A Phase 1/2 Trial of a Novel Therapeutic Vaccine (EO2401) in Combination With Immune Check Point Blockade, for Treatment of Patients With Locally Advanced or Metastatic Adrenocortical Carcinoma, or Malignant Pheochromocytoma/Paraganglioma
Phase: PHASE1
Conditions: Adrenocortical Carcinoma, Pheochromocytoma, Paraganglioma
Sponsor: Enterome



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Protocol No: EOADR1-19 
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SITE PRINCIPAL INVESTIGATOR AGREEMENT 
I, the undersigned, have read this protocol and the appendices and agree to conduct the study 
as described herein. 
 
 
 
Site Principal Investigator Signature:  
 
 
 
 
Date: 
 
 
 
 
 
Printed Name: 
 
 
 
 
 
Site location: 
 
 

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TABLE OF CONTENTS 
SIGNATURE FOR PROTOCOL APPROVAL AND RELEASE ............................................................... 2 
GLOBAL COORDINATING INVESTIGATOR AGREEMENT ............................................................... 3 
SITE PRINCIPAL INVESTIGATOR AGREEMENT ................................................................................. 4 
SYNOPSIS ...................................................................................................................................................... 16 
1 
BACKGROUND ......................................................................................................................... 19 
1.1 
BACKGROUND ADRENAL MALIGNANCIES .................................................................. 19 
1.1.1 
Characteristics of adrenocortical carcinoma .................................................. 19 
1.1.2 
Characteristics of malignant pheochromocytoma/paraganglioma ................... 20 
1.1.3 
Treatment of adrenocortical carcinoma ......................................................... 21 
1.1.4 
Treatment of malignant pheochromocytoma/paraganglioma .......................... 22 
1.2 
NOVEL THERAPIES AND IMMUNOTHERAPY IN ADRENAL MALIGNANCIES ....................... 23 
1.3 
EO2401 AN ADRENAL MALIGNANCY TARGETED THERAPEUTIC VACCINE .......................... 24 
1.3.1 
EO2401 background and non-clinical development ....................................... 24 
1.3.2 
EO2401 early clinical development ............................................................... 31 
1.3.3 
EO2401 clinical information & Rationale and high-level outline for global 
amendment #2 (leading to protocol EOADR1-19 version 3) ...................................... 32 
1.3.4 
Protocol amendment 2 leading to Protocol version 3.0 overview ................... 40 
1.3.5 
Benefit/risk assessment and description of and justification for the route of 
administration, dosage, dosage regimen, and treatment period.................................. 42 
1.3.6 
Rationale for global amendment #3 (leading to protocol EOADR1-19 version 4) 
. ................................................................................................................................... 45 
1.3.7 
Rationale for global amendment #4 (leading to protocol EOADR1-19 version 5) 
. ................................................................................................................................... 46 
1.4 
HISTORY OF AMENDMENTS .................................................................................... 49 
2 
RATIONALE ............................................................................................................................... 51 
2.1 
RATIONALE FOR THE STUDY ................................................................................... 51 
3 
STUDY OBJECTIVES AND ENDPOINTS ................................................................................. 53 
3.1 
STUDY OBJECTIVES ............................................................................................... 53 
3.1.1 
Primary objectives ......................................................................................... 53 
3.1.2 
Secondary objectives .................................................................................... 53 
3.1.3 
Exploratory objectives ................................................................................... 53 
3.2 
STUDY ENDPOINTS ................................................................................................ 54 
3.2.1 
Primary endpoint ........................................................................................... 54 
3.2.2 
Secondary endpoints .................................................................................... 55 
3.2.3 
Exploratory endpoints ................................................................................... 55 
4 
STUDY DESIGN ......................................................................................................................... 58 
4.1 
MAIN STUDY DESIGN .............................................................................................. 58 
4.2 
OVERALL STUDY DESIGN AND PLAN......................................................................... 58 
4.2.1 
Cohort 1 ........................................................................................................ 64 
4.2.2 
Cohorts 2A (non-randomized part), 2B, 3A, and 3B ....................................... 68 
4.2.3 
Randomized extension of Cohort 2A ............................................................. 69 
4.3 
END OF STUDY ...................................................................................................... 70 
4.3.1 
Planned study completion and study duration ............................................... 70 
4.3.2 
Early site closure and early study termination ................................................ 70 
4.4 
DISCUSSION OF STUDY DESIGN .............................................................................. 71 
5 
POPULATION ............................................................................................................................ 74 

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5.1 
INCLUSION CRITERIA .............................................................................................. 74 
5.2 
EXCLUSION CRITERIA ............................................................................................ 76 
5.3 
REMOVAL OF PATIENTS FROM THERAPY OR STUDY .................................................. 80 
5.3.1 
Patient withdrawal of consent ........................................................................ 80 
5.3.2 
Screen failures .............................................................................................. 80 
5.3.3 
Criteria for treatment discontinuation ............................................................. 80 
5.3.4 
Lost to follow-up ............................................................................................ 80 
5.3.5 
Criteria for study participation termination ...................................................... 81 
5.3.6 
Follow-up of patients discontinued from study treatment or withdrawn from 
study 
 .................................................................................................................................... 81 
5.3.7 
Procedures for handling incorrectly enrolled patients ..................................... 81 
5.3.8 
Patient replacement ...................................................................................... 81 
6 
TREATMENT OF PATIENTS ..................................................................................................... 82 
6.1 
DESCRIPTION OF EO2401 ..................................................................................... 82 
6.1.1 
Pharmaceutical form ..................................................................................... 82 
6.1.2 
Preparation of the formulation ....................................................................... 82 
6.1.3 
Packaging and labeling ................................................................................. 84 
6.1.4 
Storage and stability...................................................................................... 84 
6.2 
DESCRIPTION OF NIVOLUMAB ................................................................................. 84 
6.2.1 
Pharmaceutical form ..................................................................................... 84 
6.2.2 
Preparation of the formulation ....................................................................... 85 
6.2.3 
Packaging and labeling ................................................................................. 85 
6.2.4 
Storage and stability...................................................................................... 85 
6.2.5 
Expected safety profile of nivolumab ............................................................. 85 
6.3 
ADMINISTRATION OF EO2401 AND NIVOLUMAB ........................................................ 86 
6.4 
TREATMENT MODIFICATIONS .................................................................................. 88 
6.4.1 
Recommended treatment modifications for EO2401 and nivolumab in case of 
immune-related adverse reactions, and treatment modifications for adverse reactions 
to nivolumab .............................................................................................................. 88 
6.5 ADMINISTRATION-RELATED REACTIONS .................................................................... 92 
6.5.1 
Treatment of administration-related reactions ................................................ 93 
6.5.2 
Late-occurring hypersensitivity symptoms ..................................................... 94 
6.7 
STUDY TREATMENT ACCOUNTABILITY, RECONCILIATION, AND RETURN ....................... 96 
6.8 
METHOD OF TREATMENT ASSIGNMENT .................................................................... 97 
6.9 
ANCILLARY TREATMENTS ....................................................................................... 99 
6.9.1 
Prior and concomitant treatments and procedures ........................................ 99 
6.9.2 
Permitted concomitant medications ............................................................... 99 
6.9.3 
Prohibited medications and other therapies ................................................. 101 
6.9.4 
Contraception ............................................................................................. 102 
6.10 
TREATMENT COMPLIANCE ................................................................................. 102 
7 
STUDY ASSESSMENTS AND PROCEDURES ...................................................................... 103 
7.1 
STUDY SCHEDULE ............................................................................................... 103 
7.2 
SCREENING PERIOD #1 ........................................................................................ 103 
7.3 
SCREENING PERIOD #2 ........................................................................................ 110 

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7.4 
VISITS DURING STUDY TREATMENT ....................................................................... 113 
7.4.1 
Visits during EO2401 priming phase; V1, V2, V3, V4, and V5 ..................... 113 
7.4.2 
Visits during EO2401 boost period; from V6 until treatment discontinuation 114 
7.5 
VISITS DURING POST-TREATMENT FOLLOW-UP ...................................................... 116 
7.5.1 
Post-treatment visit for safety assessment; Vn+1 ........................................ 116 
7.5.2 
Post-treatment follow-up before assessed progressive disease; Vnn ........... 116 
7.5.3 
Post-treatment follow-up; Vnnn ................................................................... 117 
7.6 
SAFETY ASSESSMENTS ........................................................................................ 117 
7.7 
EFFICACY ASSESSMENTS ..................................................................................... 117 
7.8 
IMMUNOLOGICAL ASSESSMENTS ........................................................................... 118 
7.8.1 
Cell mediated immunity and associated utilization of PBMCs ...................... 118 
7.8.2 
Humoral immune responses ....................................................................... 119 
7.8.4 
Correlations between immunogenicity and other trial outcome parameters 119 
7.9 
ASSESSMENTS FOR OTHER EXPLORATORY ENDPOINTS .......................................... 119 
8 
SAFETY MONITORING ........................................................................................................... 120 
8.1 
SAFETY MONITORING DEFINITIONS ........................................................................ 120 
8.1.1 
Adverse events ........................................................................................... 120 
8.1.2 
Serious Adverse events .............................................................................. 121 
8.1.2.1 
Excluded events .................................................................................................................. 121 
8.1.3 
Suspected Unexpected Serious Adverse Reactions (SUSARs) ................... 122 
8.1.4 
Severity/intensity versus seriousness .......................................................... 122 
8.2 
PREGNANCIES .................................................................................................... 122 
8.3 
SAFETY MONITORING PERIODS ............................................................................. 122 
8.3.1 
Reporting .................................................................................................... 122 
8.3.2 
Follow-up .................................................................................................... 123 
8.4 
ASSESSING ADVERSE EVENTS .............................................................................. 123 
8.4.1 
Causality ..................................................................................................... 123 
8.4.2 
Severity/intensity ......................................................................................... 124 
8.5 
REPORTING BY THE INVESTIGATIONAL SITE ........................................................... 124 
8.5.1 
Adverse events ........................................................................................... 124 
8.5.2 
Documenting in the eCRF ........................................................................... 126 
8.5.3 
Immediately reportable events - Serious Adverse Events ............................ 126 
8.5.3.1 
Minimum notification/reporting requirements ....................................................................... 127 
8.6 
INDEPENDENT DATA MONITORING COMMITTEE (IDMC) ......................................... 128 
9 
STATISTICAL EVALUATION .................................................................................................. 130 
9.1 
ANALYSIS POPULATIONS ...................................................................................... 130 
9.2 
STATISTICAL METHODS ........................................................................................ 130 
9.3 
INTERIM ANALYSIS ............................................................................................... 131 
9.4 
DETERMINATION OF SAMPLE SIZE ......................................................................... 131 
9.4.1 
Considerations regarding Cohorts 1, non-randomized 2A, 2B, 3A, and 3B . 131 
9.4.2 
Considerations regarding the randomized extension of Cohort 2A ............... 132 
10 
ADMINISTRATIVE CONSIDERATIONS .............................................................................. 136 
10.1 
REGULATORY AND ETHICAL CONSIDERATIONS .................................................... 136 
10.2 
FINANCES AND INSURANCES ............................................................................. 136 
10.3 
INFORMED CONSENT ........................................................................................ 137 
10.4 
FUTURE USE OF PATIENT SAMPLES; SAMPLE TRACEABILITY ................................. 137 
10.5 
PATIENT DATA PROTECTION .............................................................................. 138 
10.6 
SITE MONITORING ............................................................................................ 138 

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10.7 
HANDLING OF DATA AND DATA COLLECTION ....................................................... 138 
10.8 
COLLECTION AND STORAGE OF BIOLOGICAL SAMPLES ......................................... 140 
10.9 
PROTOCOL AMENDMENTS ................................................................................. 140 
10.10 
PROTOCOL DEVIATIONS .................................................................................... 140 
10.11 
CHANGE IN INVESTIGATOR ................................................................................ 140 
10.12 
CLINICAL STUDY REPORT .................................................................................. 140 
10.13 
CONFIDENTIALITY/DISCLOSURE ......................................................................... 141 
10.14 
RECORD RETENTION ........................................................................................ 141 
10.15 
PUBLICATIONS ................................................................................................. 141 
11 
LITERATURE ....................................................................................................................... 143 
12 
APPENDICES ....................................................................................................................... 148 
12.1 
APPENDIX 1: CRITERIA 
FOR MEASUREMENT OF TUMOR RESPONSE AND 
PROGRESSION; RECIST AND IRECIST .......................................................................... 148 
12.2 
APPENDIX 2: ECOG PERFORMANCE STATUS ...................................................... 156 
12.3 
APPENDIX 3: NEW YORK HEART ASSOCIATION FUNCTIONAL CLASSIFICATION ....... 157 
12.4 
APPENDIX 4: PROTOCOL DEVIATIONS................................................................. 158 
12.5 
APPENDIX 5: THE CKD-EPI EQUATION FOR ESTIMATING GLOMERULAR FILTRATION 
RATE [63] ..................................................................................................................... 160 
12.7 
APPENDIX 7: MANAGEMENT ALGORITHMS REGARDING NIVOLUMAB FOR STUDIES 
UNDER CTCAE VERSION 5.0......................................................................................... 164 

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ABBREVIATIONS 
 
123I/131I-MIBG 
123I/131I-metaiodobenzylguanidine 
ACC 
Adrenocortical carcinoma 
AE 
Adverse event 
AIDS 
Acquired immunodeficiency syndrome 
AJCC 
American Joint Committee on Cancer 
ALT 
Alanine aminotransferase 
ALP 
Alkaline phosphatase 
ANC 
Absolute neutrophil count 
APTT 
Activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
B2M 
β-2-microglobulin 
BIRC5 
Baculoviral inhibitor of apoptosis repeat-containing 5 
BP 
Blood pressure 
bpm 
Beats per minute 
BSA 
Body surface area 
CD 
Cluster of differentiation 
CDD 
Cyclophosphamide, dacarbazine, doxorubicin 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
ConA 
Concanavalin A 
COVID 
Coronavirus disease 
CPI 
Check point inhibitor 
CR 
Complete response 
CRA 
Clinical research associate 

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CRO 
Contract research organization 
CRP 
C-reactive protein 
CSA 
Clinical study agreement 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
CVD 
Cyclophosphamide, vincristine, dacarbazine 
CVDD 
Cyclophosphamide, vincristine, dacarbazine, doxorubicin 
DB 
Database 
DCR 
Disease Control Rate 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
DP 
Drug product 
DSUR 
Development safety update report 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EDP-M 
Etoposide, doxorubicin, cisplatin, mitotane 
ELISA 
Enzyme-linked immunosorbent assay 
ELISpot 
Enzyme-linked immunospot 
ENSAT 
European Network for the Study of Adrenal Tumors 
ESMO 
European Society for Medical Oncology 
EudraCT 
European clinical trials database 
FAS 
Full analysis set 

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FDA 
Food and Drug Administration 
FIH 
First-in-human 
FOXM1 
Forkhead box M1 
FSH 
Follicle-stimulating hormone 
GCP 
Good clinical practice 
GMP 
Good manufacturing practice 
Hb 
Hemoglobin 
HBcAg 
Hepatitis B core antigen 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
HR 
Heart rate 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International 
Council 
for 
Harmonization 
of 
Technical 
Requirements for Pharmaceuticals for Human Use 
ID 
Identification number 
IDMC 
Independent data monitoring committee 
IHC 
Immunohistochemistry 
IEC 
Independent ethics committee 
IFA 
Incomplete Freund's adjuvant 
IFN- 
Interferon-gamma 
IHC 
Immunohistochemistry 
IL-13Rα2 
Interleukin-13 receptor alpha-2 
IL-6 
Interleukin-6 

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IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IRB 
Institutional review board 
IV 
Intravenous(ly) 
JAK 
Janus kinase 
KPS 
Karnofsky Performance Status 
LDH 
Lactate dehydrogenase 
LLN 
Lower limit of normal 
MedDRA 
Medical dictionary for regulatory activities 
MEN 
Multiple endocrine neoplasia 
MHC 
Major histocompatibility complex 
MMR-D 
Mismatch repair-deficient 
MPP 
Malignant pheochromocytoma/paraganglioma 
MSI-H 
Microsatellite instability-high 
NCI 
National Cancer Institute 
NCI-CTCAE 
National Cancer Institute-common terminology criteria for 
adverse events 
NCCN 
National Comprehensive Cancer Network 
NE 
Non-evaluable 
NIH 
National Institute of Health 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cells 
PI3K 
Phosphatidyl inositol 3-kinase 
PD 
Progressive disease 
PD-1 
Programmed death-1 
PD-L1 
Programmed death-ligand 1 

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PFS 
Progression-free survival 
PI 
Product information 
P-M 
Cisplatin, mitotane 
PP 
Per-protocol 
PR 
Partial response 
PT 
Preferred term 
RBC 
Red blood cells 
RNA 
Ribonucleic acid 
PV 
Pharmacovigilance 
RECIST 
Response evaluation criteria in solid tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SC 
Subcutaneous(ly) 
SD 
Stable disease 
SDHB 
Succinate dehydrogenase B 
SmPC 
Summary of product characteristics 
SoC 
Standard of care 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
Sz-M 
Streptozotocin, mitotane 
TAA 
Tumor-associated antigen 
TCR 
T cell receptor 
TEAE 
Treatment emergent adverse event 
TERT 
Telomerase reverse transcriptase 
TSH 
Thyroid-stimulating hormone 
TTP 
Time to progression 

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UCP2 
Universal cancer peptide 2 
ULN 
Upper limit of normal 
V 
Visit 
VHL 
Von Hippel–Lindau 
W 
Week 
WBC 
White blood cells 

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SYNOPSIS 
Full trial title 
A phaSe 1/2 trial of EO2401, a novel microbial-derived Peptide therapeutic vaccine, in combination 
with PD-1 check point blockadE, for treatment of patients with locally advaNced or metastatic 
adrenocortical Carcinoma, or malignant phEochromocytoma/paRaganglioma (the “Spencer” study) 
Rationale 
Treatment options for patients with unresectable malignant adrenal disease are few and new 
treatment options have not been developped recently. Novel therapeutic approaches are needed to 
enhance the treatment outcomes for patients with adrenal malignancies. An innovative option which 
is available to test in the clinic, and proposed with the current trial, is the microbiome-derived peptide 
therapeutic cancer vaccine approach in combination with nivolumab, an anti-PD-1 blockade. 
 
Objectives 
The primary objective of the phase 1 part of this trial is to evaluate safety and tolerability of EO2401 
in combination with nivolumab in patients with unresectable, previously treated, and previously 
untreated, locally advanced or metastatic adrenocortical carcinoma (ACC), and progressive 
pheochromocytoma/paraganglioma (MPP). 
The primary objective of the phase 2 part of this trial is to determine the effect of EO2401 in 
combination with nivolumab on the progression-free survival rate (PFS) at 6 months, for patients 
treated in the randomized extension of Cohort 2A (patients with ACC who had prior systemic 
therapy). 
The secondary objectives of the trial include assessment of immunogenicity of each peptide 
composing EO2401 in relation to T cells and cross-reactivity with the human Tumor Associated 
Antigens, objective response rate (ORR), time to response, and duration of response (DOR), 
progression-free survival (PFS), overall survival (OS) and safety and tolerability of EO2401 in 
combination with nivolumab in the randomized extension of Cohort 2A. 
 
Primary trial endpoints 
The primary endpoint of the phase 1 part is the number, type and severity of adverse events. 
The primary endpoint of the phase 2 part is the percentage of patients from the randomized extension 
of Cohort 2A who achieve a response during 6 months of treatment with EO2401 in combination 
with nivolumab. 
 
Secondary trial endpoints 
The secondary trial endpoints include the percentage of patients with shown immunogenicity from 
baseline to up to 24 months, the percentage of patients by trial cohort who achieve a response for up 
to 24 months, time from onset of response to progression or death due to any reason, the time interval 
from first study treatment administration to progression, or death due to any cause, and the time 
interval from first study treatment administration to death due to any cause. It also includes the 
number, type and severity of adverse events for the randomized extension of the Cohort 2A. 
 
Trial design 
The trial is a global multi-center, 5 cohorts, phase 1/2 trial, intended to investigate EO2401 in 
combination with nivolumab in the treatment of patients with ACC or MPP. The maximum treatment 
duration for each participant is 24 months followed by a long-term survival follow up until patient’s 
death or sponsor decision. 
The number of patients recruited is as follows: 
• 
Cohort 1 (patients with ACC or MPP, previously treated): 3 patients have been included in view 
of the safety profile of the study drugs. 

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• 
Cohorts 2A (patients with ACC, previously treated) and 2B (patients with ACC, previously 
untreated): 33 patients in total. 
• 
Cohorts 3A (patients with MPP, previously treated) and 3B (patients with MPP, previously 
untreated): 17 patients in total. 
• 
Randomized extension of the cohort 2A (patients with ACC, previously treated): 19 patients. 
In total, 70 patients have been administered in the study. 
The study treatment is EO2401 in combination with nivolumab for the cohorts 1, 2A, 2B, 3A and 
3B; in the randomized extension of the Cohort 2A, patients are randomized between this 
combination, EO2401 monotherapy and nivolumab monotherapy using a ratio of 4:1:1. 
Trial population 
The main inclusion criteria are patients HLA-A2 positive with histologically proven ACC or MPP 
and with at least one measurable lesion; the main exclusion criteria are patients previously treated by 
immunotherapy or treated with high doses of corticosteroids or with significant abnormal clinical 
findings or laboratory values for hematology, liver and renal function. Please refer to the protocol 
for the full list of selection criteria. 
 
Interventions 
There are 5 cohorts in this trial and the planned interventions are described in the figure below: 
Please refer to the protocol for the details of each study drug administration and each visit. 
Specific regular safety monitoring of blood values, physical examination, and ECG are implemented 
as well as monitoring of all adverse events. The disease is followed by CT scan. Stool, blood samples 
and tumor biopsies (if consent is given for this) are also collected for research purposes. 
 
Ethical considerations related to the clinical trial including the expected benefit to the 
individual patient or group of patients represented by the trial participants as well as 
the nature and extent of burden and risks 
This trial aims to assess the safety and the preliminary efficacy of EO2401 in combination with 
nivolumab in patients with ACC or MPP. EO2401 is designed to stimulate an immune response 
against tumor proteins and stimulate immune-mediated killing of tumor cells and may potentially 
lead to an anti-tumor response. EO2401 has demonstrated good tolerability in animal models and a 
good safety profile in 170 patients treated so far (70 patients in this trial and 100 in a clinical trial 
performed in patients with recurrent glioblastomas). 
The main anticipated adverse events caused by EO2401 are local administration site reactions 
(redness, local pain, swelling, inflammation, ulceration), mainly mild or moderate. The safety profile 
of EO2401 in combination with nivolumab is consistent with the one of nivolumab monotherapy, 
except the local administration sites reactions. These potential side effects will be closely monitored 
via regular blood tests and study visits. The selected peptides included in EO2401 have shown to 
induce strong immune responses in non-clinical models and considering the safety profile of the 

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combination and the preliminary clinical data observed so far, the benefit/risk ratio for the proposed 
therapeutic-vaccination approach is considered to be positive. 

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1 BACKGROUND 
1.1 
Background adrenal malignancies 
Two different primary malignancies can arise from the adrenal gland: adrenocortical 
carcinoma (ACC) from the adrenal cortex, which are in most cases steroid hormone- 
producing, 
and 
malignant 
pheochromocytoma 
from 
the 
adrenal 
medulla. 
Pheochromocytomas are catecholamine-producing (epinephrine and norepinephrine) 
neuroendocrine tumors arising from chromaffin cells which can be located, except in the 
adrenal medulla, also in extra-adrenal paraganglia, the latter referred to as paraganglioma, 
and the two entities combined are in the following, and in view of this trial protocol, referred 
to as malignant (defined as metastatic disease, i.e. presence of chromaffin tissue in non- 
chromaffin organs) pheochromocytoma/paraganglioma (MPP) [1, 2, 3, 4]. 
From a diagnostic perspective, a comprehensive hormonal analysis is recommended pre- 
surgery by the European Network for the Study of Adrenal Tumors (ENSAT; 
www.ensat.org) in all cases of an adrenal mass to support establishing the origin of the tumor 
(cortex versus medulla versus other). Furthermore, the preoperative hormone pattern may 
serve as a fingerprint of the tumor during follow-up. A hormonal work-up might include 
assessment of excess of glucocorticoids, sexual steroids and steroid precursors, 
mineralocorticoids, and catecholamines. In patients with a clearly established diagnosis of 
ACC, one can omit the workup on catecholamine excess, and conversely for established 
MPP, one can omit the steroid analyses [1]. 
Surgery is of utmost importance, and the only curative treatment modality, in the treatment 
of both ACC and pheochromocytoma both at the primary diagnosis, and when possible also 
at recurrence (especially if recurrence appears a longer time after the primary surgery). Most 
patients with ACC have disease possible to resect at presentation, however, more than half 
of the patients who have undergone complete removal of the tumor are destined to have a 
relapse, often with metastases [5]. Similarly, radical resection is not a guarantee of cure for 
pheochromocytomas either. In one series of 171 patients followed up after surgical resection 
of a chromaffin cell tumor, 29 patients (17%) had recurrent or new tumors, which were 
malignant in 15 (9%) cases [9]. 
Treatments for adrenal malignancies not amenable to surgery are further outlined in Section 
1.1.3 and Section 1.1.4. 
1.1.1 Characteristics of adrenocortical carcinoma 
ACC has an estimated incidence of ∼0.7–2 new cases per million people per year [2]. It 
follows a bimodal age distribution, with peaks in childhood and in the fourth to fifth decades 
of life. ACC is more frequent in women than in men (ratio 1.5∶1). Most ACCs are sporadic; 
however, sometimes these malignancies form part of hereditary syndromes such as the Li- 
Fraumeni syndrome, Beckwith-Wiedemann syndrome, multiple endocrine neoplasia (MEN) 
1, congenital adrenal hyperplasia, familial polyposis coli, and β-catenin mutations [5]. 
About 50–60% of patients with ACC have clinical hormone excess. Hypercortisolism 
(Cushing syndrome; including weight gain, weakness, hypertension, psychiatric 
disturbances, hirsutism, centripetal obesity, purple striae) or mixed Cushing and virilizing 
syndromes are observed in the majority of patients. Pure androgen excess is less frequent 
while estrogen or mineralocorticoid excess are very rare [2]. 
The median overall survival (OS) of all patients with ACC is about 3–4 years. Prognosis for 
patients with locally advanced inoperable and metastatic ACC is poorer, the 5-year overall 
survival being <15%. Generally, five-year survival is 60–80% for tumors confined to the 

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adrenal space, 35–50% for locally advanced disease, and much lower in case of metastatic 
disease with reported percentages ranging from 0% to 28% [1, 2]. The prognosis is, however, 
heterogeneous; for instance, extremely long survival has been reported in patients with 
oligometastatic disease possible to resect. 
The median survival of patients with advanced ACC not amenable to radical surgical 
resection treated with polychemotherapy as first line therapy in the FIRMACT trial (the first 
randomized trial in ACC) was 14.8 months [14]. 
1.1.2 Characteristics 
of 
malignant 
pheochromocytoma/paraganglioma 
The incidence of pheochromocytoma/paraganglioma is ∼2–8 per million adults per year [6]. 
Up to 40% of pheochromocytomas are associated with a variety of inherited conditions, 
including MEN 2, Von Hippel–Lindau (VHL) disease, neurofibromatosis type 1, and 
heredity 
paraganglioma 
syndromes. 
The 
peak 
incidence 
of 
occurrence 
of 
pheochromocytomas is between the third and fifth decades of life, but generally occur at a 
younger age and are more likely to be bilateral in patients with familial disease [4]. 
Approximately 10% - 15% of pheochromocytomas and paragangliomas are malignant 
(defined as metastatic disease due to lack of other specific markers; metastatic defined as 
presence of chromaffin tissue in non-chromaffin organs) [3]. However, generally 
paragangliomas are more likely to be malignant than pheochromocytomas in the adrenal 
medulla (about 40% versus 10%). It has been speculated that patients with a 
pheochromocytoma with mutations in the succinate dehydrogenase B (SDHB) gene and/or 
extra-adrenal locations, might be more prone to develop malignant tumors (30%–50%) [1]. 
Pheochromocytomas release catecholamines (epinephrine and dopamine) and their 
metabolites metanephrine and methoxytyramine, resulting in hypertension, arrythmia, 
and/or hyperglycemia. About 40% of paragangliomas secrete catecholamines. However, 
head and neck paragangliomas only secrete catecholamines about 5% of the time and often 
it is dopamine. 
Malignant MPP is characterized by prognostic heterogeneity. A retrospective multicenter 
study of malignant MPP including 169 patients from 18 European centers diagnosed 
between 1998 and 2010 indicated some main characteristics of the disease: primary 
pheochromocytoma was found in 53% of patients, tumor or hormone-related symptoms in 
approx. 57%, positive plasma or urine hormones in 81%, and identification of a SDHB 
mutation in 42 % of patients. Metastatic sites included bone (64%), lymph nodes (40%), 
lung (29%) and liver (26%); mean time between initial and malignancy diagnosis was 43 
months (0-614 months). Median follow-up was 68 months and median survival 6.7 years. 
Using univariate analysis, better survival was associated with head and neck paraganglioma, 
age <40 years, metanephrines <5-fold the upper limits of the normal range, and low 
proliferative index. In multivariate analysis, hypersecretion (Hazard Ratio 3.02 [1.65-5.55]; 
p = 0.0004) was identified as an independent significant prognostic factor of worse overall 
survival. In this trial it was not confirmed that SDHB mutations have any major prognostic 
impact in malignant MPP [7]. 
Another analysis of twenty retrospective non-comparative studies reported on 1338 patients 
with metastatic pheochromocytoma (685, 53%) and paraganglioma (611, 47%), diagnosed 
at a mean age of 43.9 ± 5.2 years. Mean follow-up was 6.3 ± 3.2 years. Of 532 patients with 
reported data, 40% had synchronous metastases. Five-year (7 studies, n = 738) and 10-year 
(2 studies, n = 55) mortality rates for patients with metastatic MPP were 37% (95% CI, 24– 
51%) and 29% (95% CI, 17–42%), respectively [8]. 

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1.1.3 Treatment of adrenocortical carcinoma 
Surgery is of utmost importance, and the only curative treatment modality, in the treatment 
of ACC both at the primary diagnosis, and when possible also at recurrence (especially if 
recurrence appears a longer time after the primary surgery). However, even if most patients 
with ACC have disease possible to resect at presentation the majority will relapse, often with 
metastatic disease [5]. 
The aggressive behavior and the high recurrence rate of ACC provide the rationale for the 
use of adjuvant therapy. Adjuvant radiotherapy to the tumor bed is considered in patients 
with incomplete/R1 resection or Rx resection [10]. Mitotane has been the reference drug for 
the management of ACC for decades. In a case control study involving 177 patients, the 
outcome of 47 patients followed in Italian reference centers that systematically adopted 
adjuvant mitotane for all patients with radically operated ACC was significantly higher (in 
terms of both disease free survival and overall survival) than the outcome of 55 Italian 
patients and 75 German patients followed in institutions not administering adjuvant mitotane 
therapy [11]. On the basis of these findings, a panel of international experts unanimously 
stated that patients with potential residual disease (R1 or Rx resection) and/or Ki67 more 
than 10% should be offered adjuvant mitotane, whereas adjuvant therapy was not considered 
mandatory in patients fulfilling all of the following criteria: stage I or II disease, 
histologically proven R0 resection; and Ki67 expressed in ≤10% of neoplastic cells [12]. 
There are no data regarding the optimal duration of adjuvant mitotane; a recommendation is 
that adjuvant mitotane should be administered for at least 2 years since the greatest frequency 
of disease recurrence is expected within this timeframe [1]. However, while mitotane is well 
tolerated by a fraction of patients, a majority find mitotane a difficult therapy that markedly 
impacts the quality of their lives. Thus, the treatment duration is assessed individually. 
Mitotane has also been used since a long time, and is also registered, in patients with locally 
advanced inoperable and metastatic ACC. Response rates vary between 13% and 35%; 
including many results derived from retrospective series in the 1960s [5, 13]. Patients with 
hormonal excess often experience clinical benefit by this strategy and continuation of 
mitotane treatment can be indicated in these patients even after radiological progression 
when alternative strategies to inhibit the hormonal excess are lacking [1]. Owing to the 
latency of mitotane to attain the therapeutic range, mitotane monotherapy is indicated in the 
management of patients with a low tumor burden and/or more indolent disease, when 
possible in combination with locoregional therapies (for instance radiofrequency ablation). 
In case of rapidly progressing extensive metastatic disease and/or radiological progression 
under mitotane, cytotoxic chemotherapy is indicated. Response rates for chemotherapy vary 
between 7% and 54% (building on an assessment of 11 prospective single-arm trial with a 
total of 239 patients), again with variability in the response criteria. The association of 
mitotane to chemotherapy seems to be more active than chemotherapy alone, although no 
randomized trials have formally demonstrated this superiority [5]. 
In the first international randomized trial in advanced or metastatic adrenocortical carcinoma 
treatment (FIRM-ACT trial), the two most active treatment regimens namely etoposide, 
doxorubicin, cisplatin, and mitotane (EDP-M) and streptozotocin and mitotane (Sz-M) were 
compared in 304 chemotherapy-naïve patients. Patients with disease progression received 
the alternate regimen. The results of this trial indicate that EDP-M is the superior regimen 
[14]. Although no statistically substantial increase in OS was documented in patients 
receiving EDP-M as the first-line therapy, significantly better response rates (23.2% versus 
9.2%) and progression-free survival (PFS), median 5.0 versus 2.1 months, were achieved 
with EDP-M in comparison with Sz-M. The rate of serious adverse events (SAEs) was 
comparable. Of note, the results of the second-line regimens replicated the rates observed 

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with the first-line therapy. Since EDP-M was superior to Sz-M in terms of progression-free 
survival either as first-line or second-line therapy, the crossover design may have attenuated 
its advantage on overall survival. On this basis, EDP-M is usually recommended as the first- 
line therapy for ACC requiring cytotoxic therapy. In patients unfit for the EDP-M regimen 
P-M may constitute a reasonable alternative [15]. 
1.1.4 Treatment of malignant pheochromocytoma/paraganglioma 
The therapeutic strategy of metastatic MPP aims to control excessive catecholamine 
secretion and tumor burden, but no curative treatment is achievable. Treatment choices 
include a wait and see policy, locoregional therapies, systemic chemotherapy, and 
radiopharmaceutical agents [6]. 
In the absence of any randomized studies and demonstrated impact on survival, the patients’ 
quality of life should always be considered. Indeed, due to the indolent course of subgroups 
of patients, a wait and see policy coupled with a watchful follow-up can be considered as an 
option in asymptomatic patients with a low tumor burden. 
An antineoplastic treatment is often recommended in case of rapid progression and/or 
symptom onset. In the absence of tumor progression, surgery of the primary tumor or 
metastases can reduce hormone secretion and may prevent complications related to a critical 
anatomical location and improve the efficacy of subsequent therapies [6]. Metastatic disease 
palliation may also benefit from local therapy with embolization and or radiofrequency 
ablation. 
Radionuclide therapy is an effective treatment and 131I-MIBG is the most frequently used. 
Approximately 50% of patients are eligible for 131I-MIBG therapy based on the uptake on 
diagnostic scans. Several studies have been published on the efficacy of 131I-MIBG treatment 
[6]; objective responses were observed in 22–47% of patients, mainly in patients with soft 
tissue metastases. 131I-MIBG therapy might be considered as a first-line approach in patients 
with a good uptake of 123I-MIBG and unresectable, progressive MPP or patients with 
symptoms (not amenable to locoregional control), or patients with a high tumor burden with 
a low number of bone metastases. 
Cyclophosphamide- and dacarbazine-based regimens combined with vincristine (CVD) or 
doxorubicin (CVDD or CDD) are the best studied chemotherapy regimens [6]. In one of the 
larger published studies (n = 52 patients), 40% of patients treated with CVD, CDD, or CVDD 
experienced clinical benefits, including a reduction in tumor size in 25% of cases [16]. 
Systemic chemotherapy is debated as a first-line therapy in patients with a low uptake of 
123I-MIBG and unresectable, rapidly progressive MPP, or patients with high tumor burden 
or with a high number of bone metastases. 
Most recently, at ESMO 2021, the first international randomized study in malignant 
progressive pheochromocytoma and paragangliomas (FIRSTMAPPP) was presented [68]. 
Patients with progressive MPP were randomized 1:1 for sunitinib therapy or placebo. The 
primary endpoint was progression-free survival (PFS) at 12 months. On the basis of a two- 
step Simon model (alpha 10%, power 90%), the investigators aimed for 74 patients, 
assuming a PFS improvement at 12 months from 20 to 40%. Eleven or more patients out of 
37 with no progression at 12 months were expected to conclude that sunitinib is effective. 
The placebo group served as an internal control to validate the hypothesis of the Simon 
design with a 12-month PFS equal to 20%. 
A total of 78 patients were enrolled (39 randomized in each arm) including 
adrenal/paraganglioma primaries, each 50%, and 60% patients with prior therapy. The 
primary endpoint was met: PFS at 12 months was 35.9% with sunitinib versus 18.9% with 

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placebo. Median PFS was 8.9 months (95% CI: 5.5-12.7) versus 3.6 months (95% CI: 3.1- 
6.1). The investigators conclusion was that sunitinib becomes the first-line option in patients 
with progressive MPP. 
1.2 
Novel therapies and immunotherapy in adrenal malignancies 
Different types of newer targeted therapies have already been tested in both ACC and MPP, 
for instance sunitinib and pazopanib [2, 17], but generally it has not led to any spectacular 
breakthroughs. 
Immunotherapy, currently changing the treatment landscape in many tumor indications have 
also been tested, or trials are under way, in ACC and MPP. Initial preliminary data in a 
limited number of patients showed an acceptable safety profile of anti-PD-1 inhibition in 
patients with metastatic ACC [18; nivolumab, NCT02720484], and hints of objective tumor 
regression [19; pembrolizumab case report]. Pembrolizumab is currently tested in phase 2 
trials for patients with advanced ACC (NCT02673333) and for patients with metastatic MPP 
(NCT02721732). In addition, there are also ongoing trials in ACC including both nivolumab 
and ipilimumab (NCT03333616 and NCT02834013). 
Data from the pembrolizumab phase 2 trial (NCT02673333) in ACC was presented at the 
2019 ASCO meeting [35]. Thirty-nine patients with a median age of 62 years (range, 19-87) 
were treated. At time of analysis, the median follow-up among survivors was 17.8 months 
(range, 5.4-34.7). The objective response rate (ORR) was 23.1% (95% CI, 11.1-39.3); 0 CR, 
9 PR. Seven patients (17.9%) had SD as best response. Among the 9 PRs, median time to 
PR was 4.1 months (range, 1.7-10.5) and median duration of response (DOR) was not 
reached (95% CI, 4.1-not reached). Three patients achieving PR have completed 2 years of 
treatment with ongoing response noted. Median PFS was 2.1 months (95% CI, 2.0-10.7), 
and median OS was 24.9 months (95% CI, 4.2-not reached); 2-year OS rate was 50% (95% 
CI, 36-69%). There was no association between tumor PD-L1 status (p > 0.95), MSI- 
H/MMR-D status (p = 0.61), or somatic alterations and objective response to pembrolizumab 
(data presented in poster at the conference). Thirteen percent (n=5) of patients had grade 3/4 
treatment-related adverse events according to the presented poster. The conclusions from the 
investigators was that pembrolizumab demonstrated antitumor activity and was well 
tolerated in advanced ACC. 
A large already published trial (n = 50) in patients with metastatic ACC included treatment 
with avelumab (anti-PD-L1 inhibition) and allowed continuation of mitotane in patients with 
metastatic ACC and prior platinum-based therapy [20]. Twenty-six percent of patients had 
received one prior line of systemic therapy, 36% two prior lines, and 38% 3 or more lines of 
prior therapy. The ORR was 6.0% (95% CI, 1.3% to 16.5%; partial response in 3 patients). 
Twenty-one patients (42.0%) had SD as best response (disease control rate, 48.0%). Median 
PFS was 2.6 months (95% CI, 1.4 to 4.0), median OS was 10.6 months (95% CI, 7.4 to 15.0), 
and the 1-year OS rate was 43.4% (95% CI, 27.9% to 57.9%). 
The objective efficacy noted in the trial with avelumab might be seen as low and different 
possible mechanisms linked to potential mechanisms of ACC immune-resistance has been 
discussed, including WNT/β-catenin pathway activation and TP53 mutations influencing 
CD8+ T cell action, low PD-L1 expression, and steroid excess (hormone-secreting disease) 
and/or steroid replacement therapy [21]. 
The avelumab trial possibly indicated a link between objective response and PD-L1 
expression; in evaluable patients with PD-L1+ (n = 12) or PD-L1− (n = 30) tumors (≥5% 
tumor cell cutoff), the objective response rate was 16.7% vs 3.3% (P = 0.192) [20]. This was 
however  not  the  case  when  pembrolizumab  was  used  (see  above  regarding  the 

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pembrolizumab phase 2 trial; NCT02673333); still assessment of PD-L1 expression in future 
immunotherapy trials in adrenal tumors seems an adequate step. 
Monitoring of steroid access seems also to be a factor for consideration in relation to 
immunotherapy trials in ACC, and the combination with mitotane might also be helpful (as 
implemented in the avelumab trial; 50% of patients continued mitotane but mitotane levels 
during the study were not recorded [20]). Mitotane, used for decades in ACC, is an adrenal 
cytotoxic agent with an unknown mechanism of action, but assumed to modify the peripheral 
metabolism of steroids and directly suppresses the adrenal cortex. A reduction in 17- 
hydroxycorticosteroids in the absence of decreased corticosteroid concentrations and 
increased formation of 6-β-hydroxycortisol have been reported [22]. There are 
recommendations for monitoring of blood concentration of mitotane and a general aim to 
reach a mitotane blood level of 14 to 20 mg/L [2, 22]. 
1.3 
EO2401 an adrenal malignancy targeted therapeutic vaccine 
1.3.1 EO2401 background and non-clinical development 
Extensive pre-clinical studies have been conducted to characterize the multi-peptide 
therapeutic cancer vaccine EO2401. Summarized information about the compound is 
presented below; for more details see the current Investigator’s Brochure (IB) of EO2401. 
Three 9- or 10-amino acid microbiome-derived peptides (EO2316, EO2317, and EO2318; 
CD8+ cytotoxic T cell epitopes) that mimic specific TAAs which are overexpressed in 
adrenal malignancies have been identified. These peptides were shown to induce a strong 
immune response in non-clinical models and represent the specificity included in EO2401. 
The microbiome-derived peptides were selected based on their prevalence in the general 
population in order to be present in an as large proportion of the population as possible. It is 
assumed that the general human population has generated a memory repertoire of tolerized 
T cells recognizing the selected microbiome-derived peptides. Thus, the strategy is to 
identify and then use these peptides to re-activate their associated memory T cells. Because 
the peptides are almost identical to known TAAs, they are assumed to activate memory T 
cells that will cross-react with the TAAs, and thereby inducing a strong attack against the 
tumor cells themselves. 
Before identifying the EO2316, EO2317, and EO2318 peptides, proof-of-concept studies 
were achieved with EO2315, a 9 amino acid microbiome-derived peptide with homology to 
a human IL13Rα2 peptide. EO2315 elicited a strong binding affinity to the human leukocyte 
antigen (HLA)-A2. This peptide drove a strong immunogenicity in non-clinical models 
(HLA-A2 transgenic mice) and T cells generated against EO2315 demonstrated cross 
reactivity against the human peptide counterpart. The ability of EO2315 to promote 
cytotoxic T cell expansion in combination with anti-programmed cell death-1 (anti-PD-1) 
was demonstrated in vivo using adoptive transfer of lymphocytes from immunized HLA-A2 
transgenic mice into tumor-engrafted nude mice. Additionally, the immunogenicity of the 
UCP2 CD4+ helper peptide was demonstrated in the HLA-A2 transgenic mouse model when 
administered together with EO2315 and shown to improve the immunogenicity driven by 
EO2315. 
After proof-of-concept of EO2315, EO2316, a 10-amino acid bacterial peptide sharing 8- 
amino acid with EO2315, was identified. While EO2316 shares the same immunogenic 
properties in mice as EO2315, EO2316 has been selected as a preferred candidate for 
EO2401 in comparison with EO2315 because of higher prevalence of EO2316 within the 
human gut microbiota. 

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EO2401 Drug Product (DP) 
EO2401 DP 
 is 
 mixture 
solution of one synthetic 
 microbiome-derived peptide (EO2316), and two 
synthetic
 microbiome-derived peptides (EO2317 and EO2318), and the 
synthetic
 UCP2 (CD4+ helper) peptide. EO2316, EO2317, and EO2318 were 
found in the human microbiota and display high homology with TAAs expressed by adrenal 
malignancies (IL13Rα2, BIRC5/survivin, and FOXM1, respectively). The total of three 
microbiome-derived peptides which mimic three different TAAs were selected to overcome 
possible tumor heterogeneity and possibly reduce tumor escape. All three peptides 
demonstrated high MHC binding affinity, and induction of strong immune responses as well 
as cross reactivity against the human corresponding peptides in non-clinical models. The 
peptide mixture EO2401 DP will be emulsified
 
before subcutaneous administration. 
 
EO2316 
EO2316 is a
 bacterial peptide which shows high homology to a cognate 
epitope on human IL13Rα2 that is known as a decoy receptor for IL-13 [46]. IL13Rα2 is an 
inhibitory subunit of the type II receptor. Normal function of IL-13 is to activate STAT6, 
which exerts transcriptional control over genes promoting apoptosis through increased 
caspase-3 activity. Sequestration of IL-13 by IL13Rα2 is considered being an apoptosis 
escape mechanism of tumor cells [47]. In addition, IL13Rα2 acts as a receptor for the 
chitinase-like protein Chi3l1 and mediates signaling leading to activation of mitogen- 
activated protein kinase/ERK, AKT, and Wnt/β-catenin pathways, all involved in the process 
of tumorigenesis [48]. The link between IL13Rα2 and tumorigenesis is supported by many 
in vitro and in vivo studies showing that increased expression of IL13Rα2 promotes tumor 
progression in several tumor models [49]. IL13Rα2 has also been shown to promote tumor 
invasion and migration, as well as to protect tumor cells from induction of apoptosis [47]. 
Importantly, IL13Rα2 appears to be expressed on cancer stem cells. It may be considered as 
a driver oncogene [50]. 
It has been shown that IL13Rα2 is overexpressed (mRNA) in primary malignant 
adrenocortical cancers compared with benign adrenocortical tumors and normal adrenal 
tissue [23, 52]. Immunohistochemistry also confirmed higher protein expression in 
malignant and benign tumors than normal adrenocortical tissues. Treatment of IL13Rα2 
expressing ACC cell lines (NCI-H295R and SW13) with an IL-13-targeting immunotoxin 
induced tumor size reduction, tumor necrosis, and a survival impact versus control. Also, 
direct IL13Rα2 knock-down decreased cellular proliferation and invasion [23]. 
Likewise, it has been shown that IL13Rα2 is overexpressed in malignant MPP and has an 
impact on prognosis of MPP [51]. 
IL13Rα2 is not, or very low expressed, in normal tissues (except in testis, which is an 
immune protected organ) [53]. Thus, IL13Rα2 could be considered as a specific tumor- 
associated protein and a good target candidate for immunotherapy using a therapeutic 
vaccine approach in adrenal tumors. 

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EO2317 
EO2317 is a
 microbiome-derived peptide with homology to BIRC5/survivin. 
Survivin is a member of the inhibitor of apoptosis gene family, which encodes negative 
regulatory proteins that function as endogenous inhibitors of caspases and preventing 
apoptotic cell death [54]. Survivin also has a role as a mitosis regulator, physically associated 
with the mitotic apparatus thereby ensuring the proper completion of various stages of cell 
division probably via the regulation of microtubule dynamics and stability [55]. These 
molecular functions are supported by a number of in vitro and in vivo pre-clinical studies 
that demonstrated that modulation of survivin expression reduced tumor growth, increased 
apoptosis, and sensitized tumor cells to chemotherapeutic drugs [56]. Overexpression of 
survivin in cancer may overcome an apoptotic checkpoint and favor aberrant progression of 
transformed cells through mitosis [57]. 
Survivin mRNA in ACC has been shown to be significantly overexpressed when compared 
with adrenocortical adenoma or normal adrenal glands [24]. IHC confirmed survivin protein 
expression in 97 % of ACCs. In 83 % of samples, staining was moderate or high and clinical 
outcome in this subgroup showed a trend towards poorer prognosis (Figure 1). In addition, 
survivin knockdown in SW13 cells significantly increased the rate of apoptosis [24]. 
In a study utilizing IHC assessment all MPP specimens stained 2+ or 3+, and there was no 
significant difference between the staining intensity of benign and malignant samples [25]. 
All normal adrenal medulla specimens stained positively with anti-survivin but to a lesser 
degree than the chromaffin cell tumors [25]. Thus, survivin represents a neuroendocrine 
marker for chromaffin cell tumors, and survivin does not appear to reliably distinguish 
benign from malignant MPP (i.e. does not identify patients at risk of recurrent disease). In 
addition, in a study of samples from Chinese patients with adrenal tumors (39 cortex 
adenoma, 
22 
cortex 
adenocarcinoma, 
35 
pheochromocytoma, 
20 
malignant 
pheochromocytoma) the expression intensity of survivin was significantly lower in adrenal 
cortex adenoma than in adrenal cortex adenocarcinoma (P<0.05), and was significantly 
lower in pheochromocytoma than in malignant pheochromocytoma (P<0.05) [26]. 

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While survivin is strongly expressed in embryonic tissues where it plays a role in 
development, expression of survivin in normal adult tissue is scarce [30]. Overall, the pattern 
of overexpression of survivin in adrenal tumors, associated with its critical role in 
tumorigenesis, makes survivin an interesting target for a therapeutic vaccine approach. 
 
EO2318 
EO2318 is a 
 peptide identified from human gut microbiome that targets 
FOXM1. It follows the same principles as for EO2316 and EO2317 so that it is highly 
homologous with the FOXM1 antigen overexpressed on tumor tissue. FOXM1 is a member 
of the Fox transcription factors involved in G1-S and G2-M progression [31]. FOXM1 
exhibits a proliferation-specific expression pattern and its expression is regulated by 
proliferation and antiproliferation signals as well as by proto-oncoproteins and tumor 
suppressors. While its expression is turned off in terminally differentiated cells, it is 
upregulated in a multitude of human solid tumors. 
In a meta-analysis including 23 studies it was found that elevated FOXM1-protein 
expression was significantly associated with worse 3-year OS (OR = 3.30, 95% CI = 2.56 to 
4.25, P < 0.00001), 5-year OS (OR =3.35, 95% CI = 2.64 to 4.26, P < 0.00001), and 10-year 
OS (OR = 5.24, 95% CI = 2.61 to 10.52, P < 0.00001) of human solid tumors [27]. Similar 
results were observed for disease-free survival. High expression level of FOXM1 was also 
associated with advanced tumor stage [27]. Thus, elevated FOXM1 expression is associated 
with poor survival in most solid tumors. 
A recent analysis has identified FOXM1 as being associated with the progression and 
prognosis of ACC and might lead to poor outcomes by regulating the cell cycle [28]. The 
below figures illustrate stage and grade plots of FOXM1 in ACC (Figure 2 A-B), and overall 
and disease-free survival (Figure 3 A-B) analyses of the association between the expression 
levels of FOXM1 and survival time in ACC [28]. 

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FOXM1 expression is higher in MPP than in the normal corresponding tissue [29]. As also 
indicated above the expression of FOXM1 in ACC is higher than in the normal 
corresponding tissue (and increases by grade and stage of ACC; Figure 2 A-B) and a Kaplan– 
Meier analyses of overall survival according to FOXM1 expression levels in ACC further 
corroborates the detrimental effect of high expression (Figure 4) [29]. 

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FOXM1 with its high expression in adrenal tumors and limited expression in the normal 
counterpart together with the general strong correlation with survival outcomes in a 
multitude of solid tumors, including ACC, is an interesting target for a therapeutic vaccine 
approach. 
 
UCP2 
In order to generate an efficient immune response, the helper peptide UCP2 will be included 
in EO2401. This Th1 helper peptide will be able to sustain efficient dendritic cell activation 
and specific cytotoxic T cell activation. UCP2 was initially described by Godet et al [32]. 
It is a telomerase derived CD4+ epitope that binds to most commonly found human MHC 
class II alleles. The role of telomerase in tumor progression is well documented. Cancer cells 
overcome senescence via telomere length maintenance mechanisms involving telomerase 
activation. Telomerase reverse transcriptase (TERT) overexpression achieved via multiple 
genetic and epigenetic mechanisms has been observed in 80% to 90% of malignant tumors. 
Ability of UCP2 to elicit specific CD4+ T cell responses have been demonstrated in in vivo 
models. Furthermore, spontaneous T cell responses against UCP2 were observed in various 
types of cancers [33]. 

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Check point blockade in the context of EO2401 
Check point inhibitors as anti-PD-1 and anti-PD-L1, approved for the treatment of different 
types of malignancies, release the breaks on the immune system; however, only a small 
subset of patients treated with these type of compounds as single-agents will achieve a 
clinical complete response (see for instance Section 1.2 regarding the use of anti-PD-L1 in 
ACC). Nevertheless, deep and durable responses in some tumor types makes these therapies 
an important step forward in the treatment of malignancies. 
Check point inhibitors 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 antigens presented by the tumor. It is likely that patients who do not respond to 
this type therapy do not have adequate 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 impact of check point inhibition, and the 
check point inhibition allows the T cell population to infiltrate the tumor and act without the 
negative impact of e.g. PD-1/PD-L1 interactions. 
Nivolumab is an anti-PD-1 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-L1 and PD-L2), and stop a negative 
regulator of T cell activation and response, thus allowing the immune system to attack the 
tumor. 
Nivolumab is approved for use for the treatment of multiple tumor types including 
melanoma, non-small cell lung cancer, malignant pleural mesothelioma, renal cell 
carcinoma, classical Hodgkin lymphoma, squamous cell cancer of the head and neck, 
urothelial carcinoma, mismatch repair deficient or microsatellite instability-high colorectal 
cancer, esophageal squamous cell carcinoma, esophageal/gastro-esophageal junction cancer, 
gastric/gastro-esophageal junction/esophageal adenocarcinoma, hepatocellular carcinoma 
[42, 43]. However, it is not currently approved for any of the adrenal malignancies (regarding 
early clinical trial experiences of anti-PD-1 blockade, including with nivolumab, see Section 
1.2). 

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1.3.2 EO2401 early clinical development 
The initial clinical development of EO2401 is planned to include two phase 1/2 trials, one 
in glioblastoma (EOGBM1-18; EudraCT 2018-002279-16) and the current trial in adrenal 
tumors (EOADR1-19). 
The early clinical development of EO2401 aims at showing that therapeutic cancer 
vaccination with EO2401 in combination with anti-PD-1 blockade is safe and tolerable, and 
can achieve expansion of T cells not only recognizing the microbiome derived peptides used 
for immunization but also recognizing the targeted nominal TAAs expressed by human 
tumor cells in patients with malignancies (i.e. immunological proof of concept). In addition, 
preliminary efficacy aspects of EO2401 are going to be studied, as will multiple translational 
exploratory endpoints. 
The development strategy encompassing trials EOGBM1-18 and EOADR1-19, assumed to 
run mainly in parallel, is selected to achieve the same objectives in different biologically 

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very diverse types of malignancies (i.e. glioblastoma, adrenocortical carcinoma, and 
malignant pheochromocytoma/paraganglioma; being not only differentiated by standard 
histology but also in relation to a multitude of other biological aspects as for example growth 
and metastases patterns) to enable early learning to advice regarding later development paths 
and possibilities. 
The first-in-human (FIH) trial is assumed to be EOGBM1-18 with a targeted start end of 
2019. The trial is a multicenter (assumed countries involved are Germany, France, Spain, 
and USA), phase 1/2 trial, in patients with unequivocal evidence of progressive or first 
recurrent glioblastoma. The study design builds on an initial cohort for assessment of mainly 
safety and tolerability of monotherapy EO2401 and EO2401 in combination with nivolumab 
(a cohort with a 3-by-3 design), and expansion cohorts for assessment of further safety and 
tolerability, immunogenicity, and preliminary efficacy during treatment with EO2401 in 
combination with nivolumab (without any EO2401 monotherapy component), and EO2401 
in combination with both nivolumab and bevacizumab concomitantly (the latter treatment 
option will only be available for sites in the USA due to local health authority authorization 
of bevacizumab for recurrent glioblastoma). 
Considering the proposed parallel conduct of trials EOGBM1-18 and EOADR1-19 it is of 
importance highlighting that both trials will be overseen by independent data monitoring 
committees (IDMCs) which, even if the populations in the two trials are very different, will 
be cross-sharing information. Of note, is also that the tasks, decision rules, etc. for the two 
IDMCs are aligned and similar, to the extent possible taking the individual trial designs into 
account. 
Details of the IDMC processes and procedures, and cohort management plans for the current 
trial and trial EOGBM1-18 are outlined in separate IDMC Charters which will be/have been 
submitted to applicable health authorities and review boards. 
For further details regarding the EOGBM1-18 trial please see the current IB of EO2401. 
 
1.3.3 EO2401 clinical information & Rationale and high-level 
outline for global amendment #2 (leading to protocol 
EOADR1-19 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. 
As described in Section 1.3.2, 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#: 19,229), and trial EOADR1-19 in patients with adrenal tumors (adrenocortical 
carcinoma [ACC], and malignant pheochromocytoma/paraganglioma [MPP]) (EudraCT#: 
019-003396-19; IND#: 19,229); and both trials are conducted under the supervision of 
IDMCs. 

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advise on possible schedule optimizations 
 
 
• Inclusion of testing of lactate dehydrogenase (LDH) as part of blood chemistry 
testing in all running cohorts, and also retrospective collection of the parameter at 
least at baseline for prognostic scoring in all patients. 
• Exclusion of stool sampling for patients in the randomized extension of Cohort 2A, 
except for those patients who specifically consent to paired tumor biopsies; for such 
patients stool sampling for microbiome analyses will still be taken at baseline.
• Adjustment of planned patient number in Cohort 3, from current 30 patients (with a 
target of 15 patients each for Cohorts 3A and 3B) to approximately 20 patients 

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In addition to above, two further types of changes are included in global amendment 2 
(leading to EOADR1-19 version 3): 
• Recommendations regarding vaccination against SARS-CoV-2/COVID-19 as 
applied in trial EOADR1-19 via investigator communications (current text is from a 
letter to the investigators 2021-NOV-24), are included in Section 6.9.2. 
• Updates of management principles for immune-related adverse events as outlined in 
Section 6.4.1, based on the most recently available labelling documents for Opdivo 
[42] and standard protocol guidance from Bristol-Myers Squibb (marketing 
authorization holder for nivolumab). 
1.3.5 Benefit/risk assessment and description of and justification 
for the route of administration, dosage, dosage regimen, and 
treatment period 
The two primary malignancies which can arise from the adrenal gland (or chromaffin cells 
located in extra-adrenal paraganglia), i.e. ACC and MPP, are tumors with quite different 
characteristics from many biological perspectives. However, from a general treatment 
perspective they show similarities: 
• Surgery is of utmost importance, and the only curative treatment modality, provided 
radical surgery can be performed. 
• Treatment options for patients with unresectable disease are few and new treatment 
options have not been added recently. 
• The currently available first line therapies in both entities are only achieving tumor 
regression in approximately one in four patients at the cost of a relatively high 
toxicity burden, especially from the utilized polychemotherapy (EDP-mitotane first 
line objective response rate 23% in ACC; CVD therapy tumor size reduction in 25% 
of patients with MPP; in addition 50% of patients with MPP might be eligible for 
131I-MIBG therapy based on uptake, if they have limited tumor burden and not 
rapidly progressive disease, objective responses with 131I-MIBG therapy were 
observed in 22–47% of patients), leading to the notion that even first line treatments 
might be challenged by new treatment concepts. 

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• Even though the median survival in patients with MPP (approx. 6-7 years) is longer 
than for patients with ACC (around 12-15 months when at a stage of need of first 
line chemotherapy treatment per the FIRMACT trial), half of the patients with MPP 
have progressive disease within one year and require active management [58]. Thus, 
it seems fair to conclude that for both entities there are unmet medical needs with 
respect to new efficacious systemic therapies. 
To date, no final human data is available on safety and efficacy of EO2401 since the early 
clinical development trials as outlined in Section 1.3.2 are still running. However, 
preliminary data is available from the current trial EOADR1-19 and a trial including patients 
with recurrent glioblastoma (EOGBM1-18), showing a safety profile consistent with 
expectations, i.e. the added event type by EO2401 to the background treatments (nivolumab 
and nivolumab/bevacizumab, depending on trial and cohort) are the expected events of local 
administration site skin reactions (e.g. erythema, induration, and pain); see further Section 
1.3.3. 
The current trial as proposed is including a combination treatment of EO2401 and nivolumab 
(anti-PD-1 blocking agent), a concept with a very comprehensive biological rationale and 
pre-clinically indicated strong efficacy benefit as compared with the utilization of EO2401 
as monotherapy (Section 1.3.1 and the current version of the EO2401 IB). 
For details regarding the non-clinical safety evaluations of EO2401 see the current IB of 
EO2401; in summary: 
• Neither off-target (non-specific), nor other adverse effects that may occur following 
binding of the peptides included in EO2401 to HLA molecules have been observed 
in HLA-A2 transgenic mice. 
• It has been demonstrated in wild type mice that activation of T-cells by vaccination 
with mouse microbial-derived peptides does not cause toxic immune reactions 
against microbial gut contents; the obtained results suggest a good tolerability and 
no obvious sign of toxicity. 
• Assessment of the safety of the concomitant administration of microbial-derived 
peptides with anti-PD-1 showed that the combination of mouse bacterial peptides 
with anti-PD-1 revealed no sign of toxicity; confirming that induction of a systemic 
immune response against a bacterial antigen does not affect gut homeostasis. 
Anti-PD-1 blockade has been applied in patients with ACC and MPP and shown to have a 
similar safety profile as in other patient groups treated with this type of compounds, and in 
addition the potential to also have efficacy in individual patients (see Section 1.2). 
From a risk perspective, based on the above and already achieved clinical experiences 
utilizing efficacious immunization approaches together with anti-PD-1 blockade [59], the 
assessment of the Sponsor, before the start of trials EOGBM1-18 and EOADR1-19 was, and 
based on preliminary data as outlined in Section 1.3.3, continues to be 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. 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 for the 
immune-related adverse reactions which might be seen during treatment with anti-PD-1 (or 

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similar compounds) alone (e.g. see the European SmPC or the US PI for nivolumab [42, 
43]). 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 6.4). Considering the disease under investigation, i.e. adrenal tumors, and the 
expression of the targeted antigens in adrenal tissue (higher in tumor than in normal tissue; 
see Section 1.3), a safety measure to monitor for adrenal function (serum cortisol) has been 
instituted in addition to the standard safety parameters usually used in trials of 
immunotherapy compounds. 
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; the expected addition 
of local injection events to the safety profile of nivolumab utilizing the combination 
EO2401/nivolumab has been confirmed (see Section 1.3.3). 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 
In this trial subcutaneous (SC) administration of EO2401 is applied based on the general 
notion that this is a well-accepted, and clinically easy and reproducible way for vaccine 
administration. The peptide dose utilized in non-clinical testing of EO2401 and its 
components was 
 
The dosage regimen for EO2401 including a priming schedule was chosen to induce an 
efficient immune response (every 2 weeks, 4 times), and to avoid exhaustion by a 4-week 

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break thereafter. The priming period is followed by a boosting period with injections every 
4 weeks to maintain an adequate immune response. The prime-boost approach was based on 
general immunization concepts, especially from the field of therapeutic cancer vaccines. 
Considering the nature of this early development trial, the maximum length of the treatment 
period was chosen in an exploratory way; it is assumed that especially the immune 
monitoring findings from the initial trials (both EOGBM1-18 and EOADR1-19) might guide 
future adjustments of the treatment duration with regard to immunizations (possibly also the 
schedule of the boosting period). Stopping treatment early at confirmed progression 
(immune therapy response criteria will be used) or individual patient safety concerns is 
considered standard oncology practice.
Nivolumab route of administration, dosage, dosage regimen, and treatment periods are 
aligned with current labeling for other indications, since there is no label specifically for 
adrenal tumors [42, 43]. Of note, the interval between nivolumab administrations is adjusted 
according to the administrations of EO2401, i.e. with every 2 weeks administrations 4 times 
followed by every 4 weeks during the boosting period of EO2401. The nivolumab schedule 
of administration was selected based on the wish to minimize the number of necessary 
patient visits. 
The expected safety profile of EO2401 in combination with nivolumab as outlined above is 
considered supportive of the initiation of an early clinical development program. Thus, given 
the potential for a therapeutic benefit of nivolumab alone in individual patients with adrenal 
malignancies (Section 1.2), tumor model data showing synergy of microbiome-derived 
peptide immunization and anti-PD-1 in combination (Section 1.3.1), and the foreseen safety 
profile of the combination of EO2401 and nivolumab as outlined above, the assessment of 
the Sponsor is that the benefit/risk ratio is positive for the start of the proposed phase 1/2 
trial EOADR1-19. 
The findings from the early part of trial EOADR1-19 described in Section 1.3.3, 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 interesting 
clinical activity in a subpopulation of patients with ACC which could be retrospectively 
defined by clinical parameters, serves as the rationale for a second global protocol 
amendment to extend Cohort 2A (patients with previously treated ACC) for further 
assessment of safety and confirmation (or not) of the ability to adjust inclusion/exclusion 
criteria to avoid treating patients with ACC without appreciable benefit of 
EO2401/nivolumab. It is the Sponsors opinion that the findings presented in Section 1.3.3 
from trials evaluating EO2401 in combination with nivolumab supports a positive benefit- 
risk for extension of trial EOADR1-19 for treatment of further patients according to the 
second global amendment (leading to EOADR1-19 version 3). 
1.3.6 Rationale for global amendment #3 (leading to protocol 
EOADR1-19 version 4) 
 
The rationale of the global amendment #3 (leading to protocol EOADR1-19 version 4) is as 
follows: 

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1.3.7 Rationale for global amendment #4 (leading to protocol 
EOADR1-19 version 5) 
 

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1.4 
History of amendments 
 
EOADR1-19 
protocol version 
(date) 
Key points of protocol version 
(only substantial changes listed) 
Version 1.0 
(12-SEP-2019) 
For initial authority submissions 

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2 RATIONALE 
2.1 
Rationale for the study 
Treatment options for patients with unresectable ACC and MPP are few and new treatment 
options have not been added recently for ACC; currently available first line therapy options 
including polychemotherapy in both entities are only achieving tumor regression in 
approximately one in four patients at the cost of a relatively high toxicity burden (Sections 
1.1.3 and 1.1.4). However, for MPP a randomized clinical trial supporting the use of 
sunitinib as an alternative to chemotherapy was presented recently (ESMO 2021; see Section 
1.1.4 [68]). 
In any case, based on the facts that the median survival in patients with ACC is 12-15 months 
(first line polychemotherapy; FIRMACT trial), and that half of the patients with MPP have 
progressive disease within one year and require active management [58], it is considered that 
therefore both entities are unmet medical needs with respect to new efficacious systemic 
therapies. 
Currently immunotherapy, including compounds of the anti-PD-1/PD-L1 group, is changing 
treatment paradigms in many tumor indications. Anti-PD-1/PD-L1 blockade has also been 
tested in ACC and MPP, and early data indicate acceptable tolerability. However, the 
efficacy in a large (for these indications) finalized trial [see Section 1.2] has not been 
overwhelming and different possible reasons for this have been discussed [21]. One relevant 
reason for immune resistance leading to low activity of PD-1/PD-L1 blockade in adrenal 
malignancies might be lack of enough T cells specific for antigens expressed by the tumor 
cells. A peptide-based therapeutic vaccination approach could counteract such a problem 
aiming at delivering immunogenic peptides corresponding to specific TAAs to patients. The 
goal would be to target the patient’s antigen presenting cells to induce efficient presentation 
of cancer epitopes to T cells that in turn leads to an efficient sustained immune response 
against cancer cells expressing the same antigens at the tumor site. 
In the past, despite promising pre-clinical results in animal models, the therapeutic cancer 
vaccination approach has not demonstrated unequivocal efficacy in patients. The lack of 
efficacy may be related to numerous factors including the status of the patient’s immune 
system, the efficacy and specificity of antigen delivery, the lack of ability of T cells to 
infiltrate the tumor microenvironment, and the tumor’s ability to escape immune-mediated 
inhibition. A definite key item for lack of efficacy is the possible in-ability of used "tumor 
antigens" to generate a strong immune response. The ability for antigens to induce strong 
responses 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. 
To counteract earlier problems with the antigens used for therapeutic cancer vaccinations, 
the concept behind the current trial includes an innovative microbiome-based approach for 
the development of therapeutic peptide cancer vaccines. Numerous peptides mimicking 
specific TAAs that are overexpressed in adrenal tumors have been identified in the human 
microbiome; such peptides can from an immunological perspective be considered as non- 
self. Specific peptides, further selected based on multiple parameters including high-affinity 
binding to MHC class I, have been shown to induce strong immune responses in non-clinical 
models, not only recognizing the microbiome-derived peptide used for immunization but 
also the nominal human TAA expressed by tumor cells (i.e. cross-reactivity have been 
shown; see the current version of the EO2401 IB). 

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Although tumor cell overexpressed TAAs are presented via the MHC class I receptors in the 
form of short peptide sequences (a prerequisite for the possibility to target the TAAs with T 
cells for tumor cell killing), 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 around 
70% of all T cells reside, is tolerant to the equivalent, non-self, microbiome-derived epitopes 
[44]; such epitopes are included in the microbiome-derived peptides developed to mimic 
adrenal TAAs as part of the compound EO2401. Furthermore, it has been demonstrated that 
the general human population has generated a memory repertoire of the mentioned tolerized 
T cells recognizing the peptides from the microbiome [45]. These T cells are surprisingly 
abundant, can be circulating, and display memory phenotypes, all properties that make them 
ideal to be targeted in a therapeutic vaccination protocol. The tolerance of the T cells can be 
overcome by repeated antigen challenges together with an adjuvant, which is the 
immunization principle proposed for the current trial (for supportive data of the use of 
adjuvant and a helper peptide at immunizations see the current version of the EO2401 IB). 
Thus, the strategy behind the current trial is to identify and then use microbiome-derived 
peptides to reactivate their associated memory T cells, where the peptides are almost 
identical to portions of known TAAs (the microbiome-derived peptides are mimicking the 
known TAAs). The mimicking peptides will activate memory T cells that will cross-react 
with the nominal TAAs, thereby enabling an attack against the tumor cells. 
Building on the already known mechanisms of action of anti-PD-1/PD-L1 blockade there is 
a strong support for the combination of EO2401 and such blockade, which in addition is 
supported by pre-clinical data obtained in a tumoral model (see Section 1.3.1 and the current 
version of the EO2401 IB). Thus, 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. An initial response might also lead to antigen spreading 
through the killing of the tumor cells by EO2401 expanded T cells and the induction of 
responses to other antigens than the ones of EO2401. 
In conclusion, novel therapeutic approaches are needed to enhance the treatment outcomes 
for patients with adrenal malignancies. An innovative option which is available to test in the 
clinic, and proposed with the current trial, is the above described microbiome-derived 
peptide therapeutic cancer vaccine approach in combination with anit-PD-1 blockade. 

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3 STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Study objectives 
3.1.1 Primary objectives 
• 
The primary objective of the phase 1 part of this trial is to evaluate safety 
and tolerability of EO2401 in combination with nivolumab in patients with 
unresectable, previously treated, and previously untreated, locally advanced or 
metastatic ACC, and progressive MPP. 
• The primary objective of the phase 2 part of this trial is to determine the effect of 
EO2401/nivolumab on the progression-free survival rate at 6 months, per 
investigator/local site assessments, for patients treated in the randomized extension of 
Cohort 2A* (patients treated with EO2401 monotherapy and nivolumab monotherapy, 
respectively, will constitute internal concurrent controls in the randomized extension). 
* Cohort 2A = patients with ACC who had prior systemic therapy for established locally 
advanced or metastatic disease 
3.1.2 Secondary objectives 
The key secondary objectives of the trial: 
• immunogenicity in relation to T cells of EO2316, EO2317, EO2318, and UCP2 that 
compose EO2401; T cell cross-reactivity with the human TAAs IL13Rα2, FOXM1, and 
BIRC5/survivin will also be evaluated (Note, blood sampling for purification of PBMC 
will only be done at baseline for patients treated with nivolumab monotherapy in the 
randomized extension of Cohort 2A, and thus immunogenicity in relation to EO2401 will 
not be done in these patients except when applicable as internal controls), 
The other secondary objectives of the trial are: 
• objective response rate (ORR), time to response, and duration of response (DOR), and 
• progression-free survival (PFS) and overall survival (OS). 
• In addition, in the randomized extension of Cohort 2A safety and tolerability of 
EO2401/nivolumab assessed versus internal concurrent controls (groups of patients 
treated with EO2401 monotherapy and nivolumab monotherapy, respectively). 
3.1.3 Exploratory objectives 
The exploratory objectives include the exploration of: 

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3.2 
Study endpoints 
3.2.1 Primary endpoint 
• The primary endpoint of the phase 1 part includes safety and tolerability of EO2401 in 
combination with nivolumab by a descriptive medical assessment of the combined 
profile of incidences of adverse events (AEs), treatment-emergent AEs (TEAEs), serious 
AEs (SAEs), deaths, reasons for treatment discontinuation/delays, and laboratory 
abnormalities using the NCI-CTCAE v5.0 grading system [60]. 
• The primary endpoint of the phase 2 part is the rate of patients without progression 
(according to iRECIST criteria [37]) or death due to any cause at 6 months after the first 
dose of randomized treatment. Six months after the first dose of randomized treatment 
will be determined for each patient and is dependent on the exact time point of evaluation 
of the CT investigation scheduled at week 25 (day 169). The primary endpoint is to be 
determined per investigator/local site assessments of progression. The denominator will 
be all patients who started the randomized treatment in Cohort 2A* and will be 
determined for each randomized treatment group separately. Patients will be followed 
up for progression or death during the first 6 months after start of randomized treatment 
regardless of whether they stop treatment and continue on other regimens. Patients who 

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4 STUDY DESIGN 
4.1 
Main study design 
This is an open-label, multicenter, phase 1/2 trial to assess safety, tolerability, 
immunogenicity, and preliminary efficacy of EO2401 in combination with nivolumab for 
treatment of patients with unresectable, previously treated, and previously untreated, locally 
advanced or metastatic ACC, or progressive MPP. 
An extension of Cohort 2A has been made via global amendment 2 (leading to protocol 
EOADR1-19 version 3.0) including patients with ACC who had prior systemic therapy for 
established locally advanced or metastatic disease as in the initial part of the study (Cohort 
2A non-randomized portion), 
 
The primary objective of the open-label, randomized, extension of Cohort 2A is to confirm 
that the retrospectively (in the initial part of the trial) defined inclusion/exclusion criteria can 
exclude patients with a profile not benefiting from study treatment by determining the effect 
of EO2401/nivolumab on the progression-free survival rate at 6 months (per 
investigator/local site assessments. Patients in the extension of Cohort 2A will be 
randomized 4:1:1 to EO2401/nivolumab, EO2401 monotherapy, and nivolumab 
monotherapy; patients treated with EO2401 monotherapy and nivolumab monotherapy, 
respectively, will constitute internal concurrent controls to ensure assay sensitivity in the 
randomized extension. 
4.2 
Overall study design and plan 
The trial is a 5-cohort study intended to recruit a maximum of approximately 120 evaluable 
patients in total: 
• Cohort 1 (previously treated patients) includes an evaluation by a safety lead-in 3-by-3 
design of EO2401 in combination with nivolumab at standard dose; patients with ACC 
and MPP will be included. Three to 12 evaluable patients will be included depending on 
the safety profile of the administered treatments. 
• Cohorts 2A (previously treated patients) and 2B (previously untreated patients) include 
an evaluation of EO2401 at the recommended dose found in Cohort 1 in combination 
with nivolumab in 30 evaluable patients (15 each for Cohorts 2A and 2B) with ACC 
(note, evaluable patients with ACC from Cohort 1 can be assessed in Cohort 2A as well, 
leading to the potential need of recruitment of less than 15 patients specifically for Cohort 
2A). 

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• Cohorts 3A (previously treated patients) and 3B (previously untreated patients) include 
an evaluation of EO2401 at the recommended dose found in Cohort 1 in combination 
with nivolumab in 30 evaluable patients (15 each for Cohorts 3A and 3B) with 
progressive MPP (note, evaluable patients with MPP from Cohort 1 can be assessed in 
Cohort 3A as well leading to the potential need of recruitment of less than 15 patients 
specifically for Cohort 3A). 
 
Generally, patients evaluable for safety will include all patients who have received at least 
one dose of EO2401. Patients who are not considered evaluable for safety and did not receive 
any dose of EO2401 will be replaced (reasons for non-evaluability and pre-treatment safety 
will be reported; note the replacement strategy is also applied for the randomized extension 
of Cohort 2A). In addition, in Cohort 1, if for reasons other than safety a patient does not 
receive 2 doses of EO2401 and complete the
 assessment, the patient will 
not be counted towards the 3-by-3 design and an additional patient should be enrolled 
(reasons for not being counted towards the 3-by-3 design will be reported, as well as 
applicable safety findings). 
There will be a 2-stage consent procedure for the trial, including a first consent for HLA- 
typing (or the use of already available information in the patients file; such information even 
if based on testing before the screening period is acceptable) since a large proportion of the 
patients will not match the HLA-A2 prerequisite to receive the HLA-A2 specific EO2401 
immunization compound. The reason for the initial minimized consent (related to the 
procedure of HLA-testing, and before testing also establishing based on available 
information that the patient has ACC or MPP, and an age ≥ 18 years) is to spare the necessity 
of all other testing for possible enrollment in the trial for patients who are not known to be 
HLA-A2 positive. The second stage of the consent procedure will be related to all other 
aspects of the trial including procedures. 
Eligible patients who meet the inclusion criteria and do not meet any of the exclusion criteria 
and have provided informed consent per above will be enrolled in the study. 
The procedures for cohort management and enrollment are outlined in a study specific 
Charter and also described in Section 6.8. 
Patients’ data will be collected until the clinical data cut-off (see section 4.3.1); the time will 
be dependent on when the patient is enrolled in the trial; survival follow-up will be collected 
until patient’s death or sponsor’s decision to stop the study( see Section 4.3); the time of 
study participation might be shorter in individual patients due to individual patient factors 

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or general trial conduct decisions (e.g. planned trial termination when reaching a pre- 
specified follow-up time). 
Study treatments will be administered until confirmed tumor progression (iRECIST criteria 
for confirmed tumor progression are to be used; see Section 12.1), intolerable toxicity, death, 
patient or Investigator decision, or planned or early termination of the study (see also Section 
5.3). At the time of stopping study treatment, appropriate other treatment will be advised by 
the Investigator on an individual patient basis. The patient should continue study follow-up 
measures for 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 early. 
Of special note, unlike RECIST 1.1, the iRECIST criteria requires the confirmation of 
progression and uses the terms iUPD (unconfirmed progression) and iCPD (confirmed 
progression). Confirmatory scans should be performed at least 4 weeks, but no longer than 
8 weeks after iUPD. Thus, in the current trial, provided that the individual patient is 
tolerating the administered treatment adequately, it is allowed continuing trial treatment 
beyond progression as assessed by the RECIST 1.1. criteria for evaluation of progression 
according to the iRECIST criteria. Provided good tolerability of the trial treatment and lack 
of new important symptoms indicating clinical tumor progression the confirmatory scans 
might be obtained at the current trials planned 8 weekly tumor assessment timepoints. 
In the context of confirmation of PD per iRECIST, and the timeline of confirmatory scans 
to be performed at least 4 weeks, but no longer than 8 weeks after iUPD, it should be 
specifically noted that in case of any signs of rapidly progressing disease establishment of 
PD and a following therapy switch should be made also earlier than 4-8 weeks after iUPD 
when necessary. 
For all cohorts, and all patients during the whole trial treatment, the following safety rules 
will apply: 

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Details of the IDMC process and procedures, and Cohort management plan are outlined in a 
separate Charters. 
The schematic trial and cohort designs are presented in Figure 6 and Figure 7. 

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4.2.2 Cohorts 2A (non-randomized part), 2B, 3A, and 3B 
Cohorts 2A (non-randomized part), 2B, 3A, and 3B are independent cohorts to recruit 
patients with ACC (Cohorts 2A and 2B) and MPP (Cohorts 3A and 3B), respectively. The 
cohorts are 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 
Cohort 1 (see above). 
Cohorts 2A (non-randomized part), 2B, 3A, and 3B will include administration of EO2401 
in combination with nivolumab from the start of treatment in the individual patients for 
assessment of safety, tolerability, immunogenicity, and preliminary efficacy of the 
combination. A total of approximately 30 evaluable patients are planned for inclusion in 
Cohort 2 (irrespective of 2A or 2B, respectively) and a total of approximately 20 evaluable 
patients are planned for inclusion in Cohort 3 (irrespective of 3A or 3B, respectively). 

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The schedule of EO2401 and nivolumab administrations are the same in Cohorts 2A (non- 
randomized part), 2B, 3A, and 3B as in Cohort 1 (see Section 4.2.1). The dose of EO2401 
will depend on the outcome of Cohort 1, i.e. it can be either full dose (1 mL of emulsified 
EO2401 DP in adjuvant), or half dose (0.5 mL of emulsified EO2401). The dose of 
nivolumab will be as outlined for Cohort 1 (see Section 4.2.1). 
For all patients in Cohorts 2A (non-randomized part), 2B, 3A, and 3B, the general safety 
rules as described in Section 4.2 applies, 
 
 
 
 
4.2.3 Randomized extension of Cohort 2A 
After analysis of the initial non-randomized part of Cohort 2, the global protocol amendment 
2 (leading to protocol EOADR1-19 version 3.0) is implementing the randomized phase 2 
portion of the trial for patients with ACC, by extension of Cohort 2A (patients who had prior 
systemic therapy for established locally advanced or metastatic disease) with an additional 
65 patients (see Section 1.3.3 and Section 4.1). 
In the randomized extension of Cohort 2A, patients will be randomized in a ratio of 4:1:1 to 
EO2401/nivolumab, EO2401 monotherapy, and nivolumab monotherapy, respectively. 
Patients treated with EO2401 monotherapy will constitute an internal concurrent 
experimental control. Patients treated with nivolumab monotherapy constitutes an internal 
concurrent control to the combination therapy to ensure assay sensitivity in the randomized 
extension, since there is information available from other trials. 
The randomized extension of Cohort 2A will include administration of study drugs per the 
following: 
• Cohort 2A-I (43 patients) = treatment with EO2401 in combination with nivolumab 
• Cohort 2A-II (11 patients) = treatment with EO2401 monotherapy 

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Reasons for early study termination may include, but are not limited to: 
• safety findings unknown to date (i.e. not previously reported in any similar 
investigational study drug trial with respect to their nature, severity, and/or duration), 
or 
significantly 
changed 
frequency, 
severity, 
or 
duration 
of 
known/anticipated/previously reported safety events, 
• medical or ethical reasons affecting the continued performance of the study, 
• difficulties in the recruitment of patients, 
• regulatory authority request, and 
• cancellation of development of EO2401. 
The Investigator may initiate study site closure at any time, provided there is reasonable 
cause, and adequate notice is given to the Sponsor in advance of the intended site closure. 
Reasons for the early closure of a study site by the Sponsor 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, and 
• inadequate recruitment of participants by the Investigator. 
4.4 
Discussion of study design 
This open label, multicenter, phase 1/2 trial, is part of an early development strategy 
including two similarly designed trials to primarily evaluate safety and tolerability of 
EO2401 in combination with anti-PD-1 blockade in diverse populations with malignancies 
(see Section 1.3.2). Secondary objectives include assessments of immunogenicity, and 
preliminary efficacy. In addition, multiple exploratory objectives to further support the 
understanding of microbiome based therapeutic cancer vaccination are also included in the 
trial. 
Adrenal malignancies are very rare disease entities with an unmet medical need making any 
clinical trial design potentially challenging (see Section 1.1 and Section 2.1). However, 
patients with these diseases are usually treated at highly specialized centers, usually 
responsible by governmental decisions or clinical practice for larger regions. Thus, one 
prerequisite for efficient recruitment is present (specialized center participation in a 
multicenter setting) and by the study design in the proposed trial, a second prerequisite, 
might be achieved; broad possibilities for recruitment (i.e. both types of adrenal 
malignancies, ACC and MPP, and accepting both previously untreated and previously 
treated patients). It is judged that accelerated learning of the impact of the trial treatment can 
be achieved by the proposed 5-cohort design, including one common initial cohort for safety 
and tolerability assessment, followed by disease entity and population specific cohorts for 
further assessments. 
It is judged that the early development nature of the trial makes an open label design 
appropriate. Also, considering that the aim of the development of EO2401 is to define a 
treatment schedule including EO2401 and anti-PD-1 blockade it is judged that for the current 
trial in adrenal malignancies it is adequate to immediately target the combination, i.e. to not 
include any EO2401 monotherapy part in Cohort 1. In the companion early development 

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5 POPULATION 
5.1 
Inclusion criteria 
1. For inclusion in Cohort 1 patients should have adrenocortical carcinoma, or malignant 
pheochromocytoma/paraganglioma, as defined below for Cohorts 2A and 3A. 
2. For inclusion in Cohorts 2A and 2B patients should have histologically confirmed (at 
primary diagnosis) unresectable locally advanced or metastatic (ENSAT/AJCC [38] 
stage 3 = tumor has spread into nearby tissues or lymph nodes, or stage 4 = metastatic 
disease) adrenocortical carcinoma. 
a. In addition, for inclusion in Cohort 2 A patients should also have received 
treatment with at least one line, but not more than two prior lines, of systemic 
therapy for established locally advanced or metastatic disease (i.e. non- 
adjuvant therapy), and should within these lines of therapy for 
advanced/metastatic disease, or as neoadjuvant/adjuvant therapy, have 
received mitotane therapy delivered at an adequate dose per below (if not 
impossible due to toxicity; situation which should be documented in the 
patient files). 
b. In addition, for inclusion in Cohort 2B patients should not have received prior 
systemic therapy for established locally advanced or metastatic disease (i.e. 
non-adjuvant therapy). 

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3. For inclusion in Cohorts 3A and 3B patients should have histologically confirmed (at 
primary diagnosis) unresectable malignant (defined as metastatic disease, i.e. presence 
of chromaffin tissue in non-chromaffin organs) pheochromocytoma/paraganglioma, and 
RECIST defined progression should have been documented during a maximum of an 18- 
months period. 
a. In addition, for inclusion in Cohort 3A patients should also have received 
treatment with at least two prior lines of systemic therapy if the patients are 
eligible for radionuclide therapy, and at least one prior line of systemic 
therapy if the patients are not eligible for radionuclide therapy. 
b. In addition, for inclusion in Cohort 3B patients should not have received prior 
systemic therapy for their malignant pheochromocytoma/paraganglioma. 
4. Patients with an age ≥ 18 years old. 
5. Patients who are human leukocyte antigen (HLA)-A2 positive. 
6. Patients with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 
with the specific meaning of ECOG 1 being "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" (see Section 12.2 [39]). 
 

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7. Patients with a life expectancy > 4 months as judged by their treating physician. 
8. Patients with at least one measurable lesion according to RECIST 1.1 (see Section 12.1; 
[36]). 
9. Males or non-pregnant, non-lactating, females who are: 
a) female, post-menopausal (serum follicle-stimulating hormone (FSH) level > 40 
mIU/mL), 
b) female and male, surgically sterile (e.g. bilaterally blocked or removed fallopian 
tubes, vas deferens), 
c) female of childbearing potential with a negative highly sensitive serum pregnancy 
test within 72 hours prior to first administration of study treatment and use of a highly 
effective contraception from signing the Informed Consent Form (ICF) through 5 
months after the last study treatment dose administered; note, the male partner should 
in addition to the use of highly effective contraception by the female patient also use 
condoms, 
d) male patient with female partners of childbearing potential must use condoms from 
signing the ICF through 5 months after the last study treatment dose administered; in 
addition, male patients must ensure that their partners of childbearing potential also 
use highly effective contraception. 
Highly effective contraception includes: 
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, intrauterine device, and 
iii) sexual abstinence when in line with the preferred and usual lifestyle of the patient 
(e.g. periodic abstinence is not considered a highly effective method). 
10. Patients willing and able to comply with the scheduled visits, treatment plan, laboratory 
tests, and other study procedures indicated in the protocol. 
11. Patients having received the information sheet and who have provided written informed 
consent prior to any study-related procedures.
5.2 
Exclusion criteria 
1. Patients treated with dexamethasone > 2 mg/day or equivalent (i.e. 13 mg/day of 
prednisone, or 53 mg/day of hydrocortisone) within 14 days before the first EO2401 
administration, unless required to treat an adverse event. 
2. Patients with prior treatment with compounds targeting PD-1, PD-L1, CTLA-4, or 
similar compounds where general resistance against therapeutic vaccination approaches 
might have developed (e.g. defects to the cellular antigen processing/presentation 

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machinery, including mutations in Janus kinas [JAK] 1, JAK2, and β-2-microglobulin 
[B2M]) allowing tumor cells to avoid recognition and attack by immune cells. 
3. Patients with prior exposure to EO2401, e.g. patients treated in Cohorts 2B or 3B of the 
current trial cannot be re-enrolled for treatment also in Cohorts 2A or 3A. 
4. Patients 
treated 
with 
immunotherapy 
(meaning 
immunostimulatory 
or 
immunosuppressive therapy; beside excluded, or allowed, compounds per other 
inclusion/exclusion criteria specifications), radionuclide therapy, radiotherapy, 
cytoreductive therapy, or received treatment with any other investigational agent within 
28 days before the first EO2401 administration. 
5. Patients with an initial diagnosis of ACC less than 9 months from start of screening part 
2. 
6. Patients with ACC and any individual lesion according to RECIST 1.1 [36] having a 
maximum diameter of more than 125 mm; irrespective if the lesion is proposed as a 
target lesion, or not, according to RECIST 1.1 (see Section 12.1; [36]). 
7. Patients with ACC with more than three organs involved by disease. 
8. Patients with ACC and uncontrolled hormonal secretion (according to the judgement of 
the treating physician). 
9. Patients with MPP and uncontrolled blood pressure (according to the judgement of the 
treating physician). 
10. Patients with abnormal laboratory values according to the following li

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a. bacterial sepsis or similarly severe infections, 
b. uncontrolled or significant cardiovascular disease, including: 
i. New York Heart Association > Grade 2 congestive heart failure 
within 6 months prior to ICF signing (see Section 12.3), 
ii. myocardial infarction within 6 months prior to ICF signing, 
iii. uncontrolled/unstable angina within 6 months prior to ICF signing, 
iv. diagnosed or suspected congenital long QT syndrome, 
v. any history of clinically significant ventricular arrhythmias (such as 
ventricular tachycardia, ventricular fibrillation, or Torsades de 
pointes), 
c. stroke within 6 months prior to ICF signing, 
d. concurrent neurodegenerative disease, and 
e. dementia or significantly altered mental status. 
15. Patients with suspected autoimmune or active autoimmune disorder or known history of 
an autoimmune neurologic condition (e.g. Guillain-Barré syndrome)
 
 
 
 
16. Patients with history of solid organ transplantation or hematopoietic stem cell 
transplantation. 
17. Patients with history or known presence of tuberculosis. 
18. Pregnant and breastfeeding patients. 
19. Patients with history or presence of human immunodeficiency virus and/or potentially 
active hepatitis B virus/hepatitis C virus infection. 
20. Patients who have received live or attenuated vaccine therapy used for prevention of 
infectious diseases including seasonal (influenza) vaccinations within 4 weeks of the first 
dose of study drug. 
21. Patients with a history of hypersensitivity to any excipient present in the pharmaceutical 
forms of the study treatments. 
22. Patients treated with herbal remedies with immunostimulating properties or known to 
potentially interfere with major organ function. 
23. Patients with known ongoing drug and alcohol abuse. 
24. Patients with known or underlying medical or psychiatric condition that, in the 
Investigator’s opinion, would make the administration of study drug hazardous to the 
patient or obscure the interpretation of toxicity determination or AEs. 
25. Patients deprived of their liberty, under protective custody, or guardship. 

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5.3 
Removal of patients from therapy or study 
5.3.1 Patient withdrawal of consent 
Patients may voluntarily withdraw from the study treatment, or the study as such, including 
procedures, at any time at his/her request for any reason. In instances where patient consent 
is withdrawn, the Investigator must clarify to which degree the patient consent is withdrawn, 
i.e. whether the patient still is willing to continue to participate in some study specific 
procedures, or not. The degree of consent withdrawal should be carefully documented in 
patient files and in study documents. 
5.3.2 Screen failures 
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 information is required to be captured (via the eCRF) for such patients to 
ensure transparent reporting to meet the standards of reporting clinical trials and to respond 
to queries from regulatory authorities. Minimal information includes age and gender, screen 
failure details (including failed eligibility criteria), and any SAEs. 
5.3.3 Criteria for treatment discontinuation 
Patients should be removed from study treatment for any of the following reasons: 
• intolerable toxicity in relation to study treatment and adverse events requiring treatment 
discontinuation according to this protocol (see Section 4.2), 
• pregnancy, 
• confirmed tumor progression according to iRECIST criteria (see Section 12.1), 
• any medical condition which may jeopardize the patient’s safety if he/she continues trial 
treatment, 
• major protocol violation (including non-compliance to study schedule by the patient) 
judged to impact safety of the patient or interpretability of the trial, 
• decision by the Investigator, Sponsor, or any regulatory authority, that treatment 
discontinuation is in the best interest of the patient, 
• patient withdrawal of consent to receive further study treatment, and 
• planned or early termination of the study (see Section 4.3). 
5.3.4 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. 

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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 
method). These contact attempts should be documented in the patient’s medical records. 
5.3.5 Criteria for study participation termination 
Reasons for patient withdrawal from the study may include, but are not limited to: 
• patient withdrawal of consent for any further trial procedures (see also Section 5.3.1), 
• patient lost to follow-up, 
• major protocol violation (including non-compliance to study schedule by the patient) 
judged to impact safety of the patient or interpretability of the trial, 
• decision by the Investigator, Sponsor, or any regulatory authority, that study 
participation discontinuation is in the best interest of the patient, 
• planned or early termination of the study (see Section 4.3). 
 
5.3.6 Follow-up of patients discontinued from study treatment or 
withdrawn from study 
The primary reason for study treatment discontinuation should be documented in the eCRF. 
In case of treatment discontinuation, patients will complete follow-up visits according to 
Section 7.5. The first follow-up visit is to be completed 30 days after completion of last dose 
of study treatment. 
In cases of withdrawal from the study, every effort should be made to obtain adequate 
information. The primary reason for withdrawal from the study should be documented in the 
eCRF. If possible, patients will complete a follow-up visit according to Section 7.5.1. 
In cases with complete informed consent withdrawal (see also Section 5.3.1), patients will 
not be followed for any reason, although date of death will be recorded, where applicable 
and possible to retrieve. 
5.3.7 Procedures for handling incorrectly enrolled patients 
If a patient is found to have been incorrectly enrolled in the study, the Sponsor must be 
notified as soon as the error is discovered. The Sponsor will decide on the appropriate action 
to take regarding study treatment and continuation of the patient in the study. 
5.3.8 Patient replacement 
Patients who have not received any dose of EO2401 and thereby are not evaluable for safety, 
will be replaced (reasons for non-evaluability and pre-treatment safety will be reported). 
Note, the replacement strategy per above is also applied for the randomized extension of 
Cohort 2A. Thus, if a patient is randomized and then withdrawn from treatment (for any 
reason) before a first dose of study medication has been delivered, the patient should be 
replaced. 
In addition, in Cohort 1, if for reasons other than safety a patient does not receive 2 doses of 
EO2401 and complete the Week 5 visit (V3) assessment, the patient will not be counted 
towards the 3-by-3 design and an additional patient should be enrolled (reasons for not being 
counted towards the 3-by-3 design will be reported, as well as applicable safety findings). 

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6.2.2 Preparation of the formulation 
Instructions for preparation of nivolumab for infusion can be found in the European SmPC 
or the US PI for nivolumab [42, 43]. 
6.2.3 Packaging and labeling 
Nivolumab will be obtained from commercial sources by the Sponsor and clearly labeled for 
use within the trial. 
Adequate supplies of nivolumab in 24 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. 
6.2.4 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 [42, 43]. 
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). 
6.2.5 Expected safety profile of nivolumab 
The following summary is based on the European SmPC [42]. 
In the pooled dataset of nivolumab as monotherapy across tumour types (n = 4646) with 
minimum follow-up ranging from 2.3 to 28 months, the most frequent adverse reactions (≥ 
10%) were fatigue (44%), musculoskeletal pain (28%), diarrhoea (26%), rash (24%),cough 
(22%), nausea (22%), pruritus (19%), decreased appetite (17%), arthralgia (17%), 
constipation (16%), dyspnoea (16%), abdominal pain (15%), upper respiratory tract 
infection (15%), pyrexia (13%), headache (13%), anaemia (13%) and vomiting (12%). The 
majority of adverse reactions were mild to moderate (Grade 1 or 2). The incidence of Grade 
3-5 adverse reactions was 44%, with 0.3% fatal adverse reactions attributed to study drug. 
In addition, nivolumab is associated with immune–related adverse reactions. With 
appropriate medical therapy, immune-related adverse reactions resolved in most cases. Table 
2 presents the percentage for immune-related adverse reactions leading to permanent 
discontinuation of nivolumab and the percentages requiring high-dose corticosteroid dosing. 
For the laboratory abnormalities observed with nivolumab monotherapy, please refer to the 
European SmPC or to the US PI [42, 43]. 
Of the 3529 patients who were treated with nivolumab monotherapy 3 mg/kg or 240 mg 
every 2 weeks and evaluable for the presence of anti-product-antibodies, 328 patients (9.3%) 
tested positive for treatment-emergent anti-product-antibodies with 21 patients (0.6%) 
testing positive for neutralising antibodies. 
Generally, no overall differences in safety regarding nivolumab were reported between 
elderly (≥ 65 years) and younger patients (< 65 years). 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. 

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Table 2 : 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. 
6.3 
Administration of EO2401 and nivolumab 

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For further information regarding administration of nivolumab, see also the European SmPC 
or the US PI for nivolumab [42, 43]. 
Note, administration-related reactions and guidelines on how to handle such reactions are 
outlined in Section 6.5. 
6.4 
Treatment modifications 
The only adjustments regarding dose for nivolumab 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 SmPC or the US PI [42, 43]. 
The dose modifications for EO2401 follow the same principles as for nivolumab, i.e. 
possible dose modifications include withholding of doses, and treatment discontinuation, 
except in the potential transition from sub-cohort 1b to sub-cohort 1c in relation to safety 
events (when a dose decrease is planned; see Section 4.2.1). 
For all cohorts, and all patients during the whole trial treatment, the safety rules are outlined 
in Section 4.2, including instructions on when to discontinue study treatments. 
Guidelines for withholding doses or permanent discontinuation of EO2401 and nivolumab 
in case of immune-related adverse reactions are outlined below in Section 6.4.1. Also, dose 
adjustments are necessary to consider in the case of administration-related reactions (see 
Section 6.5). 
In instances where the label for nivolumab prescribe that the drug should be withheld or 
discontinued due to safety events, there is, in patients with EO2401/nivolumab combination 
treatment, an option to continue EO2401 alone provided such a continuation would be 
recommended by the IDMC and supported by the Sponsor. 
If EO2401 would be stopped, nivolumab will also be stopped in the context of being trial 
treatment for patients with EO2401/nivolumab combination treatment. In such cases, the 
Investigator responsible for the patient in question will advise on adequate further treatment 
options. 
Criteria for treatment discontinuation and study participation termination are outlined in 
Section 5.3.3 and Section 5.3.5. 

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6.5 
Administration-related reactions 
The NCI-CTCAE distinguishes between hypersensitivity reactions and acute infusion 
reactions induced by cytokine release. Despite the different possible mechanisms underlying 

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hypersensitivity and infusion reactions, the clinical signs and symptoms associated with 
these reactions overlap. 
Immediate systemic reactions, infusion-related reactions (e.g. via cytokine release) and 
hypersensitivity reactions, at administration of nivolumab are not uncommon (European 
SmPC and US PI for nivolumab [42, 43]). 
Severe infusion reactions have been reported in clinical trials of nivolumab. In case of a 
severe or life-threatening infusion reaction, the nivolumab infusion must be discontinued 
and appropriate medical therapy administered. Patients with mild or moderate infusion 
reaction may receive nivolumab with close monitoring and use of premedication (and/or 
slowed rate of infusion) according to local treatment guidelines for prophylaxis of infusion 
reactions [42, 43]. 
Systemic reaction at administration of EO2401 cannot be excluded either and since this is 
an early development trial it is advisable to take precautions to be able to ameliorate 
symptoms if such would occur. 
In the current trial, the nivolumab infusion is to start 
 after the EO2401 
administration. 

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6.5.2 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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6.7 
Study treatment accountability, reconciliation, and return 
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 adequate patient. The study treatment must be dispensed from official 
study sites by authorized personnel according to local regulations. The Investigator or 
designee must maintain accurate records of the study treatment receipt, dispensing 
information, and disposition. 
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. 

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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. 
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. 
Further guidance and information for the final disposition of unused study treatment are 
provided in the pharmacy binder. 
6.8 
Method of treatment assignment 
This is an open-label non-randomized trial for Cohort 1, non-randomized part of Cohort 2A, 
Cohort 2B, Cohort 3A, and Cohort 3B, and each newly enrolled patient (upon signing the 
ICF) will be assigned a unique patient identification number assigned to the treatment after 
approval of eligibility, where applicable. Slot assignments will be managed by the Medical 
Monitor as described in the Charter for cohort management. 

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User access and permissions: 
The IWRS system for randomization will be clearly separated, by programming, from all 
other trial related computer systems; the randomization system can be programmed to 
directly release data regarding treatment assignment for a specific patient to other systems 
(e.g. systems handling drug shipments etc.). 
To use the IWRS each user must connect to an https address, enter a personal username, and 
a password. This feature guarantees the security of the system and creates an automatic audit 
trail of which person performed what actions. In accordance with 21 CFR part 11, user access 
codes are unique and never reassigned. For added security, the first time a user connects into 
the IWRS, he/she is asked to select a new password. 
The Sponsor will provide the vendor for the IWRS with a list of IWRS users; the IWRS 
vendor will keep this list up to date. Codes can be provided to users at the start of the study 
and throughout the study in case of additions to or changes in staff. User accounts would be 
deactivated for all users who are no longer participating in the study. 
Randomization design: 
Randomization to allocate patients in a ratio of 4:1:1 (Cohort 2A-1 EO2401/nivolumab : 
Cohort 2A-II EO2401 monotherapy : Cohort 2A-III nivolumab monotherapy) and to ensure 
that sites with low recruitment do not have only control patients among the initially recruited, 
will be achieved by using an IWRS system and randomization lists with fixed blocks 
including some flexibility. 
For the first 50 patients, the randomization will be stratified by site. 

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6.9 
Ancillary treatments 
6.9.1 Prior and concomitant treatments and procedures 
Prohibited treatments prior to trial enrollment are outlined in the exclusion criteria (see 
Section 5.2). 
The Investigator must record the use of all prior and concomitant medications or vaccines 
taken during 28 days prior to signing informed consent. Likewise, for the duration of the 
study both prescribed and "over-the-counter" medications, including herbal remedies, should 
be recorded in the source documents and eCRF along with: 
• reasons for use, 
• dates of administration including start and end dates, and 
• dosage information, including dose, frequency, and route of administration. 
In case of surgical procedures, or other relevant non-drug medical interventions and 
procedures, all details must be collected in the eCRF in a similar manner as for medications 
per above. 
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. 
6.9.2 Permitted concomitant medications 
All non-cancer therapies that the responsible physician feels appropriate are allowed in this 
study, except for the medications outlined in Section 6.9.3. Thus, patients should receive full 
supportive care during participation in the trial and standard of care treatment per local 
practice and according to the judgment of the Investigator or treating physician. 
Administration of steroids through a route known to result in a minimal systemic exposure 
(topical, intranasal, intro-ocular, or inhalation) is acceptable. 

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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. 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 taken 
into account (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 are offered a third (or potential further) dose during the trial, or for 
patients who have not been vaccinated against SARS-CoV-2/COVID-19 before study 
inclusion, but want to be vaccinated during their study participation, the Sponsor also 
strongly recommends vaccination. For such patients the Sponsor recommends 
administration of the dose of the COVID-19 vaccine during the boosting phase (EO2401 
administered every 4 weeks), or 2 weeks after the latest EO2401 administration (and 
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 

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Enterome via the Medical Monitor]. Should you also plan to administer a vaccine against 
influenza, we would propose the same approach with the same time intervals. 
• At screening for inclusion of patients into trial EOADR1-19, Enterome would like to 
draw your attention to Exclusion Criterion #12 (copied below) which is valid also for 
COVID-19 infections, meaning that the PI/co-PI when assessing patients for study 
inclusion should consider patient history/symptoms and the local pan/endemic situation, 
and when judged appropriate also test patients regarding SARS-CoV-2 before stating 
that the individual patient does not fulfill the exclusion criterion (in such cases 
documentation of testing, including outcome, should be made in the eCRF as an 
unscheduled test during screening): 
Exclusion criterion #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 study results, interpretation 
of patient safety, or prohibit patient understanding of the informed consent 
procedure (i.e. only consent able patients can be enrolled in the study) or 
compliance with the requirements of the protocol including (but not limited to): 
a. bacterial sepsis or similarly severe infections, 
b. … 
 
The below by FDA and EMA approved COVID-19 vaccines are acceptable for 
use in the trial (local restrictions per country specific authority of course takes 
precedence; also, new approvals by FDA and EMA should be taken into account 
when selecting vaccine type): 
 
Name 
COVID-19 
Vaccine 
developer/ 
manufacturer 
Vaccine 
platform 
Type 
of 
candidate 
vaccine 
Number 
of doses 
Timing 
between 
doses 
Route 
of 
administration 
Vaxzevria 
University 
of 
Oxford/AstraZeneca 
Non- 
Replicating 
Viral Vector 
ChAdOx1-S 
2 
28 days 
IM 
Spikevax 
Moderna/NIAID 
RNA 
LNP- 
encapsulated 
mRNA 
2 
28 days 
IM 
Comirnaty 
BioNTech/Fosun 
Pharma/Pfizer 
RNA 
3 LNP-mRNAs 
2 
21 days 
IM 
COVID-19 
vaccine 
Janssen 
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. 
 
6.9.3 Prohibited medications and other therapies 
The use of systemic corticosteroids and other immunosuppressants should be avoided 
because of their potential interference with the pharmacodynamics activity of the study 
treatment. However, in some cases, systemic corticosteroids cannot be avoided; guidance 

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regarding steroid use for patients participating in the trial is therefore outlined in Section 
6.9.2. 
The use of live or attenuated vaccine therapy for prevention of infectious diseases during 
trial participation should be avoided if possible. However, if such vaccinations would be 
considered as important for the normal care of the patient, the treating physician should 
discuss the situation with the Medical Monitor of the Sponsor and an adequate solution 
regarding timing should be found. 
Patient should be discouraged from taking medications, including herbal remedies, with 
immunostimulatory properties, or known to potentially interfere with major organ function, 
during trial participation. If needed, any such possible therapy should be discussed between 
the treating physician and the Medical Monitor of the Sponsor. 
During trial participation patients should not receive any other anti-cancer treatment than the specific 
trial treatment (EO2401 in combination with nivolumab) and treatments outlined in Section 6.9.2. 
If any other anti-cancer treatment, or procedure, would be considered for start in an individual patient, 
it is the duty of the Investigator to discuss the consideration with the Medical Monitor of the Sponsor 
for a decision on how to handle continued trial specific treatment and trial participation. 
In general, if necessary due to e.g. patient symptoms, local therapies will be promoted; depending on 
localization of the treatment versus localization of measurable lesions, a decision might be necessary 
to consider censoring the patient for progression related endpoints at the time of start of the therapy 
if there would be no measurable lesion left outside of the location of the local treatment (or assessing 
the patient as having progressive disease if relevant criteria would be fulfilled). 
Start of non-trial systemic anti-cancer treatments would lead to censoring of the patient for 
progression related endpoints at the time of start of the therapy; or assessment of the patient as having 
progressive disease if relevant criteria would be fulfilled. 
6.9.4 Contraception 
Potential postmenopausal status for female patients will be confirmed with a screening serum 
follicle-stimulating hormone (FSH) level > 40 mIU/mL. Rules for contraception during study 
participation are outlined in the inclusion criteria, see Section 5.1. 
6.10 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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7 STUDY ASSESSMENTS AND PROCEDURES 
7.1 
Study schedule 
Study assessments and procedures, and their timings (including visit windows) are 
summarized in the Study Schedule (Error! Reference source not found.). As protocol 
exemptions are not foreseen in this trial, except in case of immediate safety concerns, any 
deviation from the planned study schedule should be discussed with the Sponsor 
immediately upon occurrence or awareness to determine if the patient should continue, or 
discontinue, the study treatment. Adherence to the study design requirements, including 
those specified in the Study Schedule, is essential and required for adequate study conduct. 
7.2 
Screening period #1 
The trial will include a 2-stage consent and screening procedure (see Section 4.2). 
The initial 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 ACC or MPP, and an age ≥ 18 years (inclusion criteria #1 to 5; see Section 5.1). 
The following will be done during screening period #1: 
• 
study ICF procedure for consent #1, and 
• 
eligibility ascertained for inclusion criteria #1 to 5 (#1 to 3 as applicable 
depending on stage of trial conduct and patient tumor disease). 
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. 

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7.3 
Screening period #2 
The second stage of the consent procedure, and screening period #2, will be related to all 
other aspects of the trial, except those outlined in Section 7.2 (for remaining 
inclusion/exclusion criteria see Section 5.1 and Section 5.2). 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 evaluations must be completed and reviewed within the timeframe 
defined in the Study Schedule (Error! Reference source not found.) to confirm that potential 
patients meet all eligibility criteria. The Investigator will record adequate details of all 
patients screened and to confirm eligibility, or record reasons for screen failure, as applicable 
(see Section 5.3.2). 
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. Results obtained also the week 
before screening started 
 can be used for 
study purposes provided the study Medical Monitor’s approval is granted; this also includes 
an acceptable time window for the screening/baseline CT. 
All screening examinations will be performed locally, at the site or an affiliate site due to 
e.g. the location of the site and the patient. 
The maximum amount of blood to be taken from each patient at screening, or 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 who do not fulfill all eligibility criteria will be assigned a “screen failure”-status and 
not continue any further trial procedures; such patients will be replaced. 
The following will be done during screening period #2: 
• 
study ICF procedure for consent #2, 
• 
eligibility ascertained for inclusion and exclusion criteria (see Section 5.1 and 
Section 5.2), 
• 
documentation of; 
o patient demographics (age, ethnicity, race), 
o extended history of oncology disease(s), including dates of diagnosis and 
treatments history, 
o medical history of other (than oncology) disease processes (all prior 
significant illnesses that are relevant to patient safety or that the patient has 
experienced prior to screening; especially history of anaphylaxis or other 
reactions following vaccination, and history of immune deficiencies), and 
concomitant illness (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), 
o medications, including vaccines, and other relevant treatments (e.g. 
surgeries) during 28 days prior to signing informed consent; all applicable 
treatments (systemic and local), also before 28 days prior to informed consent 
signing, for oncology disease(s) will be collected, 
o concomitant medications/treatments, 

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• 
measurement/assessment of; 
o height and weight, 
o ECOG performance status (see Section 12.2), 
o vital signs including temperature, blood pressure (BP), and heart rate (HR) 
(BP and HR will be measured according to local standard practice); if systolic 
BP is below 100 mmHg or above 150 mmHg, and/or diastolic BP is below 
50 mmHg or above 90 mmHg, the measurement will be repeated; the HR 
measurement will be repeated when below 50 bpm or above 100 bpm, 
o major body systems via physical examination; general appearance, skin, neck 
(incl. thyroid), ENT (ears, nose, throat), lungs, heart, abdomen, lymph nodes 
(all major stations palpable), extremities, neurology, and other sites as 
applicable (i.e. symptom directed), 
• 
safety blood samples for hematology, coagulation, serum chemistry, urinalysis, 
hormones, and virus serology to be performed and evaluated locally, detailed as; 

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• 
a 12-lead electrocardiogram (ECG) will be recorded according to local site 
standard procedures, and 
• 
adverse events will be reported according to NCI-CTCAE v5.0; documentation 
of AEs/SAEs starts after trial consent has been given by the patient. 
7.4 
Visits during study treatment 
Note, measurements/assessments/sampling as outlined below are to be done before administration of 
study treatments if scheduled for the same day, if no other specific order of events is defined (e.g. 
for DTH-testing there is a special procedure and timing as outlined in Section 6.6.3). 
7.4.1 Visits during EO2401 priming phase; V1, V2, V3, V4, and V5 
Visit 1 (V1) must be performed within 
screening/baseline CT. 
Visits V1 to V4 are planned to be performed every 2 weeks
, and V5 2 weeks +/- 
 after V4. 
The following will be done during the visits
• at V1, V2, V3, and V4; 
o administration of EO2401 and nivolumab should be done per allocated 
treatment cohort
o documentation of concomitant medications/treatments, 
o measurement/assessment of; 
▪ weight, and ECOG performance status (see Section 12.2), 
▪ vital signs, and major body systems via physical examination, as 
outlined in Section 7.3, 
▪ safety blood samples for hematology, coagulation, serum chemistry, 
and urinalysis, as outlined in Section 7.3, 
o adverse events will be recorded according to NCI-CTCAE v5.0 (AEs will be 
monitored for the whole duration of the trial, but assumed recorded at visits 
for treatments, except in cases where the seriousness demands more 
immediate reporting, see Section 8), 

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• at V1, V2, V3, V4, and V5; 
o assessment of serum cortisol, TSH, and free T4, as outlined in Section 7.3 
o for women of childbearing potential, highly sensitive serum pregnancy test, 
o assessment of a 12-lead ECG, as outlined in Section 7.3, 
o a CT for tumor status assessment should be performed and tumor response 
assessment made, as outlined in Section 7.7. 
7.4.2 Visits during EO2401 boost period; from V6 until treatment 
discontinuation 
From visit V6 and onwards,
The following will be done during the visits: 
• administration of EO2401 and nivolumab should be done per allocated treatment 
cohort
 

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• at the visits for study treatment administration the following will also be done; 
o documentation of concomitant medications/treatments, 
o measurement/assessment of; 
▪ weight, and ECOG performance status (see Section 12.2), 
▪ vital signs, and major body systems via physical examination, as 
outlined in Section 7.3, 
▪ safety blood samples for hematology, coagulation, serum chemistry, 
and urinalysis, as outlined in Section 7.3, 
o adverse events will be recorded according to NCI-CTCAE v5.0 (AEs will be 
monitored for the whole duration of the trial, but assumed recorded at visits 
for treatments, except in cases where the seriousness demands more 
immediate reporting, see Section 8), 
o for women of childbearing potential, highly sensitive serum pregnancy test, 
o assessment of serum cortisol, TSH, and free T4, as outlined in Section 7.3, 
o a CT for tumor status assessment should be performed and tumor response 
assessment made, as outlined in Section 7.7. 

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7.5 
Visits during post-treatment follow-up 
7.5.1 Post-treatment visit for safety assessment; Vn+1 
A post-treatment safety assessment visit should be performed 30 days
after the last study treatment has been administered. 
The following will be done during the visits: 
• documentation of concomitant medications/treatments, 
• measurement/assessment of; 
o weight, and ECOG performance status (see Section 12.2), 
o vital signs, and major body systems via physical examination, as outlined in 
Section 7.3, 
o safety blood samples 
o for women of childbearing potential, highly sensitive serum pregnancy test, 
o assessment of a 12-lead ECG, 
• adverse events will be recorded according to NCI-CTCAE v5.0 (AEs will be 
monitored for the whole duration of the trial, but assumed recorded at visits for 
treatments, except in cases where the seriousness demands more immediate 
reporting, see Section 8), and 
7.5.2 Post-treatment follow-up before assessed progressive disease; 
Vnn 
Patients who are discontinuing all study treatment without having had confirmation of 
progressive disease according to iRECIST criteria will be followed
after the latest performed CT assessment during the time period they received study 
treatment. 
At these 
timepoints the following will be done: 
• a CT for tumor status assessment should be performed and tumor response 
assessment made, as outlined in Section 7.7, 

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• documentation of safety; after the post-treatment visit for safety assessment (see 
Section 7.5.1) has been made, only SAEs with plausible causal relationship with trial 
treatment will be documented (in addition, in case of death, an as precise cause of 
death as possible is going to be documented), and 
• if applicable, collection of information regarding further anti-cancer treatments. 
7.5.3 Post-treatment follow-up; Vnnn 
Patients will be followed
At these
 timepoints, which if the patient is unable to attend a site visit can 
be a telephone contact, the following will be done: 
• survival status documentation (in case of death, an as precise as possible cause of 
death is going to be documented), 
• documentation of safety; after the post-treatment visit for safety assessment (see 
Section 7.5.1) has been made, only SAEs with plausible causal relationship with trial 
treatment will be documented, and 
• if applicable, collection of information regarding further anti-cancer treatments. 
7.6 
Safety assessments 
Safety and tolerability of EO2401 in combination with nivolumab, the primary endpoint for 
the phase 1 part of the trial, will be assessed by a descriptive medical assessment of the 
combined profile of incidences of AEs, TEAEs, SAEs, deaths, reasons for treatment 
discontinuation/delays, and laboratory abnormalities. Adverse events will be categorized by 
their system organ class (SOC) and preferred term (PT) using the current MedDRA version 
and graded according to NCI-CTCAE v5.0 [60]. 
In addition, in the randomized extension of Cohort 2A safety and tolerability of 
EO2401/nivolumab will be assessed versus internal concurrent controls (groups of patients 
treated with EO2401 monotherapy and nivolumab monotherapy, respectively), by 
incidences of adverse events (AEs), treatment-emergent AEs (TEAEs), serious AEs (SAEs); 
AEs will be analyzed irrespective of relationship, and as related events. 
The safety monitoring procedures of the trial are described in Section 8, the specific 
parameters to monitor/assess are outlined in Section 7.3, Section 7.4, and Section 7.5, and 
the timing of assessments also described in Table 5. 
Clinical laboratory analyses as described in Section 7 will be performed by a local 
laboratory. More frequent evaluations may be performed at the Investigator’s discretion if 
medically indicated; results of such evaluations should also be recorded in (e)CRFs. Normal 
ranges for all utilized local laboratories should be provided by the sites to the Sponsor. 
7.7 
Efficacy assessments 
Computed tomography scans will be performed according to the Study Schedule
for assessments of tumor status; when adequate due to e.g. 
location of new metastatic disease, other examinations than CTs might be necessary for 
documentation of tumor status - such assessments are going to be done, and recorded in the 
trial documentation, on an individual patient basis based on the judgment of the Investigator. 
Tumor response and progression in this trial will primarily be evaluated by the 
investigators/local sites using the revised international criteria (1.1) proposed by the 
Response Evaluation Criteria in Solid Tumors (RECIST) committee [36] as well as the 
modified iRECIST guidelines [37]; see Section 12.1 for a further description of the criteria. 

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Investigators should especially note the different requirements for confirmatory scans as well 
as follow-up for the two criteria. 
Of particular importance, in the context of confirmation of PD per iRECIST, and the given 
timeline of confirmatory scans to be performed at least 4 weeks, but no longer than 8 weeks 
after iUPD, is that in case of any signs of rapidly progressing disease establishment of PD 
and a following therapy switch should be made also earlier than 4-8 weeks after iUPD when 
necessary. 
The main efficacy assessments will include ORR, DOR, PFS, and OS as outlined in Section 
3.2.2. 
The primary endpoint of the phase 2 part of the trial is the rate of patients without progression 
(according to iRECIST criteria [37]) or death due to any cause at 6 months after the first 
dose of randomized treatment. The primary endpoint is to be determined per 
investigator/local site assessments of progression. The denominator will be all patients who 
started the randomized treatment in Cohort 2A and will be determined for each randomized 
treatment group separately. Patients will be followed up for progression or death during the 
first 6 months after start of randomized treatment regardless of whether they stop treatment 
and continue on other regimens. Patients who are completely lost to follow-up will be 
counted as if they had a PFS event during the first 6 months. 

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7.9 
Assessments for other exploratory endpoints 

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8 SAFETY MONITORING 
8.1 
Safety monitoring definitions 
8.1.1 Adverse events 
International Council for Harmonization (ICH) guideline E2A defines an AE as “any 
untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship 
with this treatment”. 
According to the FDA (21CFR312.32), an AE means any untoward medical occurrence 
associated with the use of a drug in humans, whether, or not, considered drug related. 
An AE can therefore be any unfavorable and unintended sign (e.g., tachycardia, enlarged 
liver), symptom (e.g., nausea, chest pain), abnormal result of an investigation (e.g., 
laboratory finding), or disease temporarily associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
8.1.2 Serious Adverse events 
An SAE is any untoward medical occurrence that at any dose fulfills one or more of the 
following criteria: 
• results in death, 
• is immediately life-threatening, 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at immediate risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe. 
• results in persistent or significant disability/incapacity, 
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). 
• is a congenital anomaly/birth defect, 
• requires inpatient hospitalization or prolongation of existing hospitalization, and 
A hospitalization is defined as an inpatient overnight stay, but this can be shorter than 24 
hours. 
• is another medically significant event defined as an event that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may 
require intervention to prevent any of the above listed outcomes. 
 
 
8.1.2.1 Excluded events 
Hospitalization for the following reasons will not be regarded as serious (i.e. will not be 
immediately reportable): 
• routine treatment or monitoring of the disease under study, including hospitalization due 
to trial-related procedures, not associated with any deterioration of the patient’s status, 

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• elective or pre-planned treatment (before signing the ICF) for a pre-existing condition 
that is unrelated to the disease under study and has not worsened since signing the ICF, 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions for an SAE and not resulting in hospital admission, 
• underlying disease progression (the adrenal malignancy which is the basis for the patient 
enrollment in the trial) and events which are unequivocally (without doubt) related to the 
disease progression, and 
• social reasons, respite care, and in the absence of a medical condition. 
8.1.3 Suspected Unexpected Serious Adverse Reactions (SUSARs) 
SUSARs are serious events that are not listed in the Reference Safety Information section of 
the EO2401 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. In Europe, SUSARs will be 
reported as established in the EU Regulation No 536/2014. 
When EO2401 is administered in combination with nivolumab, SUSARs are serious adverse 
events related to EO2401 that are not listed in the Reference Safety Information section of 
the EO2401 Investigator Brochure (i.e. all events, except local administration site reactions 
as described in the Investigator Brochure) and/or serious adverse events related to nivolumab 
that are not listed in the nivolumab European SmPC. 
When nivolumab is administered alone, SUSARs are serious adverse events related to 
nivolumab that are not listed in the nivolumab European SmPC. 
 
8.1.4 Severity/intensity versus seriousness 
ICH E2A: The term “severe” is often used to describe the intensity (severity) of a specific 
event (as mild, moderate, or severe myocardial infarction); the event itself, however, may be 
of a relatively minor medical significance (such as a severe headache). This is not the same 
as “serious”, which is based on patient/event outcome or action criteria usually associated 
with events that pose a threat to a patient’s life or functioning. Seriousness (not severity) 
serves as a guide for defining regulatory reporting obligations. 
8.2 
Pregnancies 
Patients who are fertile must use adequate birth control methods during the trial, from 
signing the ICF through 5 months after the last study treatment dose administered (see 
Section 6.9.4). 
Pregnancy is not considered an AE unless it meets any criteria for becoming serious (see 
Section 8.1.2). However, 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 study treatment. 
The Investigator should make every effort to follow the patient until completion of the 
pregnancy and provide the corresponding information by the mean of a SAE/Pregnancy form 
within 2 weeks from awareness (see Section 8.5.3). The Sponsor Safety Group will 
periodically request from the investigator targeted follow-up information using specific 
pregnancy follow-up forms. If the events during pregnancy and/or outcome of pregnancy 

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(i.e. complications regarding mother/baby) meet the criteria for classification of an SAE, the 
Investigator must follow the procedures for SAE reporting. 
8.3 
Safety monitoring periods 
8.3.1 Reporting 
In patients exposed to study treatment, the following must be reported from the date of the 
patient’s signing the ICF until 30 days after the final administration of study treatment: 
• 
AEs regardless of their causal relationship to study treatment, 
• 
SAEs without a plausible causal relationship to study treatment, and 
• 
pregnancy of the patient. 
SAEs with a plausible causal relationship to study treatment must be reported from the date 
of the patient’s signing the ICF until indefinitely (regardless of the time elapsed from the 
final study treatment administration). 
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. 
In patients not exposed to study treatment, the reporting period for AEs (including SAEs 
regardless of causal relationship) starts with signature of the ICF and ends: 
• the date of the Investigators assessment of "screen failure"-status (see Section 5.3.2), 
or 
• the date of the patient’s consent withdrawal. 
8.3.2 Follow-up 
The Investigator assesses at each visit (or more frequently, if necessary) if there are any 
changes in AE diagnosis, severity, suspected causal relationship to clinical trial 
medication/procedure, interventions required to treat the event, and AE outcome. 
An AE causally not related to study treatment is monitored (followed-up) until resolution, 
stabilization (becoming a permanent condition), or end of the clinical trial. Clinically 
relevant laboratory abnormalities will be followed up until they return to normal or become 
stabilized (permanent condition). 
Any AE with a plausible causal relationship to study treatment as well as all SAEs 
(regardless of their causal relationship) will be followed up until the event has resolved or 
stabilized (permanent condition). 
Pregnancies will be monitored by the Investigator to determine the outcome, including 
spontaneous abortion or voluntary termination, birth details, and the presence or absence of 
any birth defects, congenital abnormalities, or maternal and newborn complications. Every 
infant should be followed up for 2 months after delivery. 
8.4 
Assessing adverse events 
Information about adverse reactions (causally related events) already known for EO2401 
monotherapy, or EO2401 in combination with nivolumab, can be found in the current 

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Physical examination findings will be compared with the baseline status and any clinically 
significant change, as assessed by the Investigator, should be documented as an AE. 
A surgical procedure is not an AE but a therapeutic measure for a condition that necessitates 
surgery. Therefore, the condition for which the surgery is required should be reported as an 
AE. 
Any pre-planned surgery (i.e. planned before signature of the ICF) or other intervention 
permitted by the protocol and the condition leading to that measure are not AEs. In such 
cases, the underlying condition needs to be documented in the patient’s medical history. 
Death itself is an outcome of an event, which needs to be described and reported using 
medical terminology. Information about death will be captured on the respective eCRF page 
along with relevant details (date of death, immediate and underlying causes of death). 
8.5.2 Documenting in the eCRF 
The reported term should be a medical diagnosis or sign/symptom of the event, not a 
procedure. Each symptom in a constellation of symptoms should be listed separately if the 
Investigator has not made a preliminary/tentative summary diagnosis. 
Fluctuations or re-occurrences of a condition, which are considered normal for the patient 
and are recorded in patient’s eCRF medical history, do not need to be reported as an AE. 
However, if the condition deteriorates during the trial it needs to be captured as an AE. 
If the same AE occurs repeatedly it must be assessed and documented separately each time, 
if there are "AE-free" time periods between the AEs. 
If possible, each AE should be evaluated to determine: 
• event term or a description of the AE in medical terms (not as reported by the patient), 
• severity grade as assessed by the Investigator (1 - 5 per NCI CTCAE v5.0), 
• its causal relationship to study treatment as assessed by the Investigator (suspected; not 
suspected), 
• event duration, including onset date and end date, 
• action taken with study treatments due to the reported event (no action taken; interruption 
of administrations; treatment permanently withdrawn; other), 
• other action taken (no action taken; medication required; surgical intervention required; 
other), 
• event seriousness (non-serious or serious AE), 
• event outcome (resolved without sequelae, resolved with sequelae, not resolved, fatal, 
unknown), and 
• disease progression-related event (yes, no). 
8.5.3 Immediately reportable events - Serious Adverse Events 
The Investigator or designated investigational site staff must immediately (within 24 hours 
) notify/report to pharmacovigilance at the Sponsor,
 
ny initial or medically relevant follow-up information about SAEs, 
or pregnancies (see Section 8.2). 

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Follow-up information is to be sent within the same timelines using the same modes of 
reporting as outlined above. 
All sites will follow their institutional requirements for submission of SAEs to their 
IRBs/IECs. 
The processing and reporting of all relevant SAEs to authorities will be done by the Sponsor 
or Sponsor’s designee according to all applicable rules/regulations. The Sponsor or designee 
will inform all investigational sites about reported relevant events according to applicable 
regulations. 
8.5.3.1 Minimum notification/reporting requirements 
The following information must be provided for a valid notification/report: 
• identification of the notifying/reporting person (e.g. name of the reporter), 
• identification of the patient (e.g. patient trial identification number), 
• concerned IMP and/or clinical trial (e.g. EO2401, trial EOADR1-19), 
• reason for notification/reporting (i.e. SAE, or pregnancy), and 
• event term. 
In addition, providing the assessment of the causal relationship is necessary for 
comprehensive evaluation by the Sponsor. 
8.6 
Independent Data Monitoring Committee (IDMC) 
The IDMC will serve as an external monitoring 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 IDMC will examine the safety data of Cohort 1, including possible transitions 
between sub-cohorts (1a, 1b, 1c, and 1d) and provide advice and guidance in relation to the 
recruitment start of Cohort 2A/B and Cohort 3A/B. 

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The major tasks for the IDMC are outlined in relation to the description of the design of the 
trial (see Section 4.2). 
The frequency of IDMC meetings will be based on the development of the safety profile of 
the study treatments and necessity to assess safety events and progression steps in the trial 
(e.g. transitions between cohorts). 
In addition, in relation to the randomized extension of Cohort 2A, the IDMC will oversee 
and validate the interim first stage analysis of the Simon's two-stage design as performed by 
the Sponsor (or designee); see Section 9.4.2. 
The IDMC members are to be international oncology/immune-oncology experts who are not 
in other ways than via the IDMC involved in the current trial. The IDMC will be described 
in detail in an IDMC Charter. 

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Statistical assessments of correlations between e.g. immunogenicity parameters (see Section 
3.2.3, Section 7.8.4, and Section 7.9) and tumor progression/response and safety outcome 
parameters will be conducted as described in the SAP. 
For the initial study part (Cohorts 1, non-randomized 2A, 2B, 3A, and 3B) statistical tests 
may be planned in the SAP or performed as needed. The importance of the tests does not 
reside in making conclusions on statistical relevance of differences, but rather identification 
of possible results that could be worth further exploration. 
The randomized extension of Cohort 2A is from a statistical perspective described in Section 
9.4.2, and the statistical methods to be used will be further outlined in the SAP. 
The primary analysis of the study will be performed when the last patient included in the 
study will reach 6 months of study treatment; additional data will be generated: 
• when all patients will have stopped the study treatment and have been followed for 
safety 
. 
• when overall survival information will have been collected for all patients who 
received the study treatment or when the sponsor decides. 
 
9.3 
Interim analysis 
The nature of the study, i.e. early exploratory development trial aiming at generating as much 
knowledge as possible before potential decisions related to further development of EO2401, 
makes it important to assess especially safety, but also efficacy and possible biomarkers, on 
an ongoing basis during trial conduct. Exploratory preliminary data from the trial might be 
utilized in relation to e.g. scientific discussions and presentations to facilitate input regarding 
possible improvements of development parameters. 
Above is not applicable for efficacy analyses related to the randomized extension of Cohort 
2A, where information only will be utilized for scientific discussions/presentations at the 
timepoint of verification of passing (or not) to the second stage of the Simon-design, and at 
the final analysis of the Simon-design. 
9.4 
Determination of sample size 
9.4.1 Considerations regarding Cohorts 1, non-randomized 2A, 2B, 
3A, and 3B 
This is an early development, open-label, exploratory, multi-cohort trial to include patients 
with very rare malignant adrenal tumors; i.e. ACC and MPP (see Section 1.1.1 and Section 
1.1.2). In this context the sample size of the trial has been determined by practical 
considerations in collaboration with experts in the field, aiming at the possibility to recruit 
different patient populations to facilitate an as fast as possible, and broad (in relation to 
patient baseline characteristics), assessment of safety and tolerability, immunogenicity, and 
preliminary efficacy; also taking into account the assumption that for efficiency the 
recruitment time should not be longer than approximately 18 months with a reasonable 
number of highly specialized trial sites. Based on these factors, the trial was initially 
designed to include an initial safety lead-in, 3-by-3 design, cohort including 3 to 12 patients, 
followed by 4 cohorts, including distinct patient populations, to be recruited in parallel each 
enrolling 15 patients evaluable for safety (see Section 4.2 regarding adjusted patient 
numbers). 

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The 3-by-3 approach for Cohort 1 include predefined stopping rules if concerning safety 
events would be encountered; in short 0 (zero) concerning safety event in 3 patients, or 1 
concerning safety event in 6 patients, are considered acceptable (see further Section 4.2.1). 
The number of evaluable patients aimed at in Cohorts 2A, 2B, 3A, and 3B, i.e. 60 evaluable 
patients in total can in the context of adrenal malignancies be seen as a large dataset for 
safety assessments. 
9.4.2 Considerations regarding the randomized extension of Cohort 
2A 

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10 ADMINISTRATIVE CONSIDERATIONS 
10.1 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, and 
• applicable laws and regulations; approval will be obtained from the appropriate 
regulatory authorities before any site is initiated in a country. 
Before study start, each Site Principal Investigator is required to sign a protocol signature 
page confirming his agreement to conduct the study in accordance with these documents and 
all of the instructions and procedures found in this protocol and to give access to all relevant 
data and records to clinical research associates (CRAs), auditors, the Sponsors quality 
assurance representatives, designated agents of the Sponsor, ECs, and regulatory authorities 
as required. 
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, and 
• 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. 
A signed and dated statement that the protocol and ICF have been approved by the ECs must 
be given to the Sponsor (or designee) before study initiation. 
10.2 Finances and insurances 
Financing and insurance will be addressed in separate site agreements. 
For each participating patient, the Sponsor has taken out insurance covering the amount 
determined by respective national laws. All participating patients will be informed about the 
existence of the insurance in the patient informed consent. They have the right to review the 
terms and conditions of the insurance. 

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10.3 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 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. 
Following the stage 1 analysis results and the IDMC recommendations and considerations 
(please refer to section 1.3.7), the patients with currently ongoing treatment in the 
randomized Cohort 2A should be given the possibility to continue study treatment per 
protocol, provided they are informed about the outcome of the stage-1 assessment of the 
Cohort 2A-I Simon 2-stage design. Oral consent and written addendum to ICF will be 
collected as per applicable regulations. 
For patients who are unable to visit the site, and in accordance with applicable laws, 
the consent form may be sent to them by post. After sufficient time for reflection and 
a possible telephone call to clarify any question the patient may have with the 
investigator or delegate, they will be asked to return the signed and dated consent 
form by post to the investigator site. All correspondence as well as a copy of the 
consent form received from the patient, must be retained, and filed in the participant’s 
medical file. 
 
10.4 Future use of patient samples; sample traceability 
Following the completion of all study testing, the remaining tissue and blood/blood 
components may be used for future biomedical research (e.g. additional analysis on PBMC). 
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. 
Blood samples being collected and stored for research purposes within this study should be traceable 
as required by local regulations, or the clinical trial authorization, as applicable. The Sponsor and 
Investigator institutions should keep their parts of the traceability records accordingly. 

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10.5 Patient data protection 
Patients will be assigned a unique identifier and will not be identified by name in eCRFs 
(data pseudonymization), 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, and by inspectors from regulatory 
authorities. 
10.6 Site monitoring 
Before study initiation, at a site initiation visit or at an Investigator’s meeting, Sponsor 
personnel (or a designated contract research organization [CRO]) will review the protocol 
and eCRFs with the Investigators and their staff. During the study, the field monitor will 
visit the site regularly to check the completeness of patient records, the accuracy of filling 
of the eCRFs, the adherence to the protocol and to GCP, the progress of enrollment, and to 
ensure that the study drug is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits. 
The Investigator must maintain source documents for each patient in the study recruited at 
the relevant site, consisting of case and visit notes (hospital or clinic medical records) 
containing demographic and medical information, laboratory data, ECGs, and the results of 
any other tests or assessments. All information on eCRFs must be traceable to these source 
documents in the patient’s file. The Investigator must also keep the original ICF signed by 
the patient (a signed copy is given to the patient). 
The Investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the eCRF filling. The Sponsor monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion 
criteria, documentation of SAEs, and the recording of data that will be used for all primary 
and safety variables. Additional checks of the consistency of the source data with the eCRFs 
are performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the patients will be disclosed. 
10.7 Handling of data and data collection 
Data will be collected and processed in accordance with the General Data Protection Regulation (EU) 
2016/679 and other national legislations as applicable. 
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. 
At an organizational level, to meet European requirements, the sponsor has appointed a certified Data 
Protection Officer (DPO) in charge of ensuring compliance with data protection regulations. The 
DPO oversees the conduct of the required Data Protection Impact Assessment (DPIA) to assess and 
protect rights and freedoms of data subjects regarding processing operations. All data processors (e.g. 
sites and vendors) are bound by a data protection agreement (DPA). If personal data are transferred 

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to a third country within the meaning of the GDPR, the DPA contains the Standard Contractual 
Clauses established by the European Commission. The DPO is also in charge of any data subject 
request and can be contacted directly by the data subject through the email provided in the 
information sheet. 
At a technical level, personal data are stored in a secured environment, encrypted, and 
partitioned from other data. The Sponsor, or designee, will supply the investigational site 
with access to a web-based EDC computer system. The designated Investigator site staff will 
not be given access to the EDC system until they have been trained. 
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, and at the Sponsor (and CRO when 
applicable). 
Data will be entered into the study database by the Investigator/Study Coordinator at each 
site. 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. 
All data generated from external sources (e.g. central laboratory) 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. 
Automatic validation programs check for data discrepancies in the eCRFs and, by generating 
appropriate error messages, allow modification or verification of the entered data by the 
Investigator staff before transfer of data to the Sponsor (or a designated CRO). 
Sponsor personnel (or a designated CRO) will review the eCRFs entered by site staff for 
completeness and accuracy (verification against source documents) and instruct the site 
personnel to make any required corrections or additions. System or manually generated 
queries are raised to the investigational site using the study EDC system. Designated 
Investigator/site staff is required to respond to the queries and make any necessary changes 
to the data. 
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. 
At the conclusion of the study, the occurrence of any protocol deviations will be 
determined (guidance can be found in Section 12.4). 
After these actions have been completed and the database has been declared to be complete 
and accurate, it will be locked. 
After database lock, the Investigator will receive a CD-ROM of the patient data for archiving 
at the investigational site. 
A specific EDC tool will be used after the database lock planned at the last safety visit of the 
last treated patient, to collect the survival data of all patients who will be followed until 
death or until sponsor decides to stop the study. 

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Following the final safety visit of the last treated patient and the subsequent database lock, 
the sponsor will internally utilize an EDC tool compliant with 21 CFR Part 11 to collect 
survival data. Survival data will be transmitted directly from the investigational sites to the 
sponsor, who will then integrate these data into the EDC system. 
 
10.8 Collection and storage of biological samples 
The details on the collection and storage of biological samples can be found in the laboratory 
manual. 
10.9 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. 
10.10 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 non-compliance 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. 
All decisions regarding the type of deviations will be made prior to commencing the final 
analysis on the finally locked database. A listing of patients with protocol deviations will be 
maintained by the Sponsor (or designee) and a listing of protocol deviations (see Section 
12.4) will be presented in the final study report. 
Investigators shall apply due diligence to avoid protocol deviations. If the Investigator feels 
a protocol deviation would improve the conduct of the study, this must be considered a 
protocol amendment, and unless such an amendment is agreed upon by the Sponsor and 
approved by the EC and concerned regulatory authorities, it cannot be implemented. 
The Investigator will report protocol deviations to their IEC/IRB per institutional reporting 
requirements. 
 
10.11 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 another Investigator. The Sponsor or designee must be notified of and agree to the change. 
Regulatory agencies will be notified with the appropriate documentation. 
10.12 Clinical study report 
A clinical study report will be prepared following the primary analysis of the study. Addenda 
to this report will be prepared when new data will have been generated. The Global 

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Coordinating Investigator should if required by local law/regulations be the Investigator who 
should review and sign the study report. 
10.13 Confidentiality/disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during 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. 
10.14 Record 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 a relevant 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 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 Principal Investigator plans to leave the investigational site so that appropriate 
arrangements can be made. 
Archiving of the clinical trial master file 
Unless other law requires archiving for a longer period, the sponsor and the investigator shall 
archive the content of the clinical trial master file for at least 25 years after the end of the 
clinical trial. 
 
10.15 Publications 
If based on preliminary data, or on completion of the study, the data warrant 
publication/presentation according to a judgement by the Global Coordinating Investigator 
after collaborative discussions with other involved Investigators (meaning such Investigators 
who have recruited patients to the trial or have had a significant participation in the trial by 
other means), the results may be published/presented, under the auspice of the Global 
Coordinating Investigator, in a recognized scientific journal, or at a scientific conference, 
subject to the provisions of the following process: 
• no publication based on the results obtained at an individual trial site (or group of 
sites) shall be made before the first multicenter publication or presentation unless 
otherwise agreed in writing. Notwithstanding the foregoing, if a multicenter 
publication is not published within twelve (12) months after completion of the 
clinical trial and final lock of the clinical trial database at all research sites that are 
part of the multicenter clinical trial or any earlier termination or abandonment of the 
clinical trial, or if the Sponsor informs the Principal Investigator that such multicenter 
publication will not take place, or if publication has been agreed otherwise, the 
Principal Investigator shall have the right to publish or present the methods and 
results of the clinical trial, 

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• in case a publication/presentation is proposed the Global Coordinating Investigator 
shall discuss the proposed publication/presentation with the Sponsor, and give the 
Sponsor a relevant time (depending on the planned publication situation; e.g. referred 
journal, or scientific conference abstract, submission) to support with data collection 
and analyses which could be the basis for a publication, 
• the Sponsor should have adequate time for review of proposed abstracts, 
manuscripts, and/or other presentation materials before submissions (time is 
dependent on the planned publication situation; adequate time for review before 
submission of a complete manuscripts to a referred journals can be considered as 30 
days, to respond with any requested revisions, including the deletion of confidential 
information which must be done). 

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11 LITERATURE 

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12 APPENDICES 
12.1 Appendix 1: Criteria for measurement of tumor response and progression; 
RECIST and iRECIST 
Response and progression in this trial will be evaluated using the revised international 
criteria (1.1) proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
committee [36] as well as the modified iRECIST guidelines [37]. Investigators should 
especially note the different requirements for confirmatory scans as well as follow-up for the 
two criteria. 
RECIST 1.1 Response and Evaluation Endpoints 
Measurable Disease 
Measurable tumor lesions (nodal, subcutaneous, lung parenchyma, solid organ metastases) 
are defined as those that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as ≥20 mm with chest x-ray and as ≥10 mm with CT scan or clinical 
examination. Bone lesions are considered measurable only if assessed by CT scan and have 
an identifiable soft tissue component that meets these requirements (soft tissue component 
≥10 mm by CT scan). Malignant lymph nodes must be ≥15 mm in the short axis to be 
considered measurable; only the short axis will be measured and followed. All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Previously irradiated lesions are not considered measurable unless progression has been 
documented in the lesion. 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions are considered non-measurable 
disease. Bone lesions without a measurable soft tissue component, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast 
disease, lymphangitic involvement of lung or skin and abdominal masses followed by 
clinical examination are all non-measurable. Lesions in previously irradiated areas are non- 
measurable, unless progression has been demonstrated. 
Target Lesions 
When more than one measurable tumor lesion is present at baseline all lesions up to a 
maximum of 5 lesions total (and a maximum of 2 lesions per organ) representative of all 
involved organs should be identified as target lesions and will be recorded and measured at 
baseline. Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. Note that pathological nodes must meet 
the criterion of a short axis of ≥15 mm by CT scan and only the short axis of these nodes 
will contribute to the baseline sum. All other pathological nodes (those with short axis ≥10 
mm but <15 mm) should be considered non-target lesions. Nodes that have a short axis <10 
mm are considered non-pathological and should not be recorded or followed. At baseline, 
the sum of the target lesions (longest diameter of tumor lesions plus short axis of lymph 
nodes: overall maximum of 5) is to be recorded. 
After baseline, a value should be provided on the CRF for all identified target lesions for 
each assessment, even if very small. If extremely small and faint lesions cannot be accurately 
measured but are deemed to be present, a default value of 5 mm may be used. If lesions are 
too small to measure and indeed are believed to be absent, a default value of 0 mm may be 
used. 

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Non-target Lesions 
All non-measurable lesions (or sites of disease) plus any measurable lesions over and above 
those listed as target lesions are considered non-target lesions. Measurements are not 
required but these lesions should be noted at baseline and should be followed as “present” 
or “absent”. 
Response 
All patients will have their BEST RESPONSE from the start of study treatment until the end 
of treatment classified as outlined below: 
Complete Response (CR): disappearance of target and non-target lesions and normalization 
of tumor markers. Pathological lymph nodes must have short axis measures <10 mm (Note: 
continue to record the measurement even if <10 mm and considered CR). Residual lesions 
(other than nodes <10 mm) thought to be non-malignant should be further investigated (by 
cytology, specialized imaging, or other techniques as appropriate for individual cases) before 
CR can be accepted. Confirmation of response is only required in non-randomized studies. 
Partial Response (PR): at least a 30% decrease in the sum of measures (longest diameter for 
tumor lesions and short axis measure for nodes) of target lesions, taking as reference the 
baseline sum of diameters. Non target lesions must be non-PD. Confirmation of response is 
only required in non-randomized studies. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor sufficient increase 
to qualify for PD taking as reference the smallest sum of diameters on study. 
Progressive Disease (PD): at least a 20% increase in the sum of diameters of measured 
lesions taking as references the smallest sum of diameters recorded on study (including 
baseline) AND an absolute increase of ≥5 mm. Appearance of new lesions will also 
constitute progressive disease (including lesions in previously unassessed areas). In 
exceptional circumstances, unequivocal progression of non-target disease may be accepted 
as evidence of disease progression, where the overall tumor burden has increased sufficiently 
to merit discontinuation of treatment or where the tumor burden appears to have increased 
by at least 73% in volume. Modest increases in the size of one or more non-target lesions 
are NOT considered unequivocal progression. If the evidence of PD is equivocal (target or 
non-target), treatment may continue until the next assessment, but if confirmed, the earlier 
date must be used. 
 
Confirmatory measurement/duration of response 
Confirmation: In non-randomized trials where response is the primary endpoint, 
confirmation of PR and CR is required to ensure responses identified are not the result of 
measurement error. This will also permit appropriate interpretation of results in the context 
of historical data where response has traditionally required confirmation in such trials. 
However, in all other circumstances, i.e. in randomized trials (phase II or III) or studies 
where stable disease or progression are the primary endpoints, confirmation of response is 
not required since it will not add value to the interpretation of trial results. However, 
elimination of the requirement for response confirmation may increase the importance of 
central review to protect against bias, in particular in studies which are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after study entry 
at a minimum interval (in general not less than 6–8 weeks) that is defined in the study 
protocol. 

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Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are first met for CR/PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded on study). The duration of overall 
complete response is measured from the time measurement criteria are first met for CR until 
the first date that recurrent disease is objectively documented. 
Duration of stable disease: Stable disease is measured from the start of the treatment (in 
randomized trials, from date of randomization) until the criteria for progression are met, 
taking as reference the smallest sum on study (if the baseline sum is the smallest, this is the 
reference for calculation of PD). The clinical relevance of the duration of stable disease 
varies in different studies and diseases. If the proportion of patients achieving stable disease 
for a minimum period of time is an endpoint of importance in a particular trial, the protocol 
should specify the minimal time interval required between two measurements for 
determination of stable disease. Note: The duration of response and stable disease as well as 
the progression-free survival are influenced by the frequency of follow-up after baseline 
evaluation. It is not in the scope of this guideline to define a standard follow-up frequency. 
The frequency should take into account many parameters including disease types and stages, 
treatment periodicity and standard practice. However, these limitations of the precision of 
the measured endpoint should be taken into account if comparisons between trials are to be 
made. 

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Table 7 : Integration of target, non-target and new lesions into response assessment 
 
iRECIST Response Assessment 
Overall response will also be assessed using iRECIST. Immunotherapeutics may result in 
infiltration of immune cells leading to transient increase in the size in malignant lesions, or 
undetectable lesions becoming detectable. The criteria are identical to those of RECIST 1.1 
in many respects but have been adapted to account for instances where an increase in tumor 
burden, or the appearance of new lesions, does not reflect true tumor progression. 
Key differences are described below. All responses defined using iRECIST criteria are 
designated with a prefix. iRECIST time-point and best overall responses will be recorded 
separately. 
 
Confirming Progression 
Unlike RECIST 1.1, iRECIST requires the confirmation of progression and uses the terms 
iUPD (unconfirmed progression) and iCPD (confirmed progression). Confirmatory scans 
should be performed at least 4 weeks, but no longer than 8 weeks after iUPD. 

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In the context of confirmation of PD per iRECIST, and the timeline of confirmatory scans 
to be performed at least 4 weeks, but no longer than 8 weeks after iUPD, it should be 
specifically noted that in case of any signs of rapidly progressing disease establishment of 
PD and a following therapy switch should be made also earlier than 4-8 weeks after iUPD 
when necessary. 
iCPD is confirmed if further increase in tumor burden, compared to the last assessment, is 
seen as evidenced by one or more of the following: 
• 
Continued increase in tumor burden (from iUPD) where RECIST 1.1 definitions of 
progression had been met (from nadir) in target, non-target disease or new lesions 
o Progression in target disease worsens with an increase of at least 5 mm in the 
absolute value of the sum 
o Continued unequivocal progression in non-target disease with an increase in 
tumor burden 
o Increase in size of previously identified new lesion (s) (an increase of at least 5 
mm in the absolute value of the sum of those considered to be target new lesions) 
or additional new lesions. 
• 
RECIST 1.1 criteria are met in lesions types (target or non-target or new lesions) where 
progression was not previously identified, including the appearance of additional new 
lesions. 
If iUPD is not confirmed at the next assessment, then the appropriate response will be 
assigned (iUPD if the criteria are still met, but no worsening, or iSD, iPR or iCR if those 
criteria are met compared to baseline). As can be seen in Table 8 and Table 9, the prior 
documentation of iUPD does not preclude assigning iCR, iPR, or iSD in subsequent time- 
point assessments or as best overall response (BOR) providing that iCPD is not documented 
at the next assessment after iUPD. 
New lesions 
New lesions should be assessed and measured as they appear using RECIST 1.1 criteria 
(maximum of 5 lesions, no more than 2 per site, at least 10 mm in long axis (or 15 mm in 
short axis for nodal lesions), and recorded as New Lesions-Target (NLT) and New Lesion- 
Non-Target (NLNT) to allow clear differentiation from baseline target and non-target 
lesions. 
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD). 
However, the measurements of target lesions should NOT be included in the sum of 
measures of original target lesions identified at baseline. Rather, these measurements will be 
collected on a separate table in the case record form. 
PD is confirmed in the New Lesion category if the next imaging assessment, conducted at 
least 4 weeks (but not more than 8 weeks) after iUPD confirms further progression from 
iUPD with either an increase of at least 5 mm in the absolute value of the sum of NLT OR 
an increase (but not necessarily unequivocal increase) in the size of NLNT lesions OR the 
appearance of additional new lesions. 

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Table 8 : Time-point iRESPONSE 
 
All patients will have their iBOR from the start of study treatment until the end of treatment 
classified as outlined below. 

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Table 9 : iRECIST best overall response 
 
Response and Stable Disease Duration (RECIST 1.1 and iRECIST) 
Response duration will be measured from the time measurement criteria for CR/PR or 
iCR/iPR (whichever is first recorded) are first met until the first date that recurrent or 
progressive disease is objectively documented, taking as reference the smallest 
measurements recorded on study (including baseline). 
Stable disease duration will be measured from the time of start of treatment until the criteria 
for progression are met, taking as reference the smallest sum on study (including baseline). 
Methods of Measurement 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Assessments should be 
identified on a calendar schedule and should not be affected by delays in therapy. While on 
study, all lesions recorded at baseline should have their actual measurements recorded at 
each subsequent evaluation, even when very small (e.g. 2 mm). If it is the opinion of the 
radiologist that the lesion has likely disappeared, the measurement should be recorded as 0 
mm. If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned. For lesions which fragment/split add together the 
longest diameters of the fragmented portions; for lesions which coalesce, measure the 
maximal longest diameter for the “merged lesion”. 
Clinical Lesions 
Clinical lesions will only be considered measurable when they are superficial and ≥10 mm 
as assessed using calipers (e.g. skin nodules). For the case of skin lesions, documentation by 
color photography including a ruler to estimate the size of the lesion is recommended. If 
feasible, imaging is preferred. 
Chest X-ray 
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. 
However, lesions ≥20 mm on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
CT, MRI 
CT is the best currently available and reproducible method to measure lesions selected for 
response assessment. This guideline has defined measurability of lesions on CT scan based 

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on the assumption that CT slice thickness is 5 mm or less. When CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). Other 
specialized imaging or other techniques may also be appropriate for individual case.4 For 
example, while PET scans are not considered adequate to measure lesions, PET-CT scans 
may be used providing that the measures are obtained from the CT scan and the CT scan is 
of identical diagnostic quality to a diagnostic CT (with IV and oral contrast). 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT is advised. 
Endoscopy, Laparoscopy 
The utilization of these techniques for objective tumor evaluation is not advised. However, 
they can be useful to confirm complete pathological response when biopsies are obtained or 
to determine relapse in trials where recurrence following complete response or surgical 
resection is an endpoint. 
Tumor Markers 
Tumor markers alone cannot be used to assess objective tumor response. If markers are 
initially above the upper normal limit, however, they must normalize for a patient to be 
considered in complete response. 
Cytology, Histology 
These techniques can be used to differentiate between PR and CR in rare cases if required 
by protocol (for example, residual lesions in tumor types such as germ cell tumors, where 
known residual benign tumors can remain). When effusions are known to be a potential 
adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis inhibitors), 
the cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease 
is advised to differentiate between response or stable disease and progressive disease. 

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12.3 Appendix 3: New York Heart Association Functional Classification 
Table 11 : New York Hear 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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12.4 Appendix 4: Protocol deviations 
Notes: 
• the term "subject" has been switched to "patient" by the Sponsor in the below text, 
and 
• in trial EOADR1-19 the terminology only includes the word "Deviation", which is 
subdivided into "Major Deviations" (corresponding to the "Protocol Violation" term 
as defined by NIH below, when the definition for "Minor Deviation" is not fulfilled), 
and "Minor Deviations" (corresponding to "Minor Protocol Deviation" as defined 
by NIH below). 
 
http://www.genome.gov/Pages/Research/Intramural/IRB/Deviation_Violation_examples8- 
07.pdf 
National Institute of Health (NIH) Institutional Review Board Professional Administrators 
Committee Version 5.1 
Regulatory Process Workgroup 11/18/2005 
Protocol Deviations and Violations 
Protocol Deviation - A protocol deviation is any change, divergence, or departure from the 
study design or procedures of a research protocol that is under the Investigator’s control and 
that has not been approved by the EC. Upon discovery, the Principal Investigator is 
responsible for reporting protocol deviations to the EC using the standard reporting form. 
Any change, divergence, or departure from the study design or procedures of a research 
protocol that affects the patient's rights, safety, or well-being and/or the completeness, 
accuracy and reliability of the study data constitutes a protocol violation. 
Changes or alterations in the conduct of the trial which do not have a major impact on the 
patient's rights, safety or well-being, or the completeness, accuracy, and reliability of the 
study data are considered minor protocol deviations. 
Protocol Violation - A protocol violation is a deviation from the EC approved protocol that 
may affect the patient's rights, safety, or well-being and/or the completeness, accuracy and 
reliability of the study data. 
If the deviation meets any of the following criteria, it is considered a protocol violation. 
Example list is not exhaustive. 
I. The deviation has harmed or posed a significant or substantive risk of harm to the 
patient. 
Examples: 
• a patient received the wrong treatment or incorrect dose, 
• a patient met withdrawal criteria during the study but was not withdrawn, and 
• a patient received an excluded concomitant medication. 
 
II. The deviation compromises the scientific integrity of the data collected for the study. 
Examples: 

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• a patient was enrolled but does not meet the protocol's eligibility criteria, 
• failure to treat patient per protocol procedures that specifically relate to primary 
efficacy outcomes (if it involves patient safety it meets the first category above), 
• changing the protocol without prior EC approval, and 
• inadvertent loss of samples or data. 
III. The deviation is a willful or knowing breach of human patient protection 
regulations, policies, or procedures on the part of the Investigator(s). 
Examples: 
• failure to obtain informed consent before initiation of study-related procedures, 
• falsifying research or medical records, and 
• performing tests or procedures beyond the individual's professional scope or 
privilege status (credentialing). 
IV. The deviation involves a serious or continuing noncompliance with federal, state, 
local, or institutional human patient protection regulations, policies, or procedures. 
Examples: 
• working under an expired professional license or certification, 
• failure to follow federal and/or local regulations, and intramural research or clinical 
center policies, and 
• repeated minor deviations. 
V. The deviation is inconsistent with the NIH Human Research Protection Program’s 
research, medical, and ethical principles. 
Examples: 
• a breach of confidentiality, and 
• inadequate or improper informed consent procedure. 
Minor Protocol Deviation is any change, divergence, or departure from the study design or 
procedures of a research protocol that has not been approved by the EC and which DOES 
NOT have a major impact on the patient's rights, safety or well-being, or the completeness, 
accuracy and reliability of the study data. 

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12.5 Appendix 5: The CKD-EPI equation for estimating glomerular filtration rate [63] 
 

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12.7 Appendix 7: Management algorithms regarding nivolumab for studies under 
CTCAE version 5.0 
These general guidelines are standard nivolumab protocol safety algorithms (28-Sep- 
2020) and recommended for inclusion also in protocol EOADR1-19 by Bristol-Myers 
Squibb (marketing authorization holder for nivolumab). 
These general guidelines constitute guidance to the Investigator and may be supplemented 
by discussions with the Medical Monitor representing the Sponsor. The guidance applies to 
all immuno-oncology agents and regimens. 
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and 
appropriately treated. 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. 
The oral equivalent of the recommended IV doses may be considered for ambulatory patients 
with low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken 
into account when switching to the equivalent dose of oral corticosteroids. 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic 
or procedure, is recommended. 
The frequency and severity of the related adverse events covered by these algorithms will 
depend on the immuno-oncology agent or regimen being used. 

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