Micr o- E n vir o n me nt  
T R A M  
T u m or Res p o nse Assess me nt Ma p  
U S  
U nite d States  
W B C  
W hite Bl o o d Cell (c o u nt) 
W H O  
W orl d Healt h  Or ga nizati o n  


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St u d y  C o de:  M D N A 5 5 -0 5 
Date: Oct 2 3, 2 0 1 9  
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1.  I N T R O D U C TI O N 
T he st u d y dr u g, M D N A 5 5, is a f usi o n pr otei n c o nsisti n g of a tar geti n g d o mai n li n ke d t o a pr o- 
a p o pt otic cell- killi n g pa yl oa d. It was disc o vere d a n d de vel o pe d b y Drs. Raj P uri ( U nite d States 
[ U S] F o o d a n d Dr u g A d mi nistrati o n [ F D A]) a n d Ira Pasta n ( Nati o nal Ca ncer I nstit ute “ N CI”) 
a n d has bee n descri be d b y vari o us researc hers i n o ver 5 0 p u blicati o ns. It is a t hera pe utic a ge nt 
t hat selecti vel y tar gets ca ncer cells t hat o ver-e x press t he i nterle u ki n- 4 rece pt or (I L 4 R). T he 
tar geti n g d o mai n is a n e n gi neere d circ ularl y per m ute d versi o n of i nterle u ki n- 4 (c pI L- 4) w hic h is 
ge neticall y f use d t o p ote nt pa yl oa d c o m prise d of a tr u ncate d versi o n of t he bacterial t o xi n, 
Pse u d o m o nas aer u gi n osa e x ot o xi n ( P E) A ( Kreit ma n et al., 1 9 9 4). It was de vel o pe d f or t he 
treat me nt of gli o blast o ma ( G B) a n d ot her a d ult a n d pe diatric ce ntral ner v o us s yste m ( C N S) 
ca ncers i ncl u di n g i m m u n os u p pressi ve cells of t he gli o blast o ma t u m or micr oe n vir o n me nt ( T M E) 
t hat fre q ue ntl y o ver-e x press t he I L- 4 rece pt or (I L 4 R; P uri et al., 1 9 9 4; K o ha n bas h et al., 2 0 1 3). 
 
T he mec ha nis m of acti o n of M D N A 5 5 is well  d oc u me nte d ( Kreit ma n et al., 1 9 9 4; Ra n d et al., 
2 0 0 0; P uri et al., 2 0 0 9) a n d is de picte d i n Fi g ure 1 . 
 
 
Fi g ure 1: Sc he m atic of M D N A 5 5 Mec h a nis m of Acti o n  
 
M D N A 5 5 bi n ds t o I L 4 R o vere x presse d o n t he s urface of t u m or cells a n d t he e ntire c o m ple x is 
e n d oc yt ose d. F oll o wi n g clea va ge a n d acti vati o n b y f uri n-li ke pr oteases f o u n d i n hi g h 
c o nce ntrati o ns i n t he e n d os o me of ca ncer cells, t he catal ytic d o mai n of t he tr u ncate d P E is 
release d i nt o t he c yt os ol w here it i n d uces cell deat h via a de n osi ne di p h os p hate ( A D P)- 
ri b os ylati o n of t he El o n gati o n Fact or- 2 a n d i n d ucti o n of a p o pt osis t hr o u g h cas pase acti vati o n 
( S ha pira a n d Be n har, 2 0 1 0). 
 
T he p ur p ose of t his statistical a nal ysis pla n ( S A P) is t o pr o vi de detaile d descri pti o ns of t he 
statistical met h o ds, data deri vati o ns a n d data dis pla ys f or st u d y pr ot oc ol M D N A 5 5- 0 5, Pr ot oc ol 
Versi o n 6. 1 “ A n O pe n- La bel N o n- Ra n d o mize d, M ulti- Ce nter P hase- 2 St u d y of C o n vecti o n- 
E n ha nce d Deli ver y ( C E D) of M D N A 5 5 i n A d ults wit h Rec urre nt or Pr o gressi ve Gli o blast o ma” 
date d J ul y 1 9, 2 0 1 9 f or Fi nal a nal ysis. T he ta ble of c o nte nts a n d te m plates f or t he ta bles, fi g ures 


Me dice n na  T hera pe utics  I nc 
Statistical A nal ysis Pla n 
Versi o n Fi nal 2. 0  
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Pa ge 9 of 3 1  
 
 
 
 
a n d listi n gs ( T F Ls) will  be pr o d uce d i n a se parate d oc u me nt. A n y de viati o ns fr o m t his S A P  will 
be descri be d a n d j ustifie d i n t he Cli nical St u d y Re p ort ( C S R). 
 
T he pre parati o n of t his S A P  has bee n base d o n I nter nati o nal C o nfere nce o n Har m o nizati o n 
(I C H) E 9. U nless ot her wise s pecifie d, all data a nal yses a n d ge nerati o n of T F Ls will be 
perf or me d usi n g S A S 9. 3 ®  or hi g her. 
2.  O B J E C TI V E S  
Pri m ar y O bjecti ve  
 
• T o  assess o verall s ur vi val ( O S). 
Sec o n d ar y O bjecti ves  
 
T he sec o n dar y o bjecti ves of t his st u d y are: 
 
• T o  assess t he effect of I L 4- R stat us o n o verall s ur vi val ( O S); 
 
• T o  assess t he safet y of M D N A 5 5 f oll o wi n g C E D;  
 
• T o  deter mi ne t he o bjecti ve res p o nse rate ( O R R) per Res p o nse Assess me nt i n Ne ur o- 
O nc ol o g y ( R A N O)- base d criteria i nc or p orati n g a d va nce d i ma gi n g m o dalities 
(c o n diti o nal o n a vaila bilit y of a d va nce d i ma gi n g data); 
 
• T o  assess pr o gressi o n-free s ur vi val ( P F S). 
E x pl or at or y O bjecti ves  
 
T he e x pl orat or y o bjecti ves of t his st u d y are: 
 
• T o  assess t he p har mac o ki netics ( P K) of M D N A 5 5 i n peri p heral plas ma;  
 
• T o  assess ser u m a nti- M D N A 5 5 a nti b o d y titers a n d, if ele vate d, deter mi ne ne utralizi n g 
a nti b o d y titers; 
 
• T o  deter mi ne t he relati o ns hi p bet wee n cli nical o utc o mes a n d res p o nse assess me nt stat us 
b y differe nt sets of i ma gi n g- base d res p o nse criteria; 
 
• T o  perf or m a d diti o nal a d h oc efficac y a n d safet y a nal yses as nee de d base d o n t he data 
ac q uire d i n t his st u d y; 
 
• T o  assess t he perf or ma nce of t he Brai nla b cat heter d uri n g i nf usi o n i n ter ms of 
distri b uti o n a n d c o n vecti o n of t he i nf usate usi n g real ti me M RI m o nit ori n g. 


Me dice n na  T hera pe utics  I nc 
Statistical A nal ysis Pla n 
Versi o n Fi nal 2. 0  
Pri vate  a n d C o nfi de ntial 
St u d y  C o de:  M D N A 5 5 -0 5 
Date: Oct 2 3, 2 0 1 9  
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3.  S T U D Y  D E SI G N  
3. 1  Ge ner al St u d y Desi g n  
T his is a si n gle-ar m, o pe n-la bel, m ultice nter st u d y i n a p pr o xi matel y 5 2 a d ults (at least 4 6 
e val ua ble) wit h  G B  t hat has rec urre d or pr o gresse d (acc or di n g t o sta n dar d R A N O criteria). T he 
st u d y will be c o n d ucte d at u p t o 1 2 cli nical sites f oll o wi n g i nstit uti o nal re vie w b oar d a p pr o val 
a n d c o m pleti o n of i nf or me d c o nse nt. 
 
Eli gi ble s u bjects will  u n der g o s ur ger y ass ociate d wit h  cat heter place me nt at w hic h ti me a tiss ue 
bi o ps y will als o be perf or me d. M D N A 5 5 will be i nf use d wit h t he o bjecti ve of ac hie vi n g 
c o vera ge of t he t u m or a n d t he perit u m oral mar gi n t o t he ma xi m u m e xte nt p ossi ble as i n dicate d 
b y distri b uti o n of a c o-i nf use d ga d oli ni u m tracer o bser ve d b y M RI. Pre-treat me nt cat heter 
traject or y pla n ni n g will be perf or me d wit h ai m t o place u p t o 4 cat heters b ut a mi ni m u m of 2, 
de pe n di n g u p o n t he t u m or size. Pla n ni n g f or cat heter place me nt will o nl y tar get t he e n ha nci n g 
re gi o n of t he t u m or o n M RI. 
 
St u d y d urati o n is 1 2 m o nt hs f or eac h s u bject wit h  t he da y of cat heter place me nt/ start of i nf usi o n 
bei n g desi g nate d as Da y 0. 
 
P ost-treat me nt f oll o w- u p assess me nt of safet y will be perf or me d 1 4 da ys after C E D i nf usi o n. 
T hereafter, efficac y a n d safet y assess me nts will  be perf or me d at 3 0, 6 0, 9 0 a n d 1 2 0 da ys after 
C E D i nf usi o n a n d e ver y 8 wee ks t hereafter u ntil 3 6 0 da ys of acti ve f oll o w u p ha ve bee n 
c o m plete d. S u bjects w h o disc o nti n ue bef ore t he Da y  3 6 0 visit will  u n der g o all t he pr oce d ures 
sc he d ule d f or t he Da y 3 6 0 visit at t he ti me of disc o nti n uati o n. 
 
S u bjects w h o c o m plete t he Da y  3 6 0 assess me nt wit h o ut disease pr o gressi o n or disc o nti n ue earl y 
wit h o ut disease pr o gressi o n will c o nti n ue t o be f oll o we d f or disease stat us u ntil pr o gressi o n 
w here p ossi ble. After pr o gressi o n ( o n st u d y or d uri n g p ost-st u d y f oll o w- u p), s u bjects will 
c o nti n ue t o be f oll o we d, w here p ossi ble, f or s ur vi val, p ost-st u d y treat me nt(s) f or G B a n d 
i ma gi n g f or G B u ntil deat h ( or ter mi nati o n of data c ollecti o n b y t he S p o ns or or wit h dra wal of 
c o nse nt b y t he s u bject). 
 
3. 2  R a n d o miz ati o n a n d Bli n di n g  
T his st u d y is a si n gle-ar m desi g n. All  s u bjects will  recei ve acti ve treat me nt. N o  ra n d o mizati o n 
will be perf or me d. N o bli n di n g pr oce d ures are e m pl o ye d. 
 
3. 3  St u d y Tre at me nt  
T he c o nce ntrati o ns of M D N A 5 5 e val uate d i n t his st u d y will be 1. 5, 3, 6, a n d 9 µ g/ m L 
a d mi nistere d i n vari o us v ol u mes t hat d o n ot e xcee d 2 4 0 µ g  (t he esta blis he d ma xi m u m t olerate d 
d ose of M D N A 5 5). 
 
I nf usi o n via eac h cat heter will be i nitiate d at t he rate of 3 μ L/ mi n/cat heter a n d gra d uall y 
i ncrease d i n a ste p wise ma n ner. T he i nf usi o n fl o w rate ca n be a dj uste d at t he discreti o n of t he 
I n vesti gat or d uri n g real ti me M RI ( wit h s u bject mai ntai ne d u n der a nest hesia) pr o vi de d t hat t he 
fl o w rate per cat heter d oes n ot e xcee d 1 0 μ L/ mi n. All  f u ncti o ni n g cat heters s h o ul d be c o n victi n g 






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i 1 P K  assesse d at Scree ni n g  ( baseli ne), as s o o n as p ossi ble  b ut  n ot  m ore  t ha n 1 h o ur  f oll o wi n g i nf usi o n e n d 
ti me, a p pr o xi matel y 3 h o urs f oll o wi n g c o m pleti o n of i nf usi o n a n d t he n (after t he ~ 3 h o ur sa m ple 
c ollecti o n) e ver y 6 h o urs ± 2 h o urs u ntil 2 4 h o urs or u ntil s u bject is disc har ge d fr o m t he h os pital 
( w hic he ver occ urs first) a n d at Da y 1 4. 
i 2 I m m u n o ge nicit y assesse d at Scree ni n g  ( baseli ne) a n d at Da ys  1 4,  3 0,  1 2 0,  2 4 0,  a n d 3 6 0/earl y 
ter mi nati o n. 
i 3 Pre -a nest hesia bl o o d dra w ( wit hi n 1 h o ur of s u bject be place d u n der a nest hesia), t his bl o o d sa m ple 
c ollecti o n a n d pr ocessi n g  will  use  a st u d y s pecific sa m ple c ollecti o n kit  a n d re q uire i m me diate (sa me 
da y) s hi p me nt t o ce ntral la b orat or y.  
J 
Baseli ne  c o n diti o ns/s y m pt o ms  will  be  c ollecte d fr o m Scree ni n g  u ntil  Da y  0 bef ore  s u bject is a nest hetize d  f or 
cat heter place me nt s ur ger y; a n y baseli ne c o n diti o n or s y m pt o m n ote d pri or t o cat heter place me nt will be 
rec or de d i n t he Me dical Hist or y. 
k  
see Secti o n 6. 3; pri or t o cat heter i nserti o n, c ore tu m or bi o ps y sa m ples (at least 3 c ores) will be c ollecte d, if t he 
ne ur os ur ge o n deter mi nes it is p ossi ble t o har vest via ble t u m or tiss ue fr o m al o n g t he pla n ne d traject or y of t he 
C E D cat heter(s); bi o ps y sa m ple tiss ue c ollecti o n a n d pr ocessi n g will use a st u d y  s pecific sa m ple c ollecti o n kit 
a n d re q uire i m me diate s hi p me nt t o t he ce ntral la b orat or y.  
l 
see St u d y  P har mac y  Ma n ual  f or i nf usate pre parati o n  a n d dis pe nsi n g  i nstr ucti o ns. 
m  F oll o wi n g  c o m pleti o n of  i nf usi o n ( o nl y after t he e n d of  i nf usi o n M RI  a n d at a n y ti me pri or  t o s u bject’s 
disc har ge  fr o m t he h os pital),  t he cat heters ca n be  re m o ve d, a n d t he i ncisi o ns cl ose d i n acc or da nce  wit h 
i nstit uti o nal practice. Re m o val of cat heters m ust be perf or me d b y a dele gate d ne ur os ur ge o n. 
n  All c o nc o mita nt me dicati o ns will be c ollecte d o n t he Electr o nic Data ca pt ure ( E D C) s yste m fr o m t he date of 
i nf or me d c o nse nt t hr o u g h 3 0 -da y  safet y peri o d.  T hereafter,  c o nc o mita nt  me dicati o ns  ass ociate d wit h  treat me nt- 
relate d S A Es a n d detaile d a nti-t u m or t hera p y will be c ollecte d. C ortic oster oi d use will be c ollecte d u ntil Da y 
6 0 or earl y wit h dra wal.  
o 
All  A Es  will  be  c ollecte d fr o m cat heter place me nt  t hr o u g h t he e n d of  st u d y visit  a n d all A Es  a n d S A Es  will  be 
f oll o we d u ntil res ol uti o n, sta bilizati o n, data c ut-off, or deat h . 
p  
S u bjects w h o c o m plete t he Da y 3 6 0 assess me nt wit h o ut disease pr o gressi o n or disc o nti n ue earl y wit h o ut 
disease pr o gressi o n will c o nti n ue t o be f oll o we d f or disease stat us u ntil pr o gressi o n. After pr o gressi o n 
( d oc u me nte d o n st u d y  or  d uri n g  p ost -st u d y f oll o w-u p),  s u bjects will  c o nti n ue t o be f oll o we d f or s ur vi val, p ost- 
st u d y treat me nt(s) f or G B  a n d i ma gi n g f or G B,  w here  p ossi ble,  u ntil  deat h  ( or ter mi nati o n of  data  c ollecti o n b y 
t he S p o nso r or wit h dra wal of c o nse nt b y t he s u bject). 
q  
P h ysical  e xa m a n d K P S  assess me nts  will  be  perf or me d  after c o m pleti o n of  i nf usi o n w he n  t he s u bject is 
a m b ulat or y pri or t o h os pital disc har ge.  
r 
Vital si g ns m o nit ori n g ( wit h o ut wei g ht para meter) will be perf or me d acc or di n g t o i nstit uti o nal best practice 
t hr o u gh o ut e ntire s ur gical w or kfl o w f or cat heter place me nt a n d C E D i nf usi o n; st u d y s pecific vital si g ns c hec k 
p oi nts  d uri n g  t he s ur gical w or kfl o w  are pri or  t o i nitiati o n of  a nest hesia,  f oll o wi n g place me nt  of  all cat heters  b ut 
pri or t o patie nt bei n g l oa de d i nt o M RI mac hi ne f or t he real-ti me i nf usi o n m o nit ori n g se g me nt a n d 
a p pr o xi matel y 1 h o ur p ost i nitiati o n of i nf usi o n; N O T E: Site will rec or d a n y a b n or mal vitals o bser ve d at a n y 
ti me d uri n g s ur gical vital si g ns m o nit ori n g as u nsc he d ule d fi n di n gs. 
s 
Vital  si g ns ta ke n after c o m pleti o n of  i nf usi o n w he n  t he s u bject is a m b ulat or y pri or  t o h os pital  disc har ge.  
t 
E C G  (tri plicate assess me nt)  will  be  perf or me d  at Scree ni n g  a n d i m me diatel y f oll o wi n g c o m pleti o n of  i nf usi o n 
( wit hi n 2 h o urs of i nf usi o n e n d ti me); tri plicate assess me nt i n 3 i m me diate traces. 
u  
Bl o o d sa m ples f or  he mat ol o g y, ser u m c he mistr y, a n d c oa g ulati o n ( Secti o n 7. 2. 1) s hall  be ta ke n i n parallel wit h 
eit her t he P K  bl o o d  c ollecti o n t hat is perf or me d  wit hi n  1 h o ur  f oll o wi n g c o m pleti o n of  i nf usi o n or  t he P K  bl o o d 
c ollecti o n t hat is perf or me d ~ 3 h o urs f oll o wi n g c o m pleti o n of i nf usi o n.  


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4.  S T U D Y  E N D P OI N T S  
4. 1  Pri m ar y Effic ac y E n d p oi nt  
• O verall s ur vi val, defi ne d as t he ti me fr o m treat me nt u ntil deat h.  
4. 2  Sec o n d ar y Effic ac y E n d p oi nts  
• O verall s ur vi val b y t u m or I L 4- R stat us; 
 
o  I L 4- R stat us of t u m or will  be deter mi ne d base d o n arc hi ve d bi o ps y fr o m t he ti me 
of i nitial dia g n osis; 
 
• O R R as deter mi ne d b y a n i n de pe n de nt ce ntral re vie w acc or di n g t o R A N O- base d criteria 
w hic h ma y i nc or p orate a d va nce d i ma gi n g m o dalities (e. g. diff usi o n, perf usi o n a n d/ or 
T R A Ms, c o n diti o nal u p o n a d va nce d i ma gi n g data bei n g a vaila ble); 
 
o  O R R is defi ne d as t he pr o p orti o n of s u bjects w h o ac hie ve d a c o m plete res p o nse 
( C R) or partial res p o nse ( P R) o ut of all treate d s u bjects; 
 
• P F S,  defi ne d as t he ti me fr o m treat me nt u ntil disease pr o gressi o n or deat h.  
4. 3  Ot her Effic ac y E n d p oi nts  
• D urati o n of res p o nse ( D O R). Defi ne d as t he ti me fr o m first res p o nse u ntil disease 
pr o gressi o n ( per R A N O- base d criteria a n d as deter mi ne d b y a n i n de pe n de nt ce ntral 
re vie w) or deat h a m o n g t h ose s u bjects ac hie vi n g a c o m plete res p o nse ( C R) or partial 
res p o nse ( P R) t o treat me nt; 
 
• D urati o n of cli nical be nefit ( D O C B). Defi ne d as t he ti me fr o m first res p o nse or disease 
sta bilizati o n u ntil disease pr o gressi o n ( per R A N O- base d criteria a n d as deter mi ne d b y a n 
i n de pe n de nt ce ntral re vie w) or deat h a m o n g t h ose s u bjects ac hie vi n g t u m or c o ntr ol: 
c o m plete res p o nse ( C R), partial res p o nse ( P R), or sta ble disease ( S D); 
 
• T o deter mi ne t he T u m or C o ntr ol Rate ( T C R) defi ne d as t he pr o p orti o n of s u bjects i n 
w h o m t he best o verall res p o nse is deter mi ne d as c o m plete res p o nse ( C R), partial 
res p o nse ( P R) or sta ble disease ( S D) base d o n differe nt sets of i ma gi n g- base d res p o nse 
criteria. Use  of s u b-t hera pe utic d oses of A vasti n will  als o be c o nsi dere d i n deter mi nati o n 
of T C R (a n d will res ult i n a varia nt of t he T C R bei n g calc ulate d); 
 
• Ti me  t o T u m or Pr o gressi o n ( T T P). Defi ne d as t he ti me fr o m treat me nt u ntil t u m or 
pr o gressi o n; d oes n ot i ncl u de deat h. 
 
4. 4  E x pl or at or y E n d p oi nts:  
• T o  deter mi ne t he relati o ns hi p bet wee n efficac y e n d p oi nts (i.e., O S,  P F S,  D O R, D O C B, 
T T P) a n d t u m or res p o nse cate g or y usi n g differe nt sets of i ma gi n g- base d res p o nse 
criteria; 


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• T o  deter mi ne t he relati o ns hi p bet wee n efficac y e n d p oi nts (i.e., O S,  P F S,  D O R, D O C B, 
T T P, T C R) a n d I L 4 R e x pressi o n stat us; 
 
• T o  deter mi ne t he relati o ns hi p bet wee n efficac y e n d p oi nts (i.e., O S,  P F S,  D O R, D O C B, 
T T P) a n d vari o us pr o g n ostic fact ors (i.e., a ge, se x, K P S, M G M T stat us, etc); 
 
• T o  deter mi ne t he relati o ns hi p bet wee n efficac y e n d p oi nts (i.e., O S,  P F S,  D O R, D O C B, 
T T P) a n d use of c o nc o mita nt me dicati o n (i.e., A vasti n, ster oi ds); 
 
• T o  deter mi ne t he relati o ns hi p bet wee n efficac y e n d p oi nts (i.e., O S,  P F S,  D O R, D O C B, 
T T P) a n d vari o us treat me nt a n d dr u g distri b uti o n para meters (i.e., M D N A 5 5 
c o nce ntrati o n, t otal d ose, v ol u me of i nf usi o n, perce nt t u m or c o vera ge, etc.); 
 
• T o  assess t he perf or ma nce of Brai nla b cat heter d uri n g i nf usi o n t hr o u g h real ti me M RI 
m o nit ori n g;  
 
N ote: All  e x pl orat or y a nal yses will  be c o n diti o nal u p o n data bei n g a vaila ble. 
 
4. 5  S afet y E n d p oi nts  
T he safet y assess me nts t o e val uate t he o verall safet y of M D N A 5 5- 0 5 will i ncl u de: 
 
• Seri o us a d verse e ve nts ( S A Es) a n d treat me nt e mer ge nt a d verse e ve nts ( T E A Es); 
 
• Vital  si g ns; 
 
• P h ysical e xa mi nati o ns; 
 
• Ne ur ol o gical e xa mi nati o ns; 
 
• Electr ocar di o gra m ( E C G); 
 
• Cli nical la b orat or y res ults ( hae mat ol o g y, ser u m c he mistr y, c oa g ulati o n, uri nal ysis);  
 
• Kar n ofs k y Perf or ma nce Stat us ( K P S). 
4. 6  Ot her E n d p oi nts  
• M D N A 5 5 P K  para meters i n peri p heral plas ma;  
 
• A nti- M D N A 5 5 a nti b o d y ( A D A) titer i n ser u m; 
 
• Ne utralizi n g a nti b o d y ( N A b) titer (if a nti- M D N A 5 5 titer is o bser ve d).  


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5.  S T U D Y  P O P U L A TI O N S  
5. 1  I nte nt t o Tre at P o p ul ati o n (I T T)/ S afet y 
A n  I T T p o p ulati o n will  c o m prise all s u bjects w h o si g n t he I C F a n d w h o recei ve a n y a m o u nt of 
st u d y dr u g. 
5. 2  M o difie d I nte nt t o Tre at P o p ul ati o n ( mI T T) 
A m o difie d I T T p o p ulati o n f or sec o n dar y res p o nse a nal yses ( mI T T) will  c o m prise all s u bjects 
w h o recei ve a n y a m o u nt of st u d y dr u g a n d ha ve a de q uate i ma gi n g (at least 1 p ost-treat me nt 
sca n) a n d cli nical data f or t he O R R a nal ysis. 
 
5. 3  Per  Pr ot oc ol P o p ul ati o n ( P P) 
T he P P p o p ulati o n will c o m prise all s u bjects i n t he mI T T p o p ulati o n w h o als o ha ve n o maj or 
pr ot oc ol vi olati o ns d uri n g t he st u d y. Efficac y a nal yses will  be c o n d ucte d o n t his p o p ulati o n i n 
s u p p ort of t he pri mar y efficac y res ults. 
 
5. 4  I L 4 R P o p ul ati o n  
T he I L 4 R a nal ysis p o p ulati o n will  be t h ose i n t he I T T p o p ulati o n w h o ha ve arc hi ve d tiss ue or 
a de q uate tiss ue a vaila ble f or a nal ysis a n d will be use d f or efficac y a nal yses i n s u b gr o u ps 
acc or di n g t o I L 4 R e x pressi o n stat us. 
 
5. 5  P K  P o p ul ati o n  
T he P K  P o p ulati o n ma y  i ncl u de all s u bjects w h o recei ve d a n y d ose of M D N A 5 5 a n d w h o ha d at 
least o ne p ost-treat me nt P K sa m ple a vaila ble. S u bjects w h o recei ve d t he hi g hest d ose 
c o nce ntrati o ns ( 6 a n d 9 u g/ m L) will be a nal yse d first. If all res ults fr o m t his c o h ort are Bel o w 
Le vel of Q ua ntitati o n ( B L Q), c o nsiste nt wit h hist orical data s h o wi n g n o e vi de nce of s yste mic 
e x p os ure wit h M D N A 5 5, n o f urt her s u bjects will be a nal yse d u nless re q ueste d b y a re g ulat or y 
a ut h orit y. 
 
5. 6  A nti- Dr u g - A nti b o d y P o p ul ati o n  
T he A D A  P o p ulati o n will  i ncl u de all s u bjects w h o recei ve d a n y d ose of M D N A 5 5 a n d w h o ha d 
a baseli ne ( pre-treat me nt) a n d at least o ne p ost-treat me nt A D A sa m ple a vaila ble. 
 
Ne utralizi n g a nti b o d y titers will  be assesse d  i n t he A D A  p o p ulati o n as a p pr o priate a n d 
a p plica ble. 
 
6.  S T A TI S TI C A L  A N A L Y SI S  C O N SI D E R A TI O N S  
6. 1  H a n dli n g of Missi n g  D at a a n d Dr o p o ut  
All a vaila ble data will be use d, a n d n o efficac y data will be i m p ute d. F or t he a nal yses of 
res p o nse, s u bjects wit h baseli ne assess me nts b ut n o p ost-treat me nt assess me nts will be n o n- 
e val ua ble. F or ti me t o e ve nt varia bles, s u bjects n ot k n o w n t o ha ve e x perie nce d a n e ve nt at t he 
ti me of a nal ysis will be ce ns ore d. 


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6. 2  H a n dli n g of Missi n g  or I nc o m plete D ate  
T o  ha n dle missi n g or partial A E  a n d c o nc o mita nt me dicati o n dates, t he f oll o wi n g r ules will  be 
a p plie d. 
 
F or partial start dates:  
 
1.  If t he m o nt h is u n k n o w n, t he n: 
a) If t he year matc hes t he year of t he d ose date, t he n i m p ute t he m o nt h a n d da y of t he d ose 
date.  
b)  Ot her wise, assi g n “Ja n uar y.” 
2.  If t he da y is u n k n o w n, t he n: 
a) If t he m o nt h a n d year matc h t he m o nt h a n d year of t he first d ose date, t he n i m p ute t he 
da y of t he d ose date. 
b)  Ot her wise, assi g n “ 0 1.” 
F or partial e n d dates: 
1.  If t he m o nt h is u n k n o w n, t he n assi g n “ Dece m ber.” 
2.  If t he da y is u n k n o w n, t he n assi g n t he last da y of t he m o nt h.  
After i m ple me nti n g t he r ules a b o ve, t o deter mi ne w het her A Es  ( or me dicati o ns) wit h  missi n g 
start or st o p dates are pretreat me nt or o n/after treat me nt, t he f oll o wi n g strate g y will be use d: 
1.  If t he start date a n d st o p date are b ot h missi n g, t he n t he m ost c o nser vati ve a p pr oac h is 
ta ke n a n d t he A E ( or me dicati o n) is treat me nt e mer ge nt ( or c o nc o mita nt me dicati o n). 
2.  If t he start date is missi n g b ut t he st o p date is n ot missi n g a n d is o n or after t he da y of 
cat heter place me nt, t he n t he m ost c o nser vati ve a p pr oac h is ta ke n a n d t he A E ( or 
me dicati o n) is treat me nt e mer ge nt ( or c o nc o mita nt me dicati o n). 
3.  If t he start date is missi n g b ut t he st o p date is n ot missi n g a n d is bef ore cat heter 
place me nt a n d after t he date of si g ne d i nf or me d c o nse nt, t he n t he me dicati o n is bef ore 
treat me nt ( or pri or me dicati o n). N ote: t his is n ot a p plica ble t o A Es  as all A E  c ollecti o n 
start fr o m date/ti me of cat heter place me nt. 
4.  If t he start date is n ot missi n g b ut t he st o p date is missi n g, t he n t he m ost c o nser vati ve 
a p pr oac h is ta ke n, a n d me dicati o n c o nc o mita nt w hile t he A E is defi ne d b y start date. 
6. 3  Visit  Wi n d o wi n g  
N ot a p plica ble f or t his st u d y. 
 
6. 4  B aseli ne Defi niti o n  
T he baseli ne val ue is defi ne d as t he last n o n missi n g assess me nt pri or t o cat heter place me nt.  
 
6. 5  Deri ve d V ari a bles  
C ha n ge fr o m Baseli ne is defi ne d as P ost baseli ne val ue – Baseli ne val ue.  






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All de m o gra p hic a n d ot her baseli ne c haracteristics will be pr o vi de d i n a listi n g f or I T T 
P o p ulati o n. Cate g orical varia bles will  be s u m marize d usi n g fre q ue ncies w hile c o nti n u o us 
varia bles will be s u m marize d usi n g mea n, S D, me dia n, mi ni m u m, a n d ma xi m u m. 
 
7. 4. 1  De m o gr a p hics  
 
T he f oll o wi n g de m o gra p hic c haracteristics will  be s u m marize d 
 
• A ge ( years) 
 
• Se x  
 
• Et h nicit y  
 
• Race  
 
A ge will  be calc ulate d as: a ge = I nte ger ≤ [(I C F date – Date  of Birt h + 1) / 3 6 5. 2 5]  
7. 4. 2  B aseli ne a n d Dise ase C h ar acteristics  
 
T he f oll o wi n g baseli ne c haracteristics of t he u n derl yi n g disease will  be s u m marize d: 
 
• Kar n ofs k y Perf or ma nce Sc ore.  
 
• M G M T  Stat us ( p ositi ve/ met h ylate d or ne gati ve/ u n met h ylate d)  
 
• Ster oi d use ( Yes, N o).  
 
• G B M gra de  
 
• Dia g n ostic met h o d of Gli o blast o ma ( C T, M RI, Bi o ps y).  
 
• Pri or Gli o blast o ma treat me nt ( S ur ger y, Ra di ot hera p y, Te m oz ol o mi de, Ot her 
C he m ot hera p y, I n vesti gati o nal, Ot her). 
 
• I nitial dia g n osis t o 1st rela pse ( m o nt hs) 
 
• I nitial dia g n osis t o c urre nt rela pse ( m o nt hs) 
 
• I nitial dia g n osis t o start of M D N A 5 5 treat me nt ( m o nt hs) 
 
• N u m ber of pri or rela pses ( 1 or 2)  
 
• Ma x  t u m or dia meter at baseli ne (c m) 
 
• T u m or v ol u me at baseli ne (c m 3) 


Me dice n na  T hera pe utics  I nc 
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• L y m p h oc yte c o u nt 
 
• Hei g ht (c m) 
 
• Wei g ht ( k g) 
 
• B o d y mass  i n de x ( B MI) 
7. 5  Me dic al Hist or y  
Me dical hist or y will be s u m marize d b y t he n u m ber a n d perce nta ge of s u bjects i n eac h s yste m 
or ga n class ( S O C), preferre d ter m ( P T), a n d o verall usi n g t he safet y p o p ulati o n. S u bjects will  be 
c o u nte d o nl y o nce at t he preferre d ter m ( P T), o nl y o nce at t he s yste m or ga n class ( S O C), a n d 
o nl y o nce at s u bject le vel f or t he c o u nti n g of t otal n u m ber of s u bjects wit h a me dical hist or y 
ter m. C o u nts will be prese nte d i n desce n di n g fre q ue nc y of S O C ter m f or t he treat me nt c ol u m n 
u nless ot her wise s pecifie d. Me dical a n d s ur gical hist or y will  be c o de d usi n g Me dical Dicti o nar y 
f or Re g ulat or y Acti vities ( Me d D R A) latest versi o n. 
 
Listi n gs of Me dical Hist or y will  be pr o vi de d f or usi n g t he Safet y P o p ulati o n.  
 
7. 6  Pri or a n d C o nc o mit a nt Me dic ati o ns/ C ortic oster oi ds  
Pri or a n d c o nc o mita nt me dicati o ns will be c o de d usi n g W orl d Healt h Or ga nizati o n- Dr u g 
Dicti o nar y a n d will  be cate g orize d b y preferre d na me a n d A T C  le vel 4 class per W H O,  w hic h 
will be s u m marize d usi n g t he Safet y P o p ulati o n f or eac h of t he 3 peri o ds: pri or t o cat heter 
place me nt, d uri n g i nf usi o n a n d p ost e n d of i nf usi o n. Listi n gs of all pri or a n d c o nc o mita nt 
me dicati o ns will be pr o vi de d f or usi n g t he Safet y P o p ulati o n. 
 
Pri or Me dicati o ns/ C ortic oster oi d: Pri or me dicati o ns will i ncl u de a n y me dicati o n ha vi n g a st o p 
date/ti me pri or t o cat heter place me nt. 
 
C o nc o mita nt Me dicati o ns/ C ortic oster oi d: C o nc o mita nt me dicati o ns, are a n y me dicati o ns ha vi n g 
a st o p date/ti me after cat heter place me nt or o n g oi n g. 
 
All   c o nc o mita nt  me dicati o ns/c ortic oster oi ds will   be  rec o ncile d  acc or di n gl y at  p oi nt  of  s u bject 
earl y wit h dra wal / or st u d y c o m pleti o n as eit her ha vi n g a st o p date or o n g oi n g. 
 
7. 7  Effic ac y A n al yses  
7. 7. 1  Pri m ar y Effic ac y A n al yses  
 
T he pri mar y efficac y assess me nt will be o verall s ur vi val defi ne d as t he date of cat heter 
place me nt u ntil deat h fr o m a n y ca use. S u bjects w h o are n ot k n o w n t o ha ve die d at t he ti me of t he 
a nal ysis will be ce ns ore d at t he date of last c o ntact. 
 
O S =  Date  of deat h/ Ce ns ore d – Date  of cat heter place me nt + 1.  


Me dice n na  T hera pe utics  I nc 
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Versi o n Fi nal 2. 0  
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Date: Oct 2 3, 2 0 1 9  
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S ur vi val rates at 6, 9, a n d 1 2 m o nt hs a n d t heir e xact 9 5 % CI f or t he pri mar y e n d p oi nt ( O S) al o n g 
wit h  t he esti mate f or me dia n a n d its 8 0 %, 9 0 % a n d 9 5 % CI, will be pr o d uce d usi n g K M  met h o d. 
K M esti mates of O S will als o be prese nte d gra p hicall y at 6, 9 a n d 1 2 m o nt hs. 
 
Sa me  s u m maries will  be pr o d uce d f or all s u b gr o u ps a n d ot her ti me-t o-e ve nt e n d p oi nts. 
 
7. 7. 1. 1  S u b gr o u p A n al yses  
S u b gr o u p a nal ysis is pla n ne d f or t he pri mar y e n d p oi nt O S  t o i n vesti gate w het her treat me nt effect 
is c o nsiste nt wit hi n t he s u b gr o u ps. F orest pl ots will  be use d t o gra p hicall y re prese nt t he s u b gr o u p 
esti mates a n d c orres p o n di n g c o nfi de nce i nter vals. All t he s u b gr o u ps are pr o vi de d i n a se parate 
d oc u me nt attac he d i n secti o n 1 1 A p pe n dices. Als o, s u b gr o u p a nal ysis is c o n diti o nal u p o n 
a vaila bilit y of data. 
 
7. 7. 2  Sec o n d ar y Effic ac y A n al yses  
 
T o Assess  t he Effect of I L 4- R St at us o n O ver all S ur vi v al ( O S) 
 
T he sec o n dar y efficac y assess me nt will  be t o assess t he effect of I L 4- R stat us o n o verall s ur vi val 
( O S). T he me dia n O S wit h its 8 0 %, 9 0 % a n d 9 5 % c o nfi de nce i nter val will be esti mate d usi n g 
t he K M met h o d, wit h I L 4- R stat us as strata. 
 
S ur vi val rates at 6, 9, a n d 1 2 m o nt hs a n d t heir e xact 9 5 % CI f or t he O S al o n g wit h t he esti mate 
f or me dia n a n d its 8 0 %, 9 0 % a n d 9 5 % CI, will  be pr o d uce d usi n g K M  met h o d. K M  esti mates of 
O S will als o be prese nte d gra p hicall y at 6, 9 a n d 1 2 m o nt hs f or eac h I L 4- R strat u m. 
 
O bjecti ve Res p o nse R ate ( O R R) 
 
O bjecti ve Res p o nse Rate ( O R R) is t he pr o p orti o n of s u bjects w h o ac hie ve d a c o m plete res p o nse 
( C R) or partial res p o nse ( P R) ( b y R A N O- base d criteria usi n g b ot h 2- di me nsi o nal a n d v ol u metric 
assess me nts a n d w hic h ma y i ncl u de t he i nc or p orati o n of a d va nce d i ma gi n g m o dalities base d o n 
a vaila bilit y of data) o ut of all treate d s u bjects. Use of s u b-t hera pe utic d oses of A vasti n will als o 
be c o nsi dere d i n deter mi nati o n of O R R (a n d will res ult i n a varia nt of t he O R R bei n g 
calc ulate d). O bjecti ve res p o nse rate will be s u m marize d usi n g perce nta ges al o n g wit h t w o-si de d 
8 0 %, 9 0 % a n d 9 5 % Cl o p per- Pears o n CI at sc he d ule d ti me p oi nts. S u bjects wit h baseli ne 
assess me nts b ut n o p ost-treat me nt assess me nts will be e xcl u de d fr o m t he O R R a nal ysis. I n 
a d diti o n, t he n u m ber a n d perce nt of s u bjects b y res p o nse C R or P R will be s u m marize d. All 
deri ve d efficac y varia bles will be dis pla ye d i n a data listi n g. 
 
Pr o gressi o n Free  S ur vi v al ( P F S) 
 
Pr o gressi o n Free S ur vi val ( P F S) is meas ure d as t he ti me fr o m cat heter place me nt t o t he date of 
c o nfir me d disease pr o gressi o n or deat h fr o m a n y ca use, w hic he ver occ urs first. F or s u bjects w h o 
are n ot k n o w n t o ha ve die d or pr o gresse d as of t he data-i ncl usi o n c ut- off date, P F S ti me will be 
ce ns ore d at t he ti me of t he last ra di ol o gic assess me nt de m o nstrati n g lac k of pr o gressi o n or, if 
d uri n g t he f oll o w- u p peri o d, t he ti me of last c o ntact i n dicati n g lac k of pr o gressi o n. 


Me dice n na  T hera pe utics  I nc 
Statistical A nal ysis Pla n 
Versi o n Fi nal 2. 0  
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Date: Oct 2 3, 2 0 1 9  
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P F S =  Date  of disease pr o gressi o n/ deat h – Date  of cat heter place me nt + 1  
 
P F S rates at 6, 9, a n d 1 2 m o nt hs a n d t heir e xact 9 5 % CI f or t he P F S al o n g wit h t he esti mate f or 
me dia n a n d its 8 0 %, 9 0 % a n d 9 5 % CI, will  be pr o d uce d usi n g K M  met h o d. All  deri ve d efficac y 
varia bles will be dis pla ye d i n a data listi n g. K M esti mates of P F S will als o be prese nte d 
gra p hicall y at 6, 9 a n d 1 2 m o nt hs. 
 
7. 7. 3  E x pl or at or y E n d p oi nts A n al yses  
 
Rel ati o ns hi p bet wee n O S  a n d T u m or Res p o nse Assess me nt  
 
Acc or di n g t o R A N O- base d criteria, a res p o n der is defi ne d b y ra di o gra p hic a n d cli nical criteria. 
Tar get lesi o n ra di ol o gical res p o nse assess me nt are defi ne d as bel o w: 
 
T w o - Di me nsi o nal Criteria: (c ha n ge i n bi- di me nsi o nal pr o d uct)  
 
• C o m plete Res p o nse ( C R): 1 0 0 % decrease i n S u m of Per pe n dic ular Dia meters ( S P D); 
 
• Partial Res p o nse ( P R):  ≥ 5 0 % decrease i n S u m of Per pe n dic ular Dia meters ( S P D); 
 
• Pr o gressi ve Disease  ( P D):  ≥ 2 5 % i ncrease i n S u m of Per pe n dic ular Dia meters ( S P D); 
 
• Sta ble Disease  ( S D): N ot C R, P R, P D;  
 
• N ot E val ua ble ( N E). 
T hree- Di me nsi o nal Criteria: (esti mate d v ol u metric c ha n ge) 
 
• C o m plete Res p o nse ( C R): 1 0 0 % decrease;  
 
• Partial Res p o nse ( P R):  ≥ 5 0 % decrease;  
 
• Pr o gressi ve Disease  ( P D):  ≥ 4 0 % i ncrease; 
 
• Sta ble Disease  ( S D): < 6 5 % decrease t o < 4 0 % i ncrease; 
 
• N ot E val ua ble ( N E). 
Best t u m or res p o nse will  be cate g orize d i nt o t w o gr o u ps: s u bjects ha vi n g a best res p o nse of 
sta ble disease or better (i.e., S D, P R, or C R) or s u bjects ha vi n g pr o gressi ve disease ( P D). 
 
All  res p o nse assess me nt will  be s u m marize d b y c o u nt a n d perce nta ges at t he sc he d ule d visits. 
T u m or res p o nse data will als o be prese nte d i n listi n g. 
T he s u b gr o u p a nal ysis will  be base d o n O S  f or all t he t u m or res p o nses fr o m t he d oc u me nt 
attac he d i n a p pe n dices secti o n 1 1. 






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Ti me t o T u m or Pr o gressi o n ( T T P) 
 
T T P  is defi ne d as t he ti me bet wee n t he date of cat heter place me nt a n d t he date of first e vi de nce 
of disease pr o gressi o n ( P D). F or s u bjects w h o d o n ot e x perie nce t u m or pr o gressi o n b y t he ti me 
of data c ut- off, T T P will be ri g ht ce ns ore d at t he date of last a de q uate disease res p o nse 
assess me nt.  
 
T T P  = Date  of e ve nt/ce ns ori n g – Date  of cat heter place me nt + 1  
 
T he a nal ysis will  be si milar t o D O R  or D O C B. All  deri ve d efficac y varia bles will  be dis pla ye d 
i n a data listi n g. T he Ka pla n- Meier esti mates of T T P will be s h o w n i n a se parate gra p h. 
 
T he a nal ysis will  be base d o n mI T T p o p ulati o n. Use  of s u b-t hera pe utic d oses of A vasti n will 
als o be c o nsi dere d i n deter mi nati o n of T T P (a n d ma y res ult i n a varia nt of t he T T P bei n g 
calc ulate d). 
 
7. 8  S afet y A n al yses  
T he f oll o wi n g assess me nts will  be use d t o e val uate t he o verall safet y of M D N A 5 5:  
 
• A d verse e ve nts; 
 
• Vital  si g ns; 
 
• P h ysical e xa mi nati o n; 
 
• Ne ur ol o gical e xa mi nati o ns; 
 
• Electr ocar di o gra m ( E C G); 
 
• Cli nical la b orat or y res ults; 
 
• K P S;  
 
• A nti b o d y Assess me nt (ser u m a nti- M D N A 5 5 a nti b o d y a n d ne utralizi n g a nti b o d y); 
 
• Relati o ns hi p of safet y t o e val uati o n of i m m u ne para meters ( A D A a n d N A b).  
All  safet y a nal ysis will  be perf or me d usi n g t he safet y p o p ulati o n. All  safet y e n d p oi nts will  be 
s u m marize d acc or di n g t o t he f oll o wi n g s u b gr o u ps: 
 
• O verall;  
 
• Gr o u pe d b y c o nce ntrati o n ( 1. 5, 3, 6, a n d 9 u g/ m L);  
 
• Gr o u pe d b y v ol u mes of i nf usi o n ( v ol u me of i nf usi o n will ha ve t w o cate g ories); 


Me dice n na  T hera pe utics  I nc 
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• Gr o u pe d b y t otal d ose (t otal d ose will  ha ve 2 cate g ories). 
7. 8. 1  A d verse E ve nts  
 
A d verse e ve nts are c o de d t o S yste m Or ga n Class ( S O C) a n d preferre d ter ms usi n g t he Me dical 
Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A) 
 c o di n g s yste m, versi o n 2 2. 0 a n d 
W H O D R U G versi o n date d Marc h, 2 0 1 6. 
All  A Es  will  be c ollecte d fr o m cat heter place me nt t hr o u g h t he e n d of st u d y visit a n d all A Es  a n d 
S A Es will be f oll o we d u ntil res ol uti o n, sta bilizati o n, data c ut- off, or deat h. 
 
Treat me nt- E mer ge nt A Es ( T E A Es): T E A E is defi ne d as a n y ne w A Es t hat occ ur fr o m start of 
cat heter place me nt o n war ds, or a n y me dical hist or y c o n diti o n/s y m pt o m w hic h w orse ns b y o ne or 
m ore C T C A E gra de fr o m cat heter place me nt o n war ds. 
 
T o  deter mi ne treat me nt-e mer ge nt A E,  partiall y missi n g A E  start dates will  be i m p ute d acc or di n g 
t o t he r ules state d i n Secti o n 6. 2. 
 
T he i nci de nce of T E A Es will be s u m marize d acc or di n g t o Me d D R A b y S O C  a n d/ or P T,  se verit y 
( base d o n C T C A E gra des versi o n 5. 0), t y pe of e ve nt, a n d relati o n t o st u d y treat me nt. If a s u bject 
e x perie nces m ulti ple A Es  u n der t he sa me P T  wit hi n a S O C, t he n t he s u bject will  be c o u nte d o nl y 
o nce f or t hat P T wit hi n t hat S O C. If a s u bject e x perie nce t he sa me A E m ore t ha n o nce wit h 
differe nt i nte nsit y or gra de, t he n t he e ve nt wit h t he hi g hest gra de will be ta b ulate d i n “ b y gra de” 
ta bles. 
 
Ta bles s u m marizi n g t he i nci de nce of A Es  will  be ge nerate d acc or di n g t o t he s u b gr o u ps i n dicate d 
a b o ve i n secti o n 7. 8 as well as f or eac h of t he f oll o wi n g: 
 
• O verall s u m mar y of A Es;  
 
• All  T E A Es  b y S O C  a n d P T;  
 
• T E A Es  b y S O C  a n d P T  a n d se verit y; 
 
• Relate d T E A Es  b y S O C  a n d P T;  
 
• S A Es  b y S O C  a n d P T;  
 
• T E A Es  lea di n g t o i nf usi o n disc o nti n uati o n b y S O C  a n d P T;  
 
• T E A Es  lea di n g t o deat h.  
All t he A E ta bles will be als o s u m marize d base d o n ha vi n g a start date/ti me falli n g wit hi n 3 
peri o ds: d uri n g i nf usi o n, 3 0 da ys p ost e n d of i nf usi o n, a n d be y o n d 3 0 da ys p ost e n d of i nf usi o n. 
All A Es will be liste d b y s u bject. B y- patie nt listi n gs will be pr o vi de d f or A Es lea di n g t o deat h, 
S A Es a n d A Es lea di n g t o disc o nti n uati o n of treat me nt. 


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Date: Oct 2 3, 2 0 1 9  
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7. 8. 2  Vit al Si g ns  
 
Vital  si g n meas ure me nts will  i ncl u de P ulse ( b p m), Res pirat or y Rate ( breat hs/ mi n), Wei g ht 
( k g/l b), S yst olic bl o o d press ure ( m m H g) a n d Diast olic bl o o d press ure ( m m H g). 
 
Vital si g ns data will be s u m marize d usi n g descri pti ve statistics f or act ual val ues a n d c ha n ges 
fr o m baseli ne. O nl y s u bjects wit h  b ot h baseli ne a n d p ost- d ose val ues will  be s u m marize d at eac h 
sc he d ule visit. 
 
All  vital si g ns data will  be pr o vi de d as a b y-s u bject listi n g. 
 
7. 8. 3  P h ysic al e x a mi n ati o n  
 
P h ysical e xa mi nati o n will  be liste d f or date, visit a n d e xa mi nati o n stat us ( yes/ n o). 
 
7. 8. 4  Electr oc ar di o gr a m ( E C G) 
 
Descri pti ve statistics f or t he act ual val ues a n d c ha n ges fr o m baseli ne o ver ti me b y visit will  be 
s u m marize d f or t he bel o w E C G para meter: 
 
• Q T  i nter val ( msec); 
 
• P R  i nter val ( msec); 
 
• Q R S d urati o n ( msec); 
 
• Q Tc  i nter val ( msec); 
 
• Heart rate ( b p m). 
I n case of m ulti ple assess me nt d o ne o n t he sa me date, t he latest assess me nt s h o ul d be c o nsi dere d 
f or t he s u m marizati o n of t he para meters. 
 
E C G o verall i nter pretati o n a n d Q Tc  pr ol o n gati o n will  be s u m marize d usi n g fre q ue nc y a n d 
perce nta ge f or eac h sc he d ule d visit f or safet y p o p ulati o n. 
 
All  E C G val ues al o n g wit h  t he cate g orical i nter pretati o n will  be prese nte d i n t he listi n gs b y 
s u bject a n d visit ti me p oi nt. 
 
7. 8. 5  Cli nic al L a b or at or y Res ults  
 
La b orat or y para meters i ncl u de: 
 
• He mat ol o g y: he m o gl o bi n, he mat ocrit, platelet c o u nt, w hite bl o o d cell ( W B C) c o u nt, a n d 
W B C differe ntial. 
 
• C oa g ulati o n: pr ot hr o m bi n ti me ( P T)/ P T T/I N R ( P T T, c orrecte d, if necessar y);  


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• Ser u m c he mistr y: A S T, A L T, lactate de h y dr o ge nase ( L D H), t otal bilir u bi n, i n direct 
bilir u bi n, al kali ne p h os p hatase, t otal pr otei n, al b u mi n, s o di u m, p otassi u m, c hl ori de, 
car b o n di o xi de, calci u m, p h os p h or us, bl o o d urea nitr o ge n ( B U N), creati ni ne, uric aci d, 
a n d gl uc ose 
 
• Uri nal ysis: p H, s pecific gra vit y, pr otei n, gl uc ose, ket o nes, bl o o d, le u k oc yte esterase, a n d 
nitrite. Micr osc o p y re q uire d o nl y t o f oll o w- u p cli nicall y si g nifica nt a b n or mal fi n di n gs 
 
• Pre g na nc y: Ser u m pre g na nc y tests will  be perf or me d at scree ni n g a n d at 3 0 a n d 1 8 0 da ys 
p ost C E D i nf usi o n f or all w o me n of c hil d beari n g p ote ntial 
 
Descri pti ve statistics f or t he act ual val ues (a n d/ or c ha n ge fr o m baseli ne) f or t he selecte d 
he mat ol o g y, c he mistr y, c oa g ulati o n a n d uri nal ysis la b orat or y para meters will  be s u m marize d at 
eac h sc he d ule d visit. Para meters wit h cate g orical val ues will be s u m marize d b y c o u nt a n d 
perce nta ges.  
 
Listi n g of all la b orat or y data wit h  val ues fla g ge d t o i n dicate t he c orres p o n di n g classificati o ns 
relati ve t o t he la b orat or y n or mal ra n ges ( L o w, N or mal, Hi g h). 
 
C oa g ulati o n ( pr ot hr o m bi n ti me [ P T], partial t hr o m b o plasti n ti me [ P T T]), i nter nati o nal 
n or malize d rati o [I N R]), uri nal ysis, a n d pre g na nc y test res ults will als o be liste d. 
 
7. 8. 6  Ne ur ol o gic al e x a mi n ati o ns  
 
Ne ur ol o gical e xa mi nati o n i ncl u des Me ntal stat us, S peec h/ C o m pre he nsi o n, Me m or y, M ot or 
f u ncti o n., Cra nial ner ves, Se ns or y, Refle xes, Seiz ures, cere bellar si g ns, pai n ot her t ha n p ost o p 
pai n, ot her. 
 
A s u m mar y of t he s hifts ( baseli ne vs p ost-i nf usi o n val ues) f or selecte d q ualitati ve Ne ur ol o gical 
e xa mi nati o n para meter res ults will be pr o vi de d. T he bel o w classificati o n w o ul d be use d t o 
c o m pare t he baseli ne wit h p ost i nf usi o n fi n di n gs. 
 
• Prese nt  
 
• A bse nt  
 
• N or mal  
 
• A b n or mal N ot Cli nicall y Si g nifica nt ( A b n or mal N C S)  
 
• A b n or mal Cli nicall y Si g nifica nt ( A b n or mal C S)  
 
• N ot D o ne