A Multicenter, Open-Label, First-in-Human, Phase 1b/2a Trial of EO2401, a Novel Multipeptide Therapeutic Vaccine, With and Without Check Point Inhibitor, Following Standard Treatment in Patients With Progressive Glioblastoma
Phase: PHASE1
Conditions: Glioblastoma, Adult
Sponsor: Enterome

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Protocol 
A MulticenteR, Open-Label, First-in-Human, PhaSe Ib/IIa Trial of EO2401, a Novel 
Multipeptide Therapeutic VAccine, with and without PD-1 Check Point Inhibitor, 
FoLlowing Standard Treatment in PatIents with ProgrEssive Glioblastoma (Rosalie study) 
Protocol Status: Final 
Protocol Date: April 27, 2022 
Protocol Version: 4.0 
Investigational Product: EO2401 
Protocol Reference Number: EOGBM1-18 
EudraCT Number: 2018-002279-16 
 
 
Sponsor: 
Enterome 
94/96 avenue Ledru-Rollin 75011 
Paris, France 
 
 
Sponsor Signatory: 
 
Chief Medical Officer 
Medical Monitor: 
 
Medical Director 
 
Enterome Medical Monitor telephone 
and e-mail for medical questions regarding 
study conduct:  
 
  
 
 
 
 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 
 

 
 
 
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SPONSOR APPROVAL 
I have read the following and approve it: 
 
 
 
 
 
 
  
 
 
Date 
Chief Medical Officer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor’s information:  
Rosalie is a musical with music by George Gershwin and Sigmund Romberg, lyrics by Ira 
Gershwin and P.G. Wodehouse. 
It was first produced on Broadway in 1928 at the New Amsterdam Theatre. 
The name of this study has been established in tribute of George Gershwin who died of 
glioblastoma in 1937: he was 38 years old. 

 
 
 
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GLOBAL COORDINATING INVESTIGATOR AGREEMENT 
I have read the following protocol and agree to conduct the study as described herein. 
 
 
 
 
 
 
 
 
 
Date 
Global Coordinating Investigator 
 
 

 
 
 
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USA COORDINATING INVESTIGATOR AGREEMENT 
I have read the following protocol and agree to conduct the study as described herein. 
 
 
 
 
 
 
 
 
 
Date 
USA Coordinating Investigator 
 

 
 
 
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INVESTIGATOR AGREEMENT 
I have read the following protocol and agree to conduct the study as described herein. 
 
 
 
 
 
 
 
Name:  
 
Date 
Principal Investigator 

 
 
 
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SYNOPSIS 
 
Title of study: A MulticenteR, Open-Label, First-in-Human, PhaSe Ib/IIa Trial of EO2401, a Novel 
Multipeptide Therapeutic VAccine, with and without PD-1 Check Point Inhibitor, FoLlowing 
Standard Treatment in PatIents with ProgrEssive Glioblastoma (Rosalie study) 
Protocol Date: V4.0, 27 April, 2022 
Indication: Progressive GB 
Number of Investigators and study centers: 
Approximately 10 Investigators in Europe and/or the United States. 
Development phase: Ib/IIa 
Objectives: 
Primary objective 
The primary objective of this first-in-human (FIH) trial of EO2401 is to evaluate the safety and 
tolerability of EO2401 as monotherapy and in combination with nivolumab, and 
nivolumab/bevacizumab in patients with progressive glioblastoma (GB). The safety and tolerability 
evaluation include assessments of different patient populations within the group of patients with 
recurrent GB: i) Cohorts 1a, 2a, and 3 evaluate patients with measurable disease, ii) Cohort 2b 
evaluates patients with non-measurable disease (after surgery of recurrent disease, i.e. adjuvant 
treatment), and iii) Cohort 2c evaluates a neoadjuvant/surgery/adjuvant treatment concept.   
Secondary objectives 
The secondary objectives are: 
• 
The evaluation of survival 
• 
The evaluation of tumor progression and response by magnetic resonance imaging (MRI) 
assessment using the Immunotherapy Response Assessment in Neuro-Oncology (iRANO) 
criteria 
• 
To assess the immunogenicity of EO2316, EO2317, EO2318, and universal cancer peptide 
2 (UCP2) that compose EO2401 
 
. Cross 
reactivities with the human tumor-associated antigens (TAAs) interleukin 13 receptor 
alpha-2 (IL-13Rα2), survivin also called baculoviral inhibitor of apoptosis repeat-
containing 5 (BIRC5), and forkhead box M1 (FOXM1) will also be tested. 
Exploratory objectives 
• To assess the neurologic function assessed by the Neurologic Assessment in Neuro-
Oncology scale 
• To explore the correlation between immunogenicity of EO2316, EO2317, EO2318, and 
UCP2 that compose the EO2401 and tumor progression and response outcome parameters 
• 
 
 
 
• To assess humoral immune responses toward EO2316, EO2317, EO2318, and UCP2 that 
compose the EO2401 
 
• 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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Methodology/study design: 
Study rationale 
As GB is the most lethal brain tumor and the prognosis for patients is very poor, there is an urgent 
medical need to develop new drugs that can be incorporated into the therapeutic care for GB 
patients. Enterome is developing an innovative cancer peptide therapeutic vaccine, EO2401, based 
on the homologies between TAAs and microbiome-derived peptides that will be administered alone 
and in combination with nivolumab, and nivolumab/bevacizumab to generate preliminary safety 
and efficacy data in patients with progressive GB. EO2401 is composed of 3 synthetic microbial-
derived peptides targeting IL-13Rα2, BIRC5 (survivin), FOXM1, and a helper peptide UCP2. 
 
 
Study design 
This is a multicenter, Phase Ib/IIa, FIH study to assess the safety, tolerability, immunogenicity, and 
preliminary efficacy of EO2401 in patients with unequivocal evidence of progressive or first 
recurrent GB confirmed by MRI as defined by the Response Assessment in Neuro-Oncology 
(RANO) criteria 
 
 
 
The FIH protocol is an open-label multi-cohort study, intended to recruit a maximum of 
approximately 100 evaluable patients in total. The design builds on a 3-by-3 approach for Cohort 1 
(as study safety lead-in, before global amendment 2) and then by the global amendment 2 (leading 
to EOGBM1-18 version 3) the planned patient numbers per cohort are: 
• 
Cohort 1a (sEN* treatment of patients with measurable disease): 3 patients in the safety 
lead-in part, plus 18 added patients by the global amendment 2 plus re-distribution of 
patients from Cohort 2b, also including extended patient management measures = total of 
21 patients (recruitment finalized before global amendment 3) 
• 
Cohort 2a (EN* treatment of patients with measurable disease): 23 patients before adding 
15 further patients by the global amendment 2 plus re-distribution of patients from Cohort 
2b, also including extended patient management measures = total of 38 patients 
(recruitment finalized before global amendment 3) 
• 
Cohort 2b (EN* adjuvant treatment, no measurable disease): lowered from 15 patients to 
6 patients by re-distribution to Cohorts 1a and 2a (recruitment finalized before global 
amendment 3), by the global amendment 2 also including extended patient management 
measures 
• 
Cohort 2c (EN* neoadjuvant treatment - surgery - adjuvant treatment); cohort added by 
the global amendment 2 to evaluate safety and feasibility of the approach in 6 patients, 
also including extended patient management measures 

 
 
 
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• 
Cohort 3 (ENB* treatment of patients with measurable disease): by global amendment 3 
target recruitment increased from 10 to 26 patients, by the global amendment 2 also 
including extended patient management measures  
*sEN = "slow" EO2401/nivolumab (delayed N for 4 weeks); EN = EO2401/nivolumab 
(combination 
treatment 
from 
start); 
ENB 
= 
EO2401/nivolumab/bevacizumab 
(bevacizumab full dose according to US label, from global amendment 3 recruiting at all 
sites and in all regions, not only recruiting in the US as initially during study conduct)     
The schematic study design with actual outcome of protocol versions 1 and 2, and Cohort Plan for 
version 3 are shown in the following schemes and details are provided in Section 3.1 of the protocol. 

 
 
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Number of patients: 
It is anticipated that a maximum of approximately 100 patients evaluable for safety will be enrolled 
into the multi-cohort study. 
There will be no formal sample size calculation for this study as this is an FIH trial. 

 
 
 
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Diagnosis and main criteria for inclusion and exclusion: 
The following are the inclusion criteria: 
1. Patients with unequivocal documented (including histological confirmation of GB at the 
primary diagnosis) first progression/recurrence of GB on MRI, as defined by RANO criteria 
2. Patients with: 
• 
for Cohorts 1, 2a, and 3: at least 1 measurable lesion  
• 
for Cohort 2b: no measurable enhancing disease (defined as less than 1x1 cm in 
maximum bi-perpendicular plane)  
• 
for Cohort 2c: documented recurrence of GB deemed to be candidate for surgery 
as standard-of-care at the local institution, and for which the resection can safely 
be postponed for 4-6 weeks per local institutional guidance and treating physician 
judgement. In addition, for inclusion in Cohort 2c the patient must consent to 
mandatory collection of tissue samples from the time of diagnosis (if logistically 
available), and the planned surgery after neoadjuvant study therapy (see also 
Section 7.1.1). 
o 
 
 
 
 
 
 
 
 
3. Patients with an age ≥ 18 years old 
4. Patients who are human leukocyte antigen (HLA)-A2 positive 
5. Patients with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 or 
Karnofsky performance status ≥ 70 
6. Patients should have received standard primary therapy, including surgery (biopsy, 
incomplete or complete resection), radiation, temozolomide, if applicable 
a. Radiation therapy must have been finished at least 28 days before first study treatment 
administration 
b. Patients who received temozolomide as adjuvant therapy must have stopped the 
treatment and have a wash-out period of at least 28 days before first study treatment 
administration (6 weeks for nitrosoureas and at least 4 weeks, or 5 half-lives if longer, 
for experimental therapies, if this type of therapies have been included as components 
of adjuvant therapy) 
c. Patients 
with 
unmethylated 
methylguanine-DNA-methyltransferase 
(MGMT) 
promoter can be included even if they have not received temozolomide prior to the 
inclusion in this clinical study). 
 
 
 
 
7. Female patients of childbearing potential must have a negative serum pregnancy test within 
72 hours prior to dosing 
8. Considering the embryofetal toxicity of the nivolumab shown on animals’ models, the 
following recommendations for contraception must be followed: 
a. If not surgically sterile, female patients of childbearing potential age must use 
highly effective contraception from signing the Informed Consent Form (ICF) 

 
 
 
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through 6 months after the last treatment dose administered. Highly effective 
contraception included: 
i. Combined (estrogen and progesterone containing) hormonal contraception 
associated with inhibition of ovulation: 
▪ 
Oral 
▪ 
Intravaginal 
▪ 
Transdermal 
ii. Progestogen-only hormonal contraception associated with inhibition of ovulation: 
▪ 
Oral 
▪ 
Injectable 
▪ 
Implantable 
iii. Intrauterine device 
iv. Intrauterine hormone-releasing system 
v. Bilateral tubal occlusion 
vi. Sexual abstinence. 
In each case of delayed menstrual period (over 1 month between menstruations), confirmation 
of absence of pregnancy is strongly recommended. This recommendation also applies to women 
of childbearing potential with infrequent or irregular menstrual cycles. 
b. If not surgically sterile, male with female partner of childbearing potential must use 
condom from signing the ICF through 8 months after the last treatment dose 
administered. Males must ensure that their partners of childbearing potential use 
highly effective contraception also. 
9. Patients having received the information sheets and who have provided written informed 
consent prior to any study-related procedures 
10. Patients willing and able to comply with the scheduled visits, treatment plan, laboratory 
tests, and other study procedures indicated in the protocol. 
The following are the exclusion criteria: 
1. Patients treated with dexamethasone > 2 mg/day or equivalent (i.e., 13 mg/day of 
prednisone) within 14 days before the first EO2401 administration, unless required to treat 
an adverse event (AE) 
 
 
 
 
 
2. Patients treated with radiotherapy, and cytoreductive therapy within 28 days (6 weeks for 
nitrosoureas) before the first EO2401 administration. In addition, patients should not have 
received any prior treatment with compounds targeting PD-1, PD-L1, CTLA-4, or similar 
compounds where general resistance against therapeutic vaccination approaches might have 
developed; also, patients should not have received systemic anti-tumor treatment or 
radiotherapy for their progressive or first recurrent GB   
3. Patients with tumors primarily located in the infra-tentorial segment 
4. Patients with known radiological evidence of extracranial metastases 
5. Patients with presence of new hemorrhage (excluding, stable Grade 1) or uncontrolled 
seizure 
6. Patients with significant leptomeningeal disease 

 
 
 
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7. Patients with abnormal (≥ Grade 2 National Cancer Institute-Common Terminology 
Criteria for AEs [NCI-CTCAE] version 5.0) laboratory values for hematology, liver, and 
renal function (serum creatinine). In detail, the following values apply as exclusion criteria: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8. For patients who are planned to receive bevacizumab: 
a. Patients with nephrotic syndrome 
b. Patients with proteinuria ≥ 2g/24 hours 
c. Patients with history or active gastrointestinal perforation and fistula 
d. Significant surgical procedure in the 4 weeks preceding the start of treatment or planned 
surgery 
e. Unhealed wound 
f. Patient with recent (4 weeks) history of hemoptysis of ½ teaspoon or more of red blood 
g. Thrombotic episode within 6 months 
h. Uncontrolled diabetes mellitus or hypertension 
i. 
Posterior reversible encephalopathy syndrome 
9. Patients with persistent Grade 3 or 4 toxicities (according to NCI-CTCAE v5.0). Toxicities 
must be resolved since at least 2 weeks to Grade 1 or less. However, alopecia or other 
persisting toxicities Grade ≤ 2 not constituting a safety risk based on Investigator’s 
judgment is acceptable 
10. Patients with contraindication to contrast-enhanced MRI 
11. Other malignancy or prior malignancy with a disease-free interval of less than 3 years 
except those treated with surgical intervention and an expected low likelihood of recurrence 
such as basal cell or squamous cell skin cancer, or carcinoma in situ. Patients with 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ are eligible 
12. Patients with clinically significant active infection, cardiac disease, significant medical or 
psychiatric disease/condition that, in the opinion of the Investigator, would interfere with 
the evaluation of EO2401 or interpretation of patient safety or study results or that would 
prohibit the understanding or rendering of informed consent (i.e. only consent able patients 
can be enrolled in the study) and compliance with the requirements of the protocol – 
including (but not limited to): 
a. Bacterial sepsis or other similarly severe infections  
b. New York Heart Association > Grade 2 congestive heart failure within 6 months prior 
to study entry 
c. Uncontrolled or significant cardiovascular disease, including: 
i. Myocardial infarction within 6 months prior to obtaining informed consent 

 
 
 
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intolerable toxicity, death, or early termination of the study at the request of the Sponsor, where 
study treatment will be stopped and appropriate standard of care will be initiated by the Investigator. 
EO2401 will be injected 
 from the start of the reconstitution. 
EO2401 will be administered first followed by nivolumab, 
 
Nivolumab will be co-administered starting with the third priming injection in Cohort 1 and from 
the beginning of the priming phase in Cohorts 2a, 2b and 3. Nivolumab will be administered as an 
intravenous (IV) infusion at a dose of 3 mg/kg every 2 weeks. 
In addition to the nivolumab, bevacizumab will be co-administered in patients included in Cohort 
3, from the beginning of the priming phase, as an IV infusion at a dose of 10 mg/kg every 2 weeks 
in combination with EO2401 and nivolumab. Bevacizumab will be administered 
 after 
the start of nivolumab administration per local practice at the study site. 
Duration of patient participation in study: 
Each patient will participate in the study for a maximum of 24 months from the time of informed 
consent through final study contact. The recruitment period will be approximately 20 months. 
Study populations: 
The following analysis populations will be included for this study: 
The All Patient Population will consist of any patient who signed informed consent including 
Screen failures. 
Full Analysis Set (FAS) will consist of any patients who received at least 1 dose of study drug 
(EO2401 alone or EO2401 in combination with nivolumab, or nivolumab/bevacizumab) for 
whom no important protocol deviations occurred. Patients who are not considered evaluable for 
this population will not be replaced. 
Safety Population will consist of any patients who received at least 1 dose of study drug (EO2401 
alone or EO2401 in combination with nivolumab, or nivolumab/bevacizumab). Patients who are 
not considered evaluable for this population will be replaced. 
Per-Protocol (PP) Population will consist of any patients who received 
 study 
drug (EO2401 alone or EO2401 in combination with nivolumab or nivolumab/bevacizumab) for 
whom no important protocol deviations occurred and have at least 1 evaluable post-Screening 
tumor assessment. Patients who are not considered evaluable for this population will not be 
replaced. 
Efficacy will be analyzed 
. Safety will be analyzed using the 
Safety Population. 
Outcome measures: 
Primary endpoint: 
The primary endpoint includes the incidences of AEs, treatment-emergent AEs (TEAEs), serious 
AEs (SAEs), deaths, and laboratory abnormalities using the NCI-CTCAE v5.0. 
Safety endpoints will be assessed by review of summaries of AEs (or TEAEs)/SAEs, unless 
otherwise stated. Adverse events will be categorized by system organ class and preferred term using 
the current Medical Dictionary for Regulatory Activities version and will be graded according to 
NCI-CTCAE v5.0. 
Secondary endpoints: 
The secondary endpoints are: 
• 
Overall survival (OS), defined as the time interval from the date of first study treatment 
administration to the date of death due to any cause 
• 
The tumor progression and response by MRI measurements every 8 weeks using the 
iRANO criteria evaluated by: 
o Progression-free Survival (PFS), using the iRANO criteria and defined as the 
time interval from the date of first study treatment administration to the date of 
first occurrence of progression or death from any cause, whichever occurs first 

 
 
 
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o Objective Response Rate (ORR), defined as the proportion of patients with 
complete response (CR) and partial response (PR) according to the iRANO 
criteria 
o Disease Control Rate (DCR), defined as the proportion of patients with CR, 
PR, and Stable Disease (SD) according to the iRANO criteria  
o Duration of Response (DoR), defined as the time interval from the date of first 
occurrence of CR or PR to the date of first documentation of disease 
progression or death from any cause, whichever occurs first. 
• 
The immunogenicity of EO2316, EO2317, EO2318, and UCP2 that compose EO2401, 
 
 
 
 
 
Exploratory endpoints: 
The exploratory endpoints will be: 
• 
Neurologic function assessed by the NANO scale 
• 
Correlation between immunogenicity of EO2316, EO2317, EO2318, and UCP2 that 
compose EO2401 and the outcome parameters PFS, ORR, DCR, DoR, and OS 
• 
 
 
• 
Humoral immune responses toward EO2316, EO2317, EO2318, and UCP2 that 
compose EO2401 
 
• 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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Statistical methods: 
All data collected in this study will be documented with the help of patient data listings and summary 
tables and figures for all demographic and baseline characteristics, medical history, efficacy, and 
safety variables. 
An interim analysis will be performed 
 
to assess safety, immune 
response, and efficacy parameters. 
 
 
 
Patients included in Cohort 2b will, depending on recruitment status and follow-up (targeted follow-
up is 6 months), be analyzed in association with the first, and/or the second interim analyses.  
 

 
 
 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................................1 
SPONSOR APPROVAL .................................................................................................................................2 
GLOBAL COORDINATING INVESTIGATOR AGREEMENT ..................................................................3 
USA COORDINATING INVESTIGATOR AGREEMENT ..........................................................................4 
INVESTIGATOR AGREEMENT ..................................................................................................................5 
SYNOPSIS ......................................................................................................................................................6 
TABLE OF CONTENTS .............................................................................................................................. 26 
LIST OF TABLES AND FIGURES ............................................................................................................. 30 
LIST OF ABBREVIATIONS ........................................................................................................................ 31 
1. 
INTRODUCTION ........................................................................................................................ 33 
1.1. 
Background on Disease ............................................................................................................. 33 
1.2. 
Study Rationale ......................................................................................................................... 37 
1.2.1. 
Investigational Medicinal Product ............................................................................................. 37 
1.2.1.1. 
EO2401 ...................................................................................................................................... 37 
 
 
1.2.1.3. 
Check Point Inhibitor in the Treatment of Malignant Gliomas ................................................. 42 
1.2.2. 
Nonclinical Studies .................................................................................................................... 47 
1.2.2.1. 
Immunogenicity of EO2316, EO2317, and EO2318 ................................................................. 47 
1.2.2.2. 
Toxicology Studies .................................................................................................................... 49 
1.2.3. 
Clinical Studies & Rationale and High Level Outline for Global Amendment #2 (leading to 
protocol EOGBM1-18 version 3) .............................................................................................. 50 
1.2.4. 
Cohort 3 clinical outcomes & Rationale and High-Level Outline for Global Amendment #3 
(leading to protocol EOGBM1-18 version 4) ............................................................................ 56 
1.3. 
Benefit-risk Assessment ............................................................................................................ 61 
2. 
OBJECTIVES AND ENDPOINTS .............................................................................................. 65 
2.1. 
Objectives .................................................................................................................................. 65 
2.1.1. 
Primary Objective ...................................................................................................................... 65 
2.1.2. 
Secondary Objectives ................................................................................................................ 65 
2.1.3. 
Exploratory Objectives .............................................................................................................. 65 
2.2. 
Endpoints ................................................................................................................................... 66 
2.2.1. 
Primary Endpoint ....................................................................................................................... 66 
2.2.2. 
Secondary Endpoints ................................................................................................................. 66 
2.2.3. 
Exploratory Endpoints ............................................................................................................... 67 
3. 
INVESTIGATION PLAN ............................................................................................................ 68 
3.1. 
Overall Study Design and Plan Description .............................................................................. 68 
3.2. 
Discussion of Study Design ....................................................................................................... 84 
3.3. 
End of Study Definition ............................................................................................................. 87 
3.4. 
Medical Care of Patients After End of Study ............................................................................ 87 
3.5. 
Selection of Doses and Regimen in the Study ........................................................................... 87 
3.5.1. 
EO2401 ...................................................................................................................................... 87 
3.5.2. 
Nivolumab ................................................................................................................................. 89 
3.5.3. 
Bevacizumab for continuous combination treatment in Cohort 3 – in US Only ....................... 90 
4. 
SELECTION OF STUDY POPULATION .................................................................................. 91 
4.1. 
Inclusion Criteria ....................................................................................................................... 91 
4.2. 
Exclusion Criteria ...................................................................................................................... 93 
4.3. 
Discontinuation Criteria ............................................................................................................ 95 
4.3.1. 
Screen Failures .......................................................................................................................... 95 
4.3.2. 
Discontinuation of Study Treatment and Patient Discontinuation ............................................. 96 
4.3.3. 
Discontinuation of Study Treatment .......................................................................................... 97 
4.3.4. 
Lost to Follow-up ...................................................................................................................... 97 
4.3.5. 
Follow-up of Patients Prematurely Discontinued from the Study Treatment Regimen or 
Withdrawn from Study .............................................................................................................. 97 
4.4. 
Study Termination ..................................................................................................................... 98 
5. 
STUDY TREATMENTS ............................................................................................................. 99 

 
 
 
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5.1. 
Treatments Administered........................................................................................................... 99 
5.2. 
Investigational Medicinal Product (EO2401) .......................................................................... 101 
5.2.1. 
Pharmaceutical Form ............................................................................................................... 101 
5.2.2. 
Preparation of the 
 ................................................................................................ 101 
5.2.3. 
Administration ......................................................................................................................... 102 
5.2.4. 
Packaging and Labeling ........................................................................................................... 102 
5.2.5. 
Storage and Stability ................................................................................................................ 103 
 
 
 
 
 
 
 
 
 
 
 
 
5.4. 
Nivolumab ............................................................................................................................... 105 
5.4.1. 
Pharmaceutical Form ............................................................................................................... 105 
5.4.2. 
Administration of Infusion ...................................................................................................... 105 
5.4.3. 
Package and Labeling .............................................................................................................. 105 
5.4.4. 
Storage and Stability ................................................................................................................ 106 
5.5. 
Bevacizumab ........................................................................................................................... 106 
5.6. 
Study Treatment Accountability, Reconciliation, and Return ................................................. 107 
5.7. 
Study Treatment Handling and Disposal ................................................................................. 107 
5.8. 
Method of Treatment Assignment ........................................................................................... 108 
5.8.1. 
Dose Modifications, Permanent Discontinuation of Treatment, or Treatment Delay .............. 109 
5.8.1.1. 
Dose Reductions ...................................................................................................................... 109 
5.8.1.2. 
Treatment Delay ...................................................................................................................... 109 
5.8.1.3. 
Treatment Discontinuation ...................................................................................................... 109 
5.9. 
Blinding ................................................................................................................................... 109 
5.10. 
Treatment Compliance ............................................................................................................ 109 
6. 
PRIOR AND CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ..................... 110 
6.1. 
Prior and Concomitant Therapy ............................................................................................... 110 
6.2. 
Prior and Concurrent Illness .................................................................................................... 110 
6.3. 
Permitted Concomitant Medications ....................................................................................... 110 
6.4. 
Contraception .......................................................................................................................... 113 
6.5. 
Prohibited Concomitant Medications ...................................................................................... 113 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...................................................................... 115 
7.1. 
Screening Period #1 ................................................................................................................. 115 
7.2. 
Screening period #2 ................................................................................................................. 115 
7.3. 
Treatment Priming Phase ......................................................................................................... 117 
7.3.1. 
Week 0 (Visit 1) ...................................................................................................................... 117 
7.3.2. 
 
 
 
7.4. 
Treatment-Boosting Period ...................................................................................................... 119 
7.4.1. 
 
 
 
 
 
 
 
7.4.5. 
Follow-up Visits (After Progression or Permanent Treatment Discontinuation)..................... 123 
7.5. 
Efficacy Assessments .............................................................................................................. 123 
7.5.1. 
Tumor and Response Evaluation ............................................................................................. 124 
7.5.1.1. 
Acquisition Imaging ................................................................................................................ 124 
7.5.1.2. 
Tumor Evaluation Using iRANO Criteria ............................................................................... 125 
7.5.2. 
Overall Survival ....................................................................................................................... 126 
7.5.3. 
Progression-free Survival ........................................................................................................ 126 
7.5.4. 
Objective Response Rate & Disease Control Rate .................................................................. 126 
7.5.5. 
Duration of Response .............................................................................................................. 126 
7.5.6. 
Neurological Assessment of Neuro-Oncology Scale ............................................................... 126 

 
 
 
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7.6. 
Safety and Tolerability Assessments ....................................................................................... 127 
7.6.1. 
Safety Plan ............................................................................................................................... 127 
7.6.1.1. 
 
 
 
 
 
 
 
 
and 
management of Dose Modifications for Adverse Reactions to Nivolumab ............................. 127 
7.6.1.2. 
Management of Infusion Reactions to Nivolumab .................................................................. 132 
7.6.1.3. 
Management of Dose Modifications for Adverse Reactions to Bevacizumab ........................ 132 
7.6.2. 
Safety Parameters and Definitions ........................................................................................... 133 
7.6.2.1. 
Adverse Events ........................................................................................................................ 133 
7.6.2.2. 
Serious Adverse Event ............................................................................................................. 135 
7.6.2.3. 
Suspected Unexpected Serious Adverse Reactions ................................................................. 136 
7.6.2.4. 
Adverse Drug Reactions .......................................................................................................... 136 
7.6.3. 
Methods and Timings for Capturing and Assessing Safety Parameters .................................. 137 
7.6.3.1. 
Follow-up of Adverse Events/Serious Adverse Events ........................................................... 137 
7.6.3.2. 
Assessment of Severity of Adverse Events ............................................................................. 137 
7.6.3.3. 
Assessment of Causality of Adverse Events ............................................................................ 137 
7.6.3.4. 
Action Taken for Adverse Events ............................................................................................ 137 
7.6.3.5. 
Adverse Event Outcome .......................................................................................................... 138 
7.6.3.6. 
Reporting Adverse Events ....................................................................................................... 138 
7.6.3.7. 
Reporting Serious Adverse Events .......................................................................................... 139 
7.6.3.8. 
Procedures for Recording Adverse Events .............................................................................. 140 
7.6.4. 
Investigator’s Notification of Adverse Events to the Sponsor ................................................. 143 
7.6.5. 
Expedited Reporting of Adverse Events to Regulatory Agencies/Authorities ........................ 144 
7.6.5.1. 
Notification to the Ethics Committee/Institutional Review Board .......................................... 144 
7.6.5.2. 
Notification to the Authorities ................................................................................................. 144 
7.6.5.3. 
Sponsor’s Notification to the Investigational Site ................................................................... 144 
7.6.6. 
Post-study Adverse Events ...................................................................................................... 144 
7.6.7. 
Independent Data Monitoring Committee ............................................................................... 144 
7.6.8. 
Pregnancy ................................................................................................................................ 145 
7.7. 
Clinical Laboratory Evaluations .............................................................................................. 145 
7.7.1. 
Tissue Sample Assessment ...................................................................................................... 146 
7.7.2. 
Immune Response Evaluation ................................................................................................. 147 
7.7.3. 
Stool Samples .......................................................................................................................... 148 
7.8. 
Vital Signs, Physical Examination, and Other Safety Evaluations .......................................... 149 
7.8.1. 
Vital Signs and ECOG or Karnofsky Performance Status ....................................................... 149 
7.8.2. 
12-Lead Electrocardiogram ..................................................................................................... 149 
7.8.3. 
Physical Examination .............................................................................................................. 149 
8. 
SAMPLE SIZE AND DATA ANALYSES ............................................................................... 150 
8.1. 
Determination of Sample Size ................................................................................................. 150 
8.2. 
Analysis Populations ............................................................................................................... 151 
8.3. 
General Considerations ............................................................................................................ 151 
8.3.1. 
Repeat and Unscheduled Readings .......................................................................................... 152 
8.3.2. 
Demographic and Other Baseline Characteristics ................................................................... 152 
8.3.2.1. 
Patient Disposition ................................................................................................................... 152 
8.3.2.2. 
Patient and Disease Characteristics ......................................................................................... 152 
8.3.3. 
Medical and Surgical History .................................................................................................. 153 
8.3.4. 
Prior and Concomitant Medications ........................................................................................ 153 
8.3.5. 
Tissue Sample Assessment ...................................................................................................... 153 
8.4. 
Efficacy Analysis ..................................................................................................................... 153 
8.4.1. 
Overall Survival ....................................................................................................................... 153 
8.4.2. 
Progression-free Survival ........................................................................................................ 153 
8.4.3. 
Objective Response Rate & Disease Control Rate .................................................................. 153 
8.4.4. 
Duration of Response .............................................................................................................. 154 
8.4.5. 
Neurological Assessment of Neuro-Oncology Scale ............................................................... 154 
8.5. 
Safety Analysis ........................................................................................................................ 154 
8.6. 
Immunogenicity ....................................................................................................................... 155 
8.7. 
 

 
 
 
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8.8. 
Interim Analysis ...................................................................................................................... 155 
9. 
REFERENCES ........................................................................................................................... 156 
10. 
APPENDICES ............................................................................................................................ 162 
APPENDIX 1 – IRANO CRITERIA........................................................................................................... 163 
APPENDIX 2 – NANO SCALE ................................................................................................................. 166 
APPENDIX 3 – ECOG AND KARNOFSKY PERFORMANCE STATUS .............................................. 168 
APPENDIX 4 – NEW YORK HEART ASSOCIATION FUNCTIONAL CLASSIFICATION ................ 169 
 
APPENDIX 6 – REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ......... 171 
 
 
 

 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ACTH 
AE(s) 
Adreno CorticoTrophic Hormone 
Adverse event(s) 
AIDS 
Acquired Immunodeficiency Syndrome 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
BIRC5 
Baculoviral inhibitor of apoptosis repeat-containing 5 
BP 
Blood pressure 
bpm 
Beats per minute 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CNS 
Central nervous system 
ConA 
Concanavalin A 
CPI 
Check Point Inhibitor 
CR 
Complete response 
CRO 
Contract Research Organization 
CSA 
Clinical study agreement 
DCR 
DILI 
Disease Control Rate 
Drug-induced liver injury 
 
 
DoR 
Duration of response 
DSS 
Drug Safety Services 
 
 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
 
 
 
 
EoT 
End of treatment 
FAS 
Full Analysis Set 
FIH 
First-in-Human 
FOXM1 
Forkhead box M1 
FSH 
Follicle-stimulating hormone 
GB 
Glioblastoma  
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
HR 
Heart rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceutical for Human 
Use 
IDH 
Isocitrate dehydrogenase 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IFA 
Incomplete Freund’s Adjuvant 

 
 
 
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Abbreviation 
Definition 
IFN-γ 
Interferon-gamma 
 
 
IL-13Rα2 
Interleukin 13 receptor alpha-2 
iRANO 
Immunotherapy Response Assessment in Neuro-Oncology 
IRB 
Institutional Review Board 
IMP 
Investigational medicinal product 
IV 
Intravenous(ly) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGMT 
Methylguanine-DNA-methyltransferase 
MHC 
Major histocompatibility complex 
MRI 
Magnetic resonance imaging 
NANO 
Neurologic Assessment in Neuro-Oncology 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for 
Adverse Events 
NTF 
ORR 
Note-to-File 
Objective response rate 
OS 
Overall survival 
P13K 
Phosphatidyl inositol 3-kinase 
 
 
PD 
Progressive disease 
PD-1 
Programmed death-1 
PD(L)-1 
Programmed death (ligand)-1 
PFS 
Progression-free survival 
PI 
PMEL 
Product Information 
Pre-melanosome protein 
PP 
Per-Protocol 
PR 
Partial response 
PsPD 
Pseudoprogression 
PT 
PTHrP 
Preferred term 
Parathyroid hormone-related protein 
RANO 
Response Assessment in Neuro-Oncology 
SAE(s) 
Serious adverse event(s) 
SC 
Subcutaneous(ly) 
SD 
Stable disease 
SmPC 
Summary of Product Characteristics 
SOC 
System organ class 
SUSAR(s) 
Suspected unexpected serious adverse reaction(s) 
TAA(s) 
Tumor-associated antigen(s) 
TEAE(s) 
Treatment-emergent adverse event(s) 
TERT 
Telomerase reverse transcriptase 
TCR 
T cell receptor 
TSH 
Thyroid-stimulating hormone 
UCP2 
Universal cancer peptide 2 
ULN 
Upper limit of normal 
VEGF 
Vascular endothelial growth factor 
VEGFR 
Vascular endothelial growth factor receptor 
WBC(s) 
White blood cell(s) 
WHO 
World Health Organization  

 
 
 
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1. INTRODUCTION 
Glioblastoma (GB) is the most frequent and aggressive brain tumor in adults with a poor 
prognosis despite established standard treatment. Annual incidence ranges from 3 to 5 newly 
diagnosed cases per 100 000 populations. The median age at diagnosis is 64 years1 and the 
incidence is slightly higher in men than women. 
The management of patients with GB remains a challenge despite aggressive multimodal 
treatment. Current standard of care for newly diagnosed GB consists of resection followed by 
concurrent radiotherapy with concomitant temozolomide and adjuvant temozolomide. 2 , 3 
However, despite initial treatment, about 70% of GB patients will experience disease 
progression within 1 year of diagnosis with less than 5% of patients surviving 5 years after 
diagnosis.4 
The management of patients with progressive and recurrent disease outside of a clinical study 
will be individualized based on different factors, such as patient age, performance status, 
extension of the initial resection, and response to initial treatment. Repeat surgery, 
reirradiation, and second line mono or combination therapy are options in this patient 
population, but minor improvement in progression-free survival (PFS) and overall survival 
(OS) have been observed with any particular regimen.2,3 Therefore, there is an urgent medical 
need to develop new drugs that can be incorporated into the therapeutic care for GB patients, 
given the opportunity to the patients to participate in experimental clinical studies. 
The recent benefit observed with immunotherapy in the treatment of other tumor types, 
together with recent advances in the understanding of neuroimmunology, has offered new 
potential therapeutic options and interest for the development of immunotherapy for malignant 
brain cancer. Clinical studies using dendritic cell vaccines, peptide-based vaccines, and 
immune Check Point Inhibitors (CPIs) are underway. However, it is likely that combination 
regimens with complimentary mechanism of action will be required to achieve a broad and 
durable tumor response.5 
1.1. 
Background on Disease 
Glioma is a cancer originating from glial cells that occurs in the brain and spinal cord. The 
majority of primary gliomas (61%) are found in the 4 lobes of the brain.4 Glial cells, the most 
common cell type found within the central nervous system (CNS), are the supportive cells of 
neurons. Gliomas are very aggressive, accounting for 70% of malignant brain tumor.6 Although 
common among CNS cancers, gliomas are relatively rare with only 97 911 incident cases 
reported from 2008 to 2012 in the United States. 7  Gliomas are more common among 
Caucasians, and malignant gliomas are more commonly found in men compared to women.8 
Gliomas are graded based on 2 histological criteria – the resemblance of tumor cells to normal 
glial cells and the degree of the tumor malignancy. The grading system is developed by the 
American Brain Tumor Association.9 
Diffuse astrocytomas (Grade II gliomas) are so named for their diffusive nature, spreading into 
nearby neural tissue. Although these tumors are diffuse, the cells typically have low to no 
mitotic activity so are considered “mid-grade” tumors. According to the most recent update of 
the World Health Organization (WHO) classification, they are characterized by an isocitrate 
dehydrogenase (IDH) mutation. These tumors are also typically treated using surgical 
resection, if possible, followed by radiochemotherapy.10 

 
 
 
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Anaplastic astrocytomas (Grade III gliomas) as well as anaplastic oligodendrogliomas and 
oligoastrocytomas are more malignant, and also actively spreading to other portions of the 
brain. These tumors are also characterized by IDH mutations, but there are also IDH wild-type 
subgroups. The differentiation between astrocytoma and oligodendroglioma is made based on 
1p/19q deletion status. The median survival time for anaplastic astrocytomas is 2 to 5 years. 
These Grade III tumors comprise 20% to 25% of malignant gliomas. Approximately 10% of 
astrocytomas will progress to Grade IV.11 Grade IV gliomas, also known as GBs, are the most 
common and most lethal of gliomas, with approximately 50% of gliomas being classified as 
GBs12 and resulting in an average life expectancy of 12 to 15 months post-diagnosis.6 Although 
there is marked variation in prognosis, symptoms, and response to treatment between the 
different types of gliomas, the morbidity and mortality are high, with even mild malignant 
types having 5-year survival rates below 50%.8 Standard of care is radiation plus procarbazine, 
lomustine, and vincristine for oligodendroglioma with 1p/19q codeletion and radiotherapy plus 
maintenance temozolomide for anaplastic astrocytoma (without 1p/19q codeletion).13 
The etiology of glioma has not been well established, but studies have demonstrated a 
correlation between glioma and several intrinsic and extrinsic factors. The only environmental 
agent that has been shown to strongly correlate with glioma is therapeutic ionizing radiation. 
Gliomas have been shown to develop within families, indicating a genetic component that 
partially contributes to susceptibility to disease. Grade IV gliomas (GB) have shown evidence 
of a genetic component through different genetic diseases that can give rise to GBs, including 
Turcot syndrome, tuberous sclerosis, neurofibromatosis type I, and multiple endocrine 
neoplasia type IIA. Certain acquired mutations have been associated with specific histological 
changes observed in glioma, where some have also been shown to be associated with low- or 
high-grade tumors.8 
A schematic depicting various modifying steps and influences on development and progression 
of glioma is shown in Figure 1. 

 
 
 
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Figure 1: 
Sequential Events That Cause Glioma Diversity 
 
Westphal and Lamszuz, 201114 
 
Glioblastoma, being the most common and the most lethal of the gliomas, is the most studied 
grade of glioma. Although morphologically and clinically indistinguishable, GB can manifest 
as either primary or secondary tumors. Approximately 90% to 95% of GB cases are considered 
primary, developing rapidly de novo in predominantly older patients without symptoms or 
evidence of low-grade pathology. Secondary GBs are rare and progress from low-grade diffuse 
gliomas like astrocytoma or anaplastic astrocytoma. Secondary GBs typically occur in younger 
patients and exhibit a much better prognosis, as compared to primary GBs.12,14 Important 
genetic factors leading to the development of GB include inactivation of the p53 and 
retinoblastoma tumor suppressor pathways, dysregulation of growth factor signaling via 
amplification and mutational activation of phosphatidyl inositol 3-kinase (PI3K) genes, and 
activation of the PI3K pathway.15 Histologically, GB is characterized by increased cellularity, 
necrosis, nuclear atypia, mitotic activity, vascular thrombosis, cellular pleomorphism, and 
glomeruloid microvascular proliferation, and clinically by its marked proliferative and invasive 
nature. 6,16,17 The prognosis for patients with GB is very poor. Median survival with a newly 
diagnosed GB is 12 to 15 months with current therapeutic interventions looking at study 
cohorts and even shorter if a real world population is considered. Twenty-five percent to 30% 
of patients survive up to 2 years and less than 5% of patients make it to a 5-year post-diagnosis 
survival.18,19 There are no curative treatments currently available. The typical management of 
these tumors involves surgical resection as much as safely possible, radiotherapy, and 
concomitant and/or adjuvant chemotherapy with temozolomide.20,21 However, disease recurs 
in almost all patients with the poor prognosis of 5 to 7 months of median survival. Current 
therapeutic modalities are insufficient to control high-grade glioma progression overall due to 
its aggressive nature. Although a variety of approaches, such as antiangiogenics22 inhibitors of 

 
 
 
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the epidermal growth factor receptor, nitrosoureas, and retreatment with temozolomide, have 
been studied in the second line, there is not an established accepted standard therapy yet. 
Commonly, a second resection whenever feasible and also reirradiation are employed despite 
limited evidence (for resurgery)13 and disappointing efficacy (second radiotherapy)23. Thus, it 
is an important medical need to continue the research in that setting and therefore, Enterome 
has selected to investigate EO2401 in the progressive GB population for the First-in-Human 
(FIH) study. 
The symptoms of glioma vary between patients, depending on which subtype a patient has, as 
well as the physical size and location of tumor within the brain. Common symptoms across 
subtypes include headaches, nausea and vomiting, muscle weakness, seizures, confusion, 
dizziness, memory loss, and changes in personality.6,24 Some of these more general symptoms 
can cause misdiagnosis due to their overlap with other infections, inflammatory diseases, and 
immunological diseases.25 Focal symptoms map to more specific regions of the brain that are 
impacted by tumor growth, including loss of vision or other senses, motor weakness localized 
to one entire side of the body (hemiparesis), loss of the ability to understand or express speech 
(aphasia), and others.20 
Diagnosis of glioma is done using various imaging techniques to visualize the brain tumor, 
including computed tomography scan, magnetic resonance imaging (MRI), positron emission 
tomography scan, and magnetic resonance spectroscopy.21 Magnetic resonance imaging is the 
preferred and guideline appropriate imaging technique for diagnosing gliomas. Once the tumor 
has been visualized, the diagnosis is made by histopathological examination of the tumor 
through tumor resection (removing the entirety or majority of the visible tumor) or, when 
resection is not possible, through fine needle aspiration biopsy. It has to be acknowledged that 
the diffuse infiltrative, network-like growth pattern precludes a complete surgical resection and 
principal render WHO Grades II-IV gliomas a whole brain disease. 
Novel approaches to treating high-grade gliomas are currently being investigated in clinical 
studies; however, only modest advancements in the treatment of GB have occurred in the past 
25 years.18,20,21 
In the last few decades, immunotherapy has become an important part of treating some types 
of cancer and is also being investigated to treat gliomas. Trials on checkpoint inhibition have 
been largely disappointing so far;26 but better focus on risk groups or molecular factors may 
change these outcomes. Immunotherapies work by activating the immune system, causing it to 
specifically attack the tumor cells.4 Tumor antigen-based vaccination represents such an 
approach that designed to enlist the patient’s own immune system to recognize attack and 
destroy tumors, in a specific and durable manner. 
Efficiency of this approach relies on the ability of the immune system to develop specific 
lymphocyte subsets able to recognize major histocompatibility complex (MHC) class I-
restricted antigens that are expressed by human cancer cells. 
Various tumor antigens have been studied for their potential to trigger immune-mediated 
responses against tumors. As a known example, interleukin 13 receptor alpha-2 (IL-13Rα2), 
survivin also called baculoviral inhibitor of apoptosis repeat-containing 5 (or BIRC5), or 
forkhead box M1 (FOXM1) are proposed targets for novel therapies in gliomas. These proteins, 
strongly upregulated in human glioma samples, are associated with disease progression and 
diminished survival in glioma patients.27,28,29. More recently, personalized approaches using 
peptides according to tumor-specific expression or mutation has gained a lot of attention and 

 
 
 
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examples like NEOVAC and GAPVAC convincingly demonstrated feasibility of tumor 
antigen-specific CD4 and CD8 responses in the tumor tissue. 
1.2. 
Study Rationale 
Currently, therapeutic modalities are insufficient to control high-grade glioma progression 
overall due to its aggressive nature. Surgical resection, as stated previously, is not always 
possible, and regrowth of tumors as well as acute morbidity is likely. As already indicated, 
radiotherapy has high toxicity, and retreating recurrences carries a higher risk due to loss in 
neurogeneration potential. Although chemotherapy has been shown to improve prognosis and 
time of progression, there are important drawbacks to this treatment modality. The major issues 
include bypassing the blood-brain barrier, interactions with antiseizure medications, resistance 
to therapy, recurrent tumors, and intrinsic factors.30 
Enterome is developing an innovative, microbiome-based approach for the development of 
therapeutic cancer vaccines. EO2401 is a multicomponent therapeutic synthetic peptide 
vaccine that will be administered as a monotherapy and in combination with nivolumab or 
nivolumab/bevacizumab to assess the safety and tolerability, and generate preliminary efficacy 
data in patients with progressive GB. 
1.2.1. 
Investigational Medicinal Product 
1.2.1.1. 
EO2401 
Peptide-based therapeutic vaccination is an immunotherapeutic approach for the treatment of 
cancer that aims to deliver immunogenic peptides corresponding to specific tumor-associated 
antigens (TAAs) to patients. The goal is to target the patient’s antigen presenting cells to induce 
efficient presentation of cancer epitopes to T lymphocytes that in turn leads to a sustained 
immune response against cancer cells expressing the same antigens at the tumor site. In the 
past, despite promising preclinical results in animal models, the cancer vaccination approach 
has not demonstrated unequivocal efficacy in patients. The lack of efficacy may be related to 
a number of factors including the status of the patient’s immune system, the efficacy and 
specificity of antigen delivery, the lack of ability of T lymphocytes to infiltrate the tumor 
microenvironment, and the tumor’s ability to escape immune-mediated inhibition. The ability 
of tumor antigens to generate a strong immune response depends on a number of factors, 
including the affinity for the MHC I or MHC II complexes, the capacity of the antigen to be 
recognized by the immune system as self or non-self, and pre-existence of T cell clones that 
are able to be efficiently reactivated by a vaccine boost and that leads to a durable immune 
response. 
Enterome is developing an innovative, microbiome-based approach for the development of 
therapeutic peptide cancer vaccines. A number of peptides mimicking specific TAAs that are 
overexpressed in GB have been identified in the human microbiome. These peptides have been 
shown to induce a strong immune response in nonclinical models. Although overexpressed 
TAAs are presented via the MHC class I receptors, these peptides are weak inducers of the 
immune system as they are self-epitopes for which (auto) reacting T cells (especially the most 
reacting ones) are naturally depleted through thymic deletion. However, the gut immune 
system, where some 70% of all T cells reside, is tolerant to the equivalent microbiome-derived 
epitopes. This “tolerance” can be overcome by repeated antigen challenges together with an 
adjuvant. 

 
 
 
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1.2.1.2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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1.2.1.3. 
Check Point Inhibitor in the Treatment of Malignant Gliomas 
Check Point Inhibitors, approved for the treatment of different types of cancer, release the 
breaks on the immune system; however, only a small subset of patients treated with CPIs will 
achieve a clinical complete response (CR). Nevertheless, deep, durable, and rapid response on 
some tumor types makes these therapies promising to treat cancer. 
The CPIs allow patient’s existing T cell population to attack the tumor and, in order for this 
therapy to be effective, the patients must have corresponding T cells able to recognize the 
specific tumor antigens. It is likely that patients who do not partially respond to this therapy do 
not have sufficient numbers of T cells to overcome tumor growth. Therapeutic vaccination 
stimulates the immune system leading to the activation of the required T cell population for a 
more effective efficacy of the treatment allowing the T cell population to infiltrate the tumor 
thanks to the CPI. 
The CPIs have been shown to be a very attractive treatment in other cancers and may optimally 
be used in combination with other therapeutic strategies, including radiation, and/or 
immunotherapies or other immunotherapies in the treatment of GB.56 
1.2.1.3.1. 
Nivolumab 
Programmed death-1 (PD-1) has been identified as an immune checkpoint pathway that tumor 
cells may exploit to evade immune surveillance. Tumor cells may block immune responses via 
the PD-1 immune checkpoint pathway by expressing the dual PD-1 ligands PD(L)-1 and 
PD(L)-2. 
PD(L)-1 and PD(L)-2 engage the PD-1 receptor on T cells in order to inactivate T cells, which 
may allow tumor cells to evade immune response. 
Check Point Inhibitors have demonstrated safety and clinical activity in different solid and 
hematological tumor types including in clinical trials in recurrent GB patients. 
Nivolumab is an anti-PD-1, which is a fully human monoclonal antibody (immunoglobulin G4) 
promoting antitumor immunity allowing the immune system to attack the tumor, blocking the 
interaction between PD-1 and its ligands (PD[L]-1 and PD[L]-2), and stop a negative regulator 
of T cell activation and response, thus allowing the immune system to attack the tumor. 
In a retrospective study of nivolumab for patients with recurrent high-grade glioma, the 
treatment showed a manageable safety profile and it was observed, in only a subset of patients, 
disease stabilization in heavily pretreated recurrent high-grade glioma.57 
A recently completed Phase III CheckMate-143 study was the first randomized clinical trial in 
recurrent GB with the PD-1 CPI nivolumab as monotherapy. Although it did not meet its 
primary endpoint of improved OS over bevacizumab monotherapy, nivolumab may still have 
a place in the successful treatment of this disease, potentially as combination therapy, as a small 
subset (8%) of patients in the CheckMate-143 study did respond to nivolumab, and with a much 
longer duration of response (DoR; 11 months) than seen with bevacizumab therapy 
(5.3 months).58 
Nivolumab is approved for use for the treatment of multiple cancer types including melanoma, 
Hodgkin lymphoma, squamous cell cancer of the head and neck, urothelial, renal cell 

 
 
 
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carcinoma, non-small cell lung, malignant pleural mesothelioma, colorectal cancer, 
hepatocellular carcinoma and esophageal cancer. It is not currently approved for GB.60, 61 
1.2.1.3.1.1. 
Expected Adverse Events Related to Nivolumab 
The following summary is based on the EU Summary of Product Characteristics (SmPC).59 
In the pooled dataset of nivolumab as monotherapy across tumor types (n = 3771) with 
minimum follow-up ranging from 2.3 to 28 months, the most frequent adverse reactions (≥ 
10%) were fatigue (46%), musculoskeletal pain (31%), diarrhea (26%), nausea (24%), cough 
(24%), rash (24%), dyspnea (18%), pruritus (18%), decreased appetite (18%), constipation 
(17%), abdominal pain (16%), upper respiratory tract infection (16%), arthralgia (15%), 
pyrexia (14%), vomiting (14%), headache (13%) and oedema (11%). The majority of adverse 
reactions were mild to moderate (Grade 1 or 2). With a minimum of 63 months follow-up in 
NSCLC, no new safety signals were identified. 
 
In addition, nivolumab is associated with immune–related adverse reactions. With appropriate 
medical therapy, immune-related adverse reactions resolved in most cases. Table 3 presents 
the percentage for immune-related adverse reactions who were permanently discontinued from 
treatment by dosing regimen. Additionally, for patients who experienced an event, Table 3 
presents the percentage of patients who required high-dose corticosteroids (at least 40-mg daily 
prednisone equivalents) by dosing regimen. 
Note: for the laboratory abnormalities observed with nivolumab monotherapy, please refer to 
the European SmPC or to the US Product Information (PI).59,60 
Of the 2085 patients who were treated with nivolumab monotherapy 3 mg/kg every 2 weeks 
and evaluable for the presence of anti-nivolumab antibodies, 11% tested positive for treatment-
emergent anti-nivolumab antibodies by an electrochemiluminescent assay and 0.7% had 
neutralizing antibodies against nivolumab.61 
Generally, no overall differences in safety regarding nivolumab were reported between 
elderly (≥ 65 years) and younger patients (< 65 years). Of the 1359 patients randomized to 
single-agent nivolumab in CHECKMATE-017, CHECKMATE-057, CHECKMATE-066, 
CHECKMATE-025, and CHECKMATE-067, 39% were 65 years or older and 9% were 75 
years or older. No overall differences in safety or effectiveness were reported between elderly 
patients and younger patients.61  
In the nivolumab non-squamous non-small cell lung cancer study (CA209057), the safety 
profile in patients with baseline renal or hepatic impairment was comparable to that in the 
overall population. These results should be interpreted with caution due to the small sample 
size within the subgroups.60 

 
 
 
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Table 3: 
Nivolumab Immune-related Adverse Reactions Leading to Permanent 
Discontinuation or Requiring High-dose Corticosteroids  
 
 
a: At least 40-mg daily prednisone equivalents. 
b: Frequency is based on the number of patients who experienced the immune-related adverse reaction. 
 
1.2.1.3.2. 
Combination of the EO2401 with a Check Point Inhibitor 
The combination of a peptide vaccine and CPIs to treat cancer appears a promising therapy that 
will be evaluated in this clinical study. Clinical studies using dendritic cell vaccines, 
peptide-based vaccines, and immune CPIs are underway. It is likely that combination regimens 
with complementary mechanism of action will ultimately be required to achieve a broad and 
durable tumor response.61 
To demonstrate the antitumoral effect of vaccine and the synergic effect with CPIs, an adoptive 
transfer of T cells in nude mice engrafted with U-87MG cells was performed. 
Immunocompromised nude mice were injected SC into the flank region with U-87MG human 

 
 
 
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tumors, normalizes remaining tumor vasculature, and inhibits the formation of new tumor 
vasculature, thereby inhibiting tumor growth. 
Worldwide, bevacizumab is authorized in different settings including colorectal cancer, 
non-squamous non-small cell lung cancer, renal cancer, cervical cancer, and ovarian/fallopian 
tube cancers. In addition, in the United States, bevacizumab is authorized for treatment of adult 
patients with recurrent GB. 
1.2.1.3.3.1. 
Expected Adverse Events Related to Bevacizumab 
The following summary is based on the EU SmPC.63 
The overall safety profile of bevacizumab is based on data from over 5700 patients with various 
malignancies, predominantly treated with bevacizumab in combination with chemotherapy in 
clinical trials. 
The most SAEs were: 
• Gastrointestinal perforations 
• Hemorrhage, including pulmonary hemorrhage/hemoptysis, which is more common in 
non-small cell lung cancer patients 
• Arterial thromboembolism 
The most frequently observed adverse reactions across clinical trials in patients receiving 
bevacizumab were hypertension, fatigue or asthenia, diarrhea, and abdominal pain. Analyses 
of the clinical safety data suggest that the occurrence of hypertension and proteinuria with 
bevacizumab therapy are likely to be dose-dependent. 
1.2.2. 
Nonclinical Studies 
A series of nonclinical safety pharmacology and toxicity studies have been conducted with the 
EO2315 in the context of proof-of-concept studies, EO2316, EO2317, or EO2318 in mice to 
support the use of EO2401 in this FIH study. Findings of relevance to this protocol are provided 
below. Further details are provided in the Investigator’s Brochure.62 
1.2.2.1. 
Immunogenicity of EO2316, EO2317, and EO2318 
Immunogenicity of candidate peptides and cross reactivity in 
 
 
 
 
 
 
 
EO2316 - 
 
 
immunization of mice with EO2316 allowed inducing T cells that were able to react strongly 
after challenge with either EO2316 or human peptide demonstrating cross reactivity. Thus, 

 
 
 
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EO2316 is strongly immunogenic and is able to drive an effective immune response against 
human peptide. 
EO2317 and EO2318 - 
 
Immunization of mice with 
EO2317 or E02318 was followed by a high ex-vivo response of splenocytes against the same 
bacterial peptide, thus demonstrating the strong immunogenicity of EO2317 or EO2318. The 
cross reactivity of these cells induced by EO2317 or EO2318 against the human corresponding 
peptides was demonstrated.62 
In summary, these immunogenicity studies showed that the 3 candidate peptides, EO2316, 
EO2317, and EO2318, induced stronger immune responses than the corresponding human 
peptides and were able to drive an effective immune response against the corresponding 
IL-13Rα2, BIRC5 (survivin), and FOXM1 human peptides. 
 
 
For further details, refer to the Investigator’s Brochure.62 
Immunogenicity of the helper peptide in 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
These results support the use of UCP2 as helper peptide in the intended 
clinical trial with EO2401. 
 
 

 
 
 
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Potential antitumor effect of the peptide candidates in a mouse xenograft GB model 
An important nonclinical investigation, including a tumoral model, strongly supporting the use 
of bacterial peptides for a therapeutic vaccine in combination with anti-PD-1 has been 
presented in Section 1.2.1.3.2. 
1.2.2.2. 
Toxicology Studies 
Although HLA-A2 transgenic animals have been used to demonstrate that the individual 
peptides in EO2401 DP peptide mixture solution are immunogenic, 
 
 
So far, nonspecific adverse effects that may occur following binding of the peptides to HLA 
molecules have not been observed in HLA-A2 transgenic mice. In addition, clinical trials have 
been completed or are ongoing using IL-13Rα2, BIRC5 (survivin), or FOXM1 as a target for 
peptides vaccination (NCT0113007764; NCT0207864865). In all of these trials, there were no 
treatment limiting AEs associated with the targeting of IL-13Rα2, BIRC5 (survivin), and 
FOXM1. 
The immune response and cross reactivity against mice peptide homologs were performed on 
standard C57BL6 and BALB/C mice and the additionally assessed safety parameters revealed 
no visible sign of toxicity: 
• No body weight change 
• No change in colon length nor weight 
• No bleeding in the stools 
• No signs of overt colitis 
• All organs, including intestine, appeared macroscopically normal. 
Universal cancer peptide 2 is used as a CD4+ helper peptide in some ongoing clinical trials, 
including in patients with non-small cell lung cancer (NCT02818426). 
 
 
 
For further details, refer to the Investigator’s Brochure.62 

 
 
 
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1.2.3. 
Clinical Studies & Rationale and High Level Outline for Global Amendment 
#2 (leading to protocol EOGBM1-18 version 3) 
To date, no final human trial data is available on safety and efficacy of EO2401, as the early 
clinical development trials are still running. 
EO2401 is evaluated in two phase 1/2 trials running in parallel, trial EOGBM1-18 in patients 
with recurrent glioblastoma (EudraCT#: 2018-002279-16; IND#: 19229), and trial EOADR1-
19 in patients with adrenal tumors (adrenocortical carcinoma [ACC], and malignant 
pheochromocytoma/paraganglioma [MPP]) (EudraCT#: 019-003396-19; IND#: 19229); both 
trials are conducted under the supervision of Independent Data Monitoring Committees 
(IDMCs). 
Trial EOGBM1-18, the current trial, is an international, multicenter, open label, multi-cohort 
study, recruiting patients at 10 sites in Germany, France, Spain, and USA, where the first 
patient started study treatment July 28, 2020. At an IDMC meeting 
, there 
was a consensus decision, after 3 evaluable patients had been treated without any reported 
safety concern event (i.e. no related adverse event of grade 3, or higher, had been reported), to 
recommend finalizing the recruitment to Cohort 1 (safety lead-in, 3-by-3 designed cohort) of 
trial EOGBM1-18, and to open Cohorts 2a and 2b for recruitment. Based on a further 3 
evaluable patients (without any safety concern events) treated in Cohorts 2a/2b, the IDMC 
 
 arrived at a consensus decision to recommend also opening of 
Cohort 3 of the trial.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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The second early clinical development trial including EO2401, i.e. EOADR1-19, is an 
international, multicenter, open label, multi-cohort study, recruiting patients at 10 sites in 
France, Germany, Italy, Netherlands, Spain, Denmark, Sweden, and USA. The study 
population is male and female HLA-A2 positive patients, at least 18 years old with either 
previously untreated, or previously treated, ACC or MPP. Cohort 1 of the trial (first patient 
starting study treatment August 11, 2020), assumed to be most important from a general safety 
perspective, included previously treated patients with ACC and MPP, and an evaluation by a 
3-by-3 design of EO2401 in combination with nivolumab. At an IDMC meeting 
 
 there was a consensus decision, after 3 evaluable patients had been treated without any 
reported safety concern event (i.e. no related adverse event of grade 3, or higher, had been 
reported), to recommend finalizing the recruitment to Cohort 1 of trial EOADR1-19, and to 
open Cohorts 2A and 3A for recruitment (patients with previously treated disease). Based on a 
further 3 evaluable patients (without any safety concern events) treated in Cohorts 2A/3A, the 
IDMC at a meeting 
 arrived at a consensus decision to recommend also 
opening of Cohorts 2B and 3B (patients with no previous treatment for advanced/metastatic 
disease).  
The IDMCs of trials EOGBM1-18 and EOADR1-19 receives monthly safety updates from the 
Sponsor, and there has not been any need to call for any further IDMC meetings beside the pre-
planned meetings outlined above 
 
 since there has been no safety concern event (as 
defined by the trial protocols and IDMC Charters) reported in any of the trials. The safety lead-
in cohorts in both trials run with minimum number of patients (each 3 patients) due to lack of 
safety issues (no safety concern events detected), and all phase 2 cohorts in both trials have 
been opened as planned for recruitment. 
The continuously ongoing safety assessment by the Sponsor regarding trials including EO2401 
is showing that the major added event type to the background treatments (i.e. nivolumab and 
nivolumab/bevacizumab, depending on trial and cohort) are the expected events of mild local 
administration site skin reactions (e.g. erythema, induration, and pain). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

 
 
 
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• 
 
 
  
 
 
      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The above findings from the early part of trial EOGBM1-18, including a satisfactory safety 
profile (i.e. expected profile and absence of emerging safety concerns), fast and strong 
induction of cytotoxic T cells targeted against tumor cells, and early signs of interesting clinical 
activity serves as the rationale for a second global protocol amendment (leading to protocol 
EOGBM1-18 version 3) to expand the trial to further optimize the treatment schedule and 

 
 
 
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patient management to achieve an as long study treatment duration as possible to increase the 
possibility to achieve enhanced efficacy, and to investigate the feasibility to administer study 
treatment in the neoadjuvant setting.  
The amendment is included in detail in the following protocol sections, especially Section 3.1 
Overall Study Design and Plan Description, and Section 6.3 Permitted Concomitant 
Medications, and summarized at a high level in the following:   
• Reminder regarding EOGBM1-18 Version 2 treatment schedules: the only difference 
between Cohort 1a and Cohort 2a (and Cohort 2b, which is the same as Cohort 2a) is 
that in Cohort 1a the two first study drug administrations are given as EO2401 
monotherapy two weeks apart (for Cohort 2a nivolumab is administered together with 
EO2401 from the start of treatment), then after a further 2 weeks the two regiments are 
the same and EO2401 is administered together with nivolumab. Cohort 3, only open 
for 
recruitment 
in 
the 
USA, 
include 
a 
combination 
treatment 
of 
EO2401/nivolumab/bevacizumab (bevacizumab dose 10mg/kg every 2 weeks according 
to the FDA label); currently 8 patients are in treatment with this regimen (from 1 to 12 
weeks, and ongoing) and no safety concern events have been reported.  
• Addition of 12 patients to Cohort 1a (i.e. same treatment schedule as Cohort 1a in the 
safety lead-in part of the trial, but with the safety measures as for Cohort 2a; also same 
inclusion/exclusion criteria, i.e. measurable disease, as for the initial safety lead-in 
cohort and Cohort 2a), and inclusion of extended patient management measures (see 
below); rationale is that only 3 patients have been treated with delayed nivolumab 
treatment and all of the 3 patients have comparably long treatment durations (i.e. a 
possible efficacy signal which needs to be substantiated). 
• Addition of 10 patients to Cohort 2a without any change of the schedule or inclusion 
criteria (i.e. measurable disease), and inclusion of extend patient management measures 
(see below); rationale is that the schedule with combination of EO2401/nivolumab from 
start seems to give a faster and more extensive T cell expansion (preferred pattern) than 
the delayed nivolumab schedule, but without adjusted patient management measures 
comparable short treatment durations; thus, goal is to, if possible, prolong treatment 
duration by more aggressive patient management at situations possibly being 
symptomatic PsPD. 
• Addition of 6 patients in a new Cohort 2c for neoadjuvant study treatment (EO2401plus 
nivolumab administered twice with 2 weeks interval; thus, population include patients 
scheduled for clinically indicated resection of first recurrent glioblastoma), confirmed 
by an interim MRI at day 14 (i.e. at V2), followed by planned surgery, and thereafter 
adjuvant study treatment (EO2401 plus nivolumab administered twice with 2 weeks 
interval, then switch to EO2401 on a 4-weekly schedule and continued nivolumab 2-
weekly), including also extended patient management measures (see below). The 
rationale for the new cohort is to preliminary assess safety and feasibility of a 
neoadjuvant/adjuvant treatment strategy, which already have shown some promise 
utilizing anti-PD1 blockade only.100, 101 In addition, the treatment setting allows 
assessments of immuno-biological effects in tissue of the combined treatment of 
EO2401 and anti-PD1 blockade. 
• Inclusion of immune testing in all running cohorts also at the visit after the first EO2401 
administration (V2); rationale is to investigate how early an expansion of T cells occur 

 
 
 
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(in EOGBM1-18 version 2, on study testing started at V3) to further advise on possible 
schedule optimizations (note, to keep blood sampling constant, testing at a later 
timepoint is cancelled in patients where V2-testing is implemented).  
• Addition of extended patient management in all running cohorts to ameliorate 
significant neurological symptoms; rationale is to avoid early study treatment stopping 
and at least allowing as many patients as possible to get to a confirmation of progression 
according to iRANO criteria, or the possibility detecting that the symptomatic 
progression could be related to PsPD. Structures measures to be included are: 
o 
In situations where added supportive medication is judged as medically 
appropriate by the treating physician due to patient brain edema with 
symptoms, low-dose bevacizumab for up to three months unless medically 
contra-indicated can be administered. The number of bevacizumab doses to 
be given during the three months window will be determined by the treating 
physician based on her/his assessment of the best interest of the patient. 
When bevacizumab is administered for symptomatic cerebral edema, study 
therapy may be continued at the discretion of the treating physician.  
▪ The rationale to use low-dose bevacizumab for treatment of brain tumor 
edema, for instance in relation to radiotherapy induced necrosis, is well 
established, and the literature has been summarized.99 An important trial 
to substantiate the use of low-dose bevacizumab was published by Levin 
et al 2011102, providing class I evidence (randomized double-blind 
placebo-controlled trial) of bevacizumab efficacy in the treatment of 
CNS radiation necrosis justifying consideration of this treatment option 
for people who suffer radiation necrosis secondary to the treatment of 
head and neck and brain cancers. Importantly, the pathophysiology 
behind radiation therapy induced necrosis, i.e. damage resulting from 
local cytokine release, increase in capillary permeability, and 
extracellular edema, is the pathophysiology at hand also in a situation of 
intense immune cell attack of a brain tumor. 
o 
In situations where symptomatic cerebral edema is more significant or 
anticipated to evolve to become more significant, the treating physician may 
also prescribe a high dose of dexamethasone followed by a rapid taper as 
tolerated and as clinically indicated. During a dexamethasone high dose 
regimen, study therapy should be interrupted. 
 
 
 
 
 
 
• 
 
 
 
 

 
 
 
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• 
 
 
 
 
 
 
 
 
 
 
In addition to above, two further types of changes are included in global amendment 2 
(leading to EOGBM1-18 version 3): 
• Recommendations regarding vaccination against SARS-CoV-2/COVID-19 as applied 
in trial EOGBM1-18 since January 2021 and forward via investigator communications, 
are included in Section 6.3. 
• Updates of management principles for immune-related adverse events as outlined in 
Section 7.6.1.1 and Table 5, based on the most recently available labelling documents 
for Opdivo (SmPC August 3, 202159) and standard protocol guidance from Bristol-
Myers Squibb (market authorization holder for nivolumab). In light of these 
adjustments, and to also follow standard protocol guidance from Bristol-Myers Squibb 
and align protocol EOGBM1-18 with protocol EOADR1-19 exclusion criteria 
regarding laboratory value exclusions have also been updated.   
 
1.2.4. 
Cohort 3 clinical outcomes & Rationale and High-Level Outline for Global 
Amendment #3 (leading to protocol EOGBM1-18 version 4) 
Safety of EO2401/nivolumab +/- bevacizumab 
As outlined in Section 1.2.3, IDMC assessments of the safety lead-in parts of both trials 
currently investigating EO2401 (EOGBM1-18 and EOADR1-19) have run with a minimum 
number of patients (each 3 patients) due to lack of safety issues (no safety concern events 
detected), and all expansion cohorts in both trials have, after further IDMC assessments, been 
opened as planned for recruitment. 
From a safety perspective 
 
 
 
 
 
 
 
An overall assessment of safety, at this stage of study conduct, does not show any clear 
differences 
between 
patients 
treated 
with 
EO2401/nivolumab 
and 
EO2401/nivolumab/bevacizumab, and in this context the combined safety profile of all patients 
treated in trial EOGBM1-18 will be referred to below. 

 
 
 
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Safety conclusion 
In conclusion, the combination of EO2401 
 
and nivolumab +/- bevacizumab used for treatment of patients with recurrent 
glioblastoma, is well tolerated with a safety profile consistent with the safety profile of 
nivolumab monotherapy, and when applicable the safety profile of bevacizumab 
monotherapy, except the addition of local administration site reactions.  
Of note, administration site reactions seen in trial EOGBM1-18 are below, or well within the 
expected frequency for any antigen 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Global amendment 3 leading to protocol EOGBM1-18 version 4 
At a high level the amendment includes the following items and rationale:  
• Expansion of Cohort 3 and broadening of recruitment outside of the USA: 
Cohort 3 include a combination treatment of EO2401/nivolumab/bevacizumab 
(bevacizumab dose 10mg/kg every 2 weeks according to the FDA label) and was only open 
for recruitment in the USA during conduct of protocol versions 1-3.  
 
 
 
 
 
  
The intention is also to open the trial for recruitment at sites outside of the USA for Cohort 
3 to broaden the base of sites with experience of the regimen. The broadening of the 
recruitment base is not assumed to influence the safety profile of the treatment since 
bevacizumab, even if not labelled in large parts of Europe, is a not seldom used compound 
for treatment of recurrent glioblastoma also in Europe.  
A further reason to expand Cohort 3 is also to enhance the possibility to compare the 
continuous use of standard dose bevacizumab (as in Cohort 3) with the neurological 

 
 
 
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symptom directed use of low-dose bevacizumab as instituted in protocol version 2 (mainly 
used in Cohorts 1a and 2a).  
• 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
1.3. 
Benefit-risk Assessment 
Glioblastoma is the most lethal brain tumor with 25% of patients surviving up to 2 years and 
less than 5% of patients making it to a 5-year post-diagnosis milestone.18,19 As of today, few 
effective treatment options exist against progressive and recurrent GB, which occurs in most 
patients following surgery and combined radiotherapy/temozolomide treatment delivered as 
primary therapy.18,19  
Repeat resection is the best available method for prolonging the survival of selected patients 
with recurrent GB, especially those with a mass effect. However, prognostic factors, such as 
age, performance status, and presumed maximal extent of resection, which must always be 
considered, may indicate that repeat resection may not be the appropriate therapeutic option. 
As with repeated resection, a lack of prospective randomized trials, and bias in selecting 
patients for single-arm trials, prevent any reliable conclusions from being made regarding the 
benefit provided by repeated irradiation in patients with recurrent malignant glioma. 
According to treatment guidelines, systemic chemotherapy is an option for treatment of patients 
with recurrent GB; even though outcomes are not impressive, clinical trials might be preferred 
for eligible patients.66,67 Lomustine is one possible chemotherapy treatment at recurrence and 
a recent trial where this compound was administered as monotherapy (n = 60) indicates the 
following efficacy: median OS 5.6 months, median PFS 1.9 months, and objective response 
rate (ORR) of 3%.68 Targeted treatments await their full breakthrough and utilization in GB, 
even though bevacizumab (anti-VEGF monoclonal antibody) has already achieved an 
authorization for treatment of adult patients with recurrent GB in the United States. 69 

 
 
 
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Bevacizumab has shown marked radiographic responses and improvement in PFS versus 
controls, but Phase III studies have failed to demonstrate an OS advantage.70 
The CheckMate-143 clinical trial was the first large-scale randomized clinical trial of 2 targeted 
therapies in recurrent GB. 71  Patients received either nivolumab (anti-PD-1 monoclonal 
antibody) 3 mg/kg or bevacizumab 10 mg/kg IV every 2 weeks, until disease progression or 
unacceptable toxicity. At the time of final analysis, this Phase III clinical trial enrolled 
369 patients with first recurrence of GB, previously treated with combination radiation and 
temozolomide. The trial failed showing an extension of OS by nivolumab treatment as 
compared to bevacizumab. In both treatment groups, the 12-month survival was 42%. The 
median survival for patients treated with nivolumab was 9.8 months as compared to 10 months 
for those receiving bevacizumab monotherapy. Median PFS was 1.5 months (nivolumab) and 
3.5 months (bevacizumab). Overall treatment response rates were 8% (nivolumab) and 23% 
(bevacizumab), and median durations of response were 11.1 months (nivolumab) and 5.3 
months (bevacizumab). 
Thus, the targeted therapies nivolumab and bevacizumab have both shown some level of 
activity in GB. However, it seems as the efficacy of the compounds as monotherapies might 
not be potent enough, but paving the way for therapeutic options adding further rational 
combination partner to enhance activity and prospects for patient with recurrent GB. 
To date, no final human trial data is available on safety and efficacy of EO2401 in combination 
with nivolumab, as the early clinical development trials are still running. However, safety data 
is available from two trials, the current trial EOGBM1-18 and a trial including patients with 
adrenal tumors (EOADR1-19), showing a safety profile currently indicating that the major 
added event type by EO2401 to the background treatments (i.e. nivolumab and 
nivolumab/bevacizumab, depending on trial and cohort) are the expected events of mild local 
administration site skin reactions (e.g. erythema, induration, and pain); see further Section 
1.2.3.  
The immunogenicity results obtained with EO2316, EO2317, and EO2318 main part of 
EO2401 in mouse models and the antitumor effect of the EO2315 peptide – used in proof-of-
concept studies – when combined with anti-PD-1 in a mouse xenograft GB model strongly 
support the use of the EO2401 in combination with anti-PD-1 in the treatment of GB. 
The combination of EO2401 and nivolumab is intended to increase the EO2401-specific T cell 
response infiltration in the tumor and the killing effects directed against the tumor cells. This 
initial response might also lead to antigen spreading through the killing of the tumor cells 
induced by EO2401 and the induction of responses to other antigens than the ones of EO2401. 
Clinical trials were conducted to evaluate the safety and the efficacy of a vaccine and a CPI 
combination therapy of a vaccine and a CPI. The first results showed an acceptable safety 
profile comparable to the safety profile of the CPI alone. Consequently, the safety profile of 
EO2401 in combination with nivolumab was before the start of trials EOGBM1-18 and 
EOADR1-19 expected to be very close to the safety profile observed with the nivolumab as 
monotherapy.54 An expectation which based on early data seems to be moving towards being 
validated (see Section 1.2.3). 
The addition of bevacizumab to the EO2401 and nivolumab combination is supported by the 
fact that GB is highly angiogenic and is associated with elevated expression of VEGF, and that 
VEGF mediates immunosuppression via inhibition of dendritic cell maturation, reduction of 
T cell tumor infiltration, and promotion of inhibitory cells in the tumor microenvironment.72 

 
 
 
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Bevacizumab blockade of VEGF is thus assumed to enhance the possibilities for EO2401 and 
nivolumab to work. In addition, bevacizumab gives the possibility for patients to possibly have 
a slightly prolonged time to progression (even if survival is not prolonged) meaning that 
patients might benefit from a longer time administration of EO2401 plus nivolumab. 
Anti-PD-1 blockade in combination with bevacizumab has been evaluated in combination in 
patients with recurrent GB and found to be well tolerated.73,74 Before the Cohort 3 (including 
EO2401, nivolumab, and bevacizumab) in the current trial will be opened (after a 
recommendation from the Independent Data Monitoring Committee [IDMC]), the safety and 
tolerability of the combination of EO2401 in combination with nivolumab has been assessed 
in Cohorts 1 and 2. 
From a risk perspective, based on the above and already achieved clinical experiences utilizing 
efficacious immunization approaches together with anti-PD-1 blockade54, the assessment of 
the Sponsor is that the safety profile of the combination of EO2401 and nivolumab will be 
similar to the well described safety profile of nivolumab, to which no addition of serious 
additional non-specific off-target safety issues are expected. Likewise, the assessment of the 
Sponsor is that the safety profile of the combination of EO2401 and nivolumab/bevacizumab 
will be similar to the safety profiles of the combination compounds. 
However, provided EO2401 induces an efficacious expansion of T cells specific for the 
targeted TAAs with ability to kill tumor cells expressing one, or multiple, of these TAAs, it 
cannot be ruled out that such antigen specific T cells might also recognize these antigens if 
expressed, and presented by MHC, at a high enough level on non-cancerous cells. Thus, if 
killing of tumor cells by T cells expanded by EO2401 immunization could occur, normal cells 
might also be killed by such T cells leading to symptoms like the immune-related adverse 
reactions which might be seen during treatment with anti-PD-1 (or similar compounds) alone 
(e.g. see the European SmPC59 or the US PI60 for nivolumab). It can be assumed that the 
immune-related adverse reactions seen during treatment with e.g. nivolumab are driven by self-
reactive T cells, even if in the case of nivolumab the specific targets for these T cells are not 
known due to the non-specific mode of action of nivolumab in relation to antigen-specificity. 
Thus, the mechanism for possible normal tissue toxicity by EO2401 immunization is assumed 
to be the same as for nivolumab induced immune-related toxicity and by that safety measures 
have been instituted which directly follows the measures already well established for 
nivolumab and similar compounds (see Section 7.6.1.1).  
In addition to above, as for all immunization approaches some degree of mild to moderate local 
injection events of short duration might be expected for EO2401. Also, as for all 
administrations of immunogens, it cannot be excluded that immediate type allergic reactions 
might occur at injections of EO2401; special precautions are outlined for this type of potential 
reactions (Appendix 7 Infusion/Treatment related Reactions). 
The following study procedures will ensure safety monitoring along the clinical trial: 
• The clinical team at investigational sites (which are expert centers) will be made aware 
of the potential side effects in order to manage the side effects efficiently 
• The patients will be monitored closely during the treatment period through regular and 
frequent visits including clinical, laboratory, and radiological exams 
• Beside the active safety oversight of the trial by the Investigators (and their teams) in 
collaboration with the Sponsor via the Medical Monitor (with associated team), an 

 
 
 
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IDMC will support the safety monitoring and give recommendations for possible 
actions in relation to trial conduct. 
 
 
 
 
and the IDMC will recommend on possible 
expansions in Cohort 1, and transition from Cohort 1 to 2a and 2b, and from Cohorts 
2a and 2b to 3. 
Given the potential for therapeutic benefit of EO2401 combined with nivolumab, and 
nivolumab/bevacizumab in patients with progressive GB based on published data (including 
some inborn activity of both nivolumab and bevacizumab as individual therapies in GB; see 
above), the promising tumor model data (showing the synergy of the microbiome-derived 
peptide and anti-PD-1) and the nonclinical toxicology data available at present support the start 
of this Phase Ib/IIa trial. 
The findings from the early part of trial EOGBM1-18 described in Section 1.2.3 and Section 
1.2.4, including a satisfactory safety profile (i.e. expected profile and absence of emerging 
safety concerns), fast and strong induction of cytotoxic T cells targeted against tumor cells, and 
early signs of interesting clinical activity serves as the rationale for a third global protocol 
amendment and supports the positive benefit-risk for expansion of trial EOGBM1-18 for 
treatment of further patients according to the third global amendment (leading to EOGBM1-18 
version 4). 

 
 
 
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2.2. 
Endpoints 
2.2.1. 
Primary Endpoint 
The primary endpoint includes the incidences of AEs, treatment-emergent AEs (TEAEs), SAEs, 
deaths, and laboratory abnormalities using the National Cancer Institute-Common 
Terminology Criteria for AEs (NCI-CTCAE) v5.0. 
Safety endpoints will be assessed by review of summaries of AEs/TEAEs/SAEs, unless 
otherwise stated. Adverse events will be categorized by system organ class (SOC) and 
preferred term (PT) using the current Medical Dictionary for Regulatory Activities (MedDRA) 
version and will be graded according to NCI-CTCAE v5.0. 
2.2.2. 
Secondary Endpoints 
The secondary endpoints are: 
• Overall survival, defined as the time interval from the date of first study treatment 
administration to the date of death due to any cause 
• The tumor progression and response by MRI measurements every 8 weeks using the 
iRANO criteria evaluated by: 
o Progression-free Survival, using the iRANO criteria (see Appendix 177,78) and 
defined as the time interval from the date of first study treatment administration 
to the date of first occurrence of progression or death from any cause, whichever 
occurs first 
o Objective Response Rate (ORR), defined as the proportion of patients with 
complete response (CR) and partial response (PR) according to the iRANO 
criteria 
o Disease Control Rate (DCR), defined as the proportion of patients with CR, PR, 
and Stable Disease (SD) according to the iRANO criteria  
o Duration of Response (DoR), defined as the time interval from the date of first 
occurrence of CR or PR to the date of first documentation of disease progression 
or death from any cause, whichever occurs first. 
• The immunogenicity of EO2316, EO2317, EO2318, and UCP2 that compose EO2401 
by 
 

 
 
 
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2.2.3. 
Exploratory Endpoints 
The exploratory endpoints will be: 
• Neurologic function assessed by the NANO scale (see Appendix 275,76) 
• Correlation between immunogenicity of EO2316, EO2317, EO2318, and UCP2 that 
compose EO2401 and the outcome parameters 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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3. INVESTIGATION PLAN 
3.1. 
Overall Study Design and Plan Description 
This is a multicenter, Phase Ib/IIa, FIH study to assess the safety, tolerability, immunogenicity, 
and preliminary efficacy of EO2401 in patients with unequivocal evidence of progressive or 
first recurrent GB confirmed by MRI as defined by the Response Assessment in Neuro-
Oncology (RANO) criteria (note: within the first 3 months after completion of radiotherapy 
and concomitant temozolomide, diagnosis of recurrence can be indistinguishable from 
pseudoprogression [PsPD] on neuroimaging).66 
The FIH protocol is an open-label, multi-cohort study intended to recruit a maximum of 
approximately 100 evaluable patients in total: 
• Cohort 1 (as study safety lead-in, before global amendment 2) includes an evaluation 
by a 3-by-3 design of EO2401 monotherapy (2 administrations of EO2401 each 
followed by a 2-weeks observation period) planned to be followed in the same 
individual patients by continued EO2401 in combination with nivolumab; 3 to 12 
evaluable patients will be included depending on the safety profile of the administered 
treatments 
o In the safety lead-in part (3-by-3 design) of the trial, 3 evaluable patients started 
treatment in Cohort 1a, after which the safety lead-in was closed after a 
recommendation from the IDMC, and Cohorts 2a and 2b opened 
o In global amendment 2 (EOGBM1-18 version 3), plus via re-distribution of 
patients from Cohort 2b, 18 evaluable patients were added to Cohort 1a for 
further evaluation of the treatment schedule with a 4-weeks delayed start of 
nivolumab (safety precautions for the added patients will follow the same 
principles as for Cohorts 2a, 2b, 2c, and 3, since Cohort 1a is no longer a safety 
lead-in part of the trial)  (recruitment finalized before global amendment 3) 
• Cohorts 2a and 2b are an evaluation of EO2401 in combination with nivolumab (both 
compounds started at the same time) planned to include approximately 48 evaluable 
patients in total (patients in Cohort 2a with at least one measurable lesion and patients 
in Cohort 2b with no measurable enhancing disease). 
o Before global amendment 2 (EOGBM1-18 version 3), 23 evaluable patients 
started treatment in Cohort 2a (after re-distribution of patients between Cohort 
1 and Cohort 2a to keep a relevant safety database; see further Section 1.2.3) 
o In global amendment 2 (EOGBM1-18 version 3), plus via re-distribution of 
patients from Cohort 2b, 15 evaluable patients were added to Cohort 2a for 
further evaluation of the treatment schedule with simultaneous start of EO2401 
and nivolumab, but with inclusion of extended patient management measures 
(recruitment finalized before global amendment 3) 
o Cohort 2b was planned to include 15 evaluable patients both before and after 
global amendment 2 (EOGBM1-18 version 3), but number of patients lowered 
to 6 by re-distribution of patients to Cohorts 1a and 2a (recruitment finalized 
before global amendment 3) 
• Cohort 2c is a cohort introduced by global amendment 2 (EOGBM1-18 version 3), to 
include 6 evaluable patients to assess safety and feasibility of a neoadjuvant/adjuvant 

 
 
 
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treatment strategy including EO2401/nivolumab (both compounds started at the same 
time)   
• Cohort 3 is an evaluation of EO2401 in combination with nivolumab and bevacizumab 
planned to include 10 evaluable patients before global amendment 3 which increased 
the target recruitment to 26 patients. 
 
 
 
 
 
Generally, patients evaluable for safety will include all patients who have received at least 
1 dose of EO2401. 
 
 
 
 
 
 Patients evaluable 
for efficacy based on the Per-Protocol (PP) population will consist of any patients who received 
at least 3
 
 for whom no important protocol deviations occurred and have at least 
1 evaluable post-Screening tumor assessment (tumor assessment is not necessary if a 
clinical/pathologically defined progressive disease [PD] is defined). Patients who are not 
considered evaluable for the PP population will not be replaced, and be included in the Full 
Analysis Set (FAS). 
Eligible patients who meet the inclusion criteria and do not meet any of the exclusion criteria 
and have provided informed consent will be enrolled in the study in Europe and/or the United 
States. 
 
 
 
The study treatments will be administered until confirmed tumor progression, intolerable 
toxicity, death, Investigator or patient decision, or early termination of the study at the request 
from the Sponsor. At the time of stopping study treatment, appropriate standard of care will be 
initiated by the Investigator. The patient should continue study follow-up measures as long as 
the individual patient consent for follow-up is not withdrawn, the site is open, and the study 
not terminated per plan or by the Sponsor. 
For all cohorts, and all patients during the whole trial treatment, the following stopping safety 
rules will apply: 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• The only adjustments regarding dose for the EO2401 combination partners nivolumab 
and bevacizumab are withholding of one or several doses, or discontinuation of 
treatment; such measures should be taken in accordance with the labeled 
recommendations in the European SmPC59,63 or the US PI60,69, which are available for 
both compounds. Dose adjustments for EO2401 also include the potential of 
withholding one or several doses (see Section 7.6.1.1), or discontinuation of treatment. 
In addition, a lowered dose might be applied in the potential transition from sub-cohort 
1b to sub-cohort 1c in relation to safety events (see further below) 
• In instances where the labels for nivolumab and/or bevacizumab prescribe that the drug 
should be withheld or discontinued due to safety events, there is an option to continue 
the remaining component(s) of the combination (i.e., either EO2401 alone or EO2401 
in combination with nivolumab or bevacizumab, respectively) provided such a 
continuation would be recommended by the IDMC and supported by the Sponsor. If 
EO2401 would be stopped, the other drugs in the combination will also be stopped in 

 
 
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Cohort 1 (see Figure 5) 
Cohort 1 in the safety lead-in part of the trial will be evaluated in a 3-by-3 design to assess, 
first safety and tolerability of EO2401 alone during a 4 weeks period (2 administrations of 
EO2401, each followed by a 2-week observation period), planned to be followed in each patient 
by further administrations of EO2401 in combination with nivolumab for assessment of safety, 
tolerability, immunogenicity, and preliminary efficacy of the combination. The safety lead-in 
part of the trial included 3 evaluable patients starting treatment in Cohort 1a, after which the 
safety lead-in was closed after a recommendation from the IDMC, and Cohorts 2a and 2b 
opened. 
In global amendment 2 (EOGBM1-18 version 3), plus via re-distribution of patients from 
Cohort 2b, 18 evaluable patients were added to Cohort 1a for further evaluation of the treatment 
schedule with a 4-weeks delayed start of nivolumab, i.e. with the same schedule as for Cohort 
1 described in this section, but with extended patient management measures (see Section 6.3). 
Recruitment to Cohort 1 was finalized before global amendment 3.  
 

 
 
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Priming injections of EO2401 will be started as soon as possible after confirmation of disease 
progression; study baseline/screening MRI should be done no longer than 14 days before the 
start of treatment (MRI confirming progression of GB might be done earlier). The initial dosing 
regimen will be 4 priming injections administered SC at 2-weekly intervals for the first 6 
weeks, followed by monthly boosting injections of EO2401 starting at 4 weeks after the fourth 
priming injection (i.e., at Week 10). In sub-cohorts 1a and 1b, the full dose of EO2401 (i.e., 
1 mL of emulsified EO2401 DP in adjuvant) will be administered, and if implemented the sub-
cohorts 1c and 1d will include half the dose of EO2401 (i.e., 0.5 mL of the emulsion will be 
injected). Thus, Cohort 1a after global amendment 2 (EOGBM1-18 version 3) should also 
include full dose of EO2401 (i.e., 1 mL of emulsified EO2401 DP in adjuvant). 
Nivolumab will be administered as an IV infusion at a dose of 3 mg/kg every 2 weeks from the 
third priming injection of EO2401 (i.e., from start of Week 4). The nivolumab infusion is to 
start 
 after the EO2401 administration. 
The safety precautions for Cohort 1a after global amendment 2 (EOGBM1-18 version 3) will 
follow the same principles as for Cohorts 2a, 2b, 2c, and 3, since Cohort 1a is no longer a safety 
lead-in part of the trial. Thus, for the added patients to Cohort 1a the general safety rules as 
described above applies, i.e. at related clinical Grade 4/5 AEs the study treatment in the 
individual patient experiencing the event will be stopped for Grade 4 AEs and the IDMC will 
convene and after assessing the situation give recommendations for further actions, and at 
related Grade 3 AEs the Investigator responsible for the patient with an event will in 
collaboration with the Sponsor make the initial assessment regarding actions; the IDMC 
support will be requested when appropriate. 
In Cohort 1, as study safety lead-in, before global amendment 2 (i.e. these rules are NOT 
applicable to patients added to Cohort 1a by global amendment 2), the patients’ recruitment 
was conducted in accordance to the following rules: 

 
 
 
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• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Sub-cohort 1a (full dose of EO2401) is planned to include 3 evaluable patients: 
o If in 3 evaluable patients no related ≥ Grade 3 AE (related Grade 3 AEs deemed not 
to constitute safety concerns by the IDMC are acceptable; see further below) occur 
during the initial 4 weeks in the individual patient, the IDMC will assess the totality 
of available safety data and recommend for decision by the Sponsor for the further 
recruitment steps (assumed would be opening recruitment of Cohorts 2a and 2b if 
there are no general safety concerns) 
o 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
o 
 
 
 
 
 

 
 
 
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further treatment plan for the individual patient experiencing the event and further 
recruitment steps (the event might be deemed by the IDMC not to constitute a safety 
concern in which case the patient can continue treatment and recruitment to the 
sub-cohort 1a continue per plan without an extension of recruitment by opening 
sub-cohort 1b; alternatively, the IDMC might deem the event to constitute a safety 
concern in which case EO2401 will be permanently stopped in the patient 
experiencing the event and recruitment extended by opening sub-cohort 1b for 
inclusion of 3 patients; a total of 3 patients should also still be included in sub-
cohort 1a). 
• Sub-cohort 1b (full dose of EO2401), if opened, is planned to include 3 evaluable 
patients: 
o If in 6 evaluable patients in total in sub-cohorts 1a + 1b, only 1 related ≥ Grade 3 
AE (additional related Grade 3 AEs deemed not to constitute safety concerns by the 
IDMC are acceptable; see further above and below) occurred during the initial 4 
weeks in the individual patients, the IDMC will assess the totality of available safety 
data and recommend for decision by the Sponsor the further recruitment steps 
(assumed would be opening recruitment of Cohort 2a and 2b if there are no general 
safety concerns) 
o 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
o 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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• Sub-cohort 1c (half dose of EO2401), if opened, is planned to include 3 evaluable 
patients: 
o If in 3 evaluable patients no related ≥ Grade 3 AE (related Grade 3 AEs deemed not 
to constitute safety concerns by the IDMC are acceptable; see further above and 
below) occur during the initial 4 weeks in the individual patients, the IDMC will 
assess the totality of available safety data and recommend for decision by the 
Sponsor the further recruitment steps (assumed would be opening recruitment of 
Cohorts 2a and 2b if there are no general safety concerns; 
 
 
o 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
o 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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• Sub-cohort 1d (half dose of EO2401), if opened, is planned to include 3 evaluable 
patients: 
o If in 6 evaluable patients in total in sub-cohorts 1c + 1d, only 1 related ≥ Grade 3 
AE (additional related Grade 3 AEs deemed not to constitute safety concerns by the 
IDMC are acceptable; see further above and below) occurred during the initial 4 
weeks in the individual patients, the IDMC will assess the totality of available safety 
data and recommend for decision by the Sponsor the further recruitment steps 
(assumed would be opening recruitment of Cohorts 2a and 2b if there are no general 
safety concerns; 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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Priming injections of EO2401 will be started as soon as possible after confirmation of disease 
progression; study baseline/screening MRI should be done no longer than 14 days before the 
start of treatment (MRI confirming progression of GB might be done earlier). The schedule of 
administration includes SC injections of EO2401 at 2-weekly intervals (4 times total) during 
the priming phase and then 4-weekly in the boosting phase starting from Week 10 (i.e., 4 weeks 
after the fourth administration of EO2401). The dose of EO2401 will depend on the outcome 
of Cohort 1, i.e., it can be either full dose 
, or half 
dose 
 Thus, Cohorts 2a and 2b should include full dose of 
EO2401 
 
Nivolumab will be administered as an IV infusion at a dose of 3 mg/kg every 2 weeks in 
combination with EO2401 starting from the first priming injection. The nivolumab infusion is 
to start 
 after the EO2401 administration. 
For all patients in Cohorts 2a and 2b, the general safety rules as described above applies, i.e., 
at related clinical Grade 4/5 AEs (the study treatment in the individual patient experiencing the 
event will be stopped for Grade 4 AEs) and the IDMC will convene and after assessing the 
situation give recommendations for further actions, and at related Grade 3 AEs the Investigator 
responsible for the patient with an event will in collaboration with the Sponsor make the initial 
assessment regarding actions; the IDMC support will be requested when appropriate. 
At the global amendment 2 extended patient management measures are include for both 
Cohorts 2a and 2b (see Section 6.3).   
After availability of safety and tolerability data for a 4-weeks period (2 administrations of 
EO2401 in combination with nivolumab, each followed by a 2-week observation period), in at 
least 3 patients of Cohorts 2 (the patients can be treated in either of the Cohorts 2a or 2b, 
respectively), the IDMC should convene and assess the totality of the safety data to recommend 
on the opening, or not, of Cohort 3. 
Cohort 2c (see Figure 6B) 

 
 
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Cohort 2c is a cohort introduced by global amendment 2 (EOGBM1-18 version 3), to include 
6 evaluable patients to assess safety and feasibility of a neoadjuvant/adjuvant treatment strategy 
including EO2401/nivolumab (both compounds started at the same time). 
The treatment strategy includes the following important elements: 
• The population includes patients assessed as candidates, and scheduled, for gross total 
resection of first recurrent GB, which can be safely postponed for 4-6 weeks according 
to local standards and treating physician's expertise. 
• All screening measures per Section 7.1 and Section 7.2 should be followed; however, 
to shorten the time until planned surgery, the target for screening period #2 is 14 days 
(+/- 7 days). Note, due to patient specific circumstances the time window can be 
extended if deemed adequate by the treating physician after consultation with the 
Sponsor Medical Monitor.  
• Neoadjuvant EO2401 (full dose SC, 
) 
plus nivolumab (IV infusion at a dose of 3 mg/kg) administered twice with 2 weeks 
interval. The nivolumab infusion is to start 
 after the EO2401 administration. 
o All safety precautions and rules (e.g. treatment stopping rules) apply as for 
Cohorts 2a/2b. 
o Table 1 Schedule of Assessments Cohort 2c should be followed, and 
assessments and procedures as outlined in Section 7.3 for V1 and V2 are also 
guiding. 
o 
 
 
 
 

 
 
 
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o If there would be no possibility to perform surgery as planned after V2, the 
patient can still be evaluated for continued study treatment (from V3 and 
onwards) according to the same rules as for patients in Cohorts 2a/2b; e.g. if the 
MRI at V2 would show progression which does not allow surgery, but the 
patient does still not have significant symptoms (or symptoms can be controlled 
by symptom management, e.g. according to Section 6.3), study treatment may 
continue per the judgement of the treating physician until either confirmation of 
progression according to iRANO criteria, or establishment of PsPD. In the latter 
case, especially in situations of tumor shrinkage (no time limit), a delayed 
surgery can be performed, if in the best interest of the patient per the judgement 
of the treating physician and the patient concur (in such cases an individualized 
planning of study treatments should be done together with the Medical Monitor).  
▪ Note, patients who are not following the overall plan for 
neoadjuvant/adjuvant study treatment including the pre-planned surgery 
are not considered as part of the 6 evaluable patients, but the full 
available data from the patients will be analyzed.  
• Planned surgery of recurrent disease:  
o Surgery, including associated treatments and measures, is a standard-of-care 
procedure outside of the clinical trial EOGBM1-18; it is indicated here to 
explain the treatment gap between the study procedures V2 and V3. Also note, 
surgery of recurrent glioblastoma is a highly individualized procedure and 
therefore exact timing cannot be stipulated; time window between V2 and V3 
is assumed to be approximately 4-6 weeks.  
o The surgery as such including normal pre-, peri-, and post-operative care will 
be considered standard-of-care, and will only be documented in summary 
fashion in the CRF (e.g.  date/time of surgery, type of procedure, outcome of 
procedure, length of primary hospitalization, reasons and lengths for possible 
further hospitalizations, and procedure related MRIs) and not considered 
AE/SAEs as long as the procedures are pre-planned or part of normal 
care/outcome of surgery for recurrent glioblastoma per judgement of the 
treating physician. 
o AEs, and when applicable per normal reporting rules SAEs, for events during 
the surgery period (time between V2 and V3, alternatively until the patient is 
declared to not be fit for further study therapy) will be reported for all events 
with a possible relationship to study drug treatment (irrespective of grade), for 
all surgery complications (irrespective of grade) which are not expected (per 
assessment by the treating physician), surgery complications ≥ Grade 3, and any 
events ≥ Grade 3.  
o In case a patient who has started study therapy cannot continue study therapy, 
e.g. study therapy in the adjuvant setting cannot be initiated after surgery, i.e. in 
case of study treatment discontinuation, a follow-up visit should be completed 
if at all possible (end-of-treatment visit including safety assessments per Table 
1) approximately 30 days after completion of last dose of study treatment.  
o A key item is collection of tissue (for patients in Cohort 2c this is a mandatory 
consent item) from performed surgery for assessment of all applicable 
objectives and endpoints as outlined in Section 2.1 and Section 2.2.  

 
 
 
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• Adjuvant EO2401 
 plus 
nivolumab (IV infusion at a dose of 3 mg/kg) administered twice with 2 weeks interval, 
then switch to EO2401 on a 4-weekly schedule in the boosting phase, and continued 
nivolumab 2-weekly. The nivolumab infusion is to start 
 after the EO2401 
administration. 
o All safety precautions and rules (e.g. treatment stopping rules) apply as for 
Cohorts 2a/2b. 
o Table 1 Schedule of Assessments Cohort 2c should be followed, and 
assessments and procedures as outlined in Section 7.3 for V3 and V4 are also 
guiding, as are visits, assessments, and procedures for the treatment-boosting 
period outlined in Section 7.4. 
• For all patients in Cohort 2c the general safety rules as described above applies, i.e., at 
related clinical Grade 4/5 AEs the study treatment in the individual patient experiencing 
the event will be stopped for Grade 4 AEs and the IDMC will convene, and after 
assessing the situation give recommendations for further actions, and at related Grade 
3 AEs the Investigator responsible for the patient with an event will in collaboration 
with the Sponsor make the initial assessment regarding actions; the IDMC support will 
be requested when appropriate. 
• At the global amendment 2 extended patient management measures are included also 
for Cohort 2c (see Section 6.3).   
 
Cohort 3 (see Figure 7) 
 
 
 
 

 
 
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Cohort 3 is planned to be initiated following a decision by the Sponsor after a recommendation 
from the IDMC based on the review of the safety and tolerability data from Cohorts 2a and 2b 
(see above). Cohort 3 will include administration of EO2401 in combination with nivolumab 
and bevacizumab from the start of treatment in the individual patients for assessment of safety, 
tolerability, immunogenicity, and preliminary efficacy of the combination. A total of 
10 evaluable patients were planned for inclusion in Cohort 3 before global amendment 3 which 
increased the target recruitment to 26 patients. 
Priming injections of EO2401 will be started as soon as possible after confirmation of disease 
progression; study baseline/screening MRI should be done no longer than 14 days before the 
start of treatment (MRI confirming progression of GB might be done earlier). The schedule of 
administration includes SC injections of EO2401 at 2-weekly intervals (4 times total) during 
the priming phase and then 4-weekly in the boosting phase starting from Week 10 (i.e., 4 weeks 
after the fourth administration of EO2401). The dose of EO2401 will depend on the outcome 
of Cohort 1, i.e., it can be either full dose 
 or half 
dose 
 Thus, Cohort 3 should include full dose of EO2401 
 
 
Nivolumab will be administered as an IV infusion at a dose of 3 mg/kg every 2 weeks in 
combination with EO2401 starting from the first priming injection. The nivolumab infusion is 
to start 
 after the EO2401 administration. 
Bevacizumab in Cohort 3 will regarding dose and schedule be used according to the US label 
for patients with recurrent GB.69  
Bevacizumab will be administered as an IV infusion at a dose of 10 mg/kg every 2 weeks, in 
combination with EO2401/nivolumab. Bevacizumab will be administered 
 after the 
start of nivolumab administration per local practice at the study sites and in accordance with 
local labels for bevacizumab (e.g. regarding methods of administration, dilutions, etc.)63, 69.  

 
 
 
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For all patients in Cohort 3, the general safety rules as described above applies, i.e., at related 
clinical Grade 4/5 AEs the study treatment in the individual patient experiencing the event will 
be stopped for Grade 4 AEs and the IDMC will convene and after assessing the situation give 
recommendations for further actions, and at related Grade 3 AEs the Investigator responsible 
for the patient with an event will in collaboration with the Sponsor make the initial assessment 
regarding actions; the IDMC support will be requested when appropriate. 
At the global amendment 2 extended patient management measures are included generally for 
all Cohorts, i.e. also for Cohort 3, but the need for use of low-dose bevacizumab to treat tumor 
edema is assumed to be very limited (see Section 6.3).   
 
3.2. 
Discussion of Study Design 
This is a multicenter, Phase Ib/IIa, FIH study to assess the safety, tolerability, immunogenicity, 
and preliminary efficacy of EO2401 in patients with unequivocal evidence of progressive or 
first recurrent GB confirmed by MRI as defined by the RANO criteria (note: within the first 3 
months after completion of radiotherapy and concomitant temozolomide, diagnosis of 
recurrence can be indistinguishable from PsPD on neuroimaging).66 
The FIH protocol is an open-label multi-cohort study, intended to recruit a maximum of 
approximately 100 evaluable patients in total: 
• Cohort 1 (as study safety lead-in, before global amendment 2) includes an evaluation 
by a 3-by-3 design of EO2401 monotherapy planned to be followed in the same 
individual patients by continued EO2401 in combination with nivolumab; 3 to 12 
evaluable patients will be included depending on the safety profile of the administered 
treatments 
o In the safety lead-in part (3-by-3 design) of the trial, 3 evaluable patients started 
treatment in Cohort 1a, after which the safety lead-in was closed after a 
recommendation from the IDMC, and Cohorts 2a and 2b opened 
o In global amendment 2 (EOGBM1-18 version 3), plus via re-distribution of 
patients from Cohort 2b, 18 evaluable patients were added to Cohort 1a for 
further evaluation of the treatment schedule with a 4-weeks delayed start of 
nivolumab (safety precautions for the added patients will follow the same 
principles as for Cohorts 2a, 2b, 2c, and 3, since Cohort 1a is no longer a safety 
lead-in part of the trial) (recruitment finalized before global amendment 3) 
• Cohorts 2a and 2b are an evaluation of EO2401 in combination with nivolumab planned 
to include approximately 48 evaluable patients in total  
o Before global amendment 2 (EOGBM1-18 version 3), 23 evaluable patients 
started treatment in Cohort 2a (after re-distribution of patients between Cohort 
1 and Cohort 2a to keep a relevant safety database; see further Section 1.2.3) 
o In global amendment 2 (EOGBM1-18 version 3), plus via re-distribution of 
patients from Cohort 2b, 15 evaluable patients were added to Cohort 2a for 
further evaluation of the treatment schedule with simultaneous start of EO2401 
and nivolumab, but with inclusion of extended patient management measures 
(recruitment finalized before global amendment 3) 

 
 
 
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o Cohort 2b was planned to include 15 evaluable patients both before and after 
global amendment 2 (EOGBM1-18 version 3), but number of patients lowered 
to 6 by re-distribution of patients to Cohort 1a and 2a (recruitment finalized 
before global amendment 3) 
• Cohort 2c is a cohort introduced by global amendment 2 (EOGBM1-18 version 3), to 
include 6 evaluable patients to assess safety and feasibility of a neoadjuvant/adjuvant 
treatment strategy including EO2401/nivolumab (both compounds started at the same 
time)   
• Cohort 3 is an evaluation of EO2401 in combination with nivolumab and bevacizumab 
planned to include 10 evaluable patients before global amendment 3 which increased 
the target recruitment to 26 patients. 
 
 
 
 
 
The target population, patients with progressive or first recurrent GB or first recurrent disease, 
utilizing the selected inclusion/exclusion criteria, which are deemed appropriate by leaders in 
the field for an FIH trial of a novel immunotherapy approach, is limited; therefore, this study 
is planned to be conducted across approximately 10 sites. 
There is clearly an unmet medical need for the selected patient population indicated by the very 
limited efficacy of current treatment approaches (see Section 1.3), and thus there is a great 
interest in continued research and to offer new treatment options to these patients. 
In Cohort 1 (as study safety lead-in, before global amendment 2), an in-principle traditional 3-
by-3 design is utilized for the initial safety and tolerability evaluation of the novel compound 
EO2401. However, since it has been clearly indicated for EO2401 in preclinical models that 
efficacy seems dependent on coadministration with CPIs, and similar findings can be found for 
other immunization approaches, it has been judged that an early combination of EO2401 with 
CPI is crucial for a relevant evaluation of the potential to induce adequate immunity in patients 
with established tumors (and also to give the patients some chance to notice any benefit from 
the treatment). Thus, after a short monotherapy period with EO2401, the individual patients, 
even in Cohort 1, are intended to continue treatment with the combination of EO2401 and CPI 
(i.e., nivolumab). 
The more optimal treatment concept, i.e., as early as possible combination of EO2401 with 
CPI, is introduced from the start of Cohorts 2a and 2b where the start of the cohort is dependent 
on adequate safety in patients treated in Cohort 1. The difference between patients to be 
recruited to Cohorts 2a and 2b is governed by inclusion criterion #2 by which patients in Cohort 
2a will have at least one measurable lesion and patients in Cohort 2b will not have any 
measurable enhancing disease. Practically, this means that patients to be recruited to Cohort 2b 
will 
have 
had 
successful 
secondary 
surgery 
for 
their 
post-primary 
treatment 
recurrent/progressive disease before inclusion into the trial. The reason to evaluate the trial 
treatment concept in both Cohorts 2a and 2b is that the outcome might be different in the two 
groups, and principles for how patients with first recurrent/progressed GB are treated are not 
globally uniform.  
After safety has been assessed in the initial patients in Cohorts 2a and 2b, a further cohort, 
Cohort 3, is intended to open, including also the anti-angiogenic treatment bevacizumab, giving 

 
 
 
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the patients a further potential possibility for a prolonged treatment period with the EO2401 
and CPI combination; it is expected that bevacizumab might prolong the time to progression 
and thereby allow an extended number of immunizations to be given. Of note is that the 
bevacizumab containing cohort is only going to include patients in the United States due to 
differences in the labeling of the drug in the United States and Europe.  
Global amendment 2 of the protocol (leading to EOGBM1-18 version 3) includes also a Cohort 
2c to assess safety and feasibility of a neoadjuvant/adjuvant treatment strategy which in other 
trials have shown interesting early signs of efficacy.100, 101 Global amendment 2 also expanding 
the sample size of the trial and introducing extended patient management measures is described 
also in Section 1.2.3.   
Thus, despite the limited efficacy of available treatments, some targeted therapies (e.g., CPI 
and angiogenesis inhibitors) which have shown some signs of efficacy in GB are utilized in the 
current trial to accomplish an early assessment of mainly safety and immunogenicity for 
EO2401 in different contexts. Considering the early nature of the trial, i.e., FIH, no control 
groups without administration of EO2401 will be included, but the information to be gained 
from the combinations might be crucial for the further planning of the development of EO2401 
in GB. 
Safety and tolerability are obviously the main assessment items in this FIH trial, and it is judged 
that the selected design has the possibility to both stringently evaluate early toxicity of EO2401 
monotherapy (via the 3-by-3 design part in Cohort 1), but considering the current immunization 
approach also the long-term impact of induced immunity and the administered drugs (via the 
demand of thorough assessments of related Grade 3/4 AEs for all patients in all cohorts 
throughout all study treatments; general safety rules per Section 3.1). 
Also, beside the active safety oversight of the trial by the Investigators (and their teams) in 
collaboration with the Sponsor via the Medical Monitor (with associated team), an IDMC will 
support the safety monitoring and give recommendations for possible actions in relation to trial 
conduct actions. The IDMC will be called on to assess related ≥ Grade 4 AEs in any patient at 
any time during the trial, or any medically important event as detected and proposed by the 
Investigators or the Sponsor. In addition, further monitoring by the IDMC is mandated in 
relation to the recruitment and treatment of patients in Cohort 1 (as study safety lead-in, before 
global amendment 2), and the IDMC will recommend on possible expansions in Cohort 1, and 
transition from Cohort 1 to 2a and 2b, and from Cohorts 2a and 2b to 3. 
It is acknowledged that the trial is intensive regarding sampling, but considering that the main 
parameter for evaluation in the trial, beside safety, is to analyze EO2401-induced immunity 
and that the tests for such analyzes unfortunately demand relatively high volumes of material 
(e.g., PBMC), it is if the trial should be adequate and relevant to perform a necessity; a 
minimization strategy with regard to sampling has been applied, still without risking to get to 
a trial without an appropriate readout. The future development of the new compound EO2401 
will be directed by the ability to analyze induced immunity adequately and thus this is a key 
aspect of the trial. 

 
 
 
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These results support the use of UCP2 as helper peptide in the 
intended clinical trial with EO2401. 
 

 
 
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In addition, according to the recommendations of the Cancer Vaccine Clinical Trial Working 
Group,89 no dose escalation was planned to be conducted in this trial. 
All together these results support the design of the priming phase of the EO2401 Phase Ib/IIa 
clinical trial 
 the use of the helper peptide 
UCP2, and the regimen of 4 EO2401 administrations (300 g of each peptide) during the 
6 weeks in the priming phase. 
3.5.2. 
Nivolumab 
The recently completed Phase III CheckMate-143 study was the first randomized clinical trial 
in recurrent GB with the PD-1 CPI nivolumab as monotherapy administered at the dosage of 
3 mg/kg. 
Although it did not meet its primary endpoint of improved OS over bevacizumab monotherapy, 
nivolumab may still have a place in the successful treatment of this disease, potentially as 
combination therapy, as a small subset (8%) of patients in the CheckMate-143 study did 

 
 
 
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respond to nivolumab, and with a much longer DoR (11 months) than seen with bevacizumab 
therapy (5.3 months).58, 98 
In the initial development, the dosage for the treatment of the other cancers for which 
nivolumab has obtained the marketed authorization was usually 3 mg/kg. 
In this Phase Ib/IIa study, nivolumab is to be administered at the dosage of 3 mg/kg as IV 
infusion every 2 weeks. 
3.5.3. 
Bevacizumab for continuous combination treatment in Cohort 3 – in US Only 
Bevacizumab will regarding dose and schedule be used according to the US label for patients 
with a recurrent GB.69 
The recommended dosage in the setting is 10 mg/kg every 2 weeks, in Cohort 3 for continuous 
treatment in this Phase Ib/IIa study, bevacizumab is administered at this frequency and at this 
dosage as an IV infusion. 
Note, global amendment 2 (leading to EOGBM1-18 version 3) includes allowance for extended 
patient management measures of tumor site edema for all cohorts, and one component of these 
measures is low-dose bevacizumab; i.e. bevacizumab might also be used as symptomatic 
therapy in Cohorts 1a, 2a, 2b, and 2c, according to the rules outlined in Section 6.3. 

 
 
 
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4. SELECTION OF STUDY POPULATION 
Only patients who meet all of the inclusion criteria and none of the exclusion criteria will be 
eligible to be recruited for this study. Prospective approval of protocol deviations to recruitment 
and enrollment criteria, also known as protocol waivers or exemptions, is not permitted. 
4.1. 
Inclusion Criteria 
To be eligible to participate in the study, patients must meet the following criteria: 
1. Patients with unequivocal documented (including histological confirmation of GB at 
the primary diagnosis) first progression/recurrence of GB on MRI, as defined by RANO 
criteria  
2. Patients with: 
• for Cohorts 1, 2a, and 3: at least 1 measurable lesion  
• for Cohort 2b: no measurable enhancing disease (defined as less than 1x1 cm in 
maximum bi-perpendicular plane) 
• for Cohort 2c: documented recurrence of GB deemed to be candidate for surgery as 
standard-of-care at the local institution, and for which the resection can safely be 
postponed for 4-6 weeks per local institutional guidance and treating physician 
judgement). In addition, for inclusion in Cohort 2c the patient must consent to 
mandatory collection of tissue samples from the time of diagnosis (if logistically 
available), and the planned surgery after neoadjuvant study therapy (see also 
Section 7.1.1). 
o 
 
 
 
 
 
 
 
3. Patients with an age ≥ 18 years old 
4. Patients who are HLA-A2 positive 
5. Patients with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 
or Karnofsky performance status ≥ 70 (see Appendix 3) 
6. Patients should have received standard primary therapy including surgery (biopsy, 
incomplete or complete resection), radiation, temozolomide, if applicable 
a. Radiation therapy must have been finished at least 28 days before first study 
treatment administration 
b. Patients who received temozolomide as adjuvant therapy must have stopped the 
treatment and have a wash-out period of at least 28 days before first study treatment 
administration (6 weeks for nitrosoureas and at least 4 weeks, or 5 half-lives if 
longer, for experimental therapies, if this type of therapies have been included as 
components of adjuvant therapy) 
c. Patients with unmethylated methylguanine-DNA-methyltransferase (MGMT) 
promoter can be included even if they have not received temozolomide prior to the 
inclusion in this clinical study. 
 

 
 
 
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7. Female patients of childbearing potential must have a negative serum pregnancy test 
within 72 hours prior to dosing 
8. Considering the embryofetal toxicity of the nivolumab shown on animals’ models, the 
following recommendations for contraception must be followed: 
a. If not surgically sterile, female patients of childbearing potential age must use 
highly effective contraception from signing the Informed Consent Form (ICF) 
through 6 months after the last treatment dose administered. Highly effective 
contraception included: 
i. Combined (estrogen and progesterone containing) hormonal contraception 
associated with inhibition of ovulation: 
▪ Oral 
▪ Intravaginal 
▪ Transdermal. 
ii. Progestogen-only hormonal contraception associated with inhibition of 
ovulation: 
▪ Oral 
▪ Injectable 
▪ Implantable. 
iii. Intrauterine device 
iv. Intrauterine hormone-releasing system 
v. Bilateral tubal occlusion 
vi. ectomized partner 
vii. Sexual abstinence. 
In each case of delayed menstrual period (over 1 month between menstruations), 
confirmation of absence of pregnancy is strongly recommended. This recommendation 
also applies to women of childbearing potential with infrequent or irregular menstrual 
cycles. 
b. If not surgically sterile, male with female partner of childbearing potential age must 
use condom from signing the ICF through 8 months after the last treatment dose 
administered. Males must ensure that their partners of childbearing potential use 
highly effective contraception also 
9. Patients having received the information sheets and who have provided written 
informed consent prior to any study-related procedures 
10. Patients willing and able to comply with the scheduled visits, treatment plan, laboratory 
tests, and other study procedures indicated in the protocol. 

 
 
 
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4.2. 
Exclusion Criteria 
Patients who meet any of the following criteria will not be eligible to participate in the study: 
1. Patients treated with dexamethasone > 2 mg/day or equivalent (i.e., 13 mg/day of 
prednisone) within 14 days before the first EO2401 administration, unless required to 
treat an AE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. Patients treated with radiotherapy, and cytoreductive therapy within 28 days (6 weeks 
for nitrosoureas) before the first EO2401 administration. In addition, patients should 
not have received any prior treatment with compounds targeting PD-1, PD-L1, CTLA-
4, or similar compounds where general resistance against therapeutic vaccination 
approaches might have developed; patients should not have received systemic anti-tumor 
treatment or radiotherapy for their progressive or first recurrent GB 
3. Patients with tumors primarily located in the infra-tentorial segment 
4. Patients with known radiological evidence of extracranial metastases 
5. Patients with presence of new intracranial hemorrhage (excluding, stable Grade 1) or 
uncontrolled seizure 
6. Patients with significant leptomeningeal disease 
7. Patients with abnormal (≥ Grade 2 NCI-CTCAE v5.0) laboratory values for 
hematology, liver, and renal function (serum creatinine). In detail, the following values 
apply as exclusion criteria: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 laboratory values judged by the treating 
physician as clinically non-relevant 
8. For patients who are planned to receive bevacizumab: 
a. Patients with nephrotic syndrome 

 
 
 
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b. Patients with proteinuria ≥ 2g/24 hours 
c. Patients with history or active gastrointestinal perforation and fistula 
d. Significant surgical procedure in the 4 weeks preceding the start of treatment or 
planned surgery 
e. Unhealed wound 
f. Patient with recent (4 weeks) history of hemoptysis of ½ teaspoon or more of red 
blood 
g. Thrombotic episode within 6 months 
h. Uncontrolled diabetes mellitus or hypertension 
i. Posterior Reversible Encephalopathy Syndrome 
9. Patients with persistent Grade 3 or 4 toxicities (according to NCI-CTCAE v5.0). 
 
 
 
10. Patients with contraindication to contrast-enhanced MRI 
11. Other malignancy or prior malignancy with a disease-free interval of less than 3 years 
except those treated with surgical intervention and an expected low likelihood of 
recurrence such as basal cell or squamous cell skin cancer, or carcinoma in situ. Patients 
with adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ are 
eligible 
12. Patients with clinically significant active infection, cardiac disease, significant medical 
or psychiatric disease/condition that, in the opinion of the Investigator, would interfere 
with the evaluation of EO2401 or interpretation of patient safety or study results or that 
would prohibit the understanding or rendering of informed consent (i.e. only consent 
able patients can be  enrolled in the study) and compliance with the requirements of 
the protocol – including (but not limited to): 
a. Bacterial sepsis or other similarly severe infections 
b. New York Heart Association > Grade 2 congestive heart failure within 6 months 
prior to study entry (see Appendix 4) 
c. Uncontrolled or significant cardiovascular disease, including: 
i. Myocardial infarction within 6 months prior to obtaining informed consent 
ii. Uncontrolled/unstable angina within 6 months prior to obtaining informed 
consent 
iii. Diagnosed or suspected congenital long QT syndrome 
iv. Any history of clinically significant ventricular arrhythmias (such as ventricular 
tachycardia, ventricular fibrillation, or Torsades de pointes). 
d. Stroke within 6 months prior to obtaining informed consent 
e. Concurrent neurodegenerative disease 
f. Dementia or significantly altered mental status. 

 
 
 
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Screen failures are defined as patients who consent to participate in the clinical study but are 
not subsequently included in the analysis population due to failure of the eligibility criteria. A 
minimal set of Screen failure information is required to ensure transparent reporting of Screen 
failure patients to meet the Consolidated Standards of Reporting Trials publishing requirements 
and to respond to queries from regulatory authorities. Minimal information includes 
demography, Screen failure details, eligibility criteria, and any SAEs. 
Patients who are HLA-A2 negative will have a “Screen failure” status. HLA-A2 testing will be 
performed locally. 
Patients who have laboratory abnormalities may be rescreened at the discretion of the 
Investigator. 
4.3.2. 
Discontinuation of Study Treatment and Patient Discontinuation 
The Investigator has the right to discontinue a patient from study treatment or withdraw a 
patient from the study at any time after discussing it with the Sponsor. In addition, patients 
have the right to voluntarily discontinue study treatment or withdraw from the study at any 
time at his/her request for any reason. In instances where consent is withdrawn, the Investigator 
must clarify whether the patient is willing to continue to be followed (i.e., for survival). 
Patients who discontinue study treatment prematurely will be asked to return to the clinical for 
follow-up assessments (see Section 7.4.5). The primary reason for premature study drug 
treatment discontinuation should be documented on the appropriate electronic Case Report 
Form (eCRF). 
Reasons for discontinuation of study treatment may include, but are not limited to: 
• Confirmed tumor/disease progression 
• Any medical condition that the Investigator or Sponsor determines may jeopardize the 
patient’s safety if he/she continues trial treatment 
• AEs requiring discontinuation 
• Pregnancy 
• Major protocol deviation (i.e., affecting the patient’s safety) 
• Investigator or Sponsor determines it is in the best interest of the patient 
• Patient noncompliance to study scheduled visits and assessments according to the 
Investigator 
• Patient withdrawal of consent to receive further study treatment. 
Reasons for withdrawal from the study may include, but are not limited to: 
• Patient withdrawal of consent to be followed up 
• Patient lost to follow-up 
• Study termination by the Sponsor or regulatory authorities. 

 
 
 
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4.3.3. 
Discontinuation of Study Treatment 
Patients who discontinue study treatment prematurely will be asked to return to the clinic for 
follow-up assessments (see Section 7.4.5). The primary reason for premature study drug 
treatment discontinuation should be documented on the appropriate eCRF. 
A patient must be withdrawn from the study for the following reasons: 
• Withdrawal of informed consent 
• If IDMC request study discontinuation due to an SAE/AE 
• For childbearing females, confirmation of pregnancy 
• Confirmed tumor/disease progression. 
A patient may be withdrawn for the following reasons: 
• Protocol violations that may impact the outcome of the study 
• Investigator’s discretion 
• Sponsor or regulatory authorities’ decision. 
4.3.4. 
Lost to Follow-up 
A patient will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible, counsel the patient on the importance of maintaining the assigned visit 
schedule, and ascertain whether or not the patient wishes to and/or should continue in 
the study. 
• In cases in which the patient is deemed lost to follow-up, the Investigator or designee 
must make every effort to regain contact with the patient (where possible, 3 telephone 
calls and, if necessary, a certified letter to the patient’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the 
patient’s medical record and in the eCRF. 
4.3.5. 
Follow-up of Patients Prematurely Discontinued from the Study Treatment 
Regimen or Withdrawn from Study 
Every effort should be made to obtain information on patients who withdraw from the study. 
The primary reason for withdrawal from the study should be documented on the appropriate 
eCRF. Patients will not be followed for any reason after informed consent has been withdrawn, 
although date of death should be recorded, where applicable and possible to retrieve. 
Patients who discontinue from the study treatment regimen will be asked to complete the final 
study procedures (see Section 7.4.5), or if the patient is unable to attend a study visit, then a 
follow-up telephone call will take place. All AEs/SAEs that are ongoing at the time of 
discontinuation, or that develop prior to the final scheduled follow-up telephone call, will be 
followed for 30 days, or until resolution or stabilization. 

 
 
 
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4.4. 
Study Termination 
The Sponsor reserves the right to close a study site or terminate the study at any time for any 
reason at the sole discretion of the Sponsor. Study sites will be closed upon study completion. 
A study site is considered closed when all required documents and study supplies have been 
collected and a study site closure visit has been performed, except for the sites without any 
patients included which could be administratively closed by a close-out letter. 
Reasons for study termination may include, but are not limited to: 
• AEs unknown to date (i.e., not previously reported in any similar investigational study 
drug trial with respect to their nature, severity, and/or duration) 
• Increased frequency and/or severity and/or duration of known, anticipated, or 
previously reported AEs (this may also apply to AEs defined as baseline signs and 
symptoms) 
• Medical or ethical reasons affecting the continued performance of the study 
• Difficulties in the recruitment of patients 
• Cancellation of drug development. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. Reasons for the early 
closure of a study site by the Sponsor or Investigator may include, but are not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) or local health 
authorities, the Sponsor's procedures, or Good Clinical Practice (GCP) guidelines 
• Inadequate recruitment of participants by the Investigator. 

 
 
 
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5. STUDY TREATMENTS 
5.1. 
Treatments Administered 
 
 
 
 
Cohort 1 
In the priming phase, patients included in sub-cohorts 1a and 1b will receive an SC injection 
of 
 EO2401 
 
 every 2 weeks for a total of 
4 injections. This will be followed by a boost phase with 1 administration every month starting 
4 weeks after the final priming injection and continued until confirmed tumor progression, 
intolerable toxicity, death, Investigator or patient decision, or early termination of the study at 
the request from the Sponsor, where study treatment will be stopped and appropriate standard 
of care will be initiated by the Investigator. 
In sub-cohorts 1a and 1b, the full dose of EO2401 
 will be 
administered and in sub-cohorts 1c and 1d it is a half dose that will be administered 
 
 
• In a rotating way by injection (so an injection site will be used every fourth time), with 
the injection sites being right and left upper extremity and right and left lower 
extremity/inguinal area, with the more specific locations being: 
o For upper extremity = SC injection in the area of armpit, or deltoid muscle of arm, 
depending on the constitution of the patient 
o For lower extremity = SC injection in the area of groin, or anterolateral thigh muscle, 
depending on the constitution of the patient. 
The CPI nivolumab will start at the third priming injection (i.e., at Week 4) as an IV infusion 
at a dose of 3 mg/kg every 2 weeks in combination with EO2401. Implantation of a port-a-cath 
can be considered by the site to administer nivolumab. 
For further information on administration of nivolumab, refer to the European SmPC or the US 
PI for nivolumab.59,60 
EO2401 will be injected 
 from the start of the reconstitution. 
EO2401 will be administered first followed by nivolumab, 
 
Cohorts 2a and 2b 
The dose of EO2401 will be determined in Cohort 1 (as study safety lead-in, before global 
amendment 2) and 
 
 
 
given as an SC injection at 2-weekly intervals (4 times 
total) during the priming phase and then 4-weekly starting from the final priming injection in 

 
 
 
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the boosting phase until progression, death, Investigator or patient decision, or early 
termination of the study, where study treatment will be stopped and appropriate standard of 
care will be initiated by the Investigator. 
 
 
 
Nivolumab will be administered as an IV infusion at a dose of 3 mg/kg every 2 weeks in 
combination with EO2401 starting from the first priming injection. Implantation of a port-a-
cath can be considered by the site to administer nivolumab. 
For further information on administration of nivolumab, refer to the European SmPC or the US 
PI for nivolumab.59,60 EO2401 will be administered first followed by nivolumab, 
 
Cohort 2c 
Neoadjuvant EO2401 
 plus 
nivolumab (IV infusion at a dose of 3 mg/kg) will be administered twice with 2 weeks interval.  
There will be a study-specific MRI at the day of the second dose of EO2401/nivolumab (V2) 
to ensure that the tumor is still suited for the intended surgery. 
After planned surgery of recurrent disease and adequate recovery, adjuvant EO2401
 
 plus nivolumab (IV infusion at a dose of 
3 mg/kg) will be administered twice with 2 weeks interval, then switch to EO2401 on a 4-
weekly schedule in the boosting phase and continued nivolumab 2-weekly.  
The nivolumab infusions are to start 
 after the EO2401 administration. 
The specifics of Cohort 2c are outlined in Section 3.1, and for further information on 
administration of nivolumab, refer to the European SmPC or the US PI for nivolumab.59,60  
 
Cohort 3 
 
 
 
 
Cohort 3 is planned to be initiated after a review of the safety and tolerability data from Cohorts 
2a and 2b (see Section 3.1), and will include administration of EO2401 in combination with 
nivolumab and bevacizumab from the start of treatment in the individual patients. 
EO2401 and nivolumab administration schedules and doses are the same as in Cohorts 2a and 
2b. 
Bevacizumab will be administered as an IV infusion at a dose of 10 mg/kg every 2 weeks in 
combination with EO2401 and nivolumab. 

 
 
 
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The sequence of administration will be starting with EO2401, followed 
 later the 
infusion of nivolumab, which will be followed 
 by the bevacizumab 
administration. 
For further information on administration of nivolumab and bevacizumab, refer to the US PIs 
and EU SmPCs for nivolumab and bevacizumab, respectively.59,60,63,69 
 
5.2. 
Investigational Medicinal Product (EO2401) 
5.2.1. 
Pharmaceutical Form 
The IMP of the study, EO2401, 
 containing 
4 peptide drug substances 
 
 
The final concentration of each peptide is 300 µg/mL. 
Further details are provided in the EO2401 Investigator Brochure.62 
5.2.2. 
Preparation of the Formulation 
The IMP is provided to the clinical sites 
 
 
 
 
 
 
 

 
 
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Labcorp Study: 43625 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.2.3. 
Administration 
EO2401 will be injected 
 from the start of the reconstitution. Each SC injection 
must be administered at different sites as described in Section 5.1. 
5.2.4. 
Packaging and Labeling 
The final emulsified EO2401 DP in adjuvant will be reconstituted by the investigational site 
pharmacy, following instructions described in the Pharmacy Manual. 
Adequate supplies of the study will be provided to each investigational site for reconstitution. 
EO2401 will be manufactured as per Good Manufacturing Practice (GMP) and supplied by the 
Sponsor as a Mixing Kit consisting of 2 component glass vials plus additional material. 

 
 
 
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For all vials, a system in accordance with GMP will be used; ensuring each dose of EO2401 
can be traced back to the respective bulk ware of the ingredients. A complete record of batch 
numbers and expiry dates of all study drugs and labels will be maintained in the Sponsor’s 
study file. 
A detailed process for ordering the IMP, handling and administration, packaging, and labeling 
the IMP will be specified in the Pharmacy Manual. 
5.2.5. 
Storage and Stability 
The study treatment must be stored in a secure limited access area according to local regulations. 
The study treatment is presented as a Mixing Kit, in 2 boxes: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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5.4. 
Nivolumab 
5.4.1. 
Pharmaceutical Form 
Nivolumab is sterile concentrate solution for infusion administration. The solution is clear to 
opalescent, colorless to pale yellow liquid that may contain a few light particles. The solution 
has a pH of approximately 6.0 and an osmolality of approximately 340 mOsm/kg. 
List of excipients includes: sodium citrate dehydrate, sodium chloride, mannitol (E421), 
pentetic acid (diethylenetriaminepentaacetic acid), polysorbate 80, sodium hydroxide (for pH 
adjustment), hydrochloric acid (for pH adjustment), water for injections. 
Refer to the SmPC and/or US PI for nivolumab. 59,60 
5.4.2. 
Administration of Infusion 
EO2401 will be administered first followed by nivolumab, 
 The prescribed dose 
for this study is 3 mg/kg every 2 weeks in combination with EO2401. 
Nivolumab infusion must not be administered as an IV push or bolus injection. Administer the 
nivolumab infusion IV over a period of 30 or 60 minutes depending on the dose, or according 
to local standard practice. The infusion should not be infused at the same time in the same IV 
line with other agents. A separate infusion line for the infusion should be used. 
An infusion set and an in-line, sterile, non-pyrogenic, low protein binding filter (pore size of 
0.2 to 1.2 μm) should be used. Nivolumab infusion is compatible with PVC and polyolefin 
containers, glass bottles, PVC infusion sets, and in-line filters with polyethersulfone 
membranes with pore sizes of 0.2 to 1.2 µm. 
Nivolumab will be co-administered starting with the third priming injection in Cohort 1 and 
from the beginning of the priming phase in Cohorts 2 and 3. 
After administration of the nivolumab dose, flush the line with sodium chloride 9 mg/mL 
(0.9%) solution for injection, or 50 mg/mL (5%) glucose solution for injection, or according to 
local standard practice. Refer to the SmPC and PI for nivolumab. 59 ,60 
Implantation of a port-a-cath can be considered by the site to administer nivolumab. 
Each mL of this medicinal product contains 0.1 mmol (or 2.5 mg) sodium, this should be taken 
into consideration when treating patients on a controlled sodium diet. 
5.4.3. 
Package and Labeling 
Nivolumab (ready-to-use) will be obtained by commercial sources and clearly labeled for use. 

 
 
 
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Adequate supplies of nivolumab in 4 and 10 mL glass vials will be provided to each 
investigational site for preparation and infusion. The vial stopper will be a coated butyl rubber 
with a grey aluminum flip-off seal. 
A detailed process for handling and administration of nivolumab will be specified in the 
SmPC.59 
5.4.4. 
Storage and Stability 
Nivolumab should be stored in the refrigerator at 2°C to 8°C in its original package in order to 
protect from light. Once opened, the medicinal product should be infused or diluted, and 
infused immediately.59 ,60 
If not used immediately, chemical and physical in-use stability of nivolumab has been 
demonstrated for 24 hours at 2°C to 8°C protected from light and a maximum of 8 hours at 
20°C to 25°C with room light (this 8-hour period of the total 24 hours should be inclusive of 
the product administration period). 
5.5. 
Bevacizumab 
Bevacizumab at the full labelled dose in the US (US PI69) will be administered to patients 
recruited to Cohort 3 at sites in the United States. The compound will be prescribed by the 
responsible physician at the site in the United States. All procedures for Cohort 3 regarding 
bevacizumab administration at sites in the USA will be according to local site accepted 
documented standards or the US PI.69 
After implementation of global amendment 3 (to protocol version 4) sites in Europe will also 
be allowed (provided all applicable authority approvals are received) to recruit patients to 
Cohort 3.  
Bevacizumab for use at European sites  will be considered as an IMP and will consequently be 
obtained by the Sponsor via commercial sources and clearly labeled for use. Adequate supplies 
of bevacizumab will be provided to each European investigational site for preparation and 
infusion. A detailed process for handling and administration of bevacizumab is specified in the 
European SmPC.63 All procedures for Cohort 3 regarding bevacizumab administration at sites 
in Europe will be according to local site accepted documented standards or the European 
SmPC.63  
5.5.1. 
Pharmaceutical form 
Bevacizumab is a concentrate for solution for infusion containing 25 mg/ml of bevacizumab. 
Generally, bevacizumab must not be administered or mixed with dextrose solution. The 
necessary amount of bevacizumab should be withdrawn and diluted to the required 
administration volume with sodium chloride 9 mg/ml (0.9%) solution for injection. The 
concentration of the final bevacizumab solution should be kept within the range of 1.4 mg/ml 
to 16.5 mg/ml. In the majority of the occasions the necessary amount of bevacizumab can be 
diluted with 0.9 % sodium chloride solution for injection to a total volume of 100 mL. 
Bevacizumab first infusion IV will be administered according to local standard practice. 

 
 
 
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No incompatibilities between bevacizumab and polyvinylchloride or polyolefin bags have been 
observed. 
Bevacizumab will be administered as an IV infusion at a dose of 10 mg/kg every 2 weeks in 
combination with EO2401 and nivolumab. 
Bevacizumab will be administered 
 after the start of nivolumab administration per 
local practice.  
Low-dose bevacizumab, implemented by the global amendment 2 (leading to EOGBM1-18 
version 3), may be used for management of tumor edema in all cohorts per the specific 
initiation, dose, time, and duration description in Section 6.3. All procedures for administration 
of bevacizumab also at a low-dose will be according to local site accepted documented 
standards or the SmPC or US PI. 63, 69 
5.5.2. 
Storage and stability 
Bevacizumab must be stored in refrigerator (+2°C to +8°C) in the outer carton in order to 
protect from light. 
Once diluted, the chemical and physical in-use stability has been demonstrated for 30 days at 
+2°C to +8°C plus an additional 48 hours at +2°C to +30°C in sodium chloride 9 mg/ml (0.9%) 
solution for injection. From a microbiological point of view, the product should be used 
immediately. If not used immediately, in-use storage times and conditions are the responsibility 
of the user and would normally not be longer than 24 hours at +2°C to +8°C, unless dilution 
has taken place in controlled and validated aseptic conditions. 
5.6. 
Study Treatment Accountability, Reconciliation, and Return 
Upon completion and termination of the study, all unused and/or partially used study treatment 
must be returned to the Sponsor or other authorized party if not authorized by the Sponsor to 
be destroyed at the site. 
All study treatments returned to the Sponsor or other authorized party must be accompanied by 
the appropriate documentation and be clearly identified. Study treatment may only be returned 
after drug accountability is completed. Returned supplies should be in their original containers 
(component vials that have clinical labels attached). 
Empty vials should not be returned to the Sponsor. Empty vials may not be destroyed until 
drug accountability is completed. It is the Investigator’s responsibility to arrange disposal of 
all empty vials according to the institutional regulations. 
The return or destruction of unused study treatment should be arranged by the site Monitor. 
5.7. 
Study Treatment Handling and Disposal 
The Sponsor will be responsible for ensuring that the quality of the study treatment is adequate 
for the duration of the study. 
It is the responsibility of the Investigator or designee to ensure that the study treatment is only 
dispensed to the patient. The study treatment must be dispensed from official study sites by 
authorized personnel according to local regulations. The Investigator or designee must 

 
 
 
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maintain accurate records of the study treatment receipt, dispensing information, and 
disposition. 
If study treatment is to be destroyed at the site, it is the Investigator’s or designee’s 
responsibility to ensure that arrangements have been made for disposal, drug accountability 
has been completed by the site Monitor, procedures for proper disposal have been established 
according to applicable regulations, guidelines, and institutional procedures, and appropriate 
records of the disposal have been documented and provided to the Sponsor or designee. 
Further guidance and information for the final disposition of unused study treatment are 
provided in the pharmacy binder. 
5.8. 
Method of Treatment Assignment 
This is an open-label, nonrandomized trial and each newly enrolled patient will be assigned a 
unique patient identification number and assigned to the treatment after approval of eligibility, 
where applicable, on a first-come first-served basis. Slot assignments will be managed via a 
cohort management plan. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study treatment will be dispensed at the study visits summarized in the Schedule of 
Assessments (Table 1A and Table 1B). 
Patients evaluable for safety and AEs will include all patients who have received at least 1 dose 
of EO2401. Patients who are not considered evaluable for safety will be replaced. Patients 
evaluable for efficacy based on the PP population will consist of any patients who received at 
least 
 (EO2401 alone or EO2401 in combination with CPI nivolumab or 
nivolumab/bevacizumab) for whom no important protocol deviations occurred and have at least 
1 evaluable post-Screening tumor assessment. Patients who are not considered evaluable for 
the PP population will not be replaced and be included in the FAS. 
Patients who are not considered evaluable for safety will be replaced and given a new 
identification number. Patients will be replaced until the desired number of evaluable patients 
is achieved in this study. The patient’s inclusion log will be filled in with patients that are 
included in the study but not considered as evaluable. 

 
 
 
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5.8.1. 
Dose Modifications, Permanent Discontinuation of Treatment, or Treatment 
Delay 
5.8.1.1. 
Dose Reductions 
The only adjustments regarding dose for the EO2401 combination partners nivolumab and 
bevacizumab are withholding of 1 or several doses, or discontinuation of treatment; such 
measures should be taken in accordance with the labeled recommendations in the European 
SmPC 59,63 or the US PI60,69, which are available for both compounds. Dose adjustments for 
EO2401 are also including the potential of withholding one or several doses (see Section 
7.6.1.1), or discontinuation of treatment. In addition, a lowered dose might be applied in the 
potential transition from sub-cohort 1b to sub-cohort 1c in relation to safety events (the dose 
of EO2401 will then be halved).  
5.8.1.2. 
Treatment Delay 
Dosing delay or discontinuation for nivolumab and/or bevacizumab may be required based on 
individual safety and tolerability. Guidelines for permanent discontinuation or withholding of 
doses are described in Table 6 in Section 7.6.1.1. 
5.8.1.3. 
Treatment Discontinuation 
For 
patients 
receiving 
a 
combination 
of 
EO2401 
+ 
nivolumab 
or 
EO2401 + nivolumab + bevacizumab, the treatment will continue according to schedule with 
EO2401 (and bevacizumab when applicable) even if nivolumab is temporarily withheld or 
discontinued, and likewise the treatment will continue according to schedule with EO2401 (and 
nivolumab when applicable) even if bevacizumab is temporarily withheld or discontinued. If 
EO2401 would be stopped, the other drugs in the combination will also be stopped in the 
context of being trial treatment. In such cases, the Investigator responsible for the patient in 
question will advise on adequate further treatment options. 
5.9. 
Blinding 
This is an open-label study; blinding procedures are not applicable. 
5.10. Treatment Compliance 
Since all treatments are administered at the clinical site by site personnel, the Investigator or 
designee must maintain accurate records of all study treatments, including dates of study drug 
receipt, quantities received and dispensed, and batch/lot numbers. In addition, the study 
treatment must be noted in the patient’s medical records and eCRF, with the date and time of 
administration and dose of each study treatment. 

 
 
 
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6. PRIOR AND CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Prior and Concomitant Therapy 
The Investigator must record the use of all prior and concomitant medications or vaccines taken 
during 30 days prior to signing informed consent and for the duration of the study both 
prescribed and over-the-counter, including herbal remedies in the source documents and eCRF 
along with: 
• Reasons for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency. 
In case of medical need for a new surgical resection, all details must be collected in the eCRF. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Patients should be discouraged from starting any new medication, both prescribed and 
over-the-counter, including herbal remedies without consulting the Investigator unless the new 
medication is required for emergency. 
See Section 3.1 regarding additional documentation requirements for concomitant therapies in 
Cohort 2c in relation to planned surgery. 
6.2. 
Prior and Concurrent Illness 
The Investigator should document all prior significant illnesses that are relevant to patient 
safety or that the patient has experienced prior to Screening. 
Additional illnesses present at the time of informed consent are to be regarded as concomitant 
illnesses. 
Illnesses first occurring or detected during the study and/or worsening of a concomitant illness 
during the study are to be documented as AEs on the eCRF and as SAEs if case seriousness 
criteria are met. 
6.3. 
Permitted Concomitant Medications 
All noncancer therapies that the responsible physician feels are appropriate are allowed in this 
study, except for the medications listed below in Section 6.5. 
Administration of steroids through a route known to result in a minimal systemic exposure 
(topical, intranasal, intro-ocular, or inhalation) is acceptable. 
In case of infusion-related reactions after the first patient is enrolled, administration of 
paracetamol and/or antihistaminic drugs is acceptable. Please refer to Appendix 7. 
Patients should receive full supportive care during and after the administration of EO2401 
injection and nivolumab or nivolumab/bevacizumab or standard of care treatment per local 
practice and according to the judgment of the Investigator or treating physician. 

 
 
 
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The use of systemic corticosteroids and other immunosuppressants at baseline, before starting 
nivolumab, should be avoided because of their potential interference with the 
pharmacodynamics activity. However, systemic corticosteroids and other immunosuppressants 
can be used after starting nivolumab to treat immune-related adverse reactions (see Section 
7.6.1.1). Dosage, frequency, dates of administration, and route of administration must be 
recorded in the dedicated eCRF pages. Preliminary results show that systemic 
immunosuppression after starting nivolumab treatment does not appear to preclude response 
on nivolumab. 
Nivolumab should not be resumed while the patient is receiving immunosuppressive doses of 
corticosteroids or other immunosuppressive therapy. Prophylactic antibiotics should be used to 
prevent opportunistic infections in patients receiving immunosuppressive therapy.60 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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Recommendations regarding vaccination against SARS-CoV-2/COVID-19 
 The Sponsor recommends strongly that patients if possible are vaccinated against SARS-
CoV-2/COVID-19 before inclusion into the study. If vaccine is available for only one 
vaccine administration before study inclusion this is also recommended, and in such cases 
the timing of the second vaccine administration (and potential further doses) are to be 
discussed and agreed with the Medical Monitor. The recommended time interval between 
a COVID-19 vaccine administration and the initial study drug administration is 2 weeks, 
however, other trial exclusion criteria should also be considered (e.g. regarding patients 
with persistent Grade 3 or 4 toxicities) when assessing possible timing of start of study 
treatment in relation to COVID-19 vaccine administration. 
 
• For patients who have not been vaccinated against SARS-CoV-2/COVID-19 before study 
inclusion, but vaccine becomes available for them during their study participation, or a 
booster dose of SARS-CoV-2/COVID-19 vaccine is deemed necessary, the Sponsor also 
strongly recommends vaccination.  For such patients the Sponsor recommends 
administration of the first dose of the COVID-19 vaccine during the boosting phase 
(EO2401 administered every 4 weeks), 2 weeks after the latest EO2401 administration (and 

 
 
 
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thereby 2 weeks before the next EO2401 administration), and in a different location [Note, 
if this time schedule would lead to unnecessarily long waiting time for COVID-19 
vaccination, alternative administration time points should be discussed with the Medical 
Monitor]; the time interval between administrations of a COVID-19 vaccine and 
nivolumab is recommended to be at least 2 days before the nivolumab 
administration  during the boosting phase (EO2401 administered every 4 weeks)  and in a 
different location. An alternative option, for patients in EOGBM1-18 and being in the 
boosting period could also be to not administer one dose of nivolumab (in this case the visit 
has to be run as planned to obtain the safety laboratory data sampling documented and the 
lack of nivolumab administration has to be related to the COVID-19 vaccination in the 
eCRF). 
 
• The currently (2021-03-24) by US Food and Drug Administration (FDA) and European 
Medicines Agency (EMA) approved COVID-19 vaccines are acceptable for use in the 
trial (local restrictions per country specific authority of course takes precedence): 
 
COVID-19 
Vaccine developer/ 
manufacturer 
Vaccine 
platform 
Type of 
candidate 
vaccine 
Number 
of doses 
(base) 
Timing 
between 
doses* 
Route of 
administration 
University of 
Oxford/AstraZeneca 
Non- 
Replicating 
Viral Vector 
ChAdOx1-S 
2 
28 days 
IM 
Moderna/NIAID 
RNA 
LNP- 
encapsulated 
mRNA 
2 
28 days 
IM 
BioNTech/Fosun 
Pharma/Pfizer 
RNA 
3 LNP-
mRNAs 
2 
21 days 
IM 
Johnson & 
Johnson/ Janssen 
Non- 
Replicating 
Viral Vector 
Ad26.COV2-
S 
1 
NA 
IM 
* Local country/site timing between doses might be different from what is stated in the table. 
 
6.4. 
Contraception 
Where sexually active, female patients of childbearing potential, or male patients with 
reproductive capacity and partners of childbearing potential, must be willing to use an 
acceptable method of contraception (see inclusion criteria) from the signing of the ICF through 
6 months (female)/8 months (male) after receiving the last dose of study drug. Acceptable 
contraception methods include a sterile sexual partner, hormonal contraceptives (oral, 
injection, transdermal patch, or implant), or intrauterine device. Refer to the inclusion criterion 
in Section 4.1 for a list of highly effective contraception. 
Postmenopausal status will be confirmed with a Screening serum follicle-stimulating hormone 
(FSH) level > 40 mIU/mL. 
6.5. 
Prohibited Concomitant Medications 
Patients are not permitted to take those medications specified in the exclusion criteria 
(Section 4.2), and the following below: 

 
 
 
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• Other investigational agents or participate in a device study within 28 days prior to 
enrollment or receive systemic anticancer therapy within 28 days and during the study, 
and will make best efforts not to start any other investigational product or device study 
within 30 days after last drug administration.  
o Note, for investigational agents there should be a wash-out period of at least 28 
days, or 5 half-lives if longer, before first study treatment administration.  
• Dexamethasone > 2 mg/day or equivalent (i.e., 13 mg/day of prednisone) within 14 
days before the first EO2401 administration, unless required to treat an AE 
The following are not permitted from 28 days prior to and during study drug administration: 
• Treatment with PD(L)-1, immunotherapy, radiotherapy, and/or any other 
investigational agents (does not apply to the defined study medications nivolumab and 
bevacizumab) 
o Note, patients should not have received any prior treatment with compounds 
targeting PD-1, PD-L1, CTLA-4, or similar compounds where general 
resistance against therapeutic vaccination approaches might have developed. 
• Other systemic anticancer therapy within 28 days or 5 half-lives if longer, prior to study 
entry, whichever is shorter 
• Live or attenuated vaccines 
• Immunostimulatory or immunosuppressive medications, including herbal remedies, or 
herbal remedies known to potentially interfere with major organ function 
 
Note, the use of high dose dexamethasone has been incorporated as part of measures to treat 
significant neurological symptoms, see Section 6.3, and such treatment is thereby not 
prohibited.   

 
 
 
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7. STUDY ASSESSMENTS AND PROCEDURES 
Study procedure and their timings are summarized in the Schedule of Assessments for 
Cohorts 1, 2 and 3 (Table 1). A visit window of ± 2 days, if nothing else stated in relation to 
Table 1, has been included in this study. As protocol waivers or exemptions are not allowed, 
with the exception of immediate safety concerns, these should be discussed with the Sponsor 
immediately upon occurrence or awareness to determine if the patient should continue or 
discontinue the study drug. Adherence to the study design requirements, including those 
specified in the Schedule of Assessments, is essential and required for study conduct. 
 
 
 
  
 
 
 
 
 
 
7.1. 
Screening Period #1 
The trial will include a 2-stage consent and screening procedure. 
The first minimized consent, and screening period #1, is related to the procedure of HLA-
testing, and before testing also establishing based on available information that the patient has 
eligible glioblastoma and an age ≥ 18 years. 
HLA-testing can be performed within the scope of the trial, but HLA-information based on 
testing before the screening period is also acceptable (no time limit is applied; patients with 
prior hematopoietic stem cell transplantation are not eligible for the trial). 
HLA-testing will be performed locally; information regarding the local lab, including methods 
used will be collected. Low resolution HLA-typing (i.e. genotyping of the HLA-A loci 2 to 2 
digits) is considered satisfactory for trial enrolment. However, 4-digit resolution typing is 
preferred; also, a more complete HLA-typing is preferred.   
All information available regarding the individual patient MHC-composition will be collected, 
i.e. also information beside the HLA-A type. Patients who are not HLA-A2 positive will be 
assigned a “screen failure”-status and not continue any further trial procedures; such patients 
will be replaced. 
7.2. 
Screening period #2 
The second stage of the consent procedure, and screening period #2, will be related to all other 
procedures, beside those described in Section 7.1, needed before being included into the trial. 
All timelines included in the protocol and related to the signature of the ICF are referring to 
the signature of this second part of the ICF. 
All Screening evaluations must be completed and reviewed within the timeframe defined in 
the Schedule of Assessments (Table 1) to confirm that potential patients meet all eligibility 

 
 
 
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criteria. The Investigator will maintain a Screening log to record details of all patients screened 
and to confirm eligibility or record reasons for Screen failure (Section 4.3.1), as applicable. 
Procedures conducted as part of the patient’s routine clinical management (e.g., blood count) 
and obtained before signing the consent form may be utilized for Screening purposes, provided 
the procedure met the protocol-specified criteria and was performed within the timeframe 
defined in the Schedule of Assessments (Table 1). 
All Screening laboratory tests will be performed locally. The brain MRI will be performed and 
read at the local site. The maximum amount of blood from each patient over the duration of the 
study including any extra assessments that may be required will not exceed volumes as stated 
by local regulations. Repeat or unscheduled samples may be taken for safety reasons or for 
technical issues with the samples. 
Patients that fail Screening will be replaced. 
The following will be conducted/collected and all results will be documented during Screening: 
• Informed consent 
• Eligibility criteria assessment according to inclusion/exclusion criteria 
• Demographics (including weight and height) and medical history to include oncologic 
history, demographics, history of other disease processes (active or resolved), and 
concomitant illness 
• IDH and MGMT status will be collected 
• 
HLA-A2 positivity confirmation (patients who are HLA-A2 negative will fail 
Screening). HLA-A2 testing will be performed locally 
• Collection of all previous chemotherapy and radiotherapy treatments 
• ECOG or Karnofsky performance status 
• Complete physical examination of major body systems 
• Vital signs (including heart rate [HR], blood pressure [BP], temperature, and respiratory 
rate) 
• 12-lead electrocardiogram (ECG; performed as a triplicate trace within 2 months before 
Screening) 
• 
 
 
 
 
 
 
 
• Brain MRI (MRI should be done within 14 days before the start of treatment) 
• NANO scale/questionnaire completion to assess neurological function 
• Assessment of AEs/toxicity 
• Assessment of prior and concomitant medications 

 
 
 
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• Clinical laboratory assessments (hematology, biochemistry, electrolytes, coagulation, 
hepatic, and renal function; see Section 7.7). All laboratory tests will be performed 
locally. HIV, HBV, HCV, s-cortisol (and ACTH when applicable; if the level of serum-
cortisol is below the lower local normal limit, an ACTH stimulation test should be 
performed), TSH and free T4, will be assessed within 28 days prior first intake of study 
medication. A polymerase chain reaction viral detection test will also be used to 
confirm HCV status when a person has immunodeficiency as this condition can be 
associated with a false negative HCV antibody test result. 
 
 
  
• Complete urinalysis 
• Pregnancy test will be performed for all female patients of childbearing potential. A 
serum pregnancy test will be performed 72 hours prior to start of treatment, if applicable. 
Postmenopausal status for postmenopausal females will be confirmed with a Screening 
serum FSH level > 40 mIU/mL 
• Blood collection 
 
 
 
• 
 
 
 
7.3. 
Treatment Priming Phase 
7.3.1. 
Week 0 (Visit 1) 
Visit 1 must be performed within 14 calendar days from baseline MRI investigation ± 2 days. 
Before the first administration of the treatment, the inclusion and exclusion criteria must be 
checked by the Investigator. 
The following assessments will be conducted: 
• Clinical laboratory assessments (hematology, biochemistry, coagulation, hepatic, and 
renal function, electrolytes). All laboratory tests will be performed locally. 
• Complete urinalysis 
• Administration of EO2401. 
 
 
 
 
 
 
 
 
• Infusion of nivolumab for Cohorts 2a and 2b and Cohort 3 

 
 
 
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• Infusion of bevacizumab only for Cohort 3 
• Demographics, except height 
• ECOG or Karnofsky performance status 
• Physical examination 
• Vital signs 
• Assessment of AEs/toxicity 
• Assessment of prior and concomitant medications 
• Blood collection 
 
 
• 
 
7.3.2. 
 
The following assessments will be conducted: 
• Clinical laboratory assessments 
 
 
 
• Complete urinalysis 
• Administration of EO2401 
• Infusion of nivolumab for Cohort 1 (for Visit 3 only), Cohorts 2a and 2b, and Cohort 3 
• Infusion of bevacizumab only for Cohort 3 
• Demographics, except height 
• ECOG or Karnofsky performance status 
• Physical examination 
• Vital signs 
• Assessment of AEs/toxicity 
• Assessment of prior and concomitant medications 
• Pregnancy test (for Visit 2, if applicable) 
• Blood collection 
 
 
  
7.3.3. 
 
The following assessments will be conducted: 
• Clinical laboratory assessments 
 
 
 
• Complete urinalysis 

 
 
 
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• Administration of EO2401 
• Infusion of nivolumab for Cohort 1, Cohorts 2a and 2b, and Cohort 3 
• Infusion of bevacizumab only for Cohort 3 
• Demographics, except height 
• ECOG or Karnofsky performance status 
• Physical examination 
• Vital signs 
• Assessment of AEs/toxicity 
• Assessment of prior and concomitant medications 
• Pregnancy test (if applicable) 
• Blood collection 
 
 
7.4. 
Treatment-Boosting Period 
Boosting injections of EO2401 will start 4 weeks after the fourth priming injection. 
The visits during this period will occur until disease progression, death, or until the end of 
study. The treatment-boosting phase will be stopped in case of confirmed tumor progression, 
intolerable toxicity, death, or the study is terminated by the Sponsor. 
7.4.1. 
 
The following assessments will be conducted: 
• Clinical laboratory assessments 
 
 
• Complete urinalysis 
• Infusion of nivolumab for Cohort 1, Cohorts 2a and 2b, and Cohort 3 
• Infusion of bevacizumab only for Cohort 3 
• Demographics, except height 
• ECOG or Karnofsky performance status 
• Physical examination 
• Vital signs 
• 12-lead ECG to be performed ± 4 days within scheduled time 
 
• 
 
 
  
 
 
 

 
 
 
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• 
 
  
• Complete urinalysis 
• Infusion of nivolumab for Cohorts 1, 2, and 3 at dose of 3 mg/kg IV every 14 days 
according to SmPC59 and US PI60 
• Infusion of bevacizumab only for Cohort 3 at the dose of 10 mg/kg every 14 days as 
per standard treatment (US PI69) 
• Demographics, except height 
• ECOG or Karnofsky performance status 
• Complete physical examination of major body systems 
• Vital signs 
• Assessment of AEs/toxicity 
• Assessment of prior and concomitant medications 
• Tumor assessment: 
 
 
 
  
• NANO scale/questionnaire completion to assess neurological function to be performed 
 
 
 
.  
• Pregnancy test (if applicable); 
 
 
 
 
• Blood collection 
 
  
• Survival status. 
7.4.4. 
End of Treatment or Early 
Discontinuation 
At Week n + 2 weeks or in case of early termination, the following will be conducted and all 
results will be documented: 
• Clinical laboratory assessments 
 
 
 
 
 
 

 
 
 
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• 
 
 
 
• In case of treatment discontinuation, and after the first follow-up visit has been 
completed (including safety blood sampling) approximately 30 days after completion 
of last dose of study treatment, further safety blood sampling (including thyroid and 
adrenal glands function testing) in the context of the trial will be stopped if not clinically 
indicated (e.g. to follow-up study treatment toxicity) per the treating physician. 
• Administration of EO2401 every 4 weeks until confirmed tumor progression, 
intolerable toxicity, death, or early termination of the study, where study treatment will 
be stopped and appropriate standard of care will be initiated by the Investigator 
• Infusion of nivolumab for Cohorts 1, 2, and 3 at dose of 3 mg/kg IV every 14 days 
according to SmPC59 and US PI60 
• Infusion of bevacizumab only for Cohort 3 at the dose of 10 mg/kg every 14 days as 
per standard treatment (US PI69) 
• Demographics, except height 
• ECOG or Karnofsky performance status 
• Complete physical examination of major body systems 
• Vital signs 
• Assessment of AEs/toxicity 
• Assessment of prior and concomitant medications 
• Tumor assessment: 
 
 
 
 
• NANO scale/questionnaire completion to assess neurological function to be performed 
 
 
 
 
• 
 
• Pregnancy test (if applicable); 
 
 
 
• Blood collection 
 
 
 
 
• Survival status. 

 
 
 
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7.4.5. 
Follow-up Visits (After Progression or Permanent Treatment 
Discontinuation) 
In case of treatment discontinuation, patients will complete monthly Follow-up Visits. The first 
Follow-up Visit will be completed approximately 
 after completion of last dose of study 
treatment. The clinical assessments performed below will be conducted. If the patient is unable 
to attend the site visit, safety follow-up via a telephone contact will be conducted and safety 
assessments recorded. The primary reason for premature study drug treatment discontinuation 
should be documented on the appropriate eCRF. 
• If tests related to the EoT/Early discontinuation visit have not been done (see Section 
7.4.4), they should be done during a follow-up visit. 
• Physical examination (in case the patient comes to site visit) 
• Vital signs (in case patient comes to site visit) 
• Assessment of AEs/toxicity (see Section 7.6.2.1, Section 7.6.3.6, and Section 7.6.3.7 
regarding reporting periods for AEs and SAEs)  
• Assessment of prior and concomitant medications 
• Tumor assessment: 
 
 
 
 
• NANO scale/questionnaire completion to assess neurological function to be performed 
 
 
 
 
• A serum pregnancy test will be conducted 
 
 
if not a new anti-tumor treatment has been initiated earlier in which case the 
study related testing will be terminated at the time of start of new anti-tumor treatment. 
• Survival status. 
7.5. 
Efficacy Assessments 
The efficacy measurements used in the evaluations of the study endpoints are widely used and 
recognized as reliable, accurate, and conform to standard of care. 
The assessment of PFS, ORR, DCR, DoR, and OS are considered secondary endpoints. The 
assessment of neurological function is considered an exploratory endpoint. 
The efficacy assessments will be performed by MRI measurements every 8 weeks using the 
iRANO criteria (see Appendix 1). 

 
 
 
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7.5.1. 
Tumor and Response Evaluation 
7.5.1.1. 
Acquisition Imaging 
 
 
 
In this study, tumor response will be performed according to the Imaging Acquisition 
Guidelines (e.g., same imaging method, type of MRI, slice of thickness) to ensure the 
standardization of the technique, limit of potential bias, and ensure quality of the data. These 
guidelines will be provided in a separate document and delivered at each investigational site. 
The brain MRI might be read centrally following the Sponsor’s decision. The brain MRI 
measurements will be conducted every 8 weeks
, as per standard practices, using 
the criteria shown in Appendix 1 (iRANO criteria77,78) and will comprise of radiological and 
clinical assessments. 
 
 the MRI scan must be performed 
. If the next scheduled treatment administration is delayed 
(toxicity/other reasons), the disease assessment should be performed as initially planned (i.e., 
despite treatment delay, see Section 5.8.1.2). 
An unscheduled MRI scan may be performed at the discretion of the Investigator to allow a 
decision on further study treatment administration for the patient. 
For patients who discontinue treatment prematurely, disease assessment in the follow-up period 
should continue according to the original schedule and follow standard clinical practice until 
confirmed PD. If other anticancer treatment would be started before confirmed PD study 
related brain MRIs can be stopped 
The same imaging method (MRI) as specified in the imaging guidelines must be used for a 
patient throughout the study and assessed by the same Investigator/radiologist during the study 
to the extent that is feasible. 
Magnetic resonance imaging rules to be applied during the study: 
• Anatomical coverage: Whole brain 
• Recommendations 
o Tumor assessments will be performed using MRI of the brain with minimal field 
strength 0.5 Tesla systems or higher (3T) 
o The same MRI system should be used throughout the study 
o Brain coverage and acquisition parameters should remain consistent across all 
imaging visits for any subject. 
Note: For this study, off protocol sequences not supported by RANO are: 
• PET-CT scans 
• MR-Spectroscopy 

 
 
 
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• Perfusion imaging. 
7.5.1.2. 
Tumor Evaluation Using iRANO Criteria 
Immunotherapeutic agents such as EO2316, EO2317, EO2318, and anti-PD(L)-1 therapy may 
produce antitumor effects by potentiating endogenous cancer-specific immune responses, 
which may manifest as initial worsening of enhancement and edema on MRI (i.e., PsPD). In 
addition, the response patterns seen with immunotherapeutics may extend beyond the typical 
time course of responses seen with cytotoxic agents, and can manifest a clinical response after 
an initial increase in tumor burden or even the appearance of new lesions. For these reasons, 
the immune-related response criteria have endorsed continuation of study therapy beyond 
initial radiographic evidence of progression for clinically stable patients undergoing immune-
based therapies. 
A major advance of the RANO criteria to assess response in neuro-oncology over the 
previously used Macdonald criteria includes recognition of the prevalence of PsPD during the 
first 3 months following completion of radiation and daily temozolomide. 90 Specifically, 
RANO permits patients with such progressive MRI findings to continue temozolomide therapy 
for up to 3 months in order to avoid inaccurately classifying such patients as progressive. 
Furthermore, RANO permits patients with progressive radiographic findings at any time to 
continue current therapy pending follow-up imaging if the etiology of progressive imaging 
findings is unclear. Standard RANO may not provide an accurate response assessment of 
immunotherapeutic agents such as pembrolizumab. 
Therefore, the following adaptations of the RANO criteria, as reflected in the iRANO criteria77, 
will be used to assess response for patients treated on this study: 
• Potential PsPD: If radiologic imaging shows initial PD, participants who are not 
experiencing significant clinical decline may be allowed to continue study treatment 
for up to 3 months. Patients who have radiographic evidence of further progression after 
up to 3 months, or who decline significantly at any time, will be classified as 
progressive with the date of disease progression back-dated to the first date that the 
participant met criteria for progression and such participants will be discontinued from 
study therapy. Although the kinetics of PsPD due to immune checkpoint blockade 
among GB patients are currently unknown, 3 months is a reasonable estimate based on: 
1) the peak time for X-ray telescope/daily temozolomide-related PsPD is usually within 
3 months of completion for GB patients90 and; 2) 3 months is also the most common 
timeframe for PsPD observed among patients with advanced melanoma or other solid 
tumors treated with PD-1/PD(L)-1 immune checkpoint blockade to date. 
Among patients on this study with initial radiographic PD, tumor assessment should be 
repeated regularly in order to confirm PD with the option of continuing treatment as described 
below while awaiting radiologic confirmation of progression. If repeat imaging shows a 
stabilization or reduction in the tumor burden compared to the initial scan demonstrating PD, 
treatment may be continued/resumed. If repeat imaging after up to 3 months confirms PD, then 
the date of disease progression will be the first date the participant met criteria for progression 
and participants will be discontinued from study therapy. Participants who have confirmed 
tumor (disease) progression will discontinue study medication and enter the follow-up/survival 
phase of the study. In determining whether or not the tumor burden has increased or decreased, 
Investigators should consider all target lesions as well as nontarget lesions. 

 
 
 
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In participants who have initial evidence of radiographic PD, it is at the discretion of the 
treating physician whether to continue a participant on-study treatment for up to 3 months 
pending confirmation of PD on follow-up imaging. This clinical judgment decision should be 
based on the participant’s overall clinical condition, including performance status, clinical 
symptoms, and laboratory data. Participants may receive study treatment while waiting for 
confirmation of PD if they are not experiencing significant clinical decline and if: 
• The participant is believed to demonstrate clinical benefit from the study regimen as 
determined by the treating physician 
• The participant is adequately tolerating study therapy. 
When feasible, study therapy should not be discontinued until radiographic progression is 
confirmed. This allowance to continue treatment despite initial radiologic progression takes 
into account the observation that some participants can have a transient tumor flare in the first 
few months after the start of immunotherapy, but with subsequent disease response. 
Participants that are exhibiting significant neurologic decline are not required to have repeat 
imaging for confirmation of PD. 
7.5.2. 
Overall Survival 
Overall survival will be defined as the time interval from the date of first study treatment 
administration to the date of death due to any cause. 
Patients who are still alive at the time of analysis (clinical cutoff) and patients who are lost to 
follow-up will be censored at their last clinical assessment date. 
7.5.3. 
Progression-free Survival 
Progression-free survival is defined as the time interval from the date of first study treatment 
administration to the date of first occurrence of progression or death from any cause, whichever 
occurs first. The PFS will be assessed using the iRANO criteria (see Appendix 1). Patients 
without an event will be censored at the date of their last evaluable tumor assessment. 
7.5.4. 
Objective Response Rate & Disease Control Rate 
The ORR is defined as the proportion of patients with CR and PR according to the iRANO 
criteria. The DCR is defined as the proportion of patients with CR, PR, and Stable Disease 
(SD) according to the iRANO criteria. 
7.5.5. 
Duration of Response 
Duration of response will be defined as the time interval from the date of first occurrence of 
CR or PR to the date of first documentation of disease progression or death from any cause, 
whichever occurs first. 
Duration of response will be calculated on responder patients. Only patients with a best overall 
response of CR or PR are considered responders. 
7.5.6. 
Neurological Assessment of Neuro-Oncology Scale 

 
 
 
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The neurological function will be assessed using the NANO scale (see Appendix 275,76). The 
NANO is a simple neurologic assessment by a means of a questionnaire conducted and reported 
by a trained health care professional who evaluates the patient in 9 domains: gait, strength, 
upper extremity ataxia, sensation, visual fields, facial strength, language, level of 
consciousness, and behavior. Each domain contains a score from 0 to 3 or 0 to 2, depending on 
the domain, with higher scores indicating worse neurologic function. The cumulative score can 
be compared over time to determine whether clinical status is stable, better, or worse as part of 
the response assessment. 
 
 
 
7.6. 
Safety and Tolerability Assessments 
Safety endpoints will be assessed by review of AE summaries, which will include TEAEs and 
SAEs, unless stated otherwise. Adverse events will be categorized by SOC and PT using the 
current MedDRA version and will be graded according to NCI-CTCAE v5.0. 
7.6.1. 
Safety Plan 
7.6.1.1. 
Management of Immune-related Adverse Reactions for Nivolumab and 
EO2401, and management of Dose Modifications for Adverse Reactions to 
Nivolumab 
For suspected immune-related adverse reactions, adequate evaluation should be performed to 
confirm etiology or exclude other causes. Based on the severity of the adverse reaction, the 
treatment should be withheld and corticosteroids administered. If immunosuppression with 
corticosteroids is used to treat an adverse reaction, a taper of at least 1-month duration should 
be initiated upon improvement. Rapid tapering may lead to worsening or recurrence of the 
adverse reaction. Non-corticosteroid immunosuppressive therapy should be added if there is 
worsening or no improvement despite corticosteroid use. Table 6 shows the recommended 
treatment management for different immune-related adverse reactions due to nivolumab; the 
same management principles should be utilized for EO2401 in case of immune-related adverse 
reactions (including potential immune cross-reactivity with normal tissue as described in 
Section 1.3 Benefit-Risk Assessment). For further guidance regarding treatment of immune-
related adverse reactions during nivolumab treatment, e.g. corticosteroid dosing and hormone 
substitution therapy at immune-related endocrinopathies, refer to the SmPC59 and US PI60 for 
nivolumab.  
Patients treated with nivolumab should be monitored continuously (at least up to 5 months after 
the last dose) as an adverse reaction with nivolumab may occur at any time during or after 
discontinuation of therapy. Patients will be reviewed on a case-by-case basis, should they need 
to discontinue nivolumab due to toxicity. See Section 3.1 regarding general safety rules and 
guidance regarding continuation of individual components of the used combinations in this 
trial. 

 
 
 
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Side effects related to nivolumab are presented in Section 1.2.1.3.1.1. See also details in the 
SmPC59 and US PI60 for nivolumab, ESMO,3, 92  and Food and Drug Administration 
guidelines.93 
In case of nivolumab treatment discontinuation due to related AE, consult Section 3.1 
regarding the possibility to continue other treatment components. 
7.6.1.2. 
Management of Infusion Reactions to Nivolumab 
Severe infusion reactions have been reported in clinical trials using nivolumab. In case of a 
severe or life-threatening infusion reaction, the nivolumab infusion must be discontinued and 
appropriate medical therapy must be administered. Patients with mild or moderate infusion 
reaction may receive nivolumab with close monitoring and use of premedication according to 
local treatment guidelines for prophylaxis of infusion reactions. 
 
Hypersensitivity 
Nivolumab should be permanently discontinued in patients exhibiting hypersensitivity/allergic 
reactions. 
The NCI-CTCAE distinguishes between hypersensitivity reactions and acute infusion reactions 
induced by cytokine release. Despite the different possible mechanisms underlying 
hypersensitivity and infusion reactions, the clinical signs and symptoms associated with these 
reactions overlap. 
Patients may be at risk of developing infusion reactions to nivolumab. Close observation of the 
patient during and following the administration of nivolumab is recommended, as expected for 
any infusion of a therapeutic humanized monoclonal antibody. If an infusion reaction occurs, 
the infusion should be discontinued and appropriate medical therapies should be administered. 
A systematic premedication is not warranted.60 
See also details in the SmPC59 and US PI60 for nivolumab, ESMO,3 and Food and Drug 
Administration guidelines,94 and please refer to Appendix 7. 
7.6.1.3. 
Management of Dose Modifications for Adverse Reactions to Bevacizumab 
Details of dose modifications for adverse reactions to bevacizumab are provided in Table 8. 
Table 8: 
Dose Modifications for Adverse Reactions to Bevacizumab 
Adverse Reaction 
Severity 
Dose Modification 
Gastrointestinal Perforation and 
fistulae 
(see 
Warnings 
and 
Precautions [5.1]) 
• 
Gastrointestinal 
perforation, 
any 
grade 
• 
Tracheoesophageal fistulae, any grade 
• 
Fistulae, Grade 4 
• 
Fistulae formation involving any 
internal organ 
Discontinue bevacizumab 

 
 
 
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Adverse Reaction 
Severity 
Dose Modification 
Wound Healing Complications 
(see Warnings and Precautions 
[5.2]) 
• 
Wound 
healing 
complications 
requiring medical intervention 
• 
Necrotizing fasciitis  
Discontinue bevacizumab 
Hemorrhage (see Warnings and 
Precautions [5.3]) 
• 
Grade 3 or 4 
Discontinue bevacizumab 
• 
Recent history of hemoptysis of ½ 
teaspoon (2.5 mL) or more 
Withhold bevacizumab 
Thromboembolic 
Events 
(see 
Warnings and Precautions [5.4, 
5.5]) 
• 
Arterial thromboembolism, severe 
Discontinue bevacizumab 
• 
Venous thromboembolism, Grade 4 
Discontinue bevacizumab 
Hypertension (see Warnings and 
Precautions [5.6]) 
• 
Hypertensive crisis 
• 
Hypertensive encephalopathy 
Discontinue bevacizumab 
• 
Hypertension, severe 
Withhold bevacizumab if 
not 
controlled 
with 
medical 
management; 
resume once controlled 
Posterior 
Reversible 
Encephalopathy Syndrome (see 
Warnings and Precautions [5.7]) 
• 
Any 
Discontinue bevacizumab 
Renal Toxicity and Proteinuria 
(see Warnings and Precautions 
[5.8]) 
• 
Nephrotic syndrome 
Discontinue bevacizumab 
• 
Proteinuria greater than or equal to 2 g 
per 24 hours in absence of nephrotic 
syndrome 
Withhold 
bevacizumab 
until proteinuria less than 
2 g per 24 hours 
Infusion Reaction (see Warnings 
and Precautions [5.10]) 
• 
Severe infusions reaction 
Discontinue bevacizumab 
• 
Clinically significant 
Interrupt infusion; resume 
at a decreased rate of 
infusion after symptoms 
resolve 
• 
Mild, clinically insignificant 
Decrease infusion rate 
Congestive Heart Failure (see 
Warnings and Precautions [5.12]) 
• 
Any 
Discontinue bevacizumab 
Reference source: US PI69 
7.6.2. 
Safety Parameters and Definitions 
7.6.2.1. 
Adverse Events 
Adverse events will be monitored throughout the study. Adverse events will be collected from 
the time informed consent is signed and continue until 30 days after the last study treatment is 
administered, until all serious or study treatment-related toxicities have resolved or are 
determined to be “chronic” or “stable,” completion of the patient’s participation, study 
termination (e.g., patient lost to follow-up), or the Investigator or designee and Sponsor agree 
that follow-up is no longer necessary, whichever occurs first. 

 
 
 
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In addition, for consistency with nivolumab clinical trial protocols as advised by Bristol-Myers 
Squibb (marketing authorization holder for nivolumab), collect all non-serious adverse events 
(not only those deemed to be treatment-related) continuously during nivolumab treatment 
periods and for a minimum of 100 days following discontinuation of nivolumab treatment. The 
most conservative approach (longest follow-up) emanating from the two principles (30 days 
and specifics per above paragraph versus 100 days following discontinuation of nivolumab 
treatment) should be followed for nivolumab. 
 
For the purpose of this study, the terms toxicity and AE are used interchangeably. 
The Investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study treatment or the study, or that caused the patient 
to discontinue the study drug or study (see Section 4.3.3). 
Definition 
An AE is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. This includes the following: 
• Any clinically significant worsening of a pre-existing condition 
• Note: Emergence of a new pathogen associated with a clinical event during therapy at 
a site other than the initial site of infection will be considered an AE 
• Any recurrence of a pre-existing condition 
• An AE occurring from overdose of a Sponsor study drug whether accidental or 
intentional (i.e., a dose higher than that prescribed by a health care professional for 
clinical reasons) 
• An AE occurring from abuse of a Sponsor study drug (i.e., use for nonclinical reasons) 
• An AE that has been associated with the discontinuation of the use of a Sponsor study 
drug. 
Note: A procedure is not an AE, but the reason for a procedure may be an AE. 
A pre-existing condition is a clinical condition (including a condition being treated) that is 
diagnosed before the patient signs the ICF and that is documented as part of the patient’s 
medical history. 
The questions concerning whether the condition existed before the start of the active phase of 
the study and whether it has increased in severity and/or frequency will be used to determine 
whether an event is a TEAE. An AE is considered to be treatment-emergent if: (1) it is not 
present when the active phase of the study begins and is not a chronic condition that is part of 
the patient’s medical history, or (2) it is present at the start of the active phase of the study or 
as part of the patient’s medical history, but the severity or frequency increases during the active 
phase. The active phase of the study begins at the time of the first dose of the study drug. The 
active phase of the study ends at the Follow-up Visit. 
Abnormal laboratory and other abnormal investigational findings (i.e., physical exam) should 
not be reported as AEs, unless they are associated with clinical signs and symptoms, lead to 

 
 
 
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treatment discontinuation, or are otherwise considered clinically relevant by the Investigator. 
In cases of surgical or diagnostic procedures, the condition/illness leading to such a procedure 
is considered as the AE rather than the procedure itself. 
In a case of fatality, the cause of death is considered as the SAE, and the death is considered as 
its outcome, and the end date of the SAE is the date of death. 
Pre-existing medical conditions/diseases/symptoms that worsen after informed consent are 
signed are considered AEs regardless of causality with study treatment. Abnormal laboratory 
values or test results constitute AEs only if they induce clinical signs and symptoms, are 
considered clinically significant, or require therapy. 
Information about all AEs, whether volunteered by the patient, discovered by the Investigator 
or designee questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded, as appropriate. 
All AEs will be treated appropriately. Such treatment may include changes in study treatment 
as listed in the dose modification section of the protocol (Section 5.8.1). 
An AE or SAE will be considered treatment-emergent if they occur any time after the first dose 
of study treatment. 
7.6.2.2. 
Serious Adverse Event 
An SAE is any AE occurring at any dose that meets one or more of the following criteria: 
• Results in death 
• Is life-threatening (see below) 
• Requires patient hospitalization or prolongation of an existing hospitalization (see 
below) 
• Results in a persistent or significant disability or incapacity (see below) 
• Results in a congenital anomaly or birth defect 
• Results in an important medical event (see below). 
Additionally, important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered as SAEs when, based on appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed above. Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not require hospitalization, or development of drug 
dependency or drug abuse. 
A life-threatening adverse event is any AE that places the patient at immediate risk of death 
from the event as it occurred. A life-threatening event does not include an event that might 
have caused death had it occurred in a more severe form but that did not create an immediate 
risk of death as it actually occurred. For example, drug-induced hepatitis that resolved without 
evidence of hepatic failure would not be considered life-threatening, even though drug-induced 
hepatitis of a more severe nature can be fatal. 

 
 
 
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Hospitalization or prolongation of a hospitalization is a criterion for considering an AE to be 
serious. In the absence of an AE, the participating Investigator should not report hospitalization 
or prolongation of hospitalization. This is the case in the following situations: 
• Hospitalization or prolongation of hospitalization is needed for a procedure required by 
the protocol. Day or night survey visits for biopsy or surgery required by the protocol 
are not considered serious. 
• Hospitalization or prolongation of hospitalization is part of a routine procedure 
followed by the study center (e.g., stent removal after surgery). This should be recorded 
in the study file. 
• Hospitalization for survey visits or annual physicals fall in the same category. 
In addition, a hospitalization planned before the start of the study for a pre-existing condition 
that has not worsened does not constitute an SAE (e.g., elective hospitalization for a total knee 
replacement due to a pre-existing condition of osteoarthritis of the knee that has not worsened 
during the study). Hospitalization is to be considered only as an overnight admission. 
Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions (i.e., the AE resulted in a significant, persistent, or permanent change, impairment, 
damage, or disruption in the patient’s bodily function/structure, physical activities, or quality 
of life). 
If there is any doubt as to whether a case constitutes an AE or SAE based on the information 
available, the case should be treated as an SAE. 
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
those situations where important medical events may not be immediately life-threatening or 
result in death, hospitalization, disability, or incapacity. These include events that may 
jeopardize the patient or may require medical intervention to prevent one or more outcomes 
listed in the definition of serious. Such events should usually be considered as serious. 
Toxicities that fall within the SAE definitions listed above must be reported as an SAE, 
regardless if they are felt to be treatment-related or not. Toxicities unrelated to treatment that 
do NOT fall within the SAE definitions above must be documented as AEs in the patient’s 
source documents and eCRF. 
7.6.2.3. 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the EO2401 Reference Safety Information section of the Investigator Brochure. Suspected 
adverse reaction means any AE for which there is a reasonable possibility that the drug caused 
the AE. For the purposes of Investigational New Drug safety reporting, “reasonable possibility” 
means there is evidence to suggest a causal relationship between the drug and the AE. As this 
is an FIH trial, all related SAEs are considered SUSARs. 
7.6.2.4. 
Adverse Drug Reactions 
All noxious and unintended responses to an IMP (i.e., where a causal relationship between an 
IMP and an AE is at least a reasonable possibility) related to any dose should be considered 
adverse drug reactions. 

 
 
 
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For marketed medicinal products, a response to a drug which is noxious and unintended and 
which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases 
or for modification of physiological function is to be considered an adverse drug reaction. 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity 
of which is not consistent with the applicable product information (e.g., Investigator’s Brochure 
for an unapproved IMP). 
7.6.3. 
Methods and Timings for Capturing and Assessing Safety Parameters 
7.6.3.1. 
Follow-up of Adverse Events/Serious Adverse Events 
Adverse events/SAEs will be followed until resolution or stabilization of the event, completion 
of the patient’s participation, or study termination, or the Investigator or designee and Sponsor 
agree that follow-up is no longer necessary, whichever occurs first. 
Assessments should be made at each visit (or more frequently, if necessary) of any changes in 
severity, the relationship to the study drug, the intervention required to treat it, and the outcome. 
Common, uncommon, and rare side effects known for nivolumab are provided in the SmPC.62 
All AEs will be immediately recorded in the patient’s source documents. 
7.6.3.2. 
Assessment of Severity of Adverse Events 
The severity grade will be based on the NCI-CTCAE v5.0. An electronic copy of the 
NCI-CTCAE v5.0 can be downloaded from https://ctep.cancer.gov. As soon as the site enters 
a grade ≥3 AE, the Medical Monitor will be immediately informed through a specific alert 
programmed in the e-CRF. 
7.6.3.3. 
Assessment of Causality of Adverse Events 
The Investigator must assess and document causal relationship between an SAE and the study 
drug on the basis of his/her clinical judgment using the following definitions. The causality 
assessment must be made based on the available information and can be updated as new 
information becomes available. 
Is there a “reasonable possibility” that EO2401, or when applicable the combination of 
EO2401 + nivolumab, or EO2401 + nivolumab + bevacizumab caused the AE (meaning there 
is evidence to suggest a causal relationship the administered treatment and the AE)? 
• Yes 
• No. 
Could the AE be explained by underlying disease or other drugs or chemicals? 
• Yes 
• No. 
7.6.3.4. 
Action Taken for Adverse Events 
The Investigator or designee will record the action taken for the AE in the eCRF. Actions taken 
will include: 

 
 
 
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• Dose not changed: The medication schedule was not changed 
• Drug interrupted: The medication schedule was modified by temporarily terminating 
the prescribed regimen of medication 
• Drug withdrawn: The medication schedule was modified through termination of the 
prescribed regimen of medication 
• Not applicable 
• Unknown. 
7.6.3.5. 
Adverse Event Outcome 
• Recovered/resolved: The patient fully recovered from the AE with no residual effect 
observed 
• Recovered/resolved with sequelae: The residual effects (e.g., symptoms or pathology) 
of the AE are still present and observable 
• Not recovered/not resolved: The AE itself is still present and observable 
• Fatal: The patient dies as a result of the AE 
• Unknown: Outcome of the AE is unknown. 
7.6.3.6. 
Reporting Adverse Events 
At each visit, the Investigator, or delegate, will determine whether or not any AEs have 
occurred. Nonleading questions such as “How are you feeling today?” or “Have you had any 
health concerns since your last visit?” should be used to elicit the patient to report any possible 
AEs. If any AEs have occurred, they will be recorded in the AE section of the eCRF and in the 
patient’s source documents. If known, the diagnosis should be recorded in preference to listing 
the individual signs and symptoms. 
Furthermore, the Investigator is responsible for ensuring that any sub-Investigator promptly 
brings AEs to the attention of the Investigator. If applicable, as per national regulation, the 
Investigator is also responsible for informing the site’s IEC/IRB of all SAEs (per IEC/IRB 
requirements). 
Adverse event reporting begins from the time informed consent is signed and ends 30 days 
after the last treatment administration or until all serious or study treatment-related toxicities 
have resolved or are determined to be “chronic” or “stable,” completion of the patient’s 
participation, study termination (e.g., patient is lost to follow-up), or the Investigator or 
designee and Sponsor agree that follow-up is no longer necessary, whichever occurs first. 
In addition, for consistency with nivolumab clinical trial protocols as advised by Bristol-Myers 
Squibb (marketing authorization holder for nivolumab), collect all non-serious adverse events 
(not only those deemed to be treatment-related) continuously during nivolumab treatment 
periods and for a minimum of 100 days following discontinuation of nivolumab treatment. The 
most conservative approach (longest follow-up) emanating from the two principles (30 days 
and specifics per above paragraph versus 100 days following discontinuation of nivolumab 
treatment) should be followed for nivolumab. 
 

 
 
 
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7.6.3.7. 
Reporting Serious Adverse Events 
All SAEs, occurring after the signing of the ICF until 30 days after the last study treatment and 
regardless of study drug relationship, must be entered into the clinical database as an AE (with 
appropriate indication that the AE represents an SAE) and must be submitted according to the 
below process (paper SAE form) to the Enterome/
 within 24 hours of 
obtaining knowledge of the event. The Investigator should enter all available information 
requested on the SAE Form. 
 
 
 
 
 
 
The SAE Form will collect data surrounding the event (e.g., the nature of the symptom[s], time 
of onset in relation to initiation of therapy, duration, intensity, and whether or not therapy was 
interrupted or discontinued). The Investigator’s assessment of the probable cause of the event 
will also be included. In addition, relevant medical history, concomitant medications, 
laboratory and diagnostic test reports, and procedures as well as all pertinent medical 
information related to the event will also be collected.  
Once an AE page has been updated in the eCRF indicating an SAE by the site, an alert from 
the clinical database will be initiated and sent to the Enterome/
. If the 
paper SAE Form has not been received by the Enterome/
 form the site 
within 24 hours after such an alert the site will be contacted and queried for the SAE Form. 
The Enterome/
 will generate SAE queries requesting incomplete, 
implausible, or missing information. It is the Investigator’s responsibility to be diligent in 
providing the answer as soon as it is available by entry of the applicable corrections in the 
eCRF and submission of the follow-up SAE report to the Enterome/
.  
The paper SAE Form will be provided to the Investigators prior to start of the study. 
When a paper form is completed, follow-up information should not be reported on the same 
form that was used for the initial reporting, but using a new form filled in only with the new 
information. Changes/completions need to be done in a Good Clinical Practice (GCP)-
compliant manner (i.e. dated and initialized). Originals of the report forms must be kept in the 
site study file. 
Initial reports of SAEs should never be left on telephone voicemails. Please always fax or email 
the SAE Forms and follow with a telephone call if needed. 
Note, all SAE Forms must be completed in English. 
 
Serious AEs to be reported to the 
 Safety Group: 

 
 
 
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Labcorp Study: 43625 
 
Facsimile:  
 
 
 
E-mail:  
 
 
 
In case of urgent questions regarding SAE reporting please call: 
 
Enterome Medical Monitor  
  
 
 
 
 
 
 
All sites will follow their institutional requirements for submission of SAEs to their IRBs/IECs. 
7.6.3.8. 
Procedures for Recording Adverse Events 
7.6.3.8.1. 
Infusion-related Reactions 
Reactions temporally associated with infusions 
Adverse events that occur during or within 24 hours after study treatment administration should 
be captured as individual signs and symptoms on the AE eCRF page rather than an overall 
diagnosis (e.g., record dyspnea and hypotension as separate events rather than a diagnosis of 
infusion-related reaction). 
7.6.3.8.2. 
Diagnosis versus Signs and Symptoms 
For AEs other than infusion-related reactions (see Section 7.6.3.8.1), a diagnosis (if known) 
should be recorded on the AE eCRF page rather than individual signs and symptoms (e.g., 
record only liver failure or hepatitis rather than jaundice, asterixis, and elevated transaminases). 
However, if a constellation of signs and/or symptoms cannot be medically characterized as a 
single diagnosis or syndrome at the time of reporting, each individual event should be recorded 
on the AE eCRF page. If a diagnosis is subsequently established, all previously reported AEs 
based on signs and symptoms should be nullified and replaced by 1 AE report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first symptom 
of the eventual diagnosis. 
7.6.3.8.3. 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between clinical visits. 
Such events should only be recorded once on the AE eCRF page. The initial severity (CTCAE 
grade) of the event will be recorded at the time the event is first reported. If a persistent AE 
becomes more severe, the most extreme severity should also be recorded on the AE eCRF page. 
If the event becomes serious, it should be reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning that the event became serious; see Section 7.6.3.7 for reporting 
instructions). The AE eCRF page should be updated by changing the event from “nonserious” 
to “serious,” providing the date that the event became serious, and completing all data fields 
related to SAEs. 
A recurrent AE is one that resolves between patient evaluation timepoints and subsequently 
recurs. Each recurrence of an AE should be recorded separately on the AE eCRF page. 

 
 
 
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7.6.3.8.4. 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an AE. A laboratory test result should be reported 
as an AE if it meets any of the following criteria: 
• Is accompanied by clinical symptoms 
• Results in a change in study treatment (e.g., treatment interruption or treatment 
discontinuation) 
• Results in a medical intervention (e.g., potassium supplementation for hypokalemia) or 
a change in concomitant therapy 
• Is clinically significant in the Investigator’s judgment. 
It is the Investigator’s responsibility to review all laboratory findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality should 
be classified as an AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., 
alkaline phosphatase and bilirubin 5 times the ULN associated with cholecystitis), only the 
diagnosis (i.e., cholecystitis) should be recorded on the AE eCRF page. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded on the AE eCRF page, along with a descriptor indicating 
if the test result is above or below the normal range (e.g., “elevated potassium,” as opposed to 
“abnormal potassium”). If the laboratory abnormality can be characterized by a precise clinical 
term per standard definitions, the clinical term should be recorded as the AE. For example, an 
elevated serum potassium level of 7.0 mEq/L should be recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
only be recorded once on the AE eCRF page (see Section 7.6.3.8.3 for details on recording 
persistent AEs). 
7.6.3.8.5. 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an AE. A vital sign result should be reported as 
an AE if it meets any of the following criteria: 
• Accompanied by clinical symptoms 
• Results in a change in study treatment (e.g., treatment interruption or treatment 
discontinuation) 
• Results in a medical intervention or a change in concomitant therapy 
• Clinically significant in the Investigator’s judgment. 
It is the Investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality should be 
classified as an AE. 
Vital sign measurements outside the normal ranges will be assessed as “abnormal, not clinically 
significant” or “abnormal, clinically significant” by the Investigator. In the latter case, the 

 
 
 
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abnormal vital sign measurement will be reported as an AE and further investigated as 
clinically indicated. 
7.6.3.8.6. 
Abnormal Liver Function Values 
The finding of an elevated ALT or AST (> 3 ×ULN) in combination with either an elevated 
total bilirubin (> 2 ×ULN) or clinical jaundice in the absence of cholestasis or other causes of 
hyperbilirubinemia is considered to be an indicator of severe liver injury. Therefore, 
Investigators must report as an AE the occurrence of either of the following: 
• Treatment-emergent ALT or AST > 3 ×ULN in combination with total 
bilirubin > 2 ×ULN 
• Treatment-emergent ALT or AST > 3 ×ULN in combination with clinical jaundice. 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the AE eCRF page (see Section 7.6.3.6) and in 
addition reported to the Sponsor via email from the site. Potential events of drug-induced liver 
injury (DILI) will be reported as SAEs if seriousness criteria are fulfilled (see Section 7.6.3.7). 
All patients with potential DILI will be closely followed until abnormalities return to normal 
or baseline or until all attempts to determine resolution of the event are exhausted. 
7.6.3.8.7. 
Death 
Deaths that occur during the protocol-specified AE reporting period that are attributed by the 
Investigator solely to disease progression should be recorded only on the EoT eCRF page. All 
other on-study deaths, regardless of relationship to study drug, must be recorded on the AE 
eCRF page and immediately reported to the Sponsor. The IDMC will Monitor the frequency 
of deaths from all causes. 
Death should be considered an outcome and not a distinct event. The event or condition that 
caused or contributed to the fatal outcome should be recorded as the single medical concept on 
the AE eCRF page. Generally, only one such event should be reported. The term “sudden 
death” should only be used for the occurrence of an abrupt and unexpected death due to 
presumed cardiac causes in a patient with or without pre-existing heart disease, within 1 hour 
of the onset of acute symptoms or, in the case of an unwitnessed death, within 24 hours after 
the patient was last seen alive and stable. 
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
“unexplained death” should be recorded on the AE eCRF page. If the cause of death later 
becomes available (e.g., after autopsy), “unexplained death” should be replaced by the 
established cause of death. 
Since death is a seriousness criterion (see Section 7.6.2.2), the events leading to death should 
be reported to the CRO following the instructions in Section 7.6.3.7. 
7.6.3.8.8. 
Pre-existing Medical Conditions 
A pre-existing medical condition is one that is present at the Screening Visit for this study. 
Such conditions should be recorded on the Medical History eCRF page. 
A pre-existing medical condition should be recorded as an AE only if the frequency, severity, 
or character of the condition worsens during the study. When recording such events on the AE 

 
 
 
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eCRF page, it is important to convey the concept that the pre-existing condition has changed 
by including applicable descriptors (e.g., “more frequent headaches”). 
7.6.3.8.9. 
Disease Progression 
Events that are clearly associated with progression of the underlying disease should not be 
recorded as an AE. These events will be captured as efficacy assessment data only. In most 
cases, the expected pattern of progression will be based on protocol-defined response criteria 
(e.g., iRANO). In rare cases, the determination of clinical progression will be based on 
symptomatic deterioration. However, every effort should be made to document progression 
using objective criteria. 
Hospitalization due solely to progression of the underlying cancer should not be reported as an 
SAE. 
Deaths that are attributed by the Investigator solely to progression of disease should only be 
reported on “End of Study” eCRF page and not as an SAE. All other on-study events that led 
to death during the protocol-specified AE reporting period, regardless of relationship to study 
drug, must be recorded on the “AE” eCRF page as SAEs and immediately reported to the 
Sponsor, as specified in Section 7.6.3.7, reporting of SAEs. 
7.6.3.8.10. 
Adverse Events Associated with an Overdose or Error in Treatment 
Administration 
Study drug overdose is the accidental or intentional use of the drug in an amount higher than 
the dose being studied. An overdose or incorrect administration of study drug is not an AE 
unless it results in untoward medical effects. 
Any study drug overdose or incorrect administration of study drug should be noted on the Study 
Drug Administration eCRF page. 
All AEs associated with an overdose or incorrect administration of study drug should be 
recorded on the AE eCRF page. If the associated AE fulfils serious criteria, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 7.6.3.7 for reporting instructions). 
7.6.4. 
Investigator’s Notification of Adverse Events to the Sponsor 
All Investigators will be thoroughly instructed and trained on all relevant aspects of the 
Investigator’s reporting obligations for SAEs. This information, including all relevant contact 
details, is summarized in the investigational site file. This information will be updated as 
needed. Serious AEs occurring during the study must immediately (within 24 hours of 
Investigator awareness) be reported per Section 7.6.3.7. 
Serious AEs occurring after the protocol-defined observation period will be processed by the 
Sponsor according to applicable regulations (see Section 7.6.6). 

 
 
 
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7.6.5. 
Expedited Reporting of Adverse Events to Regulatory Agencies/Authorities 
7.6.5.1. 
Notification to the Ethics Committee/Institutional Review Board 
Notification to the IEC/IRB about all relevant events (e.g., SAEs/SUSARs) will be performed 
by the Sponsor or Sponsor’s designee and/or by the Investigator according to all applicable 
rules/regulations. 
7.6.5.2. 
Notification to the Authorities 
The processing and reporting of all relevant events (e.g., SAEs) to the authorities will be done 
by the Sponsor or Sponsor’s designee and/or by the Investigator according to all applicable 
rules/regulations. 
7.6.5.3. 
Sponsor’s Notification to the Investigational Site 
The Sponsor or designee will inform all investigational sites about reported relevant events 
according to applicable regulations. The Sponsor or Sponsor’s designee will send the events to 
a site once the site initiation visit has occurred and will stop sending to the site once the last 
patient has completed their EoT Visit. 
7.6.6. 
Post-study Adverse Events 
The Sponsor should be notified if the Investigator becomes aware of any SAEs that occurs after 
the end of the AE reporting period (see Section 7.6.2.1), if the event is believed to be related 
to prior study treatment. 
The Investigator should report these post-study events to the Sponsor or its designee, either by 
faxing or by scanning and emailing the SAE Reporting Form using the fax number or email 
address provided to Investigators. 
7.6.7. 
Independent Data Monitoring Committee 
The IDMC will serve as a monitory advisory group for the study. The primary role of the IDMC 
will be to examine the safety and tolerability of study participates throughout the duration of 
the study. The IDMC will be created to further protect the rights, safety, and well-being of 
patients who will be participating in the trial by monitoring their progress and results. 
 
 
 
The major tasks for the IDMC are outlined in relation to the description of the design of the 
trial (see Section 3.1). 
The frequency of IDMC meetings will be based on the development of the safety profile of the 
trial treatments and necessity to assess safety events and progression steps in the trial (e.g., 
transitions between cohorts). 
 
 
 

 
 
 
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The IDMC comprises qualified, international experts 
 
 
who are not Investigators in the study and not otherwise directly associated with 
the Sponsor. The IDMC will be described in detail in the IDMC Charter. 
7.6.8. 
Pregnancy 
Although not considered an AE, it is the responsibility of the Investigator or their designee to 
report any pregnancy in a patient or the patient’s sexual partner that occurs during the study. 
All patients who become pregnant must immediately discontinue the study drug and be 
withdrawn from the study. The patient will be followed to completion/termination of the 
pregnancy. This information is important for both drug safety and public health concerns. If a 
patient is found to be pregnant after the study treatment was administered, the Investigator 
should report this to the CRO and Sponsor immediately and document the pregnancy on the 
Pregnancy Form in the eCRF. 
The Investigator must make every effort to follow the patient until completion of pregnancy 
and provide the corresponding information by the mean of a SAE/Pregnancy form within 2 
weeks from awareness (same reporting procedures apply as for SAE reporting, see Section 
7.6.3.7). The Enterome/
 will periodically request the investigator for 
targeted follow-up information using specific pregnancy follow-up forms. If the events during 
pregnancy and/or outcome of pregnancy (i.e., complications regarding mother/baby) meet the 
criteria for classification of an SAE (see Section 7.6.2.2), the Investigator must follow the 
procedures for reporting SAEs outlined in Section 7.6.3.7. 
7.7. 
Clinical Laboratory Evaluations 
The timepoints at which these samples will be collected are shown in the Schedule of 
Assessments (Table 1). 
 
 
 
 
 
The following clinical laboratory assessments (not exhaustive list) will be performed: 
• Hematology panel: 
 
• Blood chemistry/electrolytes: 
 
  
• Renal function: 
 
• Hormonal function: 
 
 
• Coagulation panel: 
  
• Urinalysis 
. 
A full list of laboratory parameters is provided in Appendix 5. 

 
 
 
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Any clinically significant abnormal laboratory value should be immediately rechecked, 
whenever possible, for confirmation before making any decision for the concerned patient. It 
should be graded by NCI-CTCAE criteria v5.0 and documented as an AE/SAE PP requirement. 
For procedures on reporting abnormal laboratory values and liver function values, refer to 
Section 7.6.3.8.4 and Section 7.6.3.8.6, respectively. 
 
 
 
 
A serum pregnancy test will be conducted 
 
 
 
This is not required for females who have 
undergone and have documentation of a hysterectomy. 
Pregnancy tests will be performed as clinically indicated, or as required by local regulations, 
thereafter.  
Pregnancy tests may be performed at other visits at the discretion of the Investigator. 
Postmenopausal status will be confirmed 
 
7.7.1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 

 
 
 
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7.7.2. 
Immune Response Evaluation 
Cell-mediated cytotoxicity is a key element in the proposed mechanism of action of the 
peptides composing EO2401. 
 
 
 Selection of an ex-vivo monitoring technique that 
provides the best measure of immune reactivity is important in determining potential 
correlations between clinical and immunologic responsiveness to specific immunotherapy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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7.7.3. 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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7.8. 
Vital Signs, Physical Examination, and Other Safety Evaluations 
7.8.1. 
Vital Signs and ECOG or Karnofsky Performance Status 
Measurement of vital signs will include an assessment of HR, systolic and diastolic BP, 
temperature, and respiratory rate. 
Blood pressure and HR will be measured 5 minutes in a sitting or semi-recumbent position by 
means of oscillometry, using an automatic BP measuring device. It is recommended that the 
patient rests for 5 minutes before BP is measured. 
 
 
 
 
 
Vital sign measurements outside the normal ranges will be assessed as “abnormal, not clinically 
significant” or “abnormal, clinically significant” by the Investigator. In the latter case, the 
abnormal vital sign measurement will be reported as an AE and further investigated as 
clinically indicated (see Section 7.6.3.8.5). 
The ECOG or Karnofsky performance status will be collected throughout the study 
(see Appendix 3). 
7.8.2. 
12-Lead Electrocardiogram 
A single standard 12-lead ECG will be conducted as a triplicate trace at Screening and should 
be performed within 2 months before Screening. These 3 ECG will be performed within a 5-
minute interval between each of these 3 ECGs. Additional ECGs may be performed during the 
study as indicated in the Schedule of Assessments (Table 1) 
 
 
 ECG will be performed in case of medical needs. 
Electrocardiogram performed at different timepoints and at early discontinuation of the study 
will be conducted prior treatment (EO2401 and/or nivolumab bevacizumab, as appropriate) 
administration and at the discretion of the Investigator. New or worsened abnormalities should 
be recorded as AEs on the eCRF. 
Patients will be monitored by standard 12-lead ECG conducted according to local practice. 
7.8.3. 
Physical Examination 
Physical examination will include an examination of major body systems. 
 
 
 
Height will be measured once during Screening. Body weight will be measured throughout the 
study to EoT or early discontinuation of the study at every clinic visit, if possible. Vital signs 
may be repeated for clinically significant abnormal findings at the discretion of the Investigator. 
Abnormal findings on physical exam will be documented in the source documentation and 
eCRF. New or worsened abnormalities should be recorded as AEs, if applicable. 

 
 
 
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8. SAMPLE SIZE AND DATA ANALYSES 
8.1. 
Determination of Sample Size 
As this is the FIH trial of EO2401, there is no formal statistical analysis planned. Individual 
patient data and summary tables of data will be presented. The design builds on a 3-by-3 
approach for Cohort 1 
 and then a goal of 
having a sufficient, but not unnecessarily high, number of evaluable patients for safety data, 
immunogenicity, and early efficacy assessments in each of the cohorts (for safety and 
feasibility only, assessments less patients are accepted); the actual and planned patient numbers 
per cohort are: 
• Cohort 1a (sEN treatment of patients with measurable disease): 3 patients in the safety 
lead-in part, plus 18 added patients by the global amendment 2 plus re-distribution of 
patients from Cohort 2b, also including extended patient management measures = total 
of 21 patients (recruitment finalized before global amendment 3) 
• Cohort 2a (EN treatment of patients with measurable disease): 23 patients before 
adding 15 further patients by the global amendment 2 plus re-distribution of patients 
from Cohort 2b, also including extended patient management measures = total of 38 
patients (recruitment finalized before global amendment 3) 
• Cohort 2b (EN adjuvant treatment, no measurable disease): lowered from 15 patients 
to 6 patients by re-distribution to Cohorts 1a and 2a (recruitment finalized before global 
amendment 3), by the global amendment 2 also including extended patient 
management measures 
• Cohort 2c (EN neoadjuvant treatment - surgery - adjuvant treatment); cohort added by 
the global amendment 2 to evaluate safety and feasibility of the approach in 6 patients, 
also including extended patient management measures 
• Cohort 3 (ENB treatment of patients with measurable disease): by global amendment 
3 target recruitment increase from 10 to 26 patients, by the global amendment 2 also 
including extended patient management measures  
• Total of approximately 100 patients; sEN = "slow" EO2401/nivolumab (delayed N for 
4 weeks); EN = EO2401/nivolumab (combination treatment from start); ENB = 
EO2401/nivolumab/bevacizumab (bevacizumab full dose according to US label, and 
only recruiting in the US)     
 
 
 
 
 
 
 
 
 
 
  

 
 
 
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Data obtained from this study will be used to power future studies, and for this purpose the 
three key cohorts, i.e. Cohorts 1a/2a/3, all include more than 20 patients. 
Given the exploratory nature of this Phase Ib/IIa study, the sample size is not based on power 
calculation. The number of patients to be included will provide sufficient safety and 
tolerability, and immunogenicity data, as well as preliminary efficacy data without exposing 
too many patients. 
8.2. 
Analysis Populations 
The following analysis populations will be included for this study: 
The All Patient Population will consist of any patient who signed informed consent including 
Screen failures. 
Full Analysis Set will consist of any patients who received at least 1 dose of study drug 
(EO2401 alone or EO2401 in combination with nivolumab, or nivolumab/bevacizumab) for 
whom no important protocol deviations occurred. Patients who are not considered evaluable 
for this population will not be replaced. 
Safety Population will consist of any patients who received at least 1 dose of study drug 
(EO2401 alone or EO2401 in combination with nivolumab or nivolumab/bevacizumab). 
Patients who are not considered evaluable for this population will be replaced. 
Per-Protocol Population will consist of any patients who received 
 study 
drug (EO2401 alone or EO2401 in combination with nivolumab or nivolumab/bevacizumab) 
for whom no important protocol deviations occurred and have at least 1 evaluable 
post-Screening tumor assessment. Patients who are not considered evaluable for this population 
will not be replaced, and be included in the FAS. 
Efficacy will be analyzed using both the FAS and PP Populations. Safety will be analyzed 
using the Safety Population. 
8.3. 
General Considerations 
The following is an overview of the statistical analysis methods to be used in this study. Details 
on the statistical analyses will be given in the Statistical Analysis Plan. 
A data review meeting will be held before database lock. Protocol deviations will be reviewed 
during the data review meeting. Furthermore, assignment of patients to the analysis set will be 
performed. 
All data collected in this study will be documented with the help of patient data listings and 
summary tables and figures. Data listings will be provided for the different analysis populations 
as specified in the Statistical Analysis Plan (SAP). Summary statistics and statistical analysis, 
where required, will be performed for patients included in the relevant analysis populations 
(Safety/FAS/PP). Unless stated otherwise, descriptive summary statistics will include 
frequency counts and percentages for categorical variables and number of observations, mean, 
standard deviation, median, minimum, and maximum and the first and third quartiles for 
continuous variables. 

 
 
 
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Missing values will not be imputed. 
 
 
 
 
 
 
In addition, an update of OS analysis and listings of efficacy and safety parameters for patients 
who are still alive in the study after the interim analysis will be performed on a regular basis 
(every 3 to 6 months, as appropriate). 
The timing of the final analysis will be defined in the Statistical Analysis Plan and possibly 
amended in relation to the outcome of interim analysis 1 and 2. 
The final analysis will be done when the last patient completes the study treatment, all 
assessments for disease response, and monthly Follow-up Visits (see Sections 7.4.4 and 7.4.5). 
The first Follow-up Visit will be completed approximately 30 days after termination of study 
treatment. 
 
 
 
It is planned for all patients to be followed for survival for 24 months after last patient 
enrollment, if possible, via hospital records or other registers. 
Statistical analysis will be performed using SAS version 9.4 or later. 
8.3.1. 
Repeat and Unscheduled Readings 
Repeat assessments occur when the original result requires confirmation. Repeat assessments 
are handled and documented per the SAP. Prior to first dosing, all assessments taken in addition 
to the original assessment are defined as pre-dose repeats. Post-dose repeat assessment is 
defined as assessments collected within 15 minutes of the actual time of the original 
assessment. 
8.3.2. 
Demographic and Other Baseline Characteristics 
8.3.2.1. 
Patient Disposition 
The number and percentage of patients screened and treated will be presented by cohort and 
listed per the SAP. The reasons for patients discontinued from treatment will be summarized 
by cohort. In addition, the number of patients screened and included in each analysis population 
will be displayed by center. 
8.3.2.2. 
Patient and Disease Characteristics 
Descriptive summary statistics and frequency counts of demographic (age, sex, race, ethnicity, 
body weight, and height) and disease characteristics will be presented by cohort and overall 
per the SAP. Demographic and disease variables will also be listed. 

 
 
 
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8.3.3. 
Medical and Surgical History 
Medical and surgical history includes relevant history other than GB. The information will be 
coded using the current version of MedDRA. Coding terms and Investigator terms will be given 
in the listings. 
8.3.4. 
Prior and Concomitant Medications 
All medications will be coded using the WHO Drug Dictionary and Anatomical Therapeutic 
Chemical Classification system with version numbers as defined in the SAP. Coding terms and 
Investigator terms will be given in the listings. 
Prior medications will be defined as none study medication with a stop date prior to the first 
dose of study treatment. 
8.3.5. 
Tissue Sample Assessment 
Descriptive summary statistics and frequency counts of IL-13Rα2/BIRC5 (survivin)/FOXM1 
and PD(L)-1 expression using IHC technique will be presented by cohort and overall per the 
SAP. 
8.4. 
Efficacy Analysis 
The efficacy assessments in this study are considered secondary and exploratory 
 
 The 
definition of these efficacy endpoints is provided in Section 2.2.3. Routine tumor follow-up 
including tumor staging will be evaluated using descriptive statistics and frequency tables as 
appropriate. 
The efficacy assessments will be performed by MRI measurements every 8 weeks using the 
iRANO criteria (see Appendix 1). 
8.4.1. 
Overall Survival 
The OS will be summarized descriptively overall and per cohort using the Kaplan-Meier 
method. The median survival time will be presented with its associated 95% confidence 
interval (CI). The results will also be presented graphically in Kaplan-Meier plot. Survival rate 
assessments will be made at timepoints defined in the Statistical Analysis Plan. 
8.4.2. 
Progression-free Survival 
The PFS will be summarized descriptively overall and per cohort using the Kaplan-Meier 
method. The median PFS time will be presented with its associated 95% CI. The results will 
also be presented graphically in a Kaplan-Meier plot. 
8.4.3. 
Objective Response Rate & Disease Control Rate 
The ORR will be estimated overall and per cohort and provided with its 95% CI. The DCR will 
be estimated overall and per cohort and provided with its 95% CI. 
 

 
 
 
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8.4.4. 
Duration of Response 
Response duration will be calculated on responder patients (CR and PR) only and will be 
displayed as time to event parameter using the Kaplan-Meier analysis. 
8.4.5. 
Neurological Assessment of Neuro-Oncology Scale 
The NANO score will be summarized descriptively as outlined in the SAP. 
8.5. 
Safety Analysis 
Safety variables include incidence of AEs (or TEAEs), SAEs, laboratory test results, vital signs, 
ECOG performance, and ECG results. All safety analyses will be based on the Safety 
Population. No formal statistical analysis of the safety data will be performed. 
Summary tables will be provided for all TEAEs by cohort. The incidence of AEs, related 
AEs/TEAEs, SAEs, and AEs leading to discontinuation of the study treatment will be presented 
by the current MedDRA version, SOC and PT. In addition, the incidence of AEs by severity 
will be presented by SOC and PT. Listings will be produced for all AEs (TEAEs and 
non-treatment-emergent). Listings will be provided for those patients who experience an SAE, 
including death, or who experience an AE associated with early withdrawal from the study or 
from study drug treatment. 
The TEAE summary tables will include counts of patients. Therefore, if a patient experiences 
more than 1 episode of a particular AE, the patient will be counted only once for that event. If 
a patient has more than 1 TEAE that is coded to the same PT, the patient will be counted only 
once for that PT. Similarly, if a patient has more than 1 TEAE within an SOC, the patient will 
be counted only once in that SOC. 
Clinical laboratory test variables will be summarized by cohort and visit using descriptive 
statistics (number of patients, mean, standard deviation, minimum, maximum, and mean 
change from Screening). Shift tables (low, normal, high) between Screening and post-
Screening timepoints will be presented by laboratory test and cohort. Laboratory tests with 
categorical results that cannot be analyzed by change from baseline or shift table analysis will 
not be included in these summaries, but will be listed. 
In addition, for all clinical laboratory tests when possible to convert a conversion to 
NCI-CTCAE grades will be done and summaries based on NCI-CTAE grades will be 
presented, by actual values, grading, and by shift tables from baseline to worst value during the 
trial for individual patients. 
Data obtained from laboratory tests not required by the protocol will not be summarized, but 
will be listed. 
Descriptive statistics of vital signs and ECG results at each visit will be presented by cohort 
and will be listed. Shift tables (low, normal, high) between Screening and post-Screening 
timepoints will be presented by vital sign assessment and cohort. 
Concomitant medications will be summarized by cohort and data will be listed. 
Physical examination findings will only be listed for each patient. 

 
 
 
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8.6. 
Immunogenicity 
The immunogenicity testing 
 
 will be performed in PBMC collected at the timepoints indicated in 
the Schedule of Assessments (Table 1) for each patient. 
8.7. 
 
 
 
8.8. 
Interim Analysis 
An interim analysis will be performed 
 
 to assess safety, 
immune response, and efficacy parameters. 
 
 
 
Patients included in Cohort 2b will, depending on recruitment status and follow-up (targeted 
follow-up is 6 months), be analyzed in association with the first, and/or the second interim 
analyses. 
There are no plans for early termination of the trial due to superiority or futility of this FIH trial 
of EO2401 based on the interim results. At the interim analysis, descriptive analyses will be 
provided with no formal statistical testing. 
In addition, an update of OS analysis and listings of efficacy and safety parameters for patients 
who are still alive in the study after the interim analysis will be performed on a regular basis 
(every 3 to 6 months as appropriate). 
Details on the statistical analyses will be given in a separate Statistical Analysis Plan to cover 
the interim analysis. 

 
 
 
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10. APPENDICES 
 

 
 
 
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Appendix 1 – iRANO Criteria 
The goal of this modified response criteria is to meaningfully evaluate radiographic response and 
progression while simultaneously allowing therapies that may have transient effects on contrast 
enhancement but therapeutic benefit to be treated equally. This is particularly important in the 
context of platform trials, where many different therapies may be compared against a common 
control and there is a significant risk of over or under estimating tumor burden with a single 
evaluation timepoint. By allowing patients to stay on therapy longer, a more comprehensive and 
accurate assessment of therapeutic benefit can be performed on retrospective examination. A 
universal set of principles and guidelines, rather than treatment-specific response criteria, may 
allow us to fully understand the possible therapeutic benefits and potential limitations of promising 
new therapies for patients with GB.79 
The main guidance regarding specific measurements for response and progression in this trial (see 
Table below) is from Ellingson et al., Modified Criteria for Radiographic Response Assessment in 
GB Clinical Trials78 and should be followed. However, note in relation to PD that the confirmatory 
scan is stated to be done more than or equal to 4 weeks after the initial scan showing “preliminary 
PD,” which also allows the integration of the guidance given in Okada et al., iRANO: A Report of 
the RANO Working Group77. 
Thus, the following adaptations of the RANO criteria, as reflected in the iRANO criteria77, will be 
used to assess response for patients treated on this study: 
• Potential PsPD: If radiologic imaging shows initial progressive disease (PD), participants 
who are not experiencing significant clinical decline may be allowed to continue study 
treatment for up to 3 months. Patients who have radiographic evidence of further 
progression after up to 3 months, or who decline significantly at any time, will be classified 
as progressive with the date of disease progression back-dated to the first date that the 
participant met criteria for progression and such participants will be discontinued from 
study therapy. Although the kinetics of PsPD due to immune checkpoint blockade among 
GB patients is currently unknown, 3 months is a reasonable estimate based on: 1) the peak 
time for X-ray telescope/daily temozolomide-related PsPD is usually within 3 months of 
completion for GB patients90 and; 2) 3 months is also the most common timeframe for 
PsPD observed among patients with advanced melanoma or other solid tumors treated with 
PD-1/PD(L)-1 immune checkpoint blockade to date. 
See also protocol Sections 7.5.1.1 and 7.5.1.2 for additional guidance. 
Response 
Criteria 
Complete 
Response 
(CR) 
Requires all of the following: 
• 
Disappearance of all enhancing measurable and nonmeasurable disease sustained 
for at least 4 weeks. The first scan exhibiting disappearance of all enhancing 
measurable and nonmeasurable disease is considered “preliminary CR.” If the 
second scan exhibits measurable enhancing disease with respect to the 
“preliminary CR” scan, then the response is not sustained, noted as 
pseudoresponse (PsR), and is now considered “preliminary PD” (note confirmed 
PD requires at least 2 sequential increases in tumor volume). If the second scan 

 
 
 
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continues to exhibit disappearance of enhancing disease or emergence of 
nonmeasurable disease (less than 10 mm bidimensional product), it is considered 
a durable CR. 
Note: Patients with nonmeasurable disease only at baseline cannot have CR; the best 
response possible is SD. 
Partial 
Response 
(PR) 
Requires all of the following: 
• 
≥ 50% decrease in sum of products of perpendicular diameters or ≥ 65% decrease 
in total volume of all measurable enhancing lesions compared with baseline, 
sustained for at least 4 weeks. The first scan exhibiting ≥ 50% decrease in sum of 
products of perpendicular diameters or ≥ 65% decrease in total volume of all 
measurable enhancing lesions compared with baseline is considered “preliminary 
PR.” If the second scan exhibits PD with respect to the “preliminary PR” scan, 
then the response is not sustained, noted as PsR, and is now considered 
“preliminary PD” (note confirmed PD requires at least 2 sequential increases in 
tumor volume). If the second scan exhibits SD, PR, or CR, it is considered a 
durable PR and the patient should continue on therapy until confirmed PD is 
observed 
• 
Steroid dose should be the same or lower compared with baseline scan 
• 
Stable or improved clinical assessments. 
Note: Patients with nonmeasurable disease only at baseline cannot have PR; the best 
response possible is SD. 
Progressive 
Disease 
(PD) 
NOTE: see above regarding adaptation according to the iRANO criteria77 
Defined by any of the following: 
• 
At least 2 sequential scans separated by ≥ 4 weeks both exhibiting ≥ 25% increase 
in sum of products of perpendicular diameters or ≥ 40% increase in total volume 
of enhancing lesions. The first scan exhibiting ≥ 25% increase in sum of products 
of perpendicular diameters or ≥ 40% increase in total volume of enhancing lesions 
should be compared to the smallest tumor measurement obtained either at baseline 
(if no decrease) or best response (on stable or increasing steroid dose) and is noted 
as “preliminary PD.” If the second scan at least 4 weeks later exhibits a subsequent 
≥ 25% increase in sum of products of perpendicular diameters or ≥ 40% increase 
in total volume of enhancing lesions relative to the “preliminary PD” scan, it is 
considered “confirmed PD” and the patient should discontinue therapy. If the 
second scan at least 4 weeks later exhibits SD or PR/CR, this scan showing 
“preliminary PD” is noted as “pseudoprogression” (PsPD), and the patient should 
continue on therapy until a second increase in tumor size relative to the PsPD scan 
is observed. Note that any new measurable (> 10 mm ×10 mm) enhancing lesions 
should not be immediately considered PD, but instead should be added to the sum 
of bidimensional products or total volume representing the entire enhancing tumor 
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• 
In the case where the baseline or best response demonstrates no measurable 
enhancing disease (visible or not visible), then any new measurable (> 10 mm ×10 
mm) enhancing lesions are considered PD after confirmed by a subsequent scan ≥ 
4 weeks exhibiting ≥ 25% increase in sum of products of perpendicular diameters 
or ≥ 40% increase in total volume of enhancing lesions relative to the scan first 
illustrating new measurable disease. The first scan exhibiting new measurable 
disease is noted as “preliminary PD.” If the second scan at least 4 weeks later 
exhibits a subsequent ≥ 25% increase in sum of products of perpendicular 
diameters or ≥ 40% increase in total volume of enhancing lesions relative to the 
“preliminary PD” scan, it is considered “confirmed PD” and the patient should 
discontinue therapy. If the second scan at least 4 weeks later exhibits SD, CR, PR, 
or becomes nonmeasurable, this scan showing “preliminary PD” is noted as PsPD, 
and the patient should continue on therapy until a second increase in tumor size 
relative to the “preliminary PD,” or PsPD, scan is observed. Note that any new 
measurable (> 10 mm ×10 mm) enhancing lesions on the subsequent scan 
following the preliminary PD scan should not be immediately considered 
confirmed PD, but instead should be added to the sum of bidimensional products 
or total volume representing the entire enhancing tumor burden 
• 
Clear clinical deterioration not attributable to other causes apart from tumor (e.g., 
seizures, medication adverse effects, therapy complications, stroke, infection) or 
attributable to changes in steroid dose 
• 
Failure to return for evaluation as a result of death or deteriorating condition. 
Stable 
Disease 
(SD) 
Requires all of the following: 
• 
Does not qualify for CR, PR, or PD as defined above. Note this also applies to 
patients that demonstrate PsR when the confirmation scan does not show PD or 
PsPD when the confirmation scan does not show PR/CR 
• 
In the event that corticosteroid dose was increased (for new symptoms/signs) 
without confirmation of disease progression on neuroimaging, and subsequent 
follow-up imaging shows that the steroid increase was required because of disease 
progression, the last scan considered to show SD will be the scan obtained when 
the corticosteroid dose was equivalent to the baseline dose. 

 
 
 
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Appendix 2 – NANO Scale 
 

 
 
 
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Nayak et al, 201776 

 
 
 
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Appendix 3 – ECOG and Karnofsky Performance Status 
ECOG Performance Status 
Grade 
Description 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care, but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
Source: As published in Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern cooperative 
oncology group. Am J Clin Oncol. 1982;5:649-655. 
Karnofsky Performance Status 
Grade 
Description 
100 
Normal no complaints; no evidence of disease 
90 
Able to carry on normal activity; minor signs or symptoms of disease 
80 
Normal activity with effort; some signs or symptoms of disease 
70 
Cares for self; unable to carry on normal activity or to do active work 
60 
Requires occasional assistance, but is able to care for most of his personal needs 
50 
Requires considerable assistance and frequent medical care 
40 
Disabled; required special care and assistance 
30 
Severely disabled; hospital admission is indicated although death not imminent 
20 
Very sick; hospital admission necessary; active supportive treatment necessary 
10 
Moribund; fatal processes progressing rapidly 
0 
Dead 

 
 
 
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Appendix 4 – New York Heart Association Functional Classification 
Class 
Patient Symptoms 
Class I (None) 
No limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, or dyspnea (shortness of breath) 
Class II (Mild) 
Slight limitation of physical activity. Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation, or dyspnea 
Class III (Moderate) 
Marked limitation of physical activity. Comfortable at rest, but less than 
ordinary activity causes fatigue, palpitation, or dyspnea 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort. Symptoms of 
cardiac insufficiency at rest. If any physical activity is undertaken, discomfort 
is increased 
 

 
 
 
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Appendix 6 – Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines 
• Applicable International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceutical for Human Use (ICH) Good Clinical Practice (GCP) 
Guidelines 
• Applicable laws and regulations. 
The protocol, protocol amendments, Informed Consent Form (ICF), Investigator’s Brochure, and 
other relevant documents (e.g., advertisements) must be submitted to an Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) by the Investigator and reviewed and approved 
by the IRB/IEC before the study is initiated. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC 
• Notifying the IRB/IEC of serious adverse events (SAEs) or other significant safety findings 
as required by IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other applicable local 
regulations. 
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
Written informed consent for the study will be obtained from all patients before any 
protocol-specific procedures are conducted. The ICF generated by the Sponsor or designee will be 
approved (along with the protocol) by the IRB/IEC. 
Information about the study will be given to the patient both verbally and in writing. The written 
patient information sheet will explain the objectives of the study and its potential risk and benefits. 
The patient should have adequate time to read the information sheet and to ask the Investigator 

 
 
 
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any questions. The Investigator must be satisfied that the patient has understood the information 
provided before written consent is obtained. If there is any doubt as to whether the patient has 
understood the written and verbal information, the patient should not enter the study. 
If a patient agrees to participate, he/she will be asked to sign and date the study ICF, which will be 
retained by the Investigator. A copy of the signed ICF will be given to the patient. The informed 
consent process must be documented in the patient’s source documents. The original ICF must be 
retained by the Investigator and made available for inspection by the Study Monitor. 
Future Use of Patient Samples 
Following the completion of all study testing, the remaining tissue and blood/blood components 
(e.g., additional analysis on PBMC) may be used for Future Biomedical Research. This research 
will help to understand response against other tumor-associated antigens not included in the current 
peptide mix and possibly DNA sequencing. If a patient requests destruction of his/her tissue and 
blood samples and the samples have not yet been de-identified, the Sponsor will destroy the 
samples under specific regulations and notify the Investigator in writing that the samples have 
been destroyed. Patients will be asked whether or not they consent to the (optional) future use of 
patient samples. This consent will be documented separately and patients will not be excluded 
from study participation if they do not consent to this future use of residual samples. 
Patient Data Protection 
Patients will be assigned a unique identifier and will not be identified by name in eCRFs, 
study-related forms, study reports, or any related publications. Patient and Investigator personal 
data will be treated in compliance with all applicable laws and regulations. In the event the study 
protocol, study report, or study data are included in a public registry, all identifiable information 
from individual patients or Investigators will be redacted according to applicable laws and 
regulations. 
The patient must be informed that his/her personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to the 
patient. The patient must also be informed that his/her medical records may be examined by 
Sponsor or Contract Research Organization (CRO) auditors or other authorized personnel 
appointed by the Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
Investigator Documentation Responsibilities 
All individual, patient-specific study data will be entered into a 21 CFR Part 11-compliant 
electronic data capture (EDC) system on an eCRF in a timely fashion. All data generated from 
external sources (e.g., central laboratory, ECG central readers) and transmitted to the Sponsor or 
designee electronically will be integrated with the patient’s eCRF data in accordance with the Data 
Management Plan. 
An eCRF must be completed for each patient who signs an ICF and undergoes any pre-Screening 
or Screening procedures, according to the eCRF completion instructions. The Sponsor, or CRO, 
will review the supporting source documentation against the data entered into the eCRFs to verify 

 
 
 
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the accuracy of the electronic data. The Investigator will ensure that corrections are made to the 
eCRFs and that data queries are resolved in a timely fashion by the study staff. 
The Investigator will sign and date the eCRF via the EDC system’s electronic signature procedure. 
These signatures will indicate that the Investigator reviewed and approved the data on the eCRF, 
the data queries, and the site notifications. 
Electronic Data Capture 
The CRO will supply the investigational site with access to a web-based EDC computer system. 
Edit checks and data logic checks are at the point of entry and are validated according to company 
standard operating procedures. All data entered into the system are transferred to a secure database 
maintained by the CRO. 
Access to the EDC system at the site, for vendors, at the Sponsor, and at the CRO is password 
protected. Study access is granted to site personnel only after they have been trained in the use of 
the EDC system by web-based training at the investigational site. 
The EDC system contains a system generated audit trail that captures any changes made to a data 
field, including who made the change, and the date and time it was made. This information is 
available at the Investigator’s site, at the CRO, and at the Sponsor. 
Data entries made in the EDC screens should be completed within 5 days of the patient’s study 
visit and must be supported by source documents maintained for all patients enrolled in the study. 
The data collection tool for this study will be the validated electronic system. Patient data necessary 
for analysis and reporting will entered and transmitted via the electronic system. Clinical data 
management will be performed in accordance with applicable standards and data cleaning 
procedures. For data coding (e.g., adverse events [AEs], medication), internationally recognized 
and accepted dictionaries will be used. 
After database lock has been declared, all data will be delivered to the Sponsor. 
Study Monitoring and Data Quality Assurance 
The Sponsor or Sponsor’s designee performs quality control and assurance checks on all clinical 
studies that it conducts. Before enrolling any patients in this study, the Investigator will review the 
protocol, the EO2401 Investigator Brochure, the eCRF and instructions for their completion, the 
procedure for obtaining informed consent, and the procedure for reporting AEs and SAEs. The 
Sponsor’s designee will monitor the conduct of the study at the site and will verify eCRF against 
source documents. Additionally, the Sponsor’s designee will use automated validation programs 
to help identify missing data, selected protocol deviations, out-of-range data, and other data 
inconsistencies. Requests for data clarification or correction will be electronically provided to the 
Investigator for resolution. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor or Sponsor’s designee. Inspection of site facilities (e.g., 
pharmacy drug storage areas, laboratories) and review of study-related records will occur to 

 
 
 
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evaluate the study conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 
Review of Source Documents 
The Investigator agrees that the Study Monitor (and other qualified personnel as appropriate) will 
be allowed to conduct site visits to the investigational facilities for the purpose of reviewing source 
records pertinent to the study. The Investigator will make the study files available during 
monitoring visits. These files will also be available for inspection by representatives of the Sponsor, 
competent authorities and/or the IRB. Patients will not be identified by name on any of the study 
documents utilized by the Sponsor for their analysis, and confidentiality of information in medical 
records will be preserved. Every effort will be made to maintain the confidentiality of the patient 
unless disclosure is required by regulations. 
Protocol Amendments 
Any substantial amendments in the research protocol during the period, for which the IEC/IRB 
approval had already been given, will not be initiated without submission of an amendment for 
IEC/IRB review and approval. 
These requirements for approval will in no way prevent any immediate action from being taken 
by the Investigator in the interest of preserving the safety of all patients included in the trial. 
Protocol Deviations 
A protocol deviation is any departure from the defined procedures and treatment plans as outlined 
in the protocol version submitted and previously approved by the IEC/IRB. Protocol deviations 
have the potential to place participants at risk and can also undermine the scientific integrity of the 
study thus jeopardizing the justification for the research. Protocol deviations are unplanned and 
unintentional events. 
Important protocol deviations, such as significant noncompliance or other serious unforeseen 
deviations deemed to invalidate the data collected in lieu of the purpose of the study will lead to 
exclusion of data from analysis. In case of non protocol deviations, data will not be excluded from 
the data analysis. 
All decisions regarding the type of deviations (important or non-important) will be made prior to 
commencing the final analysis on the final locked database. A listing of all patients with protocol 
deviations will be maintained by the Sponsor and a listing of all important protocol deviations will 
be presented in the final study report. 
Investigational sites will report protocol deviations to their IEC/IRB per institutional reporting 
requirements. 
Change in Investigator 
If any Investigator retires, relocates, or otherwise withdraws from conducting the study, the 
responsibility for maintaining records may be transferred to the Sponsor or designee, IRB, or 

 
 
 
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another Investigator. The Sponsor or designee must be notified of and agree to the change. 
Regulatory agencies will be notified with the appropriate documentation. 
Criteria for Termination of the Study or Study Center/Site 
Early termination of the study 
If the Sponsor or its designee, the Investigator, or regulatory agency discovers any condition 
arising during the study that indicate that the study or the study site should be terminated, this 
action may be taken after appropriate consultation between the Sponsor or its designee and the 
Investigator. The Sponsor or its designee has the right to terminate the participation of either an 
individual site or the study at any time, for any reason, which may include the following: 
• The incidence and severity of AEs in this or other studies indicates a potential health hazard 
to patients 
• Patient enrollment is unsatisfactory 
• Data recording is inaccurate or incomplete 
• Investigator(s) do(es) not adhere to the protocol or applicable regulatory guidelines in 
conducting this study 
• Submission of knowingly false information from the study site to the Sponsor or its 
designee or regulatory authorities. 
In the event that the study is terminated early, the Sponsor or its designee will provide specific 
guidance to investigational sites regarding the end of study procedures. 
Clinical Study Report 
A clinical study report will be prepared following the completion of the study. 
Confidentiality/Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential. The Investigator (or 
designee) agrees not to disclose such information in any way without prior written permission 
from the Sponsor. 

 
 
 
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Records Retention 
Essential documents must be retained for longer than 5 years after completion of the study, 2 years 
after the final marketing authorization in an ICH region or until at least 2 years have elapsed since 
the discontinuation of clinical development of the study drug. If it becomes necessary for the 
Sponsor or the Competent Authority to review any documentation relating to the study, the 
Investigator must permit access to such records. 
Study files may be discarded upon written notification by the Sponsor. To avoid error, the 
Investigator must contact the Sponsor before destroying any records or reports pertaining to the 
study, to ensure that retention is no longer required. Other source documents, such as patient’s 
medical records, must be retained for the maximum period of time permitted by the hospital or 
institution and until such time when the Investigator is informed by the Sponsor that there is no 
further need to do so. 
In addition, in accordance with the Investigator agreement, the Sponsor should be contacted if the 
site’s Principal Investigator plans to leave the investigational site so that appropriate arrangements 
can be made. 
Publications 
If on completion of the study the data warrant publication, the Investigator may publish the results 
in recognized (refereed) scientific journals subject to the provisions of the clinical study agreement 
(CSA). Unless otherwise specified in the CSA, the following process shall occur: 
The institution and Investigator shall not publish or present data from an individual study center 
until the complete multicenter study has been presented in full or for 2 years after the termination 
of the multicenter study, whichever occurs first. Subsequent publications must refer to the 
multicenter findings. Thereafter, if the Investigator expects to participate in the publication of data 
generated from this site, the institution and Investigator shall submit reports, abstracts, 
manuscripts, and/or other presentation materials to the Sponsor for review before submission for 
publication or presentation. The Sponsor shall have 60 days to respond with any requested 
revisions, including (without limitation) the deletion of confidential information. The Investigator 
shall act in good faith upon requested revisions, except the Investigator shall delete any 
confidential information from such proposed publications. The Investigator shall delay submission 
of such publication or presentation materials for up to an additional 90 days in order to have a 
patent application(s) filed. 

 
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Appendix 7 – Treatment-related Reactions 
Immediate systemic reactions, infusion-related reactions and hypersensitivity reactions, at 
administration of nivolumab can be considered to be common (European SmPC and US PI 59, 60 
for nivolumab; see also Section 7.6.1.1 and 7.6.1.2 for further guidance), and it can occur also at 
administration of bevacizumab (European SmPC and US PI63,69 for bevacizumab; see also Section 
7.6.1.3 for further guidance). Systemic reaction at administration of EO2401 cannot be excluded 
either, and since this is an FIH trial it is reasonable to take precautions to be able to ameliorate 
symptoms if such would occur. 
In the current trial, the nivolumab infusion is to start 3 hours after the EO2401 administration, and 
when applicable (Cohort 3) the bevacizumab infusion is to start 3 hours after the nivolumab 
administration. Thus, in the combination therapy parts of the trial, patients will be observed up to 
3-4 hours when nivolumab is administered together with EO2401, and 7-8 hours when 
bevacizumab is also administered. In Cohort 1 where there is administration of EO2401 only, 
patients will be observed for 3 hours (except the first patient injected who will be observed for 
6 hours). 
NOTE: At administration of the treatment compounds of this trial, immediate treatment of severe 
allergic reactions should be available, including staff well trained in resuscitation, IV access for 
administration of fluids, antihistamines and corticosteroids, and epinephrine for intramuscular 
injection. 
Treatment of Administration-related Infusion Reactions 
If such reactions would occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgias, hypotension, hypertension, bronchospasm, or other allergic-like reactions. All Grade 
3 or 4 infusion reactions should be reported within 24 hours to the Sponsor via the Medical Monitor 
and be reported as an SAE if it meets the criteria. Infusion reactions should be graded according 
to NCI-CTCAE guidelines (see Section 7.6.3.8.1 for further guidance). 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate: 
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not 
indicated). 
• Remain at bedside and monitor patient until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 
50 mg (or equivalent) and/or acetaminophen 325 to 1000 mg orally at least 30 minutes 
before additional administrations. 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [e.g., antihistamines, nonsteroidal 
anti-inflammatory 
drugs, 
narcotics, 
corticosteroids, 
bronchodilators, 
IV 
fluids]; 
prophylactic medications indicated for ≤ 24 hours). 

 
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• Stop the infusion, begin an IV infusion of normal saline, and treat the patient with 
diphenhydramine 50-mg IV (or equivalent) and/or acetaminophen 325- to 1000-mg PO; 
remain at bedside and monitor patient until resolution of symptoms. Corticosteroid and/or 
bronchodilator therapy may also be administered as appropriate. If the infusion is 
interrupted, then restart the infusion at 50% of the original infusion rate when symptoms 
resolve; if no further complications ensue after 30 minutes, the rate may be increased to 
100% of the original infusion rate. Monitor patient closely. If symptoms recur, then no 
further drug will be administered at that visit. 
• For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325- to 
1000-mg PO should be administered at least 30 minutes before infusions. If necessary, 
corticosteroids (up to 25-mg IV of SoluCortef or equivalent) may be used. 
For Grade 3 or 4 symptoms: (Severe reaction, Grade 3: prolonged [i.e., not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[e.g., renal impairment, pulmonary infiltrates]. Grade 4: Life-threatening; pressor or 
ventilatory support indicated). 
• Immediately discontinue infusion of the compound. Begin an IV infusion of normal saline 
and treat the subject as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of 
a 1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10 000 solution 
injected slowly for IV administration, and/or diphenhydramine 50-mg IV with 
methylprednisolone 100-mg IV (or equivalent), as needed. The patient should be monitored 
until the Investigator is comfortable that the symptoms will not recur. Investigators should 
follow their institutional guidelines for the treatment of anaphylaxis. Remain at bedside 
and monitor patient until recovery of the symptoms. Further treatment of the patient should 
be held and assessments made per the general and specific safety rules of the trial 
(depending on cohort of the trial; see Section 3.1). 
Late-occurring Hypersensitivity Symptoms 
• In case of late-occurring hypersensitivity symptoms (e.g., appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given 
(e.g., oral antihistamine or corticosteroids). 
 
 
 
 
 
 

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