A First-in-human, Open-label Dose Escalation Followed by Dose Expansion Phase I/IIa Trial to Evaluate the Safety, Preliminary Efficacy and Pharmacokinetics of Intratumoral CyPep-1 Monotherapy and in Combination With Pembrolizumab in Patients With Advanced Solid Cancers.
Phase: PHASE1
Conditions: Advanced Solid Tumor Malignancy
Sponsor: Cytovation AS

Clinical Trial Protocol 
Sponsor: Cytovation
Version: 10.0
Trial Code: CyPep-1
Date: 30Jan2023
EudraCT: 2019-003317-33
Protocol prepared by:   
COVER PAGE
CONFIDENTIAL                                                                               CLINICAL TRIAL PROTOCOL
A first-in-human, open-label, dose escalation followed by dose expansion phase I/IIa trial to 
evaluate the safety, preliminary efficacy and pharmacokinetics of intratumoral CyPep-1
monotherapy and in combination with pembrolizumab in patients with advanced solid cancers.
Trial name:
CICILIA
Trial code:
CyPep-1
EudraCT number:
2019-003317-33
Trial development phase:
I/IIa
Investigational medicinal product:
CyPep-1 / pembrolizumab
Indication
Advanced solid cancers
Version:
10.0
Date:
30Jan2023
Document history: This version of the Clinical Trial Protocol includes:
V1 (23Sep2019) up to V9.0 (4Jul2022)
Sponsor Signatory:
, 
CONFIDENTIAL
This Clinical Trial Protocol contains privileged or confidential information, which is the property of Cytovation
ASA. Information may not be disclosed to a third party without written authorization from Cytovation ASA.
NCT number: 04260529

Clinical Trial Protocol 
Sponsor: Cytovation
Version: 10.0
Trial Code: CyPep-1
Date: 30Jan2023
EudraCT: 2019-003317-33
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SIGNATURES
Sponsor’s Agreement:
Title
A first-in-human, open-label, dose escalation followed by dose 
expansion phase I/IIa trial to evaluate the safety, preliminary 
efficacy and pharmacokinetics of intratumoral CyPep-1
monotherapy and in combination with pembrolizumab in 
patients with advanced solid cancers.
Trial Code
CyPep-1
Investigational Product
CyPep-1 / pembrolizumab
Version / Date
10.0 / 30Jan2023
Sponsor Representative 
Sponsor Address
Solheimsgaten 11
5058 Bergen
Norway
By signing below, the Sponsor approves the Protocol as outlined.
Cytovation ASA
,
Bergen, Norway
Signature and date:

Clinical Trial Protocol 
Sponsor: Cytovation
Version: 10.0
Trial Code: CyPep-1
Date: 30Jan2023
EudraCT: 2019-003317-33
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Investigator’s Agreement:
Title
A first-in-human, open-label, dose escalation followed by dose 
expansion phase I/IIa trial to evaluate the safety, preliminary 
efficacy and pharmacokinetics of intratumoral CyPep-1
monotherapy and in combination with pembrolizumab in 
patients with advanced solid cancers.
Trial code
CyPep-1
Investigational Product
CyPep-1 / pembrolizumab
Version / Date
10.0 / 30Jan2023
I have read this protocol and agree to conduct this study in accordance with all stipulations 
of the protocol and in accordance with all relevant local regulations, the current International 
Council
for
Harmonisation (ICH) of Technical Requirements for Registration of 
Pharmaceuticals for Human Use Guideline for Good Clinical Practice (GCP), and with the 
principles of the most recent version of the Declaration of Helsinki.
Investigator name
Signature
Date
Institution Name
Site #
City and State/Province
Country

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Version: 10.0
Trial Code: CyPep-1
Date: 30Jan2023
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CONTACT DETAILS
Cytovation ASA
CHIEF EXECUTIVE OFFICER
Solheimsgaten 11
5058 Bergen
Norway
PHARMACOVIGILANCE 
MANAGER
t
 
MEDICAL MONITOR
 
CRO PROJECT MANAGER
MEDICAL WRITER
 
Central laboratories
PK / CHEMOKINES / LOGISTICS

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Sponsor: Cytovation
Version: 10.0
Trial Code: CyPep-1
Date: 30Jan2023
EudraCT: 2019-003317-33
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PATHOLOGY AND IMMUNE CELL 
PHENOTYPING
TCR-CLONALITY

Clinical Trial Protocol 
Sponsor: Cytovation
Version: 10.0
Trial Code: CyPep-1
Date: 30Jan2023
EudraCT: 2019-003317-33
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TABLE OF CONTENTS
Section
Page
COVER PAGE .................................................................................................................... 1 
SIGNATURES..................................................................................................................... 2 
CONTACT DETAILS .......................................................................................................... 4 
TABLE OF CONTENTS...................................................................................................... 6 
LIST OF TABLES ............................................................................................................... 9 
LIST OF FIGURES.............................................................................................................. 9 
List of Abbreviations ............................................................................................. 10 
Definition of Terms ................................................................................................ 13 
PROTOCOL SYNOPSIS................................................................................................... 14 
SCHEDULE OF ASSESSMENTS .................................................................................... 37 
1. 
INTRODUCTION...................................................................................................... 48 
1.1 
Name and Description of Investigational Medical Product and of 
Pembrolizumab ............................................................................................. 48 
1.2 
CyPep-1 for Treatment of Advanced Solid Cancers.................................. 48 
1.2.1 
Background .................................................................................. 48 
1.2.2 
Clinical Rationale ......................................................................... 48 
1.2.3 
Treatment with CyPep-1............................................................... 49 
1.3 
Pharmaceutical and Therapeutic Background of Pembrolizumab .......... 50 
1.4 
Population to be Studied ............................................................................. 50 
1.5 
Non-Clinical Data of CyPep-1 ...................................................................... 50 
1.6 
Clinical Data of CyPep-1 .............................................................................. 52 
1.6.1 
Safety and Efficacy of CyPep-1.................................................... 52 
1.7 
Pre-clinical and Clinical Trials with Pembrolizumab................................. 53 
1.8 
Justification for Pembrolizumab Dose ....................................................... 53 
1.9 
Potential Risks and Benefits ....................................................................... 54 
1.9.1 
Risks ............................................................................................ 54 
1.9.2 
Benefits ........................................................................................ 55 
1.9.3 
Management of Risks................................................................... 55 
1.9.4 
Benefit/Risk Ratio......................................................................... 56 
2. 
TRIAL OBJECTIVES AND ENDPOINTS................................................................ 57 
2.1 
Objectives...................................................................................................... 57 
2.1.1 
Primary Objectives ....................................................................... 57 
2.1.2 
Secondary Objectives .................................................................. 57 
2.1.3 
Exploratory Objectives ................................................................. 57 
2.2 
Endpoints ...................................................................................................... 57 
2.2.1 
Primary Endpoints........................................................................ 57 
2.2.2 
Secondary Endpoints ................................................................... 58 
2.2.3 
Exploratory Endpoints .................................................................. 58 
3. 
TRIAL DESIGN........................................................................................................ 59 
3.1 
Overall Trial Design ...................................................................................... 59 
3.1.1 
Dose Escalation Committee......................................................... 62 
3.1.2 
Dose Limiting Toxicities / Treatment Limiting Toxicities............... 63 
3.2 
Measures to Minimize Bias .......................................................................... 64 
3.3 
Duration of Subject Participation................................................................ 64 
3.4 
Trial Stopping Rules..................................................................................... 64 
3.5 
End of Trial.................................................................................................... 65 
4. 
SELECTION OF TRIAL POPULATION .................................................................. 66 
4.1 
Inclusion Criteria .......................................................................................... 66 
4.2 
Exclusion Criteria ......................................................................................... 69 
4.3 
Withdrawal, Discontinuation, and Replacement of Subjects ................... 72 
4.3.1 
Withdrawal and Discontinuation................................................... 72 

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4.3.2 
Replacement of Subjects ............................................................. 73 
5. 
TRIAL TREATMENT ............................................................................................... 75 
5.1 
Manufacturing and Labelling of Investigational Medical Product............ 75 
5.1.1 
Identity.......................................................................................... 75 
5.1.2 
Packaging and Labelling .............................................................. 75 
5.2 
Instructions for Use, Handling, and Storage.............................................. 75 
5.3 
Treatment Regimen ...................................................................................... 75 
5.3.1 
Administration of IMP (CyPep-1).................................................. 76 
5.3.1.1 
CyPep-1 Dose Levels................................................................... 76 
5.3.1.2 
CyPep-1 Injection Volume............................................................ 76 
5.3.1.3 
Sequence of CyPep-1 Administration for Phase IIa Arm D Only . 77 
5.3.2 
Administration of Pembrolizumab................................................. 78 
5.3.3 
Meals and Dietary Restrictions..................................................... 78 
5.3.4 
Selection of CyPep-1 Doses in the Trial....................................... 79 
5.3.5 
Duration of the Treatment Regimen............................................. 80 
5.3.6 
Dose Modification......................................................................... 80 
5.3.6.1 
Dose Modifications and Management of CyPep-1 associated AEs
..................................................................................................... 80 
5.3.6.2 
Dose modification and toxicity management for immune-related 
AEs associated with pembrolizumab............................................ 81 
5.3.6.3 
Dose modification and toxicity management of infusion-reactions 
related to pembrolizumab............................................................. 83 
5.3.7 
Other allowed dose interruption for pembrolizumab..................... 85 
5.3.8 
Blinding ........................................................................................ 85 
5.4 
Method of Assigning Subjects to Treatment.............................................. 85 
5.5 
End of Treatment .......................................................................................... 85 
5.6 
Prior and Concomitant Medication and Therapy....................................... 85 
5.6.1 
Permitted Medication and Other Treatments ............................... 85 
5.6.2 
Prohibited Medication and Other Treatments............................... 86 
5.6.3 
Rescue Medications & Supportive Care....................................... 87 
5.7 
Treatment Compliance ................................................................................. 87 
5.8 
Pregnancy and Contraception..................................................................... 88 
5.8.1 
Use in Nursing Women ................................................................ 89 
5.9 
Post-trial Treatment...................................................................................... 89 
5.9.1 
Continued Access pembrolizumab............................................... 89 
5.10 Accountability Procedures .......................................................................... 89 
6. 
INVESTIGATIONAL PLAN...................................................................................... 90 
6.1 
Assessment Overview.................................................................................. 90 
6.2 
Trial Assessment Specifications................................................................. 93 
7. 
ADVERSE EVENTS .............................................................................................. 101 
7.1 
Definitions ................................................................................................... 101 
7.1.1 
Adverse Event (AE).................................................................... 101 
7.1.2 
Treatment-Emergent Adverse Event (TEAE)............................. 101 
7.1.3 
Adverse Drug Reaction (ADR) ................................................... 101 
7.1.3.1 
Tumor lysis syndrome (TLS) ...................................................... 101 
7.1.4 
Unexpected Adverse Drug Reaction.......................................... 102 
7.1.5 
Serious Adverse Event (SAE) .................................................... 102 
7.1.6 
Suspected Unexpected Serious Adverse Reaction (SUSAR).... 102 
7.1.7 
Toxic Death ................................................................................ 102 
7.1.8 
Pregnancy .................................................................................. 102 
7.2 
Monitoring, Reporting, and Documentation of Adverse Events (AEs).. 103 
7.2.1 
Monitoring of AEs....................................................................... 103 
7.2.1.1 
Events of Clinical Interest (Arm B) ............................................. 103 
7.2.1.2 
Treatment of Overdose (Arm B)................................................. 104 

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7.2.1.3 
Time Period and Frequency for Collecting AE, SAE and Other 
Reportable Safety Event Information (Arm B)............................ 104 
7.2.2 
Documentation of AEs................................................................ 104 
7.2.2.1 
Severity of AEs........................................................................... 105 
7.2.2.2 
Relationship to Trial Treatment .................................................. 105 
7.2.3 
Reporting of SAEs...................................................................... 106 
7.2.4 
SUSARs ..................................................................................... 106 
7.2.5 
Pharmacovigilance Contact for Reporting SAEs........................ 107 
8. 
STATISTICAL METHODS..................................................................................... 108 
8.1 
Statistical Analytical Plan .......................................................................... 108 
8.1.1 
Data Sets to be Analyzed........................................................... 108 
8.1.2 
Summary Statistics..................................................................... 108 
8.1.3 
Adverse Events .......................................................................... 108 
8.1.4 
Efficacy Analyses ....................................................................... 109 
8.1.5 
Pharmacokinetic Analysis (PK) .................................................. 109 
8.1.6 
Immunological Analysis.............................................................. 109 
8.1.7 
Concomitant Treatment.............................................................. 110 
8.1.8 
Exploratory Analyses.................................................................. 110 
8.2 
Determination of Sample Size ................................................................... 110 
8.3 
Disposition, Demographic and Other Baseline Characteristics............. 112 
8.4 
Procedures for Reporting any Deviation(s) from the Original Statistical 
Analysis Plan .............................................................................................. 112 
8.5 
Exposure to Treatment............................................................................... 112 
8.6 
Safety Analysis for Dose Selection........................................................... 112 
8.7 
Follow-up Analysis of Post-Trial Survival Data ....................................... 112 
9. 
DATA MANAGEMENT AND MONITORING......................................................... 113 
9.1 
Data Collection, Validation, and Handling................................................ 113 
9.2 
Data Review................................................................................................. 113 
9.3 
Medical Coding ........................................................................................... 114 
9.4 
Health Economics Data Collection ........................................................... 114 
10. 
ADMINISTRATIVE ASPECTS............................................................................... 115 
10.1 Quality Control and Quality Assurance.................................................... 115 
10.2 Maintenance of Subject Records .............................................................. 115 
10.3 Investigator Site File (ISF).......................................................................... 115 
10.4 Handling of Investigational Product(s)..................................................... 116 
10.5 Drug Accountability.................................................................................... 116 
10.6 Procedures for Protocol Amendments..................................................... 116 
10.7 Protocol Deviations.................................................................................... 116 
10.8 Clinical Trial Report.................................................................................... 117 
11. 
ETHICAL AND LEGAL CONSIDERATIONS........................................................ 118 
11.1 Competent Authority / Independent Ethics Committees ........................ 118 
11.2 Site Review.................................................................................................. 118 
11.3 Informed Consent....................................................................................... 118 
11.4 Trial Discontinuation and Closure ............................................................ 119 
11.5 Confidentiality............................................................................................. 119 
11.6 Financing and Insurance ........................................................................... 120 
11.7 Statement of Compliance........................................................................... 120 
11.8 Publication Policy....................................................................................... 120 
11.9 Conflict of Interest Policy .......................................................................... 121 
12. 
REFERENCE LIST ................................................................................................ 122 
13. 
APPENDICES........................................................................................................ 125 
Appendix A: List of Non-clinical Studies Mentioned in the Protocol.............. 125 
Appendix B: Eastern Cooperative Oncology Group Performance Status 
Scoring (Oken MM et al, 1982)................................................................... 126 

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Trial Code: CyPep-1
Date: 30Jan2023
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Appendix C: Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 ................................................................................................... 127 
Appendix D: Description of the iRECIST Process for Assessment of Disease 
Progression................................................................................................. 128 
Appendix E: Medication for Hypersensitivity Type Reactions Anticipated to be
Possibly Occurring Due to CyPep-1 Administration............................... 131 
Appendix F: High-level Summary of itRECIST and the Comparison of itRECIST 
with iRECIST ............................................................................................... 132 
LIST OF TABLES
Table 1. Schedule of Assessments........................................................................................37 
Table 1a. Schedule of Assessments Phase I Dose Escalation and Phase IIa Arms A and 
C for Cycle 1 (CyPep-1 Monotherapy).................................................................37 
Table 1b. Schedule of Assessments Phase I Dose Escalation and Phase IIa Arms A and 
C (Starting Cycle 2 and all subsequent cycles monotherapy) 24..........................39 
Table 1c. Schedule of Assessments Phase IIa Arm B (Cycle 1 CyPep-1 plus 
pembrolizumab combination)...............................................................................40 
Table 1d. Schedule of Assessments Phase IIa Arm B (Starting Cycle 2 and all 
subsequent cycles of CyPep-1 plus pembrolizumab combination)24...................42 
Table 1e. Schedule of Assessments Phase IIa Arm D (CyPep-1 Monotherapy) ...................43 
Table 2. Trial Interventions.....................................................................................................75 
Table 3.  Dose Modification and Toxicity Management Guidelines for Immune-related 
AEs Associated with Pembrolizumab ..................................................................81 
Table 4.  Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines...84 
Table 5.  Overview of Assessments.......................................................................................90 
LIST OF FIGURES
Figure 1. Mode of action of CyPep-1......................................................................................49 
Figure 2. Schematic trial design ............................................................................................59 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
List of Abbreviations 
ADR
Adverse drug reaction
AE
Adverse event
ALAT
Alanine transaminase
ANC
Absolute neutrophil count
APTT
Activated partial thromboplastin time
ART
Anti-retroviral therapy 
ASAT
Aspartate transaminase
ATC
Anatomical Therapeutic Chemical
AUC
Area under the curve
BE
Belgium
BRAF
B-Raf gene
CA
Competent Authority
Cavg
Average concentration over the dosing interval
CD3 zeta
CD
Cluster of differentiation
CL
Clearance
Cmax
Maximum plasma concentration
Cmin
Minimum plasma concentration
cm
Centimetre
CNS
Central nervous system
CR
Complete response
CT
Computerized tomography
CrCl
Creatinine clearance
CRA
Clinical Research Associate
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
Cytotoxic T-lymphocyte-associated protein 4
CV
Curriculum vitae
DCF
Data Clarification Form
DEC
Dose Escalation Committee
DLT
Dose-limiting toxicity
ECG
Electrocardiogram
ECI
Events of Clinical Interest
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic Data Capture
EEA
European Economic Area
E-R
Exposure-response
EU
European Union
GCP
Good Clinical Practice
GDPR
General Data Protection Regulation
GFR
Glomerular filtration rate
GLP
Good Laboratory Practice

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HIV
Human immunodeficiency virus
HPV
Human papillomavirus
IB
Investigator Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
ICI
Immune checkpoint inhibitor
IEC
Independent Evaluation Committee
Ig
Immunoglobulin
IgG4
Immunoglobulin G4
IMP
Investigational Medicinal Product
IMPD
Investigational Medicinal Product Dossier
iRECIST
Immune Response Evaluation Criteria in Solid Tumors
ISF
Investigator site file
IT
Intratumoral
itRECIST
Intratumoral Response Evaluation Criteria in Solid Tumors
IV
Intravenous 
ITT
Intention to treat set
LAG-3
Lymphocyte activation gene-3
LLT
Lowest level term
mAb
Monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
MTD
Maximum tolerated dose
NCI
National Cancer Institute
NL
Netherlands
NSCLC
Non-small cell lung cancer
NT-I
Non-Target-Injected
NT-NI
Non-Target-Non-Injected
ORR
Objective response rate
OS
Overall survival
PD
Progressive disease/ Disease progression
PD-1
Programmed cell death protein 1
PD-L1 programmed death ligand 1
Programmed death ligand 1
PFS
Progression-free survival
PK
Pharmacokinetic
Protein kinase-C theta
PR
Partial Response 
pRBC
Packed red blood cell
PT-INR
Prothrombin time – international normalized ratio
QW
Once weekly
Q2W
Every 2 weeks
Q6W
Every 6 weeks
Q8W
Every 8 weeks
RBC
Red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
Recommended Phase 2 Dose

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SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical Analysis Plan
SCLC
Small cell lung cancer
SD
Stable Disease
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SITC
Society for Immunotherapy of Cancer
SmPC
Summary of Product Characteristics
SoA
Schedule of assessments
SoC
Standard of Care
SOC
System Organ Class
SOP
Standard Operating Procedure
t1/2
Half-life
TCR
T cell receptor
T-I
Target-Injected
TLT
Treatment limiting toxicity
tmax
Time to reach Cmax
T-NI
Target-Non-Injected
Treg
Regulatory T cell
ULN
Upper limit of normal
US
Ultrasound
VD
Volume of distribution
WBC
White blood cell
WHO
World Health Organization
WOCBP
Woman of childbearing potential
ZAP70
Zeta-chain-associated protein kinase

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Definition of Terms 
Term
Definition
Competent Authority 
(CA)
A government body or government appointed body that has legal authority 
to approve or disapprove clinical studies.
Dose Limiting Toxicity 
(DLT)
DLTs are defined taking into account available toxicity and safety data for 
CyPep-1 and will be assessed during Phase I of the trial. 
Treatment Limiting 
Toxicity (TLT)
TLTs are defined taking into account available toxicity and safety data for 
CyPep-1 as assessed during Phase IIa of the trial and for pembrolizumab 
based on IBs.
Lost to Follow-up
Subjects who fail to return for two consecutive scheduled visits and cannot 
be contacted by the trial site staff.

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PROTOCOL SYNOPSIS
Name of the Sponsor/Company:
Cytovation
Trial Code: 
CyPep-1
Name 
of 
Investigational 
Medicinal 
Product:
CyPep-1 / pembrolizumab
EudraCT No.: 
2019-003317-33
Development Phase of the Trial:
Phase I/IIa
Trial under an IND: 
IND No.: NA
TITLE OF THE TRIAL:
“A first-in-human, open-label dose escalation followed by dose expansion phase I/IIa trial to 
evaluate the safety, preliminary efficacy and pharmacokinetics of intratumoral CyPep-1
monotherapy and in combination with pembrolizumab in patients with advanced solid 
cancers.”
NUMBER OF TRIAL CENTERS:
Approximately 14 sites in 3 countries.
NAME AND DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCT:
CyPep-1 is a synthetic linear 27-amino acid peptide with an acetylated amino group at the 
N-terminus and an amido group at the C-terminus. All optically active amino acid residues 
are in D-configuration with the exception of achiral glycine. 
CyPep-1 is formulated in a clear and colorless aqueous solution (5 mg/mL).
TRIAL BACKGROUND:
CyPep-1 has been shown to selectively target tumor cell membranes based on their altered 
molecular composition, which in turn leads to lysis of tumor cells by removal of the cell 
membrane. 
Figure 1. Mode of action of CyPep-1.
This mode of action of CyPep-1 induces tumor cell death resulting in the release of tumor 
antigens, and potentially induces a tumor-specific immune response by in-situ immunization
(Figure 1). 

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Preclinical toxicology studies have shown a favorable safety profile and potent anti-tumor 
activity of CyPep-1 in several tumor models. CyPep-1 was shown to modulate the tumor 
microenvironment by increasing the presence of CD8+ T-cells and by potentiating the effects 
of immune checkpoint inhibitors (ICIs; please see Investigator Brochure). As such, we 
hypothesize that intratumoral (IT) injection with CyPep-1 leads to transformation of 
immunological “cold” and ICI treatment-resistant tumors into “hot” and immunological active 
tumors that can be successfully treated with immune-modulating agents.
TRIAL RATIONALE:
Treatment with ICIs has been shown to result in long lasting anti-tumor responses in 
selective patients with different tumor indications. However, only a subset of these patients 
obtains durable remission. Studies have indicated the presence of intratumoral CD8+ T-cells 
to be a positive predictive factor for response to ICI therapy. Thus, treatment strategies that 
aim at recruiting tumor antagonizing cellular components of the immune system hold great 
promise and are currently a main focus in oncology research.
Current evidence revealed an association between tumor mutational burden and tumor 
immunogenicity. In order to proliferate, antigenic tumors develop mechanisms that enable 
them to evade immune-mediated destruction through a process termed immunoediting. 
However, while mutational load represents a predictive factor for ICI response, its predictive 
power seems modest; rather, ICI efficacy may be associated with the presence of specific 
neoantigen-generating mutations. This observation suggests that a qualitative neoantigen-
directed immunotherapy holds great potential. New therapeutic modalities in this category 
should ideally meet two critical criteria: 1) exposing tumor specific antigens, and 2) inducing 
an inflamed tumor microenvironment. Furthermore, the capacity of such therapeutic 
modalities may result in an extended patient population of responders and potentially 
increase the overall efficacy of ICIs.
Conceptually, clinical proof-of-concept of this strategy has been established by lytic viruses, 
and preliminary evidence indicates that oncolytic treatment can induce systemic anti-tumoral 
responses. We envision that CyPep-1, due to its unique antigen-exposing properties, could 
be a potent and less toxic oncolytic therapy option. In addition, CyPep-1 offers attractive 
pharmacological properties such as long shelf life, easy scalability and negligible batch-to-
batch variations. As such, CyPep-1 may represent a unique “tumor-agnostic” compound,
boosting the effect of established immunotherapy across multiple tumor types. Lastly, 
preclinical studies showing that CyPep-1 can synergize with anti-PD-1 antibody treatment in 
terms of decreased tumor volumes and prolonged survival highlight the possible clinical 
utility of CyPep-1 in the combination setting with ICIs
This Phase I/IIa trial is designed to assess the safety, tolerability, pharmacokinetics, and 
pharmacodynamics of CyPep-1 when administered directly into malignant tumors, in 
monotherapy and in combination with anti-PD-1 antibody pembrolizumab. Additionally, we 
will monitor antitumor effects on injected lesions and distant non-injected deposits. As part 
of the exploratory analysis, it is planned to determine local and systemic immunological 
effects after CyPep-1 administration, alone and in combination with anti-PD-1.
TRIAL POPULATION:
Phase I (dose escalation) and Phase IIa CICILIA:
Histologically or cytologically confirmed locally advanced (unresectable) or metastatic 
tumors (solid tumors or lymphoma) with an accessible tumor lesion for intratumoral injection 
of CyPep-1 that meet one of the following criteria:
a. Relapsed following or progressed through standard therapy.
b. Have a disease for which no standard effective therapy exists.

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NUMBER OF SUBJECTS:
The sample size is determined by clinical rather than statistical considerations.
The number of subjects in Phase I (dose escalation) will depend on the number of dose 
levels tested before a Dose Limiting Toxicity (DLT) is observed and the Maximum Tolerated 
Dose (MTD) is determined. It is anticipated that 12 subjects will be included in this phase of 
the trial.
It is planned that 9 subjects will be enrolled in Phase IIa (dose expansion of CyPep-1
monotherapy, Arm A) of the trial. The number of subjects may be expanded to 18 for a total 
of 24 subjects evaluable at RP2D, in case in the first 12 subjects at RP2D, a responder per 
iRECIST is observed or 2 subjects with stable disease per iRECIST are observed.
For Arm B, CyPep-1 at RP2D plus pembrolizumab, a total of 15 subjects is planned to be 
enrolled.
For Arm C, a total of 9 subjects is planned to be enrolled to evaluate at least two dose levels 
of CyPep-1 based on results of Phase I.
For Arm D, a total of approximately 30 subjects are planned to be enrolled.
OBJECTIVES:
The primary objectives are:
To evaluate the safety and tolerability of IT administration of CyPep-1, as 
monotherapy and in combination with pembrolizumab.
To identify the recommended phase II dose (RP2D) of CyPep-1, as monotherapy 
and in combination with pembrolizumab.
The secondary objectives are:
To assess the preliminary anti-tumor efficacy of CyPep-1, as monotherapy and in 
combination with pembrolizumab.
To characterize the pharmacokinetics (PK) of CyPep-1.
The additional exploratory objectives are:
To assess the preliminary anti-tumor efficacy of CyPep-1, as monotherapy and in 
combination with pembrolizumab, in injected lesions and non-injected lesions,
separately.
To assess survival after treatment with CyPep-1, as monotherapy and in combination 
with pembrolizumab.
To assess the immune modulating properties of treatment with CyPep-1, as 
monotherapy and in combination with pembrolizumab.
TRIAL ENDPOINTS: 
Primary endpoints:
Type and number of adverse events (AEs) according to National Cancer Institute 
(NCI) – Common Terminology Criteria for Adverse Events (CTCAE) criteria v5.0, 
and additional safety parameters of CyPep-1 as monotherapy and in combination 
with pembrolizumab. 
Dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD) for 
determination of RP2D of CyPep-1 as monotherapy and treatment-limiting toxicities 
(TLTs) of CyPep-1 in combination with pembrolizumab.

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Secondary endpoints:
Objective response rate (ORR), defined by complete and partial responses, 
according to immune Response Evaluation Criteria in Solid Tumors (iRECIST)
based on investigator’s assessment.
Time to and duration of response and duration of stable disease.
The plasma concentration time profile of CyPep-1 and, if detectable, the derived PK 
parameters (i.e., area under the curve [AUC], peak plasma concentration [Cmax], time 
to reach Cmax [tmax], systemic clearance (CL), elimination half-life (t1/2) and volume of 
distribution [VD]).
Exploratory endpoints:
For all Phase IIa arms: ORR in injected lesions and non-injected lesions, separately,
per itRECIST* [Goldmacher 2020]). 
Progression-free survival (PFS) per iRECIST based on investigator’s assessment.
Overall survival (OS).
The relative change in number of tumor infiltrating CD8+ T-cells in the injected and, 
whenever available, non-injected tumor biopsies.
The association between the relative change in tumor infiltrating CD8+ T-cells and 
response rate in the injected lesions (per itRECIST) and all lesions (per iRECIST).
The change in T-cell receptor (TCR) clonality levels in peripheral blood and (when 
available) biopsied lesions.
Changes in the tumor microenvironment (injected and, whenever available, 
non-injected tumor biopsies) via expression of selected candidate immune markers: 
 
 
 
For Arms A, B, and C: 
 
-
Peripheral blood phenotyping of selected immune cell markers.
*itRECIST will be programatically calculated using data
obtained from iRECIST
assessments following the itRECIST principle summarized in Appendix F Figure 1.
OVERALL TRIAL DESIGN: 
This is a combined Phase I/IIa, open-label, dose escalation followed by dose expansion 
trial in subjects with advanced solid cancers. The trial consists of two phases and multiple 
arms, as shown in the diagram below (Figure 2). 

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Figure 2. Schematic trial design 
Phase I (dose escalation, N=12) and Phase IIa (dose expansion Arm A, N=9 up to 18; 
combination Arm B, N=15; dose expansion liver metastases Arm C, N=9; dose expansion 
melanoma Arm D, N=30).
Abbreviations: RP2D: recommended phase 2 dose.
Phase I – dose escalation:
In this phase of the trial, safety and tolerability will be documented and the MTD/RP2D will 
be determined. Cohorts of 3 subjects will receive IT injections with CyPep-1. The DLT 
observation period for each dose level will be 6 weeks (5 weeks of trial treatment and 1 week 
of safety follow-up).
Screening will occur during the 4 weeks prior to start of CyPep-1 treatment.
In three dose cohorts of 3 subjects each, subjects will receive CyPep-1 IT at different 
concentrations (dose escalation) and volumes (depending on tumor size), i.e., 0.5 mg/mL, 2 
mg/mL, or 5 mg/mL, respectively. These dose concentrations have been selected based on 
previous pre-clinical experience with CyPep-1.
Each subject will receive IT injection(s) with CyPep-1 on Day 1 of Weeks 1, 3, and 5, 
respectively. After each CyPep-1 administration, subjects will be required to stay at the clinic 
for at least 4 hours for safety and, for those in which PK will be assessed, also for PK
monitoring. The data from the additional three subjects in cohort 3 will be used for further 
confirmation of RP2D. The following CyPep-1 administrations are planned as continuous 
Q2W administrations. 
For each dose cohort, at least 24 hours must elapse between each subject to start treatment
with CyPep-1. No intra-subject dose escalation is allowed.
The decisions on dose escalation and MTD will be taken by the Dose Escalation Committee 
(DEC) after reviewing safety data (including DLTs) from all subjects who have entered the 

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previous dose cohort and have completed the DLT observation period. The DEC is 
comprised of all the investigators or designees, as well as the medical monitor and 
representatives of the sponsor.
In Phase I, subject replacement for subjects who drop out for any reason, except DLTs, will 
only occur before the DLT observation period is completed and is allowed if a subject does 
not receive all three CyPep-1 administrations, unless due to CyPep-1-related toxicity. No 
subject replacement will occur for subjects who withdraw later.
After completion of Phase I, all results will be evaluated by the DEC. This will include safety 
data and if available, other supportive clinical data (i.e., efficacy, pharmacokinetics, tumor 
biopsy analyses) from all subjects included in Phase I of the trial. The DEC will confirm the 
MTD or RP2D (in case the MTD is not reached).
All additional arms can start once Phase I data has been evaluated by the DEC and an
RP2D is determined for CyPep-1.
Phase I has been completed in August 2021 and the RP2D of CyPep-1 was determined at 
5 mg/mL.
Phase IIa – dose expansion (Arm A):
In this phase, safety and tolerability will be further evaluated in an expanded cohort of 
9 subjects at the RP2D of CyPep-1, determined in Phase I. Screening- and treatment-
schedules will be the same as in Phase I, except for the 24-h observation period before start
of treatment of the next subject, which is not applicable.
At the RP2D, in case of a responder per iRECIST or of 2 subjects with stable disease per 
iRECIST, the number of subjects will be expanded to a total of 18 (to evaluate overall data 
from a total of 24 subjects treated at RP2D for CyPep-1 monotherapy taking the 6 subjects 
from cohort 3 into account).
Replacement of subjects in the Phase IIa expansion monotherapy arms is not planned.
Phase IIa – combination arm (Arm B):
The safety and tolerability of CyPep-1 in combination with pembrolizumab will be evaluated 
in a cohort of 15 subjects in total, using a staggered approach. Initially, 3 subjects will receive 
CyPep-1 at RP2D in combination with pembrolizumab Q6W and each subject will be 
observed for 24 h before the next subject can be administered with CyPep-1. After the first 
3 subjects completed the TLT observation period of 6 weeks with no TLTs observed and 
after reviewing the safety data (including TLTs) by the DEC, the inclusion of all remaining 
subjects at RP2D of CyPep-1 in combination with pembrolizumab can be initiated. In the
absence of any TLTs in the initial 3 subjects, the 24-h observation period before start of 
treatment of the next subject is no longer applicable. Should any TLTs be observed in the 
first 3 subjects at the RP2D of CyPep-1 in combination with pembrolizumab, an additional 3 
subjects in this dose group will be included. If 1 out of 6 subjects have a TLT, the remainder 
of the 15 subjects will be treated at the RP2D. In the unlikely case that 2 or more of the 6
subjects experience any TLTs at RP2D of CyPep-1, a recommendation to dose de-escalate 
CyPep-1 and to what dose or to continue the combination part of the trial will be made by 
the DEC. The same screening schedule is planned and CyPep-1 will be administered 
according to the same treatment schedule as in Phase I.
For arm B, replacement of the first three subjects is allowed if a subject drops out for any 
reason, and does not receive all three CyPep-1 injections during the TLT observation period,
unless due to CyPep-1- and/or pembrolizumab-related toxicity. No subject replacement will 
occur for subjects who discontinue later.

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Phase IIa – dose expansion liver metastases (Arm C):
The safety and tolerability of at least two dose levels of CyPep-1, the RP2D and the dose 
immediately below that, are planned to be evaluated when CyPep-1 is administered 
intratumorally using ultrasound guidance to one metastatic lesion in the liver. The two dose 
levels are planned to be investigated adhering to the “3+3” design and will follow the 
procedures as described for the dose escalation (Phase I) (Section 3.1). The first three 
subjects will receive CyPep-1 at the lower dose level and each subject will be observed for 
24 h before CyPep-1 administration to a next subject (cohort 4). After the third subject at that 
dose finished the DLT observation period of 6 weeks (5 weeks CyPep-1 treatment plus 1 
week safety follow-up), the DEC will recommend on the start of the cohort to be administered 
at RP2D based on the review of the safety data (cohort 5). After the DLT observation period 
for the first three subjects at RP2D for CyPep-1 and the review of all safety data, the DEC 
will recommend on the inclusion of all remaining subjects. In the absence of any DLTs in the 
first 3 subjects, the 24-h observation period before start treatment of the next subject is not 
applicable. Should a DLT be observed in the first three subjects at the RP2D of CyPep-1,
an additional three subjects in this dose group will be included. In case that two or more 
subjects experience DLTs at RP2D of CyPep-1, a decision to dose de-escalate and to what
dose and how to continue Arm C will be made by the DEC.
For Arm C, replacement for subjects who drop out for any reason, except DLTs, before the 
DLT observation period is completed is allowed when a subject did not receive all three 
CyPep-1 administrations. No subject replacement will occur for subjects who discontinue 
later.
Phase IIa – dose expansion melanoma (Arm D):
The safety and tolerability of CyPep-1 at RP2D will be further evaluated with focus on 
assessing efficacy signals of CyPep-1 monotherapy in up to 30 subjects with melanoma.
Although safety information will be collected, there will not be a formal DLT observation 
period.
As part of the continuous safety monitoring of the trial, reports with cumulative safety data 
of Arm D subjects will be shared with all investigators, competent authorities, and ethical 
committees of countries where the trial is conducted at the following time points:
After the first three subjects completed three weeks of treatment with CyPep-1.
After the first three, six, and 12 subjects completed six weeks of treatment with 
CyPep-1.
In the occurrence of AEs fulfilling DLT criteria or other safety alerts, the DEC will convene 
to review the safety data and provide recommendations on the continuation of dosing.
Replacement of subjects who dropped out before V8 (at week 8) due to any reasons other 
than CyPep-1 toxicity is allowed. No subject replacement will occur for subjects who 
withdraw later than V8.
For both phases and all trial arms, subjects will stay in the trial until end of trial or until 
confirmed disease progression, unacceptable toxicity, death or discontinuation for any other 
reason.
DOSE ESCALATION AND SCHEDULE: 
Dose escalation (Phase I of the trial) will be conducted to determine the MTD or RP2D using 
a standard “3+3” design, with at least three subjects treated at each dose-level. Arm C in the 
dose expansion (phase IIa of the trial) will follow a similar dose escalation for the two dose
levels planned (RP2D and the dose immediately below). Dose escalation will proceed 
according to the following rules:

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Number of subjects with 
DLT*
Escalation decision rule
0 out of 3 subjects
Enter 3 subjects at the next planned dose level.
1 out of 3 subjects
Enter 3 additional subjects at this dose level:
If 0 of these additional subjects experience a DLT, 
proceed to the next dose level.
If 1 or more of the additional 3 subjects experience a DLT, 
then dose escalation to higher dose levels is stopped.
Three additional subjects may be entered at the second 
highest dose if only 3 subjects have been treated at that 
dose level. Alternatively, a new dose level may be 
introduced between the second highest dose and the 
MTD (3 additional subjects).
6 subjects at the 
highest dose level below 
the MTD
This dose level is declared the MTD or RP2D.
*Assessed as related to the trial drug (CyPep-1) at any given dose level.
Scheduling of treatment of CyPep-1 and pembrolizumab (Arm B) will be as follows: CyPep-1
will be administered every 2 weeks (Q2W) and pembrolizumab will be administered following 
a Q6W schedule.
For Arm B, on the visits that CyPep-1 and pembrolizumab are administered on the same 
day, CyPep-1 is planned to be administered 30 to 60 min after pembrolizumab has been
administered. In case of pembrolizumab-related toxicity, treatment with CyPep-1 will be 
delayed and planned after a review by the investigator and medical monitor. If CyPep-1
treatment is delayed > 7 days, that dose will be omitted. If the delay of > 7 days is during the 
TLT observation period, the subject will be replaced.
For Phase I, Phase IIa Arms A and C, CyPep-1 administration is planned as Q2W injections.
If CyPep-1 treatment is delayed > 7 days, that dose will be omitted. If CyPep-1 treatment is 
delayed for > 6 weeks during the DLT period (first 3 injections), the subject should be 
discontinued from the trial.
For Arm D, CyPep-1 administration is planned as QW injections until the second 
iRECIST/itRECIST assessment at week 16, followed by a Q2W dosing scheme. In case
CyPep-1 treatment is delayed for > 3 weeks (first 3 injections), the investigator and the 
Medical Monitor must assess on a case-by-case basis the decision whether the subject 
should be discontinued from the trial. Treatment delay due to TEAEs will be considered for 
treatment discontinuation.
Radiological assessment to determine occurrence of (un)confirmed PD will be performed 
Q8W from the start of treatment for all trial phases and arms. Treatment will continue until 
confirmed PD, unacceptable toxicity, death or consent withdrawal, loss to follow up, or trial 
end, whichever occurs first.
DOSE LIMITING TOXICITY: 
A DLT is defined by the occurrence of any of the following toxicities according to CTCAE 
v5.0 during treatment Cycle 1 and that are considered by the investigator to be possibly, 
probably, or definitely related to CyPep-1:
1.
Es of any etiology, except:
Nausea, vomiting, or diarrhea will be considered a DLT only if it persists at Grade 

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discretion, subjects who experience nausea, vomiting, or diarrhea after receiving
CyPep-1 may receive antiemetic or anti-diarrheal medication prior to subsequent 
doses of CyPep-1.
c
intervention.
For Phase I, Arms A and C: Alanine amino transferase (ALAT) or aspartate amino 
transferase (ASAT) toxicities:
o
ALAT or ASAT > 5 x upper limit of normal (ULN) (> 7.5 x ULN for subjects 
with liver metastases), unless greater than 14 days.
o
ALAT or ASAT > 5 x ULN (> 7.5 x ULN for subjects with liver metastases) 
accompanied by an elevation in total bilirubin of > 2.5 x ULN (not 
explained by obstruction), regardless of duration, will be considered a 
DLT.
2.
Any other toxicity occurring at any time during the trial that in the view of the 
participating investigators and the medical monitor represents a clinically significant 
hazard to the subject.
DEFINITION OF TREATMENT LIMITING TOXICITY (CyPep-1 plus pembrolizumab 
combination)
All TLTs will be graded using NCI CTCAE v5.0 based on the investigator assessment. The
TLT window of observation will be during Cycle 1.
The occurrence of any of the following toxicities during Cycle 1 will be considered a TLT, if 
assessed by the investigator to be possibly, probably, or definitely related to trial treatment 
administration. 
1.
Grade 4 nonhematologic toxicity (not laboratory).
2.
days, except thrombocytopenia:
Grade 4 thrombocytopenia of any duration
Grade 3 thrombocytopenia associated with clinically significant bleeding
3.
TLT, with the 
diarrhea, nausea, or 
vomiting without use of anti-emetics or anti-diarrheal per standard of care; Grade 3 
rash without use of corticosteroids or anti-inflammatory agents per standard of care.
4.
Any Grade 3 or Grade 4 non-hematologic laboratory value if:
Clinically significant medical intervention is required to treat the participant or
The abnormality leads to hospitalization, or
The abnormality persists for >1 week.
The abnormality results in a Drug-induced Liver Injury (DILI) 
Exceptions: Clinically nonsignificant, treatable, or reversible laboratory 
abnormalities including liver function tests, uric acid, etc.
5.
Febrile neutropenia Grade 3 or Grade 4:
Grade 3 is defined as ANC <1000/mm3 with a single temperature of 
>38.3 degrees C (101 degrees F) or a 
(100.4 degrees F) for more than 1 hour
Grade 4 is defined as ANC <1000/mm3 with a single temperature of 
>38.3
(100.4 degrees F) for more than 1 hour, with life-threatening consequences and 
urgent intervention indicated.
6.
Prolonged delay (>2 weeks) in initiating Cycle 2 due to treatment-related toxicity.
7.
Any treatment-related toxicity that causes the participant to discontinue treatment 
during Cycle 1.

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8.
Missing >25% of CyPep-1 doses as a result of drug-related AE(s) during the first 
cycle.
9.
Grade 5 toxicity.
DURATION OF SUBJECT PARTICIPATION:
Each subject will undergo up to 4 weeks of screening. For Phase I, Phase IIa Arms A, B and 
C subjects will undergo a DLT/TLT observation period of 6 weeks (5 weeks of CyPep-1 ±
pembrolizumab treatment plus 1 week observation). In absence of DLT/TLTs, treatment with 
CyPep-1 continues until confirmed PD, unacceptable toxicity, death or consent withdrawal,
loss to follow up, or trial end, whichever occurs first.For the combination arm (Arm B), Q6W 
administration of pembrolizumab is allowed up to 24 months (18 cycles). For Arm D, without 
a DLT period, each subject will undergo QW CyPep-1 treatment until the second 
iRECIST/itRECIST assessment at week 16, followed by a Q2W dosing scheme. Hereafter, 
there will be efficacy (PFS) follow-up every 8 weeks, or until confirmed PD, unacceptable 
toxicity, death, withdrawal of consent, loss to follow-up, or trial end, whichever occurs first.
Start of inclusion: Q1 2020
Planned last subject last trial visit: last subject’s last follow-up visit 
The end of treatment is defined as the last subject’s end-of-treatment visit. The end of trial 
is defined as the last subject’s last visit. For the purposes of data summarization, data 
analyses will be performed after the last enrolled subject has completed 3 months of trial 
participation. Subjects may still be in the trial at the time of data summarization, as all 
subjects may continue to participate until confirmed disease progression, unacceptable 
toxicity, or discontinuation for any other reason.
INCLUSION AND EXCLUSION CRITERIA: 
Inclusion criteria: 
For Phase I and Phase IIa Arms A and C:
1.
Histologically or cytologically confirmed locally advanced (unresectable) or 
metastatic tumors (solid tumor or lymphoma) with an accessible tumor lesion for 
intratumoral injection of CyPep-1 malignancy (including lymphomas) that is either:
a. Refractory to standard-of-care treatment 
b. Have a disease for which there is no standard therapy considered appropriate. 
Metastatic deposits (including cutaneous/subcutaneous lesions and metastatic 
deposits in lymph nodes) of tumors for which IT injections may be performed are 
eligible. 
Pure 
cutaneous 
infiltrations 
(e.g., 
breast 
cancer 
cutaneous 
carcinomatosis) are ineligible.
2.
1 to 3 non-ulcerated transcutaneously accessible lesion(s) for injection and 
measurable as defined by iRECIST. All other tumor lesion(s) may be selected for 
efficacy follow-up but will not be subjected to treatment with CyPep-1.
3.
Presence of tumor lesion(s) (that have not been previously irradiated) suitable for 
biopsy at screening and at Week 6.  
For Arm C:
4.
Confirmation of the presence of at least 1 liver metastasis by imaging.
5.
Subjects must have measurable disease which is equal to one or more metastatic 
liver lesions that can be accurately and serially measured that are greater than 1 cm 
dimension and for which the longest diameter is greater or equal to 1 cm as measured 
by CT (computed tomography)scan or magnetic resonance imaging (MRI). The 
metastatic liver lesion must not be in an area that received prior localized therapies.

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6.
Metastatic liver lesion for injection with >50% radiological visible necrosis must be 
avoided and the lesion must be located where any tumor swelling will not lead to gall 
bladder tract obstruction or lead to bleeding risk. 
 
For Arm D:
7.
Histologically or cytologically confirmed diagnosis of advanced (unresectable Stage 
III) or metastatic (Stage IV: M1a and/or M1b) melanoma considered incurable by 
Standard of Care. For metastatic melanoma, only cutaneous, subcutaneous,  lymph 
node, or lung metastases are allowed.
8.
Previously exposed to ICI(s) and be categorized following the SITC Immunotherapy 
Resistance Taskforce (Kluger 2020) meeting one of the following:
a.
Have primary resistance: PD-(L)-
have the 
best response as one of the following:
i.
PD,
ii.
SD for <6 months.
b.
Have secondary resistance: PD-(L)-
response CR, PR, or SD >6 months.
c.
Have adjuvant therapy resistance: recurrence subcategorized into primary 
resistance/early relapse occurred <12 weeks after the last dose, and late 
relapse occurred
must have progressed to treatment with BRAF inhibitors.
d.
Have neoadjuvant therapy resistance including subjects with or without major 
pathologic response and subsequent PD that fulfills criteria for primary or 
secondary resistance
e.
Discontinued from ICI(s) therapy due to immune-related adverse events 
grade 3 or 4 other than endocrine insufficiencies treatable with hormonal 
replacement therapy, and meet one of the following:
i.
Remain on SD at discontinuation of PD-(L)1 inhibitor in combination 
with ipilimumab or show regrowth after <12 weeks of the last dose
ii.
Have not achieved a CR with single-agent PD-(L)1 inhibitor or 
combination of PD-(L)1 with LAG-3 inhibitor
9.
At least 1 non-ulcerated lesion, not exceeding 5 cm in (the longest) diameter, for 
intratumoral injection(s) and measurable as defined by iRECIST. 
10. Resolution of toxicity due to prior therapy returned to baseline or < Grade 2, except 
for alopecia or other irreversible immune-mediated AEs, as defined by CTCAE v5.0. 
and SITC ICI-related AEs (Brahmer et al, 2021).
11. Prior treatment(s) delivered by IT injection to the to-be injected lesion(s), including 
investigational agents, is allowed.
For Phase I and Phase IIa Arms A, C, and D in addition:
12.
13. Estimated life expectancy of at least 3 months.
14. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 
(Appendix B).
15. Resolution of toxicity due to prior therapy to Grade < 2 (except for alopecia and 
transaminases in case of liver metastases) as defined by CTCAE v5.0 (Appendix C).
16. Ability to give written informed consent and to comply with the protocol. 
17. All subjects of childbearing potential (defined as < 2 years after last menstruation or 
not surgically sterile) must have a negative highly sensitive pregnancy test at 
screening (urine/serum) and agree to use highly effective method for contraception 
according to the EU Clinical Trial Facilitation Group guidance from time of signing the 
informed consent form (ICF) until at least 120 days after the last administration of 

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CyPep-1. The partners of subjects with childbearing potential must also apply 
contraceptive methods and are recommended not to donate sperm. 
18. A male participant must agree to use contraception and refrain from sperm donation 
during the treatment period and for at least 120 days after the last dose of trial 
medication. 
19. Adequate bone marrow, liver, and renal function:
a.
9/L
b.
c.
9/L
d.
(Gilbert’s disease)
e.
f.
Glomerular Filtration Rate [GFR] to be 
calculated by CKD-EPI formula).
For Phase IIa Arm B:
Participants are eligible to be included in Arm B of the trial only if all of the following criteria 
apply:
Type of Participant and Disease Characteristics
20. The participant provides written informed consent for the trial.
21. Be 
18 years of age on day of signing informed consent.
22. Participant with histologically or cytologically confirmed diagnosis of advanced 
(unresectable Stage III) or metastatic (Stage IV) solid tumor malignancy (including 
lymphomas) that is refractory to standard-of-care treatment or for which there is no 
standard 
therapy 
considered 
appropriate. 
Metastatic 
deposits 
(including 
cutaneous/subcutaneous lesions and metastatic deposits in lymph nodes) of tumors 
for which IT injections may be performed are eligible. Pure cutaneous infiltrations 
(e.g., breast cancer cutaneous carcinomatosis) are ineligible.
23. Subjects must have progressed on treatment with an anti-PD1/L1 monoclonal 
antibody (mAb) administered either as monotherapy, or in combination with other 
checkpoint inhibitors or other therapies. Treatment progression is defined by meeting 
all of the following criteria:
a.
Has received at least 2 doses of an approved anti-PD-1/L1 mAb.
b.
Has demonstrated clinical or radiological disease progression (PD) after PD-
1/L1
24. A male participant must agree to use contraception and refrain from sperm donation 
during the treatment period and for at least 120 days after the last dose of trial 
medication.
25. A female participant is eligible to participate if she is not pregnant, not breastfeeding, 
and at least one of the following conditions applies:
a.
Not a woman of childbearing potential (WOCBP) 
b.
A WOCBP (defined as < 2 years after last menstruation or not surgically 
sterile) must have a negative highly sensitive pregnancy test at screening 
(urine/serum) and must follow contraceptive guidance (highly effective 
method for contraception according to the EU Clinical Trial Facilitation Group 
guidance) from time of signing the ICF until at least 120 days after the last 
administration of trial medication. The partners of subjects with childbearing 
potential must also apply contraceptive methods and are recommended not 
to donate sperm.

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26. 1 to 3 non-ulcerated transcutaneously accessible lesion(s) for injection and 
measurable as defined by iRECIST. All other tumor lesion(s) may be selected for 
efficacy follow-up but will not be subjected to treatment with CyPep-1.
27. Presence of tumor lesion(s) (that have not been previously irradiated) suitable for 
biopsy at screening and at Week 6.
28. Have an ECOG performance status of 0 to 1 (Appendix B).
29. Have adequate organ function as defined in the following table. Specimens must be 
collected within 10 days (or less) prior to the start of trial treatment.
Adequate Organ Function Laboratory Values: 
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
Platelets
000/µL
Hemoglobin
1
Renal
Creatinine OR
Measured or calculated2 creatinine clearance
(GFR can also be used in place of creatinine or 
CrCl)
>1.5 × institutional ULN
Hepatic
Total bilirubin
×
ULN for participants 
with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
×
× ULN for participants with liver 
metastases)
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT) =aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; 
ULN=upper limit of normal.
1 Criteria must be met without packed red blood cell (pRBC) transfusion within the prior 2 weeks. 
Participants can be on stable dose of e
2 Creatinine clearance (CrCl) should be calculated per institutional standard.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
specific chemotherapies.
30. Only for subjects with lymphoma: have measurable disease defined as at least one 
lesion that can be accurately measured in at least two dimensions with spiral CT 
scan. Minimum measurement must be > 15 mm in the longest diameter by > 10 mm 
in the short axis.
31. Estimated life expectancy of at least 3 months.
32. HIV infected participants must be on anti-retroviral therapy (ART) and have a well-
controlled HIV infection/disease defined as:
a.
Participants on ART must have a CD4+ T-cell count 
350 cells/mm3 at time 
of screening.
b.
Participants on ART must have achieved and maintained virologic 
suppression defined as confirmed HIV RNA level below 50 copies/mL or the 
lower limit of qualification (below the limit of detection) using the locally 
available assay at the time of screening and for at least 12 weeks prior to 
screening.

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c.
Participants on ART must have been on a stable regimen, without changes 
in drugs or dose modification, for at least 4 weeks prior to study entry (Day 
1).
Exclusion criteria: 
For Phase I and Phase IIa Arms A, C, and D: subjects who meet ANY of the following criteria 
at screening will be excluded from trial entry:
1.
There is no limit to the number of prior treatment regimens, but prior treatment(s) 
should not include compounds delivered by IT injection to the to-be injected lesion(s),
including investigational agents. Subjects with prior IT therapies are allowed in Arm 
D.
2.
Participation in another clinical trial within 4 weeks prior to first dose of CyPep-1.
3.
Anti-cancer therapy within 4 weeks prior to the first dose of CyPep-1 (within 2 
weeks for palliative radiotherapy, within 1 week for endocrine therapy). 
4.
Major surgical procedure within 14 days prior to the first dose of CyPep-1.
5.
Live vaccine within 30 days prior to first dose of CyPep-1.
6.
Expected to require any other form of systemic or localized antineoplastic therapy 
while in this trial. Localized palliative radiotherapy for pain relief is allowed on tumor 
lesions that are not selected for evaluation of treatment response. 
7.
Clinical evidence of an active second malignancy that is progressing or requires 
active treatment, except for curatively treated early stage (carcinoma in situ or stage 
1) carcinomas or non-melanoma skin cancer. 
8.
Active autoimmune disease requiring immunosuppressive therapy.
9.
Any condition requiring continuous systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalents) or other immunosuppressive agents within 
2 weeks prior to first dose of CyPep-1. Inhaled, intranasal or topical (only on areas 
outside the injected lesion[s]) and physiological replacement doses of up to 10 mg 
daily prednisone equivalent are permitted in the absence of active auto-immune 
disease. 
10. Abnormal or clinically significant coagulation parameters:
a.
Prothrombin Time – International Normalized Ratio (PT-INR)
1.5 ULN
b.
Activated Partial Thromboplastin Time (APTT)
1.5 ULN
Subjects being treated with anticoagulants are excluded if the coagulation 
parameters are outside the therapeutic intervals as described in the SmPC for the 
administered treatment.
11. Subjects on anticoagulants with temporarily stop and start, supported by low 
molecular weight heparin (or other anticoagulation therapy at the discretion of the 
investigator and/or per local standard of care) during treatment period.
12. Known hypersensitivity to any component of CyPep-1.
13. Prior allogeneic tissue/solid organ transplant, stem cell or bone marrow transplant.
14. Known active human immunodeficiency virus (HIV). Subject is eligible when normal 
levels of CD4 are present. 
15. Central nervous system (CNS) metastasis that is symptomatic or progressing or that 
requires current therapy (e.g., evidence of new or enlarging CNS metastasis,
carcinomatous meningitis or new neurological symptoms attributable to CNS 
metastasis). 
16. QTcF > 480 ms, history of long or short QT syndrome, Brugada syndrome, or known 
history of QTc prolongation, or Torsade de Pointes.
17. Women who are pregnant or breastfeeding. 

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18. Any serious and/or unstable pre-existing medical, psychiatric or other condition which 
in the investigator’s opinion could interfere with subject safety, obtaining written 
informed consent, or compliance with the trial protocol. 
19. Has an active acute or chronic infection requiring systemic therapy at the time of 
CyPep-1 injection. Note: Subjects treated for mild/moderate infection with oral 
antibiotics only may be included based on consultation with the study medical monitor 
and the sponsor.
Additional exclusion criteria for Phase IIa Arm C:
20. Subject is a candidate for hepatic surgery or local regional therapy of liver metastases 
with curative intent.
21. More than one third of the liver is estimated to be involved with metastases.
22. There is invasion by cancer into the main blood vessels such as the portal vein, 
hepatic vein or the vena cava.
23. Subject is currently receiving or has received liver metastatic-directed therapy (eg: 
radiation, ablation, embolization) less than 4 weeks prior to enrolment or hepatic 
surgery. 
 
Exclusion criteria specific for Phase IIa Arm B:
Participants are excluded from the trial if ANY of the following criteria apply at screening:
Pregnancy Exclusion
24. A WOCBP who has a positive urine pregnancy test (within 72 hours) prior to trial 
treatment. If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required.
Prior/Concomitant Therapy
25. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with 
an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4,
OX 40, CD137), and was discontinued from that treatment due to a Grade 3 or higher 
irAE. 
26. Has received prior systemic anti-cancer therapy including investigational agents 
within 4 weeks (within 1 week for endocrine therapy) prior to first dose of CyPep-1.
Note: Participants must have recovered from all AEs due to previous therapies to 
1 or baseline as defined by CTCAE v5.0 (Appendix C). Participants with 
-related AEs 
Grade
ible.
Note: If the participant had major surgery, this should not have been within 14 days 
prior to the first dose of CyPep-1 and the participant must have recovered adequately 
from the procedure and/or any complications from the surgery prior to starting study 
intervention.
27. Has received prior (palliative) radiotherapy within 2 weeks of start of trial treatment. 
Participants must have recovered from all radiation-related toxicities, not require 
corticosteroids, and not have had radiation pneumonitis. A 1-week washout is 
-CNS disease.
28. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of 
CyPep-1. Note: Administration of killed vaccines are allowed.
29. Has received prior compounds delivered by IT injection to the to-be injected lesion(s),
including investigational agents.
30. Expected to require any other form of systemic or localized antineoplastic therapy 
while in this trial. Localized palliative radiotherapy for pain relief is allowed on tumor 
lesions that are not selected for evaluation of treatment response.
31. Ongoing pembrolizumab-related toxicity event(s) as per TLT definition.

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Prior/Concurrent Clinical Trial Experience
32. Is currently participating in or has participated in a trial of an investigational agent or 
has used an investigational device within 4 weeks prior to the first dose of trial 
treatment.
Note: Participants who have entered the follow-up phase of an investigational trial
may participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
33. Has had an allogeneic tissue/solid organ transplant.
Diagnostic assessments
34. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of CyPep-1.
35. Has a known additional malignancy that is progressing or has required active 
treatment within the past 3 years, except for curatively treated early stage (carcinoma 
in situ or stage 1) carcinomas or non-melanoma skin cancer.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of 
the skin or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded.
36. Has known active CNS metastases and/or carcinomatous meningitis. Participants 
with previously treated brain metastases may participate provided they are 
radiologically stable, i.e., without evidence of progression for at least 4 weeks by 
repeat imaging (note that the repeat imaging should be performed during study 
screening), clinically stable and without requirement of steroid treatment for at least 
14 days prior to first dose of study treatment. 
37.
/or any of its excipients 
or to another mAb, as well as any known hypersensitivity to any component of 
CyPep-1.
38. Has an active autoimmune disease that has required systemic treatment in past 
2 years (i.e., with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) 
is not considered a form of systemic treatment and is allowed.
39. Has a history of (non-infectious) pneumonitis / interstitial lung disease that required 
steroids or has current pneumonitis / interstitial lung disease.
40. Has an active infection requiring systemic therapy.
41. HIV-infected participants with a history of Kaposi sarcoma and/or Multicentric 
Castleman Disease.
42. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active 
Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by a 
local health authority.
43. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the participant's participation 
for the full duration of the trial, or is not in the best interest of the participant to 
participate, in the opinion of the treating investigator.
44. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
45. Has received radiation therapy to the lung that is >30 Gy within 6 months of the first 
dose of trial treatment (applicable only for subjects with non-small cell lung cancer 
[NSCLC], mesothelioma and small cell lung cancer [SCLC]).
TREATMENT REGIMENS:

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CyPep-1 Treatment Regimen and Dose Levels:
For Phase I and Phase IIa, Arms A, B and C, CyPep-1 will be administered intratumorally 
Q2W, on Day 1, 15, and 29 of each cycle. In the absence of DLT/TLTs during Cycle 1,
treatment continues with Q2W IT injections of CyPep-1. For Arm D, CyPep-1 will be 
administered intratumorally QW until the second iRECIST/itRECIST assessment at week 
16, followed by a Q2W dosing scheme. For all phases/arms, treatment will continue until 
confirmed PD, unacceptable toxicity, death, or consent withdrawal, loss to follow up, or trial 
end, whichever occurs first (for discontinuation refer to Section 4.3.1).
Administration will be through a needle inserted trans-dermally. The needle should be 
redirected along multiple tracks to ensure even dispersion of CyPep-1 throughout the lesion. 
For Arm C, CyPep-1 will be administered via intralesional injection with ultrasound guidance 
into one metastatic liver lesion. A detailed guidance for intratumoral administration of CyPep-
1 is presented in the Study Procedural Manual.
The CyPep-1 concentration for each dose cohort during dose escalation (Phase I) is as 
follows:
Dose cohort
CyPep-1 concentration
1
0.5 mg/mL
2
2 mg/mL
3
5 mg/mL
The total amount of CyPep-1 injected will depend on the tumor volume(s). Effort should be 
made to administer the maximum planned injection volume of CyPep-1 as planned per lesion 
size.
CyPep-1 Injection Volume:
The volume delivered to each lesion selected for injection will be determined based on the
longest diameter measured by the most accurate measurement technique available for each 
lesion (e.g. caliper, CT, or
MRI) at screening and every 8 weeks
during the 
iRECIST/itRECIST assessments. A chosen technique used at screening will be consistently 
used throughout the study. Lesion sizes need to be checked before each injection by either 
caliper (mandatory for Arm D and to-be-injected cutaneous/subcutaneous lesions for Phase 
IIa Arms A and B) or other imaging modalities used to guide CyPep-1 injections, i.e. 
ultrasound, CT, or MRI. For Arm C, the lesion size measurement will be performed by the
same imaging modality used to guide CyPep-1 injections. To ensure consistency of the 
measurements, the sites need to strive for having the same operator to perform all 
measurement for a chosen measuring technique. If there are major changes in the lesion 
size, the injection volume may be adjusted based on the ultrasound measurements per 
investigator’s opinion and consultation with the Medical Monitor is possible.
For both phases of the trial, the cumulative maximal injected volume will be 4 mL per 
treatment day, corresponding to a cumulative maximal dose of 20 mg of CyPep-1 (depending 
on the dose concentration). Effort should be made to administer the maximum planned 
injection volume of CyPep-1 as planned per lesion size (see tables below).
For Phase I and Phase IIa Arms A and B, the to-be-injected volume may be divided for 
injection over 1-3 tumor lesions (e.g., one large lesion or 2-3 relatively small lesions). In case 
more than 3 lesions are good candidates for injection, the to be injected lesions selection 
can be discussed with the sponsor and the medical monitor.
For Arm C, CyPep-1 will be administered with ultrasound guidance into one metastatic liver 
lesion. The same single metastatic lesion is to be injected with CyPep-1 based on lesion
size. 

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For Arms A and B, for a lesion > 7 cm, the same lesion should be considered to be injected 
weekly with up to 4 mL of CyPep-1 for the first 6 weeks (on Day 1, 8, 15, 22, 29 and 36),
independent of the potential change in lesion size, followed by Q2W 4 mL administrations of 
CyPep-1.
For Arm D, the to-be-injected volume for injection is preferably divided over as many lesions 
as possible. The longest diameter of the lesions for injection is ideally smaller than 2 cm and 
should not exceed 5 cm.
For subjects in Arms A, B and C, the injection volume will be:
Measured Lesion Diameter (cm)
Injected volume (mL)
1
1
> 1 and
2
2
> 2
4
For subjects in Arm D, the injection volume will be:
Measured Lesion Diameter (cm)
Injected volume (mL)
0.79
0.1
0.80 to 0.99
0.2
1.00 to 1.24
0.5
1.25 to 1.50
1.5
1.51 to 2.49
3.0
2.50
4.0
For all subjects, if a lesion disappears at any time, the investigator may choose another 
lesion for subsequent injections. Previously non-injected lesions may also be injected if 
necessary (e.g. safety reasons), per investigator’s discretion. 
Sequence of CyPep-1 Administration for Phase IIa Arm D only:
Lesion Map 
A lesion map that will guide the preferred sequence of injection of the identified Lesion Sets
must be created prior to the first CyPep-1 injection (detailed in Study Procedural Manual). A
lesion map will contain the following information:
For superficial lesions: 
Digital color photography of the lesions must be taken and the mark-ups of individual 
lesions (or lesion groups) with lesion ID are overlayed on top of the digital 
photography. 
Silhouette of body parts must be used to present the relative location of the lesions. 
All digital color photography containing a ruler held next to the longest diameter of 
the lesion to indicate the size of the lesion, and the lesions marked-up with lesion 
IDs, together with the silhouette of body parts indicating the location of the lesions, 
need to be submitted to eCRF with inspection readiness for the reported responses.
In the case of bilateral lesions, the laterality of the lesions must be documented on 
the lesion map.
For deep lesions: 
CT or MRI scan will be used for iRECIST/itRECIST assessment at baseline, and the 
location of lesions provided by the CT/MRI scan will be used.
In the case of bilateral lesions, the laterality of the lesions must be documented on 
the lesion map.
Once the lesion map is created, Lesion Sets for sequential CyPep-1 injections will be 
planned and documented in the source. The size of the injected lesions and the lesion map 
should be updated when assessments of local measurements of tumor lesions, iRECIST 
and itRECIST assessments are performed during the treatment period.

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Lesion Sets
A Lesion Set will be composed of multiple lesions, and will be administered with CyPep-1
during the same treatment visit for three consecutive doses. Unless there are no other lesion 
sets to be injected, each Lesion Set will not receive more than three consecutive doses of 
CyPep-1. In the case of bilateral lesions, both of the bilateral lesions should be included in 
the same Lesion Set if feasible considering the maximum injected volume allowed per 
treatment visit (4 mL).
The sequence of CyPep-1 Administration
After three doses of CyPep-1, the next lesion set will be administered with CyPep-1. The 
ideal next to-be-injected Lesion Set should be located as far as possible from the last injected 
Lesion Set on the lesion map to activate different draining lymph nodes and thus optimize a
systematic immune response against the tumor. Once all injectable lesions have been 
injected and the subject remains on treatment, a new lesion map that permits reprioritizing 
of the to-be-injected Lesion Sets will be created, taking into account size changes of 
individual lesions, e.g., an individual lesion enlarged or regressed after initial 3 doses of 
CyPep-1 injections. 
Pembrolizumab Treatment Regimen for Phase IIa Arm B only:
The dose of pembrolizumab in combination with CyPep-1 in the combination arm will be 400
mg Q6W. Dosing of CyPep-1 will be aligned such that subjects will receive both 
pembrolizumab and the first dose of CyPep-1 on the same day (C1V1). After C1V1,
pembrolizumab dosing will continue following a Q6W dosing scheme until 18 cycles, 
confirmed PD, unacceptable toxicity or consent withdrawal.
DOSE-MODIFICATION CRITERIA:
CyPep-1: No major toxicity is expected. There may be minor local toxicity or tumor ulceration 
due to the treatment procedure, which can be treated according to Standard of Care.
In case of toxicity, the administration of CyPep-1 may be delayed at the discretion of the 
investigator and is to be discussed with the medical monitor. Neither a dose reduction, nor 
intra-subject dose escalation of CyPep-1 is allowed. 
Dose modification of pembrolizumab in Arm B will be according to the provided dose 
modification and toxicity management guidelines (refer to Section 5.3.6).
SAFETY ASSESSMENTS:
Safety will be assessed by means of physical examinations, body weight, vital signs, ECOG 
performance status, laboratory evaluations (hematology, biochemistry, coagulation, 
urinalysis), electrocardiograms (ECG), and recording of concurrent ilness/therapy and 
adverse events (as defined by CTCAE v5.0). All assessments will be performed as indicated 
in the Schedule of Assessments (SoA, Table 1). Additional assessments may be performed 
as clinically indicated.
EFFICACY ASSESSMENTS:
Clinical efficacy of CyPep-1 monotherapy (Phase I dose escalation and Phase IIa Arms A,
C, and D) and in combination with pembrolizumab (Phase IIa Arm B) will be measured by 
radiologic assessments (i.e., caliper, CT, MRI) every 8 weeks, starting from C1V1 for all 
phases and arms as baseline. The imaging modality must be the same for all efficacy 
measurements.
Radiologic assessments will be evaluated based on the investigator’s assessments at the 
clinical sites according to the consensus guideline iRECIST (Appendix D, based on modified 

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RECIST) and response (iCPD, iUPD, iSD, iPR, iCR) will be defined taking into account the 
total disease burden (as required per iRECIST using modified RECIST). 
ORR in injected and non-injected lesions per itRECIST will be estimated by statistical 
programming using data collected from iRECIST assessments.
The following tumor lesion(s) will be followed-up for efficacy:
One or more injected lesion(s) that are treated with CyPep-1 injection. 
All other non-injected lesion(s) that are not treated with CyPep-1 injection.
For Phase I Cohort 3 and all Phase IIa arms, in addition to iRECIST, (exploratory) 
ORR in injected and non-injected lesions will be assessed per itRECIST (Appendix 
F). For Phase I Cohort 3, Phase IIa Arms A, B, and C, data will be extracted 
retrospectively from eCRF.
Upon start of CyPep-1 treatment, subjects will be followed for PFS (every 8 weeks) and OS. 
PFS will be radiologically assessed at the trial sites until disease relapse or progression
(based on all lesions), death due to any cause, withdrawal of consent, loss to follow-up, or 
until the end of the trial, whichever occurs first. A phone call for survival status (OS) will be 
done every 3 months after confirmation of PD and until the end of the trial.
Confirmation of clinical progressive disease:
In order to account for the possibly delayed onset of CyPep-1 action and for subjects who 
are of acceptable clinical performance status (as deemed by the investigator), if PD is 
recorded and provided that the tumor enlargement is smaller than 50% compared to the 
previous measurement, the subject will remain in the trial and will be reassessed 
radiologically after 4 weeks. All lesion(s) are to be evaluated for clinical progression:
If the lesion(s) continue(s) to enlarge, the original PD will be considered as the “first 
documented PD” and there will be an End of Treatment (EoT) visit.
If lesion(s) remain(s) unchanged or decrease(s) in size, assessments should 
continue as per protocol (i.e., the next radiological assessment will be performed 
after an 8-week interval). In this case, the first measured PD will be disregarded. 
In case of unconfirmed PD after the first (or subsequent) 3 Q2W injections of CyPep-1, the 
subject should continue Q2W administrations (start of another cycle of CyPep-1) until 
confirmed PD. If PD is confirmed 4 weeks later, then the subject will be taken off-trial and 
move to the EoT visit.
PHARMACOKINETIC ASSESSMENTS:
During the trial treatment period, the plasma concentration time profile of CyPep-1 will be 
evaluated and, if detectable plasma drug levels are identified, the derived PK parameters 
will be assessed. These include area under the curve (AUC), peak plasma concentration 
(Cmax), time to reach Cmax (tmax), systemic clearance (CL), elimination half-life (t1/2) and 
volume of distribution (VD). PK assessment is planned for the first 9 subjects of Phase I, all
subjects of Phase IIa Arm C, and the first 12 subjects of Phase IIa Arm D.
EXPLORATORY ASSESSMENTS: 
A tumor biopsy of the injected lesion(s) and, if applicable, of additionally selected lesion(s) 
that are not to be injected, will be obtained at screening and at Week 6 (one week after 3rd
CyPep-1 injection). The screening tumor biopsy is preferably as fresh as possible, but may 
have been obtained within 90 days of first administration of CyPep-1.

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At least one biopsy of the injected tumor lesion(s) should be available at screening and at 
Week 6 (one week after 3rd CyPep-1 injection from the start of treatment). If the subject is 
willing to provide additional tumor material for exploratory analysis, also a biopsy of 
non-injected tumor lesion(s) will be taken.
After receiving additional cycle(s) of treatment with Q2W injections of CyPep-1, a biopsy of 
any new injected lesion(s) can be taken (not mandatory) before the first treatment and after 
6 weeks. 
The following will be assessed in the tumor biopsies:
Number and relative change of tumor infiltrating CD8+ T-cells.
Expression of immune markers: 
 
 
 
The following will be assessed in peripheral blood (timepoints defined in SoA):
Peripheral blood phenotyping of selected immune cell markers.
Additional analyses for immune markers may be performed.
STATISTICAL METHODS: 
A statistical analysis plan (SAP) will provide details of the methods of analysis to address all 
trial objectives. 
Phase IIa Arm A: At RP2D in case a responder per iRECIST is observed or 2 subjects with 
stable disease (SD) per iRECIST are observed in the first 12 subjects, the number of subjects 
will be expanded to a total of 24 (CyPep-1 monotherapy). Response evaluation will be based 
on the sum of diameter of all target lesions. ORR is defined as best response (CR/PR) or 
SD as >16 weeks from onset of SD. The first 12 subjects are the number of subjects at RP2D 
taking the subjects from the dose escalation part into account.
Formal assessment of response will be based on the first 12 evaluable subjects as follows: 
in case of no responders in 12 subjects, the likelihood of a 20% ORR is 6.9%; in case of one 
responder in 12 subjects, the likelihood of a 20% ORR is 26.5%. Assuming stable disease 
to occur in 30% of subjects, in case no subject has stable disease in the first 12 evaluated 
subjects, the likelihood is 1.4%; in case one subject has stable disease in the first 
12 evaluated subjects, this becomes 8.5%, while with two subjects having stable disease, 
this becomes 25.2%. Therefore, in case of either one of 12 subjects having an objective 
response or two of 12 subjects having stable disease, the number of subjects in Arm A may 
be increased to a total of 24 subjects (meaning 18 subjects in Arm A; based on the total 
number of subjects at RP2D during dose escalation plus the number of subjects at RP2D in 
Arm A). In case, these outcomes are not observed, Arm A will enrol the planned 9 subjects.
The sample size for Phase IIa Arm D is based on a desired precision by which preliminary 
clinical efficacy (ORR for injected lesions) may be evaluated. Using 90% 1-sided Clopper-
Pearson exact confidence intervals, lower bounds identified in the table below would apply.
90% 1-sided Confidence Intervals for the Number of Responders in N=30 Subjects
Number or 
Responders
Observed 
ORR
One-sided 90% 
Lower Bound
1
3.3%
0.4%

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2
6.7%
1.8%
3
10.0%
3.7%
4
13.3%
5.9%
5
16.7%
8.3%
6
20.0%
10.9%
7
23.3%
13.5%
8
26.7%
16.2%
9 
30.0% 
19.0% 
For example, the lower bound for an observed ORR of 13.3% when there are 4 responders 
would be higher than 5% (i.e. 5.9%); the lower bound if 6 responders are observed would be 
10.9%, which is greater than 10%, allowing for a sufficient sample to review preliminary 
effectiveness of CyPep-1 monotherapy for Arm D subjects. 
Safety parameters:
All subjects receiving at least one IT injection with CyPep-1 or one pembrolizumab infusion 
will be evaluable for safety.
AE incidence rates will be described by the frequency of AEs, categorized by preferred term 
and system organ class according to CTCAE v5.0. AEs will be summarized by severity and 
relationship to CyPep-1. The incidence of AEs and DLTs/TLTs will be evaluated for each 
dose level, and for all subjects combined.
Vital signs and body weight, 12-lead ECG parameters, laboratory data (hematology, 
biochemistry, coagulation, urinalysis) will be summarized using descriptive statistics. Shift 
tables showing changes from baseline will be generated where appropriate. 
Efficacy parameters:
Efficacy will be determined from the number of subjects with complete response, partial 
response, stable disease or progressive disease, according to iRECIST based on the
investigator’s assessments. PFS (percentage of subjects alive and progression-free after 
trial treatment start) will also be determined. These clinical response data will be 
summarized. 
ORR (proportion of subjects with a best overall response of PR or, CR) will be evaluated 
based on iRECIST. 
For Phase I Cohort 3 and all Phase IIa arms, ORR (proportion of subjects with a 
best overall response of PR or, CR) will be evaluated by two additional approaches
based on itRECIST:Injected response: considering only the targeted-injected 
lesions.
Non-injected response: considering only the targeted-non-injected lesions. 
Pharmacokinetic parameters:
Subjects who have received CyPep-1 and have provided one evaluable pre-dose and at 
least one post-dose PK blood sample will be evaluable for PK.
Standard methodology will be used to estimate PK parameters. Concentration-time profiles 
will be derived for subjects with pre- and post-dose samples.
Immunological parameters:
The relative changes in CD8+ T-cell infiltration (CD8+ expression) in the biopsied injected, 
and whenever available, non-injected lesion(s) between screening and Week 6 will be 
assessed. 

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The association between the relative changes in CD8+ T-cell infiltration and response rate 
in the injected lesions (per itRECIST) and all lesions (per iRECIST) will be assessed.
The change in T-cell receptor (TCR) clonality levels will be assessed in the available 
peripheral blood samples. To assess the hypothesis that CyPep-1 increases the TCR 
clonality systematically, which suggests that T-cells are targeting the tumor, the clonality
diversity metric will be computed for all subjects providing peripheral blood samples at 
screening and/or Week 6 of every CyPep-1 treatment cycle. Based on preliminary on file 
data of TCR clonality analysis in peripheral blood dated Nov 2022, the dataset collected is 
sufficient for the intended analysis and further sampling will provide no additional insights.
Uncertainty about the representativeness of data generated with blood samples regarding 
TCR changes in the tumor microenvironment has lead Cytovation to reconsider this 
scientific relevance of this assay. Therefore, Cytovation decided to stop collecting blood 
samples for TCR clonality analysis for all subjects. TCR sequencing might be performed 
on the available remaining tumor biopsy material from the analyses of changes in the tumor 
microenvironment. Overlaps of T cell clones in respect to expansion and breadth of T cell 
clonality before and after intratumoral injection with CyPep-1, as monotherapy and in 
combination with pembrolizumab (central analysis) will be analyzed.
The change in tumor microenvironment is examined via the expression of selected candidate 
immune markers by immunohistochemistry. For each marker, a difference in expression will 
be explored. 
Changes in cytokine levels and in frequency of various immune cell types in peripheral blood 
(immunophenotyping) will be explored.

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1.
INTRODUCTION
The information given in this section is an overview of the pre-clinical and clinical development 
program for CyPep-1 that underpins the proposed Phase I/IIa clinical trial. Further specific and 
more detailed information is provided in the Investigator’s Brochure (IB) for the Investigational
Medicinal Product (IMP) CyPep-1 injectable solution.
Additionally, this section also contains information on the immune checkpoint inhibitor (ICI) 
pembrolizumab, which will be used in combination with the IMP CyPep-1 in this Phase I/II a 
clinical trial. 
1.1
Name and Description of Investigational Medical Product and of Pembrolizumab
CyPep-1 is a synthetic linear 27-amino acid peptide with an acetylated amino group at the 
N-terminus and an amido group at the C-terminus. All optically active amino acid residues are 
in D-configuration with the exception of achiral glycine. 
CyPep-1 is a white to off-white powder, formulated in a clear and colorless NaCl 0.9% aqueous 
solution (5 mg/mL).
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting 
its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 
2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity and potent 
receptor blocking activity for PD-1. Pembrolizumab has an acceptable preclinical safety profile 
and is in clinical development as an intravenous (IV) immunotherapy for advanced 
malignancies. Keytruda® (pembrolizumab) is indicated for the treatment of patients across a 
number of indications. For more details on specific indications, refer to the IB.
Refer to the IB/approved labeling for detailed background information on pembrolizumab 
(MK-3475).
1.2
CyPep-1 for Treatment of Advanced Solid Cancers
1.2.1
Background
Treatment with ICIs has been shown to result in long lasting anti-tumor responses in selective 
subjects with different tumor indications. However, only a subset of these subjects obtains 
durable remission. Several studies have previously indicated the presence of intratumoral 
CD8+ T cells to be a positive predictive factor for response to ICI therapy (Herbst et al, 2014;
Kitano et al, 2018; Oliva et al, 2019; Prelaj et al, 2019). Thus, treatment strategies aimed at 
recruiting tumor antagonizing cellular components of the immune system hold great promise 
and are currently a main focus in oncology research (Zappasodi et al, 2018).
1.2.2
Clinical Rationale
Current evidence reveals an association between mutational tumor burden and tumor 
immunogenicity (Snyder et al, 2014; Schumacher et al, 2015; Samstein et al, 2019). In order 
to grow, antigenic tumors must develop mechanisms that enable them to evade 
immune-mediated destruction through a process termed immunoediting (Vesely et al, 2013). 
However, while mutational load represents a predictive factor for ICI therapy (Gibney et al, 
2016; Huerter et al 2018), its predictive power is modest; rather, it seems associated with the 
presence of specific neoantigen-generating mutations (Snyder et al, 2014). This observation, 
supported by both preclinical- and clinical-evidence, suggests that a qualitative neoantigen-
directed immunotherapy holds great potential. New therapeutic modalities in this category 
should ideally meet two critical criteria: 1) display tumor specific antigens and 2) induce an 

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inflamed tumor microenvironment. Furthermore, the capacity of such therapeutic modalities 
may result in an extended patient population of responders and potentially increase the 
overall efficacy of ICIs. 
Conceptually, clinical proof-of-concept of this strategy has been established by lytic viruses, 
and preliminary evidence indicates that oncolytic treatment can induce systemic anti-tumoral 
responses (Ribas et al, 2017). Due to its unique antigen-exposing properties (please see the 
IB for further information), CyPep-1 could be a more potent and less toxic oncolytic therapy. In 
addition, CyPep-1 offers attractive pharmacological properties such as long shelf life, easy 
scalability, and negligible batch-to-batch variations. As such, CyPep-1 may represent a unique 
“tumor-agnostic” compound bolstering the effect of established immunotherapy across multiple 
tumor types. Lastly, preclinical studies showing that CyPep-1 can synergize with anti-PD-1
antibody treatment in terms of decreased tumor volumes and prolonged overall survival 
highlight the possible clinical utility of CyPep-1 in the combination setting with ICIs.
Cytovation is developing CyPep-1 for the treatment of advanced solid cancers. This Phase I/IIa
trial will assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of CyPep-1
when administered directly into tumor lesions, in monotherapy and in combination with the 
anti-PD-1 antibody pembrolizumab. Additionally, the trial will assess antitumor effects of 
CyPep-1 on injected lesions and distant non-injected deposits, as well as local and systemic 
immunological effects of CyPep-1, alone and in combination with anti-PD-1.
1.2.3
Treatment with CyPep-1
CyPep-1 is a chemically synthesized peptide with oncolytic properties, whose mode of action 
consists of selective targeting of tumor cell membranes based on their altered molecular 
composition and lysing of tumor cells by removing the surrounding cell membrane. This mode 
of action 1) kills cancer cells, 2) releases tumor antigens and 3) potentially induces a 
tumor-specific immune response by in situ immunization. Preclinical toxicology studies 
have shown a favorable safety profile and potent anti-tumor activity of CyPep-1 in several 
cancer types. CyPep-1 modulates the tumor microenvironment by increasing the presence of 
CD8+ T cells and potentiates the effects of ICIs (please see the IB for further information). As 
such, intratumoral injection with CyPep-1 can transform immunological "cold" and treatment 
resistant tumors into "hot" and immunological active tumors that can be successfully treated 
with immune-modulating agents such as anti-PD-1 antibodies (Figure 1).
Figure 1. Mode of action of CyPep-1.

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1.3
Pharmaceutical and Therapeutic Background of Pembrolizumab
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades (Disis, 2010). Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in 
various malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; 
hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. Tumor-infiltrating 
lymphocytes can be expanded ex vivo and reinfused, inducing durable objective tumor 
responses in cancers such as melanoma (Dudley et al., 2005; Hunder et al., 2008).
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T-cells 
under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) 
superfamily member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor 
signaling upon engagement of its ligands (PD-L1 and/or PD-L2) (Greenwald et al., 2005;
Okazaki et al., 2001).
The structure of murine PD-1 has been resolved (Zhang et al., 2004). PD-1 and its family 
members are type I transmembrane glycoproteins containing an Ig-variable–type (IgV-type) 
domain responsible for ligand binding and a cytoplasmic tail responsible for the binding of 
signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, 
an immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif. Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and 
SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading 
kinase 
C-
-chain-associated protein kinase (ZAP70), which are involved in the 
CD3 T-cell signaling cascade (Okazaki et al., 2001; Chemnitz et al., 2004; Sheppard et al., 
2004; and Riley, 2009). The mechanism by which PD-1 down-modulates T-cell responses is 
similar to, but distinct from, that of CTLA-4, because both molecules regulate an overlapping 
set of signaling proteins (Parry et al., 2005; Francisco, 2010). As a consequence, the PD-1/PD-
L1 pathway is an attractive target for therapeutic intervention in subjects with locally advanced 
or metastatic disease.
1.4
Population to be Studied
Phase I and IIa CICILIA:
Histologically or cytologically confirmed locally advanced (unresectable) or metastatic tumors 
(solid tumors or lymphoma) with an accessible tumor lesion for intratumoral injection of 
CyPep-1 that meet one of the following criteria:
a. Relapsed following or progressed through standard therapy.
b. Have a disease for which no standard effective therapy exists.
1.5
Non-Clinical Data of CyPep-1
The nonclinical studies of CyPep-1 conducted to date, which include pharmacology, 
pharmacokinetics and metabolism, and toxicology studies, were designed to support the 
initiation of clinical trials in subjects with solid tumors (CyPep-1 solution formulation;
Appendix A).

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More than eleven nonclinical studies performed to date indicate the following with regard to 
the nonclinical profile of CyPep-1:
Pharmacology
In vitro experiments were performed with multiple cancer cell lines and normal human cells. 
CyPep-1 exerted a rapid cytotoxic effect on cancer cells and scanning electron microscopy 
demonstrated a dose dependent membranolytic effect. The compound was further tested
in vivo in a 4T1 murine breast cancer model. A significant reduction in tumor growth was 
observed in the tumors of the treatment group with an average volume of 1.1 cm3, whereas 
the control tumors had grown to an average size of 3.5 cm3 (p<0.0001) after 24 days 
(Szczepanski et al, 2014). The survival analyses showed that the animals assigned to the 
treatment group lived significantly longer (median survival: 32 days) than those of the control 
group (median survival: 20 days), indicating a clear treatment effect of CyPep-1 (Szczepanski 
et al, 2014). Similar results were observed in the B16-F10 melanoma and CT26 colorectal 
adenocarcinoma mouse models, where CyPep-1 potentiated the effect of checkpoint inhibition.
Treatment led to reduced tumor-volume and -weight, and increased survival. Lastly, preclinical 
studies in mice with B16-F10 melanoma tumors showed a reduction in both primary and 
contralateral tumor volumes, of which the primary tumors were injected with CyPep-1. The 
reduction in tumor volumes was enhanced when CyPep-1 was administered in combination 
with an anti-PD-1 antibody. This highlights the capacity of CyPep-1, either alone or in 
combination with an anti-PD-1 antibody, to delay growth of injected and non-injected tumors. 
No immunogenic effects have been observed with CyPep-1 in heathy animals (please see the 
IB for further information).
Pharmacokinetics
Radioactive labelled CyPep-1 was administered systemically to a Wistar rat model 
(Szczepanski et al, 2014). The basic pharmacokinetic profiles showed distribution to and 
accumulation in the liver, spleen, and kidneys. The half-live of CyPep-1 in plasma was 
3.15 min. In a recent study (B-02852), the PK profile after a single intravenous (bolus) or 
subcutaneous administration of CyPep-1 to Sprague-Dawley rats was further assessed. 
Neither severe clinical observations, nor mortality or premature sacrifice were reported during 
the duration of the study. Irrespective of the type of administration, no treatment-related effects 
were observed up to the end of the observation period (6 hours post-dose). After a single 
intravenous administration at dose levels of 0.5, 1.0 and 3.0 mg/kg, the concentration of 
CyPep-1 in rat plasma reached the highest concentration (329.0, 724, and 3620 ng/mL, 
respectively) at 5 min. Thereafter, the test item concentration decreased gradually, being 
below the lower limit of quantification 6 hours after administration. After a single subcutaneous 
administration at a dose level of 3.0 mg/kg, the concentration of CyPep-1 in rat plasma reached 
the highest concentration (31.3 ng/mL, respectively) at 15 min after the administration. 
Thereafter, the test item concentration decreased gradually, being below the lower limit of 
quantification 2 hours after administration. The bioavailability was 4.78%.
Toxicity
In animal studies, CyPep-1 was administered IV (0.5 mg/kg to 20 mg/kg in rats and 0.1 mg/kg 
to 7 mg/kg in dogs; Study 507379) or topically (formulated as 1.0% cream; AB22310 and 
AB22311). For all Good Laboratory Practices (GLP) studies, the test products contained 
CyPep-1 alone or with compendial excipients that have been previously approved for use in 

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pharmaceutical and dermatologic products. The following conclusions were derived from the 
toxicity studies of IV CyPep-1 (Appendix A):
Systemic administration of CyPep-1 was well tolerated in rats at levels of up to 
10 mg/kg upon single IV bolus injection, and at levels of 3 mg/kg/day upon repeat 
(7-day) IV bolus administration (Study 506066)
At a dose of 0.5 mg/kg/day, systemic administration of CyPep-1 was well tolerated for 
4 weeks, with no clinical signs observed and minimal pathology findings 
(Study 506092). 
There were no CyPep-1-related effects on body weight, body temperature, pupil size 
(Study 614721), respiratory rate, tidal volume, and minute volume (Study 614716) at 
single IV doses of 0.5, 1, or 3 mg/kg
CyPep-1 is not mutagenic in a standard battery of in vitro and in vivo genotoxicity tests 
(Studies 01027002, 01027003)
No cardiotoxicity was observed upon CyPep-1 administration (Study 614700)
Upon sub-cutaneous administration of 3 mg/kg in rats, CyPep-1 could not be detected 
in plasma after 2 hours.
Based on the non-clinical development programs completed to date, the safety profile of 
CyPep-1 has been established. The non-clinical program supports the use of CyPep-1 in 
clinical trials. 
Details of the results for the pre-clinical testing of CyPep-1 can be found in the IB and in the
Investigational Medicinal Product Dossier (IMPD).
1.6
Clinical Data of CyPep-1
1.6.1
Safety and Efficacy of CyPep-1
The intratumoral formulation of CyPep-1 has not yet been assessed in clinical trials. All
available safety information for Phase I of this ongoing trial is summarized in the IB (please 
see V3.0). Overall, no DLTs or any CyPep-1-related SAE were reported.
A randomized, placebo-controlled, double-blind, single center Phase I trial to explore safety, 
tolerability, and pharmacodynamics of CyPep-1 as topical formulation (1.0% w/w cream) 
administered to subjects with cutaneous human papillomavirus (HPV) warts has been 
completed.
The primary objectives are to evaluate safety and tolerability of CyPep-1 when applied to 
healthy skin for up to one week and cutaneous warts for up to four weeks. The trial has no 
secondary objectives. The exploratory objectives are to evaluate the activity and explore the 
efficacy of CyPep-1 across wart subgroups defined by HPV-type and lesion age, after four 
weeks of treatment, and after six and twelve weeks of post-treatment follow-up, when applied 
to cutaneous common warts. 
The trial has two parts: Part 1 follows a target area of 5x5 cm healthy skin to study tolerability 
and safety of the formulation. During this part, also a maximum of three common warts, 
preferably at the dorsal or palmar side of the hand / finger(s), are treated. Several assessments
are performed to determine pharmacodynamics and to explore possible efficacy after a 
treatment period of 1 week.
Part 2 evaluates the pharmacodynamics and efficacy of CyPep-1 after a treatment period of 
4 weeks and is planned to be initiated after the execution of an interim analysis (a blind data 
review) of Part 1.

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In total, 8 subjects with at least one common wart of 3-10 mm located, preferably, at the dorsal 
or palmar side of the hand / finger(s) were enrolled (N=4 active, N=4 placebo). A target area 
of 5x5 cm of healthy skin on the upper back as well as 1-3 common warts were treated for 
1 week on a daily basis with CyPep-1/placebo topical cream (0.15 mg/wart). Study medication 
was applied under occlusion using respectively hypoallergenic transparent film dressings for 
common warts (2 x 2 cm) and the upper back (6 x 7 cm). The treated areas were occluded up 
to 24 hours.
The interim study analysis performed on the subjects treated with CyPep-1 cream in Part 1 of 
the trial revealed no serious adverse events (SAEs). The majority of AEs were of mild nature 
and non-treatment emergent. Five AEs were classified as moderate, four of which were 
classified as non-treatment emergent (2 headaches, increase in transaminases and 
erysipelas) and one classified as treatment-emergent (headache). One AE was classified as 
severe: vasovagal collapse during blood sampling and considered as non-treatment emergent. 
A small number of AEs were classified as treatment emergent (coded as possibly related to 
the IMP) because they occurred within hours after IMP administration. The concomitant 
medication that was used post-dose was related to treatment of AEs. Besides a transient 
elevation of transaminases in one subject, there were no clinically significant changes 
observed in vital signs, laboratory values or electrocardiogram (ECG). In general, the IMP 
topical administration was well tolerated, and no systemic trends were noted in any of the 
parameters measured. No discontinuations due to AEs occurred and no treatment
interruptions were necessary. Furthermore, since the randomization is 1:1, the AEs seemed
rather evenly distributed and presumably comparable between the CyPep-1 cream and
Placebo groups. Therefore, it can be concluded that seven consecutive days of topical 
application of CyPep-1 cream on the warts as well on an enlarged surface of 25cm2 was safe 
and locally very well tolerated. Part 2 of the trial, assessing efficacy of CyPep-1, is ongoing. 
In conclusion, the results of the preclinical studies with CyPep-1 and those of the interim 
analysis of the aforementioned clinical trial with CyPep-1 as topical formulation, including the 
favorable tolerability profile, support the initiation of clinical trials in subjects with solid tumors 
(CyPep-1 solution formulation). 
1.7
Pre-clinical and Clinical Trials with Pembrolizumab
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T cells and ultimately 
leads to tumor rejection, either as a monotherapy or in combination with other treatment 
modalities (Hirano, 2005; Blank, 2004; Weber, 2010; Strome, 2003; Spranger, 2014;
Curran, 2010; Pilon, 2010).
Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have 
demonstrated antitumor responses in models of squamous cell carcinoma, pancreatic 
carcinoma, melanoma, acute myeloid leukemia and colorectal carcinoma (Strome, 2003;
Curran, 2010; Pilon, 2010; Nomi, 2007; Zhang, 2004). In such studies, tumor infiltration by 
CD8+ T cells and increased IFN-
indicating that the mechanism underlying the antitumor activity of PD-1 checkpoint inhibition 
involved local infiltration and activation of effector T cell function in vivo (Curran, 2010).
Experiments have confirmed the in vivo efficacy of anti-mouse PD-1 antibody as a 
monotherapy, as well as in combination with chemotherapy, in syngeneic mouse tumor models 
(see the IB).
1.8
Justification for Pembrolizumab Dose
The planned dose of pembrolizumab for this trial is 400 mg every 6 weeks (Q6W).
A 400 mg Q6W dosing regimen of pembrolizumab is expected to have a similar benefit-risk 
profile as 200 mg Q3W, in all treatment settings in which 200 mg Q3W pembrolizumab is

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currently appropriate (Lala et al., 2020). Specifically, the dosing regimen of 400 mg Q6W for 
pembrolizumab is considered adequate based on modeling and simulation (M&S) analyses, 
given the following rationale:
Pharmacokinetic (PK) simulations demonstrating that in terms of pembrolizumab 
exposures –
o
Average concentration over the dosing interval (Cavg) (or area under the curve 
[AUC]) at 400 mg Q6W is similar to that at the approved 200 mg Q3W dose, thus 
bridging efficacy between dosing regimens.
o
Trough concentrations (Cmin) at 400 mg Q6W are generally within the range of those 
achieved with 2 mg/kg or 200 mg Q3W in the majority (>99%) of patients.
o
Peak concentrations (Cmax) at 400 mg Q6W are well below the Cmax for the highest 
clinically tested dose of 10 mg/kg Q2W, supporting that the safety profile for 400 mg 
Q6W should be comparable to the established safety profile of pembrolizumab. 
o
Exposure-response (E-R) for pembrolizumab has been demonstrated to be flat 
across indications, and OS predictions in melanoma and non-small cell lung cancer 
(NSCLC) demonstrate that efficacyat 400 mg Q6W is expected to be similar to that 
at 200 mg or 2 mg/kg Q3W, given the similar exposures; thus 400 mg Q6W is 
expected to be efficacious across indications.
1.9
Potential Risks and Benefits
1.9.1
Risks
In toxicology studies in mice, CyPep-1 administered as IV solution or topical cream was well 
tolerated for up to four weeks at doses higher that those planned to be used in this trial, with 
no clinical signs observed and minimal pathology findings. At single IV doses of 0.5, 1, or 
3 mg/kg administered to rats, CyPep-1 had no effects on body weight, body temperature, pupil 
size, respiratory rate, and tidal and minute volume. In addition to the lack of effects listed 
above, in multiple in vitro (0.025 mg/mL) and in vivo (most commonly used: 5 mg/mL) studies, 
CyPep-1 had no mutagenic or cardiotoxic effects. Therefore, no specific adverse reactions are 
to be inferred at the clinical starting dose of 0.5 mg/mL of CyPep-1 or the subsequent proposed 
doses as “expected” based on preclinical experience. 
Nevertheless, CyPep-1 is a soluble synthetic peptide with the potential risk of inducing allergic 
reactions. Possible AEs associated with an allergic reaction can include fever, chills, 
headache, weakness, nausea, vomiting, diarrhea, low blood pressure, respiratory symptoms, 
and rashes. Additionally, since the mode of action of CyPep-1 includes potential stimulation of 
the immune response, there is a likelihood of immune-related AEs. Generally, such AEs have 
been observed after specific blocking of inhibitory receptors expressed on T cells (e.g. PD-1) 
rather than after induction of tumor-specific immune responses. If CyPep-1 elicits a particularly 
strong T-cell immune response in a few subjects predisposed to develop autoimmunity, 
immune-related AEs may nonetheless be observed. 
In addition to potential risks related to administration of CyPep-1 (e.g. leakage into circulation),
there are also procedural risks related to blood sampling, other possible subcutaneous 
injections and diagnostic procedures. Blood sampling and subcutaneous injections may cause 
pain, bleeding, bruising, and/or infections at the site of cannula insertion. Rare complications 
due to blood sampling are syncope, thrombophlebitis, as well as accidental punctures of an 
artery or nerve.
The risks of pembrolizumab administration are detailed in the IB of the compound.
Pembrolizumab has been documented to cause immune-related adverse reactions, for which 
a series of measures are recommended (see Section 3.1.2 and Section 5.3.6).

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1.9.2
Benefits 
This is the first clinical trial with the CyPep-1 injectable solution. The principal aim of this trial 
is to obtain safety and preliminary efficacy data when CyPep-1 is intratumorally administered 
to subjects with solid tumors for whom no other treatment options currently exist, as 
monotherapy and in combination with pembrolizumab. In addition to the minimal risk using the
starting dose of 0.5 mg/mL of CyPep-1, preclinical experience as well as the safety profile of 
cohort 1 with the compound indicate a potential benefit that might be expected in terms of 
clinical efficacy. Preclinical assays describing the synergy of CyPep-1 with anti-PD-1 antibody 
treatment indicates the potential benefit of this therapeutic combination in patients with cancer. 
The safety and efficacy data, together with the pharmacokinetic and pharmacodynamic data
obtained from this trial, will help establish the treatment regimen and recommended doses 
suitable for subsequent clinical trials in the target population. Treatment of subjects with 
CyPep-1, as monotherapy and in combination with pembrolizumab, is hypothesized to result 
in improvement or stabilization of the disease state of the subjects.
1.9.3
Management of Risks
To minimize the risk to subjects and maximise safety, the following factors have been 
incorporated into the study design. Detailed safety and laboratory assessments will be 
performed.
All clinical observations will be evaluated by the investigator on an ongoing basis.
Each subject must stay on site for at least 4 hours after study drug administration on 
each treatment day (vital signs will be assessed on each treatment day pre-dose and 
at 15 minutes, 30 minutes, and 1, 2, and 4 hours post-dose during the first treatment 
cycle and on Day 1 of each additional treatment cycle). If only pembrolizumab is 
administered, subjects are not required to stay at the site for 4 hours for vital signs 
assessments. For Arm D, for subjects who have no clinically significant abnormal vital 
signs reported during the first four doses of CyPep-1 (in Week 1 to 4), the post-dosing 
safety monitoring at the clinic can be shortened to 1 h on all the subsequent dosing 
days.
Premedication is mandatory prior to the first IT dose of CyPep-1. Premedication is 
started 30-60 minutes before the IT injection, and continues for up to 24-48 hours after 
the procedure was completed, if necessary. An antihistamine (e.g., 25 to 50 mg 
clemastine) is mandatory with optional anxiolytics if deemed appropriate by the 
investigator. Only for subjects experience pain during or after IT administration, it is 
recommended to provide celecoxib 400 mg as premedication every 6 hours for 24-48 
hours. Premedication should be administered for subsequent CyPep-1 doses based 
upon clinical judgment and presence/severity of prior reactions. This regimen may be 
modified based on local treatment standards and guidelines as appropriate.
For all subjects in Phase I, the first 3 subjects in Arm B, and the subjects in Arm C 
cohort 4, there must be a window of at least 24 hours between each subject’s treatment 
start. This is not applicable for the subjects in Phase IIa Arm A, remaining subjects in 
Arm B, Arm C cohort 5, and Arm D.
CyPep-1 will not be administered if at the time of the planned administration the subject 
is suffering from severe infection or receiving steroid-based immunosuppressive 
therapy (excluding topical steroids).
The study agent must be administered in a clinical setting where emergency 
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immediately available to treat systemic reactions under the direct supervision of a 
physician.
To minimize the risks to subjects upon administration of pembrolizumab, the following 
measures are recommended, depending on the situation (Sections 5.3.6.2 and 5.3.6.3 for 
complete list of considerations on dose modification of pembrolizumab based on the 
occurrence and severity of immune- or infusion-related AEs):
Suspected Stevens-Johnson syndrome or toxic epidermal necrolysis: withhold until 
recovery to Grades 0-1; if this does not occur within 12 weeks after last dose of 
equivalent per day within 12 weeks, pembrolizumab should be permanently 
discontinued.
Confirmed Stevens-Johnson syndrome or toxic epidermal necrolysis: permanent drug 
discontinuation.
Grade 3 or 4 myocarditis, encephalitis, or Guillain-Barre syndrome: withhold until 
recovery to Grades 0-1 or, if above conditions apply, permanently discontinue.
Phase IIa Arm B:
CyPep-1 monotherapy can continue if there is unacceptable toxicity to pembrolizumab. 
Pembrolizumab monotherapy can continue if there is unacceptable toxicity to CyPep-1.
Related dose modification rules for CyPep-1 and pembrolizumab is detailed in Section 5.3.6).
1.9.4
Benefit/Risk Ratio
The anticipated risks, based on the non-clinical experience with the CyPep-1 injectable 
solution
and the clinical experience with the standard of care anti-PD-1 antibody 
pembrolizumab, are expected to be manageable. The importance of the objective of this trial 
is considered to outweigh the risks and burdens to the subjects. Measures are implemented 
to minimize burdens and risks for subjects. Subjects will be monitored closely for the 
occurrence of any significant clinical events and treatment will only continue if it is considered 
safe and appropriate to do so. The benefit/ risk assessment is favorable and justifies the 
planned trial in subjects with solid tumors at a situation with no therapeutic options available.

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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
Objectives
2.1.1
Primary Objectives
The primary objectives are:
To evaluate the safety and tolerability of intratumoral administration of CyPep-1, as 
monotherapy and in combination with pembrolizumab.
To identify the recommended phase II dose (RP2D) of CyPep-1, as monotherapy and 
in combination with pembrolizumab.
2.1.2
Secondary Objectives
The secondary objectives are:
To assess the preliminary anti-tumor efficacy of CyPep-1, as monotherapy and in 
combination with pembrolizumab.
To characterize the pharmacokinetics (PK) of CyPep-1.
2.1.3
Exploratory Objectives
The exploratory objectives are:
To assess the preliminary anti-tumor efficacy of CyPep-1, as monotherapy and in 
combination with pembrolizumab, in injected lesions and non-injected lesions,
separately.
To assess survival after treatment with CyPep-1, as monotherapy and in combination 
with pembrolizumab.
To assess the immune mondulating properties of treatment with CyPep-1, as 
monotherapy and in combination with pembrolizumab.
2.2
Endpoints
2.2.1
Primary Endpoints
The primary endpoints are:
Type and number of AEs according to National Cancer Institute (NCI) – Common 
Terminology Criteria for Adverse Events (CTCAE) criteria v5.0, and additional safety 
parameters of CyPep-1 as monotherapy and in combination with pembrolizumab.
Dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD) for
determination of RP2D of CyPep-1 as monotherapy and treatment-limiting toxicities 
(TLTs) of CyPep-1 in combination with pembrolizumab.

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2.2.2
Secondary Endpoints 
The secondary endpoints are:
Objective response rate (ORR), defined by complete and partial responses, according 
to immune Response Evaluation Criteria in Solid Tumors (iRECIST) based on the 
investigator’s assessment.
Time to and duration of response and duration of stable disease.
The plasma concentration time profile of CyPep-1 and, if detectable, the derived PK 
parameters (i.e., area under the curve [AUC], peak plasma concentration [Cmax], time 
to reach Cmax [tmax], systemic clearance [CL], elimination half-life [t1/2] and volume of 
distribution [VD]).
2.2.3
Exploratory Endpoints
The exploratory endpoints are:
For all Phase IIa arms: ORR in injected lesions and non-injected lesions, separately,
per itRECIST* [Goldmacher 2020]).
Progression-free survival (PFS) per iRECIST based on the investigator’s assessment.
Overall survival (OS).
The relative change in number of tumor infiltrating CD8+ T-cells in the injected and,
whenever available, non-injected tumor biopsies.
The association between the relative change in tumor infiltrating CD8+ T-cells and 
response rate in the injected lesions (per itRECIST) and all lesions (per iRECIST).
The change in T-cell receptor (TCR) clonality levels in peripheral blood and (when 
available) biopsied lesions.
Changes in the tumor microenvironment (injected
and, whenever available, 
non-injected tumor biopsies) via expression of selected candidate immune markers:
 
 
 
For Arms A, B, and C: 
Peripheral blood phenotyping of selected immune cell markers.
*itRECIST will be programatically calculated using data obtained from iRECIST assessments 
following the itRECIST principle summarized in Appendix F Figure 1.

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3.
TRIAL DESIGN 
3.1
Overall Trial Design
This is a combined Phase I/IIa, open-label, dose escalation followed by dose expansion trial 
in subjects with advanced solid cancers. The trial consists of two phases and multiple arms,
as shown in the diagram below (Figure 2).
Figure 2. Schematic trial design 
Phase I (dose escalation, N=12) and Phase IIa (dose expansion Arm A N=9*; combination 
Arm B N=15 and dose expansion liver metastases Arm C, N=9; dose expansion melanoma 
Arm D, N= 30).
Abbreviations: RP2D: recommended phase 2 dose.
*In case in the first 12 subjects at RP2D, a responder per iRECIST (ORR based on best response or 2 subjects 
with stable disease per iRECIST are observed (SD based on duration >16 weeks from onset of SD), the number 
of subjects will be expanded to a total of 24 (CyPep-1 monotherapy; cohort 3 of Phase I and in Phase IIa Arm A).
Phase I– dose escalation:
In this phase of the trial, safety and tolerability will be documented and the MTD/RP2D will 
be determined. Cohorts of 3 subjects will receive intratumoral injections with CyPep-1. The 
DLT observation period for each dose level will be 6 weeks (5 weeks of trial treatment and 
1 week of safety follow-up). The following CyPep-1 administrations are planned as 
continuous Q2W administrations.
Screening will occur during the 4 weeks prior to start of CyPep-1 treatment.
In three dose cohorts of 3 subjects each, subjects will receive CyPep-1 intratumorally at 
different concentrations (dose escalation) and volumes (depending on tumor size), i.e., 

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0.5 mg/mL, 2 mg/mL, or 5 mg/mL, respectively. These dose concentrations have been 
selected based on previous preclinical experience with CyPep-1.
Dose escalation (Phase I of the trial) will be conducted to determine the MTD or RP2D using 
a standard “3+3” design, with at least three subjects treated at each dose-level. Arm C (from 
Phase IIa) will follow a similar dose escalation of two dose levels (RP2D and the dose 
immediately below). Dose escalation will proceed according to the following rules:
Number of subjects with 
DLT*
Escalation decision rule
0 out of 3 subjects
Enter 3 subjects at the next planned dose level.
1 out of 3 subjects
Enter 3 additional subjects at this dose level:
If 0 of these additional subjects experience a DLT, proceed 
to the next dose level.
If 1 or more of the additional 3 subjects experience a DLT, 
then dose escalation to higher dose levels is stopped. 
Three additional subjects may be entered at the second 
highest dose if only 3 subjects have been treated at that 
dose level. Alternatively, a new dose level may be 
introduced between the second highest dose and the MTD 
(3 additional subjects).
highest dose level below 
the MTD
This dose level is declared the MTD or RP2D.
*Assessed as related to the trial drug (CyPep-1) at any given dose level.
Each subject will receive IT injection(s) with CyPep-1 in Week 1, 3, and 5, respectively. After 
each CyPep-1 administration, subjects will be required to stay at the clinic for at least 4 hours
for safety and, for those in which PK will be assessed, also for PK monitoring. The data from 
the additional three subjects in cohort 3 will be used for further confirmation of RP2D. 
For each dose cohort, at least 24 hours must elapse between each subject to start treatment 
with CyPep-1. No intra-subject dose escalation is allowed.
In Phase I, subject replacement for subjects that drop out for any reason, except DLTs, will 
only occur before the DLT observation period is completed and is allowed if a subject does 
not receive all three CyPep-1 administrations, unless due to CyPep-1-related toxicity. No 
subject replacement will occur for subjects who withdraw later. 
After completion of Phase I, all results will be evaluated by the DEC. This will include safety
data and if available, other supportive clinical data (i.e. efficacy, pharmacokinetics, tumor 
biopsy analyses) from all subjects included in Phase I of the trial. The DEC will confirm the 
MTD or RP2D (in case the MTD is not reached).
All additional arms of the CICILIA trial can start once Phase I data has been evaluated by the 
DEC and an MTD or RP2D is confirmed for CyPep-1.
Phase IIa – dose expansion (Arm A):
In this phase, safety and tolerability will be further evaluated in an expanded cohort of 
9 subjects at the RP2D of CyPep-1, determined in Phase I. Screening and CyPep-1

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administration will be according to the schedule described for Phase I , except for the 24-h
observation period before start of treatment of the next subject, which is not applicable.
In case in the first 12 subjects at RP2D, a responder per iRECIST (ORR as CR/PR as best 
response) or 2 subjects with stable disease (SD with duration >16 weeks from onset) per 
iRECIST are observed, the number of subjects will be expanded to a total of 24 (CyPep-1
monotherapy; subjects cohort 3 of Phase I and in Phase IIa Arm A).
Phase IIa – combination arm (Arm B):
The safety and tolerability of CyPep-1 in combination with pembrolizumab will be evaluated in 
a cohort of 15 subjects in total, using a staggered approach. Initially, 3 subjects will receive 
CyPep-1 at RP2D in combination with pembrolizumab and each subject will be observed for 
24 h before the next subject can be administered with CyPep-1. After the first 3 subjects 
completed the TLT observation period of 6 weeks with no TLTs observed and after reviewing 
the safety data (including TLTs) by the DEC, the inclusion of all remaining subjects at RP2D 
of CyPep-1 in combination with pembrolizumab can be initiated. In the absence of any TLTs, 
the 24-h observation period before start treatment of the next subject is no longer applicable. 
Should any TLTs be observed in the first 3 subjects at the RP2D of CyPep-1 in combination 
with pembrolizumab, an additional 3 subjects will be included in this dose group.
6 subjects have a TLT, the remainder of the 15 subjects will be treated at the RP2D. In the 
unlikely case that 2 or more of the 6 subjects experience any TLTs at RP2D of CyPep-1, a 
recommendation to dose de-escalate and to what dose or to continue the combination part of 
the trial will be made by the DEC. The same screening is planned, and CyPep-1 will be 
administered according to the same schedule as in Phase I.
Scheduling of treatment of CyPep-1 and pembrolizumab (Arm B) will be as follows: CyPep-1
will be administered every 2 weeks (Q2W) and pembrolizumab will be administered following 
a Q6W schedule starting on Day 1, as per standard of care. Radiological assessment to 
determine occurrence of (un)confirmed PD will be performed Q8W from the start of treatment. 
Treatment will continue until confirmed PD, unacceptable toxicity or consent withdrawal, loss 
to follow up, or trial end, whichever occurs first.
Phase IIa – dose expansion liver metastases (Arm C):
The safety and tolerability of at least two dose levels of CyPep-1, namely the RP2D and the 
dose immediately below that, are planned to be evaluated when CyPep-1 is administered 
intratumorally using ultrasound guidance to one metastatic lesion in the liver. The two dose 
levels are planned to be investigated adhering to the 3+3 design and will follow the procedures
as described for the dose escalation (Phase I) (Section 3.1). The first three subjects will receive 
CyPep-1 at the lower dose level and each subject will be observed for 24 h before CyPep-1
administration to a next subject (cohort 4). After the third subject at that dose finished the DLT 
observation period of 6 weeks (5 weeks CyPep-1 treatment plus 1 week safety follow-up), the 
DEC will decide on the start of the cohort to be administered at RP2D based on the review of 
the safety data (cohort 5). In the absence of any DLTs in the first 3 subjects, the 24-h
observation period before start treatment of the next subject is not applicable. After the DLT 
observation period for the first three subjects at RP2D for CyPep-1 and the review of all safety 
data, the DEC will recommend on the inclusion of all remaining subjects. Should a DLT be 
observed in the first three subjects at the RP2D of CyPep-1, an additional three subjects in this 
dose group will be included. In case that two or more subjects experience DLTs at RP2D of 
CyPep-1, a recommendation to dose de-escalate and to what dose and how to continue Arm 
C will be made by the DEC.
Phase IIa – dose expansion melanoma subjects (Arm D):

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The safety and tolerability of CyPep-1 at RP2D will be further evaluated with focus on 
assessing efficacy signals of CyPep-1 monotherapy in up to 30 subjects with melanoma. 
Although safety information will be collected, there will not be a formal DLT observation period. 
The dosing scheme starts with a once weekly (QW) CyPep-1 administration until the second 
iRECIST/itRECIST assessment at week 16, followed by a Q2W dosing scheme. 
As part of the continuous safety monitoring of the trial, reports with cumulative safety data of 
Arm D subjects will be shared with all investigators, competent authorities, and ethical 
committees of countries where the trial is conducted at the following time points:
After the first three subjects completed three weeks of treatment with CyPep-1.
After the first three, six, and 12 subjects completed six weeks of treatment with 
CyPep-1.
In the occurrence of AEs fulfilling DLT criteria or other safety alters, the DEC will convene to 
review the safety data and provide recommendations on the continuation of dosing.
For both phases and all trial arms, subjects will stay in the trial until end of trial or until confirmed 
disease progression, unacceptable toxicity, death or discontinuation for any other reason.
Information regarding subject replacement for each arm is detailed in Section 4.3.2.
3.1.1
Dose Escalation Committee 
The decisions on dose escalation and CyPep-1 MTD/RP2D will be taken by the Dose 
Escalation Committee (DEC) after reviewing safety data (including DLTs) from all subjects who 
have entered Phase I of the trial and have completed the DLT observation period. 
The DEC will review all data after all subjects in the highest dose cohort completed DLT 
observation period and before enrolment of subjects in the expansion cohort at RP2D in 
monotherapy and combination with pembrolizumab cohort can be initiated. 
For Phase IIa of the trial, the decision to de-escalate the dose of CyPep-1 based on observed 
the severity and relatedness of safety events (DLT/TLT criteria for CyPep-1) and to what dose
(either dose level of the next lowest dose level from Phase I or 50-70% of current dose level),
will also be made by the DEC after reviewing available safety data (including TLTs). Dose 
modifications for pembrolizumab in the combination arm will also be taken into consideration 
(refer to Section 5.3.6).
Based on the review of this data, recommendations will be made regarding the further conduct 
and the scientific and ethical integrity of the trial. 
The DEC is comprised of all the investigators or designees, as well as the medical monitor and 
representatives of the sponsor. The DEC, chaired by the medical monitor, will strive for a 
consensus opinion regarding the data reviewed. If DEC consensus is not possible, the DEC 
chair will assemble and present majority and dissembling opinions for all recommendations
considered. If any of the DEC members cannot be present during the meeting due to the short 
notice, the DEC will be held (not postponed) provided that a minimum of 2 members are 
present. The DEC members may be allowed to provide their recommendations electronically 
to the DEC chair, prior to the meeting.
At the end of the DEC teleconference, the DEC will provide one of the following 
recommendations to the sponsor:
1.
The trial is proceeding in line with the trial protocol.
2.
The trial is not proceeding in line with the trial protocol and/or there is a possible change 
in the benefit/risk ratio. 

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The sponsor will act upon these recommendations as appropriate, i.e., the final decision will 
rest with the sponsor. The sponsor designee will notify the trial team (i.e., the responsible 
project manager at 
) of the final decision regarding the DEC recommendations, 
including any actions to be taken. The 
project manager will communicate the DEC 
recommendations and/or final decision of the sponsor to all investigators, Independent Ethics 
Committees (IECs) and Competent Authorities (CAs), if applicable.
3.1.2
Dose Limiting Toxicities / Treatment Limiting Toxicities
A DLT is defined by the occurrence of any of the following toxicities according to CTCAE v5.0 
during treatment Cycle 1 and that are considered by the investigator to be possibly, probably, 
or definitely related to CyPep-1:
3.
AEs of any etiology, except:
o
Nausea, vomiting, or diarrhea will be considered a DLT only if it persists at 
investigator’s discretion, subjects who experience nausea, vomiting, or 
diarrhea after receiving CyPep-1 may receive antiemetic or anti-diarrheal 
medication prior to subsequent doses of CyPep-1.
o
therapeutic intervention.
o
o
For Phase I, Arms A and C:
Alanine amino transferase (ALAT) or Aspartate amino transferase 
(ASAT) toxicities:
ALAT or ASAT > 5 x upper limit of normal (ULN) (> 7.5 x ULN for 
subjects with liver metastases), unless greater than 14 days.
ALAT or ASAT > 5 x ULN (> 7.5 x ULN for subjects with liver 
metastases) accompanied by an elevation in total bilirubin of > 2.5 x 
ULN (not explained by obstruction), regardless of duration, will be 
considered a DLT.
4.
Any other toxicity occurring at any time during the trial that in the view of the 
participating investigators and the medical monitor represents a clinically significant 
hazard to the subject.
All TLTs will be graded using NCI CTCAE v5.0 based on the investigator assessment. The
TLT window of observation will be during Cycle 1.
The occurrence of any of the following toxicities during Cycle 1 will be considered a TLT, if 
assessed by the investigator to be possibly, probably, or definitely related to trial treatment 
administration. 
1.
Grade 4 nonhematologic toxicity (not laboratory).
2.
days, except thrombocytopenia:
Grade 4 thrombocytopenia of any duration
Grade 3 thrombocytopenia associated with clinically significant bleeding
3.
Any non-
TLT, with the 
usea, or 
vomiting without use of anti-emetics or anti-diarrheal per standard of care; Grade 3 
rash without use of corticosteroids or anti-inflammatory agents per standard of care.
4.
Any Grade 3 or Grade 4 non-hematologic laboratory value if:
Clinically significant medical intervention is required to treat the participant or
The abnormality leads to hospitalization, or
The abnormality persists for >1 week.

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The abnormality results in a Drug-induced Liver Injury (DILI) 
Exceptions: 
Clinically 
nonsignificant, 
treatable, 
or 
reversible 
laboratory 
abnormalities including liver function tests, uric acid, etc.
5.
Febrile neutropenia Grade 3 or Grade 4:
Grade 3 is defined as ANC <1000/mm3 with a single temperature of >38.3 degrees 
C (101 degrees F) or a 
for more than 1 hour
Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3 degrees 
for more than 1 hour, with life-threatening consequences and urgent intervention 
indicated.
6.
Prolonged delay (>2 weeks) in initiating Cycle 2 due to treatment-related toxicity.
7.
Any treatment-related toxicity that causes the participant to discontinue treatment 
during Cycle 1.
8.
Missing >25% of CyPep-1 doses as a result of drug-related AE(s) during the first cycle.
9.
Grade 5 toxicity.
3.2
Measures to Minimize Bias
This is an open-label non-randomized trial; blinding and randomization are not applicable.
3.3
Duration of Subject Participation
Each subject will undergo up to 4 weeks of screening, followed by a DLT/TLT observation 
period of 6 weeks (5 weeks of CyPep-1 treatment plus 1 week observation). In absence of 
DLT/TLTs, treatment continues with Q2W intratumoral injections of CyPep-1. For the 
combination arm (Arm B), plus Q6W administration of pembrolizumab for up to 24 months (18 
cycles). For Arm D, after screening, each subject will undergo QW CyPep-1 treatment until the 
second iRECIST/itRECIST assessment at week 16, followed by a Q2W dosing scheme. 
Continuous treatment cycles of CyPep-1 and/or pembrolizumab are planned and should follow 
the Q2W administration schedule until confirmed PD, unacceptable toxicity, death, or consent 
withdrawal, loss to follow up, or trial end, whichever occurs first.
Hereafter, there will be efficacy (PFS) follow-up every 8 weeks, or until confirmed PD, death, 
withdrawal of consent, loss of subject to follow-up, or trial end, whichever occurs first.
Start of inclusion: Q1 2020
Planned last subject last follow-up visit: last subject’s last visit for follow-up
For both phases and all trial arms, subjects will stay in the trial until end of trial or until confirmed 
disease progression, unacceptable toxicity, death or discontinuation for any other reason. 
Phase IIa Arm B:
The maximum number of cycles of pembrolizumab is 18 with an approximately duration of 
2 years. Then pembrolizumab will be stopped. CyPep-1 treatment may continue.
3.4
Trial Stopping Rules
The investigator or the sponsor may terminate this trial prematurely for any reasonable cause. 
The IECs and CAs should be informed promptly. 
Conditions that may warrant termination include, but are not limited to:
The discovery of an unexpected, significant, or unacceptable risk to the subjects 
enrolled in the trial, or potential trial subjects 

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The incidence or severity of AEs in this trial posing an unacceptable risk to the subjects 
enrolled in the trial. 
A decision by the sponsor to suspend or discontinue testing, evaluation, or 
development of the product. 
The identification of a trial-stopping criterion in a subject will result in the permanent 
discontinuation of CyPep-1 as monotherapy and in combination with pembrolizumab in this 
subject and the enrolment will be temporarily held until an appropriate evaluation of the cause 
of the toxicity has been determined and a correction action plan is established if needed. 
The Medical Monitor should be notified immediately i.e. within 24 hours of learning of their 
occurrence, and the subject should be followed for safety as clinically indicated until the toxicity 
resolves and, in the opinion of the investigator, no further follow-up regarding the toxicity is 
needed (minimum of at least 14 days after last dose of CyPep-1 as monotherapy and in 
combination with pembrolizumab).
If the competent authority obtains information that raises doubts about the safety or scientific 
validity of the clinical trial, the competent authority can suspend or prohibit the trial. Before the 
competent authority reaches its decision, it shall, except where there is imminent risk, ask the 
sponsor and/or the investigator for their opinion, to be delivered within one week (Directive 
2001/20/EC, Article 12, Section 1).
The investigator will be notified by the sponsor if the trial is terminated or placed on hold. The 
relevant IECs and CAs will also be informed according to appropriate regulatory requirements.
If the trial is prematurely terminated or suspended for any reason, the investigator/Institution 
should promptly inform the trial subjects and should assure appropriate therapy and follow-up
for the subjects.
3.5
End of Trial
The end of trial is defined as the last subject’s last visit.
For the purposes of data summarization, data analyses will be performed after the last enrolled 
subject has completed 3 months of trial participation. Subjects may still be in the trial at the 
time of data summarization, as all subjects may continue to participate until confirmed disease 
progression, unacceptable toxicity, or discontinuation for any other reason. Subjects who 
continue will follow the protocol as per SoA.
Phase IIa Arm B:
The maximum number of cycles of pembrolizumab is 18 with an approximately duration of 
2 years. Then pembrolizumab will be stopped. CyPep-1 treatment may continue.

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4.
SELECTION OF TRIAL POPULATION
4.1
Inclusion Criteria
For Phase I and Phase IIa Arms A and C:
1. Histologically or cytologically confirmed locally advanced (unresectable) or metastatic
tumors (solid tumor or lymphoma) with an accessible tumor lesion for intratumoral 
injection of CyPep-1 malignancy (including lymphomas) that is either:
a. Refractory to standard-of-care treatment 
b. Have a disease for which there is no standard therapy considered appropriate.
Metastatic deposits (including cutaneous/subcutaneous lesions and metastatic 
deposits in lymph nodes) of tumors for which IT injections may be performed are 
eligible. Pure cutaneous infiltrations (e.g., breast cancer cutaneous carcinomatosis) 
are ineligible.
2. 1 to 3 non-ulcerated transcutaneously accessible lesion(s) for injection and 
measurable as defined by iRECIST. All other tumor lesion(s) may be selected for 
efficacy follow-up, but will not be subjected to treatment with CyPep-1.
3. Presence of tumor lesion(s) (that have not been previously irradiated) suitable for biopsy 
at screening and at Week 6.  
For Arm C:
4. Confirmation of the presence of at least one liver metastasis by imaging.
5. Subjects must have measurable disease which is equal to one or more metastatic liver 
lesions that can be accurately and serially measured; that are greater than 1 cm 
dimension andfor which the longest diameter is greater or equal to 1 cm as measured 
by CT (computed tomography) scan or magnetic resonance imaging (MRI). The 
metastatic liver lesion(s) must not be in an area that received prior localized therapies.
6. Metastatic liver lesion(s) for injection with >50% radiological visible necrosis must be 
avoided and the leasion must be located where any tumor swelling will not lead to gall 
bladder tract obstruction or lead to bleeding risk.
For Arm D:
7. Histologically or cytologically confirmed diagnosis of advanced (unresectable Stage III) 
or metastatic (Stage IV: M1a and/or M1b) melanoma considered incurable by the 
standard of care. For metastatic melanoma, only cutaneous, subcutaneous,  lymph 
node, or lung metastases are allowed.
8. Previously exposed to ICI(s) and be categorized following the SITC Immunotherapy 
Resistance Taskforce (Kluger 2020) meeting one of the following:
a.
Have primary resistance: PD-(L)-
have the
best response as one of the following: 
i.
PD, 
ii.
SD for <6 months.
b.
Have secondary resistance: PD-(L)-
response CR, PR, or SD >6 months.
c.
Have adjuvant therapy resistance: recurrence subcategorized into primary 
resistance/early relapse occurred <12 weeks after the last dose, and late 
relapse occurred
have progressed to treatment with BRAF inhibitors.
d.
Have neoadjuvant therapy resistance including subjects with or without major 
pathologic response and subsequent PD that fulfills criteria for primary or 
secondary resistance

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e.
Discontinued from ICI(s) therapy due to immune-related adverse events grade 
3 or 4 other than endocrine insufficiencies treatable with hormonal replacement 
therapy, and meet one of the following:
i.
Remain on SD at discontinuation of PD-(L)1 inhibitor in combination with 
ipilimumab or show regrowth after <12 weeks of the last dose
ii.
Have not achieved a CR with single-agent PD-(L)1 inhibitor or 
combination of PD-(L)1 with LAG-3 inhibitor
9. At least 1 non-ulcerated lesion, not exceeding 5 cm in (the longest) diameter, for
intratumoral injection(s) as a target lesion as defined by iRECIST.
10. Resolution of toxicity due to prior therapy returned to baseline or < Grade 2, except 
for alopecia or other irreversible immune-mediated AEs, as defined by CTCAE v5.0. 
and SITC ICI-related AEs (Brahmer et al, 2021).
11. Prior treatment(s) delivered by IT injection to the to-be injected lesion(s), including 
investigational agents, is allowed.
For Phase I and Phase IIa Arms A, C, and D in addition:
12.
13. Estimated life expectancy of at least 3 months.
14. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 
(Appendix B).
15. Resolution of toxicity due to prior therapy to Grade < 2 (except for alopecia and 
transaminases in case of liver metastases) as defined by CTCAE v5.0 (Appendix C).
16. Ability to give written informed consent and to comply with the protocol. 
17. All subjects of childbearing potential (defined as < 2 years after last menstruation or 
not surgically sterile) must have a negative highly sensitive pregnancy test at 
screening (urine/serum) and agree to use highly effective method for contraception 
according to the EU Clinical Trial Facilitation Group guidance from time of signing the 
informed consent form (ICF) until at least 120 days after the last administration of 
CyPep-1. The partners of subjects with childbearing potential must also apply 
contraceptive methods and are recommended not to donate sperm.
18. A male participant must agree to use contraception and refrain from sperm donation 
during the treatment period and for at least 120 days after the last dose of trial 
medication. 
19. Adequate bone marrow, liver, and renal function:
a.
9/L
b.
c.
9/L
d.
, except for subjects with familial bilirubinemia 
(Gilbert’s disease)
e.
f.
Glomerular Filtration Rate [GFR] to be 
calculated by CKD-EPI formula)
For Phase IIa Arm B:
Participants are eligible to be included in Arm B of the trial only if all of the following criteria 
apply:
Type of Participant and Disease Characteristics
20. The participant provides written informed consent for the trial.
21. Be 
18 years of age on day of signing informed consent.

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22. Participant with histologically or cytologically confirmed diagnosis of advanced 
(unresectable Stage III) or metastatic (Stage IV) solid tumor malignancy (including 
lymphomas) that is refractory to standard-of-care treatment or for which there is no 
standard 
therapy 
considered 
appropriate. 
Metastatic 
deposits 
(including 
cutaneous/subcutaneous lesions and metastatic deposits in lymph nodes) of tumors 
for which IT injections may be performed are eligible. Pure cutaneous infiltrations (e.g., 
breast cancer cutaneous carcinomatosis) are ineligible.
23. Subjects must have progressed on treatment with an anti-PD1/L1 monoclonal antibody 
(mAb) administered either as monotherapy, or in combination with other checkpoint 
inhibitors or other therapies. Treatment progression is defined by meeting all of the 
following criteria:
a.
Has received at least 2 doses of an approved anti-PD-1/L1 mAb. 
b.
Has demonstrated disease progression (PD) after PD-1/L1 based on clinical 
progression and / or based on RECIST v1.1 as defined by the 
Investigator/treating physician.
24. A male participant must agree to use contraception and refrain from sperm donation 
during the treatment period and for at least 120 days after the last dose of trial 
medication.
25. A female participant is eligible to participate if she is not pregnant, not breastfeeding, 
and at least one of the following conditions applies: 
a.
Not a woman of childbearing potential (WOCBP) 
b.
A WOCBP (defined as < 2 years after last menstruation or not surgically sterile)
must have a negative highly sensitive pregnancy test at screening (urine/serum) 
and
must follow contraceptive guidance (highly effective method for 
contraception according to the EU Clinical Trial Facilitation Group guidance) 
from time of signing the ICF until at least 120 days after the last administration 
of trial medication. The partners of subjects with childbearing potential must 
also apply contraceptive methods and are recommended not to donate sperm. 
26. 1 to 3 non-ulcerated transcutaneously accessible lesion(s) for injection and measurable 
as defined by iRECIST. All other tumor lesion(s) may be selected for efficacy follow-up
but will not be subjected to treatment with CyPep-1.
27. Presence of tumor lesion(s) (that have not been previously irradiated) suitable for 
biopsy at screening and at Week 6. 
28. Have an ECOG performance status of 0 to 1 (Appendix B).
29. Have adequate organ function as defined in the following table. Specimens must be 
collected within 10 days (or less) prior to the start of trial treatment.
Adequate Organ Function Laboratory Values:
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
Platelets
000/µL
Hemoglobin
1
Renal
Creatinine OR
Measured or calculated2 creatinine clearance
(GFR can also be used in place of creatinine or CrCl)
>1.5 × institutional ULN
Hepatic
Total bilirubin
with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
×
× ULN for participants with liver 
metastases)

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ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT) =aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal.
1 Criteria must be met without packed red blood cell (pRBC) transfusion within the prior 2 weeks. Participants 
2 Creatinine clearance (CrCl) should be calculated per institutional standard.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of specific 
chemotherapies.
30. Only for subjects with lymphoma: have measurable disease defined as at least one 
lesion that can be accurately measured in at least two dimensions with spiral CT scan.
Minimum measurement must be > 15 mm in the longest diameter by > 10 mm in the 
short axis.
31. Estimated life expectancy of at least 3 months.
32. HIV infected participants must be on anti-retroviral therapy (ART) and have a well-
controlled HIV infection/disease defined as:
a.
Participants on ART must have a CD4+ T-cell count 
350 cells/mm3 at time of 
screening.
b.
Participants on ART must have achieved and maintained virologic suppression 
defined as confirmed HIV RNA level below 50 copies/mL or the lower limit of 
qualification (below the limit of detection) using the locally available assay at 
the time of screening and for at least 12 weeks prior to screening.
c.
Participants on ART must have been on a stable regimen, without changes in 
drugs or dose modification, for at least 4 weeks prior to study entry (Day 1).
4.2
Exclusion Criteria
For Phase I and Phase IIa Arms A, C, and D: Subjects who meet ANY of the following criteria 
at screening will be excluded from trial entry:
1.
There is no limit to the number of prior treatment regimens, but prior treatment(s) should 
not include compounds delivered by IT injection to the to-be injected lesion(s), including 
investigational agents. Subjects with prior IT therapies are allowed in Arm D.
2.
Participation in another clinical trial within 4 weeks prior to first dose of CyPep-1.
3.
Anti-cancer therapy within 4 weeks prior to the first dose of CyPep-1 (within 2 weeks for 
palliative radiotherapy, within 1 week for endocrine therapy). 
4.
Major surgical procedure within 14 days prior to the first dose of CyPep-1.
5.
Live vaccine within 30 days prior to first dose of CyPep-1.
6.
Expected to require any other form of systemic or localized antineoplastic therapy while 
in this trial. Localized palliative radiotherapy for pain relief is allowed on tumor lesions 
that are not selected for evaluation of treatment response.
7.
Clinical evidence of an active second malignancy that is progressing or requires active 
treatment, except for curatively treated early stage (carcinoma in situ or stage 1) 
carcinomas or non-melanoma skin cancer.
8.
Active autoimmune disease requiring immunosuppressive therapy.
9.
Any condition requiring continuous systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalents) or other immunosuppressive agents within 
2 weeks prior to first dose of CyPep-1. Inhaled, intranasal or topical (only on areas 

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outside the injected lesion[s]) and physiological replacement doses of up to 10 mg daily 
prednisone equivalent are permitted in the absence of active auto-immune disease. 
10. Abnormal or clinically significant coagulation parameters.:
o
Prothrombin Time – International Normalized Ratio (PT-INR)
1.5 x ULN
o
Activated Partial Thromboplastin Time (APTT)
1.5 x ULN 
Subjects being treated with anticoagulants are excluded if the coagulation parameters 
are outside the therapeutic intervals as described in the SmPC for the administered 
treatment.
11. Subjects on anticoagulants with temporarily stop and start, supported by low molecular 
weight heparin (or other anticoagulation therapy at the discretion of the investigator 
and/or per local standard of care) during treatment period.
12. Known hypersensitivity to any component of CyPep-1.
13. Prior allogeneic tissue/solid organ transplant, stem cell or bone marrow transplant.
14. Known active human immunodeficiency virus (HIV). Subject is eligible when normal levels 
of CD4 are present. 
15. Central nervous system (CNS) metastasis that is symptomatic or progressing or that 
requires current therapy (e.g., evidence of new or enlarging CNS metastasis,
carcinomatous meningitis
or new neurological symptoms attributable to CNS 
metastasis). 
16. QTcF > 480 ms, history of long or short QT syndrome, Brugada syndrome, or known 
history of QTc prolongation, or Torsade de Pointes.
17. Women who are pregnant or breastfeeding. 
18. Any serious and/or unstable pre-existing medical, psychiatric or other condition which 
in the investigator’s opinion could interfere with subject safety, obtaining written 
informed consent, or compliance with the trial protocol.
19. Has an active acute or chronic infection requiring systemic therapy at the time of CyPep-
1 injection. Note: Subjects treated for mild/moderate infection with oral antibiotics only 
may be included based on consultation with the study medical monitor and the sponsor.
Additional exclusion criteria for Phase IIa Arm C:
20. Subject is a candidate for hepatic surgery or local regional therapy of liver metastases 
with curative intent.
21. More than one third of the liver is estimated to be involved with metastases.
22. There is invasion by cancer into the main blood vessels such as the portal vein, hepatic 
vein or the vena cava.
23. Subject is currently receiving or has received liver metastatic-directed therapy (e.g.
radiation, ablation, embolization) less than 4 weeks prior to enrolment or hepatic surgery.
Exclusion criteria specific for Phase IIa Arm B:
Participants are excluded from the trial if ANY of the following criteria apply at screening:
Pregnancy Exclusion
24. A WOCBP who has a positive urine pregnancy test (within 72 hours) prior to trial 
treatment. If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required.
Prior/Concomitant Therapy
25. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 
40, CD137), and was discontinued from that treatment due to a Grade 3 or higher irAE. 

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26. Has received prior systemic anti-cancer therapy including investigational agents within 
4 weeks (within 1 week for endocrine therapy) prior to first dose of CyPep-1.
Note: Participants must have recovered from all AEs due to previous therapies to 
1 or baseline as defined by CTCAE v5.0 (Appendix C).
2 neuropathy may be eligible. Participants with endocrine-related AEs Grade
treatment or hormone replacement may be eligible.
Note: If the participant had major surgery, this should not have been within 14 days prior 
to the first dose of CyPep-1 and the participant must have recovered adequately from the 
procedure and/or any complications from the surgery prior to starting study intervention.
27. Has received prior (palliative) radiotherapy within 2 weeks of start of trial treatment. 
Participants must have recovered from all radiation-related toxicities, not require 
corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted 
f radiotherapy) to non-CNS disease.
28. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of 
CyPep-1. Note: Administration of killed vaccines are allowed.
29. Has received prior compounds delivered by IT injection to the to-be injected lesion(s),
including investigational agents. 
30. Expected to require any other form of systemic or localized antineoplastic therapy while 
in this trial. Localized palliative radiotherapy for pain relief is allowed on tumor lesions 
that are not selected for evaluation of treatment response. 
31. Ongoing pembrolizumab-related toxicity event(s) as per TLT definition. 
Prior/Concurrent Clinical Trial Experience
32. Is currently participating in or has participated in a trial of an investigational agent or has 
used an investigational device within 4 weeks prior to the first dose of trial treatment.
Note: Participants who have entered the follow-up phase of an investigational trial may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
33. Has had an allogeneic tissue/solid organ transplant.
Diagnostic assessments
34. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of CyPep-1.
35. Has a known additional malignancy that is progressing or has required active treatment 
within the past 3 years, except for curatively treated early stage (carcinoma in situ or 
stage 1) carcinomas or non-melanoma skin cancer.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin
or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone 
potentially curative therapy are not excluded.
36. Has known active CNS metastases and/or carcinomatous meningitis. Participants with 
previously treated brain metastases may participate provided they are radiologically 
stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note 
that the repeat imaging should be performed during study screening), clinically stable and 
without requirement of steroid treatment for at least 14 days prior to first dose of study 
treatment. 
37.
or 
to another mAb, as well as any known hypersensitivity to any component of CyPep-1.
38. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment and is allowed.

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39. Has a history of (non-infectious) pneumonitis / interstitial lung disease that required 
steroids or has current pneumonitis / interstitial lung disease.
40. Has an active infection requiring systemic therapy.
41. HIV-infected participants with a history of Kaposi sarcoma and/or Multicentric Castleman 
Disease.
42. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis 
C virus (defined as HCV RNA [qualitative] is detected) infection.
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by a local 
health authority.
43. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the participant's participation for the 
full duration of the trial, or is not in the best interest of the participant to participate, in the 
opinion of the treating investigator.
44. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
45. Has received radiation therapy to the lung that is >30 Gy within 6 months of the first dose 
of trial treatment (applicable only for subjects with NSCLC, mesothelioma and small cell 
lung cancer [SCLC]).
4.3
Withdrawal, Discontinuation, and Replacement of Subjects
4.3.1
Withdrawal and Discontinuation
Subjects are free to withdraw consent from participation in the trial at any time and for any 
reason upon request. Withdrawal from the trial will not affect or prejudice the subjects’ further 
care or treatment. 
Subjects may be withdrawn from trial treatment and/or assessments at any time, if deemed 
necessary by the investigator. 
Examples of reasons for withdrawal/discontinuation of subjects from this trial are: 
Screening failure;
The decision of a subject to withdraw from the trial (i.e. if the subject withdraws informed 
consent);
Pregnancy;
Failure to comply with the trial visits and procedures;
Subject is lost to follow-up (defined as a subject who has failed to return for two 
consecutive scheduled visits and cannot be contacted by the study site staff);
Subject fulfils any other criteria that, in the opinion of the investigator, justifies 
discontinuation of the subject from the trial.
Subjects experience side effects and/or require concomitant medications for treatment 
of HIV infection and/or its complications that are incompatible with continued study 
treatment (exceptions are permissible but should be discussed with the Sponsor and 
the medical monitor).
Subjects who withdraw from trial due to withdrawal of consent, inability or unwillingness of the 
subject to comply with trial procedures or are lost to follow-up are considered as trial dropouts
and will not perform the follow-up visits.
Subjects who discontinue treatment with CyPep-1 for safety reasons (Section 7.2.1) or due to 
concomitant medication or therapy (Section 5.6) will not necessarily be considered withdrawn 
from the trial unless there are other reasons for withdrawal. They should return for all following 
visits and assessments until the last follow-up visit. For Arm B, treatment with pembrolizumab 
may continue at the discretion of the investigator.

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A subject may be discontinued from study treatment but continue to be monitored in the study 
for any of the following reasons:
Discontinuation of treatment may be considered for subjects who have attained a 
confirmed complete response (CR) and have been treated for at least 8 cycles (at least 
24 weeks), receiving for combination treatment: 2 cycles of the combination including 
2 doses of pembrolizumab beyond the date when the initial CR was declared. 
Completion of 18 (for Q6W dosing) administrations (approximately 2 years) with 
pembrolizumab
(Note: The number of administrations is calculated starting with the first dose of 
pembrolizumab.)
Any study intervention-related toxicity specified as a reason for permanent 
discontinuation as defined in the guidelines for dose modification due to AEs in Section 
5.3.6. If CyPep-1 treatment is delayed > 7 days, that dose will be omitted. If the delay 
of > 7 days is during the TLT observation period, the subject will be replaced.
For Phase I, Phase IIa Arms A and C, if CyPep-1 treatment is delayed for > 6 weeks during 
the DLT period (first 3 injections), the subject should be discontinued from the trial. For Arm B, 
treatment with pembrolizumab may continue at the discretion of the investigator. For Arm D, 
in case CyPep-1 treatment is delayed for > 3 weeks (first 3 injections), the investigator and the 
Medical Monitor must assess on a case by case basis the decision whether the subject should 
be discontinued from the trial. Treatment delay due to TEAEs will be considered for treatment 
discontinuation.
For any subject who is withdrawn or discontinued from the trial, the reason, date and 
subsequent planned replacement therapy (if applicable), must be recorded in the electronic 
case report form (eCRF) and in the medical record. (S)AEs ongoing at trial withdrawal will be 
followed up for outcome information until resolution or stabilization (see Section 7.2.1).
When a subject is withdrawn or discontinued from active trial follow-up after having received 
at least one intratumoral CyPep-1 injection, and if the subject agreed on the ICF, every effort 
will be made to report serious adverse events (SAEs) until at least 3 months after the last 
intra-tumoral CyPep-1 injection administered for both trial phases.
If a subject withdraws consent from specific assessment(s) following intratumoral CyPep-1
injection (i.e. tumor biopsy, radiological or hematological assessments, etc.), all other 
assessments should be completed as per protocol and a protocol deviation should be recorded
for both trial phases.
If a subject is withdrawn or discontinued from the trial, all data collected until the time of 
withdrawal will be used in the analyses. 
4.3.2
Replacement of Subjects 
In Phase I, replacement for subjects who drop out for any reason, except DLTs, will only occur 
before the DLT observation period is completed and is allowed if a subject does not receive all 
three CyPep-1 administrations, unless due to CyPep-1-related toxicity.
No subject replacement will occur for subjects who withdraw later or for subjects who are part 
of the Phase IIa expansion monotherapy Arms A and D.

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For Arm B, replacement of the first 3 subjects is allowed if a subject drops out for any reason, 
and does not receive all three CyPep-1 injections of the first cycle, unless due to CyPep-1
and/or pembrolizumab related toxicity (TLT) during the TLT observation period. In case of 
pembrolizumab-related toxicity, treatment with CyPep-1 will be delayed and planned after a 
review by the investigator and medical monitor. If CyPep-1 treatment is delayed > 7 days, that 
dose will be omitted. If the delay is > 7 days during the TLT observation period, the subject will 
be replaced. No subject replacement will occur for subjects who discontinue later.
For Arm C, replacement for subjects who drop out for any reason, except DLTs, before the 
DLT observation period is completed is allowed when a subject did not receive all three CyPep-
1 administrations. No subject replacement will occur for subjects who discontinue later.

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5.
TRIAL TREATMENT
5.1
Manufacturing and Labelling of Investigational Medical Product 
5.1.1
Identity 
CyPep-1 is a synthetic linear 27-amino acid peptide with an acetylated amino group at the 
N-terminus and an amido group at the C-terminus. All optically active amino acid residues are 
in D-configuration with the exception of achiral glycine. CyPep-1 is formulated in a clear and 
colorless aqueous solution (5 mg/mL).
5.1.2
Packaging and Labelling 
The intratumoral formulation of CyPep-1 is a liquid dosage form for subcutaneous 
administration supplied in single-use vials. The CyPep-1 5 mg/mL solution consists of the drug 
substance CyPep-1 dissolved in 0.9% NaCl solution. Each vial contains a deliverable volume 
of 2 mL of CyPep-1 solution corresponding to 10 mg of the drug substance CyPep-1, present 
as acetate salt. An additional overfill is included in each vial to ensure that the labelled amount 
of 10 mg of CyPep-1 (corresponding to 14 mg of the acetate salt) can be delivered.
5.2
Instructions for Use, Handling, and Storage 
The preliminary proposed shelf life of the CyPep-1 injectable solution is 18 months upon the 
date of manufacture, when stored at 5 ± 3°C (protected from light). The product may be kept 
outside the proposed storage condition at temperatures up to 25°C for up to 3 days to cover 
short-term temperature excursions (e.g. during shipping, labelling, and handling).
Pembrolizumab should be used, handled and stored in line with institutional guidelines. 
5.3
Treatment Regimen
The overall study treatment regimen is defined as intratumoral CyPep-1 as monotherapy 
(Phase I and Phase IIa Arms A, C and D) and in combination with pembrolizumab (Phase IIa 
Arm B).
The interventions to be used in this trial are outlined below in Table 2.
Table 2. Trial Interventions 
Intervention 
Name
Dosage 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/Treatment 
Period
Sourcing
Pembrolizumab 
(MK-3475)
Solution for 
infusion
100 mg/vial
400 mg 
Q6W
IV infusion
Until end of trial or 
confirmed PD, 
unacceptable 
toxicity, death or 
discontinuation for 
any other reason for 
a maximum of 18 
treatment cycles.
As 
provided 
by
sponsor 
CyPep-1
Solution for 
injection
See Section 5.3.1
Intratumoral
See Section 5.3.1
Provided 
centrally 
by the 
Sponsor

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5.3.1
Administration of IMP (CyPep-1)
Administration will be through a needle inserted trans-dermally. The needle should be 
redirected along multiple tracks to ensure even dispersion of CyPep-1 throughout the lesion. 
For Arm C, CyPep-1 will be administered via intralesional injection with ultrasound guidance 
into one metastatic liver lesion. 
A detailed guidance for intratumoral administration of CyPep-1 is presented in the Study 
Procedural Manual.
5.3.1.1
CyPep-1 Dose Levels
For Phase I, in three dose cohorts of 3 subjects each, subjects received CyPep-1 intratumorally 
at different concentrations (dose escalation) and volumes (depending on tumor size), i.e., 0.5 
mg/mL, 2 mg/mL, or 5 mg/mL, respectively. 
The CyPep-1 concentration for each dose cohort of the dose escalation (Phase I) was as 
follows:
Dose cohort
CyPep-1 concentration
1
0.5 mg/mL
2
2 mg/mL
3
5 mg/mL
Subjects in Phase IIa expansion arms (Arms A, B and D) of the trial will be treated at the 
CyPep-1 RP2D dose determined in Phase I. Based on the review of all safety data for the
three dose cohorts and recommendation by the DEC (dated 09 Sep 2021), a RP2D for CyPep-
1 is 5.0 mg/mL to be taken forward in Phase IIa.
During the dose expansion in liver metastases (Arm C), the safety and tolerability of at least 
two dose levels of CyPep-1, the RP2D (cohort 5) and the dose immediately below that (cohort 
4), are planned to be evaluated when CyPep-1 is administered intratumorally into 1 single 
lesion in the liver. 
5.3.1.2
CyPep-1 Injection Volume
The total amount of CyPep-1 injected will depend on the tumor volume(s). The volume 
delivered to each lesion selected for injection will be determined based on the longest
diameter measured by the most accurate measurement technique available for each lesion 
(e.g. caliper, CT, or MRI) at screening and every 8 weeks during the iRECIST/itRECIST 
assessments. A chosen technique used at screening will be consistently used throughout the 
study. Lesion sizes need to be checked before each injection by either caliper (mandatory for 
Arm D and to-be-injected cutaneous/subcutaneous lesions for Phase IIa Arms A and B) or 
other imaging modalities used to guide CyPep-1 injections, i.e., ultrasound, CT or MRI, . For 
Arm C, , the lesion size measurement will be performed by the same imaging modality used 
to guide CyPep-1 injections. To ensure consistency of the measurements, the sites need to 
strive for having the same operator to perform all measurement for a chosen measuring 
technique. If there are major changes in the lesion size, the injection volume may be adjusted 
based on the ultrasound measurements per investigator’s opinion and consultation with the 
Medical Monitor is possible.
For both phases of the trial, the cumulative maximal injected volume will be 4 mL per 
treatment day, corresponding to a cumulative maximal dose of 20 mg of CyPep-1 (with the 
maximal concentration of 5 mg/mL of CyPep-1, which is the RP2D). Effort should be made 
to administer the maximum planned injection volume of CyPep-1 as planned per lesion size
(see tables below).

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For Phase I, Phase IIa Arms A and B, the to-be-injected volume may be divided for injection 
over 
1-3 tumor lesions (e.g., one large lesion or 2-3 relatively small lesions). In case more than 
3 lesions are good candidates for injection, the to be injected lesions selection can be 
discussed with the sponsor and the medical monitor.
For Phase IIa Arm C, CyPep-1 will be administered with ultrasound guidance into one 
metastatic liver lesion. The same single metastatic lesion is to be injected with CyPep-1 based 
on lesion size. 
For Phase IIa Arms A and B, for a lesion > 7 cm, the same lesion should be considered to be 
injected weekly with up to 4 mL of CyPep-1 for the first 6 weeks (on Day 1, 8, 15, 22, 29 and 
36), independent of the potential change in lesion size, followed by Q2W 4 mL administrations 
of CyPep-1. The visits on Days 1, 15, 29 and 36 will follow the assessments as per schedule. 
The visits on Days 8 and 22 will follow the assessments as per D15 (C1V2; excluding central 
lab sampling for cytokine analysis and blood sampling for immune cell phenotyping).
For Phase IIa Arm D, the to-be-injected volume for injection is preferably divided over as many 
lesions as possible. The longest diameter of the lesions for injection is ideally smaller than 2 
cm and should not exceed 5 cm. 
For subjects in Arms A, B and C, the injection volume will be:
Measured Lesion Diameter (cm)
Injected volume (mL)
1
1
> 1 and
2
2
> 2
4
For subjects in Arm D, the injection volume will be:
Measured Lesion Diameter (cm)
Injected volume (mL)
0.79
0.1
0.80 to 0.99
0.2
1.00 to 1.24
0.5
1.25 to 1.50
1.5
1.51 to 2.49
3.0
2.50
4.0
5.3.1.3
Sequence of CyPep-1 Administration for Phase IIa Arm D Only
Lesion Map 
A lesion map that will guide the preferred sequence of injection of the identified Lesion Sets
must be created prior to the first CyPep-1 injection (detailed in Study Procedural Manual). A
lesion map will contain the following information:
For superficial lesions: 
Digital color photography of the lesions must be taken and the mark-ups of individual 
lesions ( or lesion groups) with lesion ID are overlayed on top of the digital photography. 
Silhouette of body parts must be used to present the relative location of the lesions. 
All digital color photography containing a ruler held next to the longest diameter of the 
lesion to indicate the size of the lesion, and the lesions marked-up with lesion IDs, 
together with the silhouette of body parts indicating the location of the lesions, need to 
be submitted to eCRF with inspection readiness for the reported responses. 
In the case of bilateral lesions, the laterality of the lesions must be documented on the 
lesion map.
For deep lesions: 
CT or MRI scan will be used for iRECIST/itRECIST assessment at baseline, and the 
location of lesions provided by the CT/MRI scan will be used.

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In the case of bilateral lesions, the laterality of the lesions must be documented on the 
lesion map.
Once the lesion map is created, Lesion Sets for sequential CyPep-1 injections will be planned 
and documented in the source. The size of the injected lesions and the lesion map should be 
updated when assessments of local measurements of tumor lesions, iRECIST and itRECIST 
assessments are performed during the treatment period. 
Lesion Sets
A Lesion Set will be composed of multiple lesions, and will be administered with CyPep-1
during the same treatment visit for three consecutive doses. Unless there are no other Lesion 
Sets to be injected, each Lesion Set will not receive more than three consecutive doses of 
CyPep-1. In the case of bilateral lesions, both of the bilateral lesions should be included in the 
same lesion set if feasible considering the maximum injected volume allowed per treatment 
visit (4 mL).
The sequence of CyPep-1 Administration
After three doses of CyPep-1, the next Lesion Set will be administered with CyPep-1. The ideal 
next to-be-injected lesion set should be located as far as possible from the last injected Lesion 
Set on the lesion map to activate different draining lymph nodes and thus optimize a systemic 
immune response against the tumor. Once all injectable lesions have been injected and the 
subject remains on treatment, a new lesion map that permits reprioritizing of the to-be-injected 
lesion sets will be created, taking into account size changes of individual lesions, e.g., an
individual lesion enlarged or regressed after initial 3 doses of CyPep-1 injections. 
5.3.2
Administration of Pembrolizumab
The dose of pembrolizumab in combination with CyPep-1 in the combination arm (Arm B) will 
be 400 mg Q6W. Pembrolizumab will be administered using IV infusion on Day 1 of each 6-
week treatment cycle after all procedures and assessments have been completed. 
Dosing of CyPep-1 will be aligned such that subjects will receive both pembrolizumab and the 
first dose of CyPep-1 on the same day (C1V1). After C1V1, pembrolizumab dosing will 
continue following a Q6W dosing scheme until 18 cycles, confirmed PD, unacceptable toxicity,
death, or consent withdrawal. Trial treatment of pembrolizumab may be administered up to 3 
days before or after the scheduled Day 1 of each cycle due to administrative reasons after the 
first administration (C1D1).
On the visits that CyPep-1 and pembrolizumab are administered on the same day, CyPep-1 is 
planned to be administered 30 to 60 min after pembrolizumab is administered. In case of 
pembrolizumab-related toxicity, treatment with CyPep-1 will be delayed and planned after a 
review by the investigator and medical monitor.
Pembrolizumab will be administered as a dose of 400 mg using a 30-minute IV infusion. Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.
However, given the variability of infusion pumps from site to site, a window between -5 minutes 
and +10 minutes is permitted (i.e., infusion time is 30 minutes [-5 min/+10 min]).
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion and administration of infusion solution.
5.3.3
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhoea, nausea, or vomiting.

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5.3.4
Selection of CyPep-1 Doses in the Trial
In Phase I of the trial, CyPep-1 will be administered intratumorally in escalating doses as 
follows:
1.
Cohort 1: 0.5 mg/mL on Day 1 of Weeks 1, 3, and 5 (Days 1, 15, and 29)
2.
Cohort 2: 2 mg/mL on Day 1 of Weeks 1, 3, and 5 (Days 1, 15, and 29)
3.
Cohort 3: 5 mg/mL on Day 1 of Weeks 1, 3, and 5 (Days 1, 15, and 29)
Continuous Q2W administration of CyPep-1 is planned after Day 29.
Selection of these doses was based on previous preclinical experience with CyPep-1
(Szczepanski et al, 2014). The total amount of CyPep-1 injected will depend on the tumor 
volume. The volume delivered to each lesion selected for injection will be determined based 
on the longest diameter measured by the most accurate measurement technique available for 
each lesion (e.g. caliper, CT, or MRI) at screening and every 8 weeks during the 
iRECIST/itRECIST assessments (see Section 5.3.1.2). Before each injection, the longest
diameter of the lesion will be measured. The approximate injected volume per lesion will be 1
- 4 mL for lesions <1.5 cm, 2 - 4
cm, 3 - 4 mL for lesions > 4 cm. Efforts 
should be made to administer the maximum volume of CyPep-1 per administration as per dose 
level.
For Phase IIa Arms A, B and C, weekly administration schedule for the first 6 weeks should be 
considered for a lesion > 7 cm followed by Q2W administration.
The proposed CyPep-1 starting dose for the clinical trial is obtained from the therapeutic range 
identified in the nonclinical in vitro (0.025 mg/mL) and in vivo intratumoral studies (1-5 mg/mL
(refer to IB). The data suggests that the starting dose of 0.5 mg/mL in the tumor 
microenvironment is within the identified range to achieve an initial and meaningful biological 
effect. Since intravascular administration can occur during intratumoral injection, the NOEL 
from IV administration studies was considered relevant to identify the first dose. Based on the 
7 days toxicology study of repeat IV bolus with CyPep-1, the NOEL of 3,0 mg/kg was identified 
in rats. The corresponding HED is 0,48 mg/kg (0.16 x 3,0 mg/kg). For a 70 kg person this 
equals 33.6 mg. As the maximal cumulative starting dose in trial is 2 mg, a safety factor of 16.8
has 
been 
taken 
into 
account, 
considering 
that 
the 
route 
of 
administration 
is intratumoral instead of IV with limited systemic exposure anticipated.
Planned doses in the trial:
2 mg/mL (cumulative 8 mg) and 5 mg/mL (cumulative 20 mg)
CICILIA Phase I dose escalation used IT administered CyPep-1 (comparable to 
subcutaneous administration study showing ~100-fold lower Cmax / ~20-fold lower 
AUC compared to IV with an ~ 5% bioavailability).
AE summary of RP2D determined during Phase I: 5 mg/mL dose (20 mg CyPep-1) 
resulted in related TEAEs of injection site pain Grade 1 and 2 (AE number = 12) without 
DLTs, SAEs or AEs leading to discontinuation.
In Phase IIa of the trial, all subjects will receive intratumoral CyPep-1 at the doses specified in 
Section 5.3.1.
Phase I, the dose escalation part of the CICILIA trial, has been completed. The determined 
RP2D of IT administered CyPep-1 was 5 mg/mL. The MTD was not reached. The CyPep-1
dose to be applied in Phase IIa Arms A, B and D is 5 mg/mL.

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For cohorts 4 and 5 of Phase IIa Arm C, the doses of CyPep-1 to be investigated are 2 mg/mL 
and 5 mg/mL, respectively.
5.3.5
Duration of the Treatment Regimen
Intratumoral CyPep-1
Each subject will undergo up to 4 weeks of screening, followed by a DLT/TLT observation 
period of 6 weeks (5 weeks of CyPep-1 treatment plus 1 week observation). In absence of 
DLT/TLTs, treatment continues with Q2W intratumoral injections of CyPep-1 until confirmed 
PD, unacceptable toxicity, death, withdrawal of consent, loss to follow-up, or trial end, 
whichever occurs first. For Arm D, after screening, each subject will undergo QW CyPep-1
treatment until the second iRECIST/itRECIST assessment at week 16, followed by a Q2W 
dosing scheme until confirmed PD, unacceptable toxicity, death or consent withdrawal, loss to 
follow-up, or trial end, whichever occurs first.
Pembrolizumab (intravenous)
Pembrolizumab will be administered as specified in Section 5.3.2.
In case a subject discontinues treatment with CyPep-1 in the combination arm (Arm B) and the 
subject remains eligible to participate in the trial after review by the Investigator and medical 
monitor, pembrolizumab treatment is planned to continue at Q6W as per institutional guidelines 
until PD, unacceptable toxicity, death, or consent withdrawal for a maximum of 18 treatment 
cycles. All assessments continue to be reported as per the schedule of assessments.
In case a subject discontinues with pembrolizumab in the combination arm (Arm B) and the 
subject remains eligible to participate in the trial after review by the Investigator and medical 
monitor, CyPep-1 treatment is planned to continue at Q2W until PD, unacceptable toxicity,
death, or consent withdrawal. All assessments continue to be reported as per the schedule of 
assessments.
5.3.6
Dose Modification
CyPep-1 dose modifications are not planned. In case of CyPep-1 related toxicity, a dose delay 
may be considered after review by the investigator and medical monitor.
5.3.6.1
Dose Modifications and Management of CyPep-1 associated AEs
CyPep-1 associated hematological and non-hematological adverse effects according to 
CTCAE v5.0 toxicity grade may occur. Toxicity management and dose modifications are listed 
below:
Dose adjustments according to CTCAE toxicity grade for drug-related AEs
Occurrence
Grade 1 Grade 2
Grade 3
Grade 4
First 
appearance
No 
action 
with 
study 
drug.
No action 
with study 
drug.
Interrupt treatment until 
resolved to Grade 0-1 (or 
according to inclusion 
criteria). If interruption is < 14
days, restart at next lower 
dose level. If interruption is 
14 days, check with Medical 
Monitor.
Discontinue study 
drug.

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Second 
appearance
Discontinue study drug.
5.3.6.2
Dose modification and toxicity management for immune-related AEs
associated with pembrolizumab
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the 
last dose of pembrolizumab treatment and may affect more than one body system
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical study data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab, administration of corticosteroids and/or other 
supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin 
biopsy may be included as part of the evaluation. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification 
and toxicity management guidelines for irAEs associated with pembrolizumab are provided in 
Table 3.
Table 3. Dose Modification and Toxicity Management Guidelines for Immune-related 
AEs Associated with Pembrolizumab
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. 
Other immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids. 
2.
Pembrolizumab must be permanently discontinued if the irAE does not resolve or the corticosteroid 
mg/day within 12 weeks of the last pembrolizumab treatment. 
3.
weeks.
4.
If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to 
Grade 1 after corticosteroid taper.
irAEs
Toxicity grade 
(CTCAE V5.0)
Action with 
pembrolizumab 
Corticosteroid and/or 
other therapies 
Monitoring and follow-up
Pneumonitis 
Grade 2
Withhold 
Administer 
corticosteroids 
(initial dose of 
1 to 2 mg/kg 
prednisone or 
equivalent) 
followed by taper
Add prophylactic 
antibiotics for 
opportunistic 
infections
Monitor participants 
for signs and 
symptoms of 
pneumonitis
Evaluate participants 
with suspected 
pneumonitis with 
radiographic imaging 
and initiate 
corticosteroid 
treatment
Recurrent 
Grade 2, 
Grade 3 or 4 
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold
Administer 
corticosteroids (initial 
dose of 1 to 2 mg/kg 
prednisone or 
equivalent) followed 
by taper
Monitor participants 
for signs and 
symptoms of 
enterocolitis (ie,
diarrhea, abdominal 
pain, blood or mucus 

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Recurrent Grade 
3 or Grade 4
Permanently 
discontinue
in stool with or without 
fever) and of bowel 
perforation (ie.
peritoneal signs and 
ileus)
Participants with 
diarrhea
suspecting colitis 
should consider GI 
consultation and 
performing endoscopy 
to rule out colitis
Participants with 
diarrhea/colitis should 
be advised to drink 
liberal quantities of 
clear fluids. If sufficient 
oral fluid intake is not 
feasible, fluid and 
electrolytes should be 
substituted via IV 
infusion
AST or ALT 
elevation or 
Increased 
Bilirubin
Grade 2 a
Withhold
Administer 
corticosteroids (initial 
dose of 0.5 to 1
mg/kg prednisone or 
equivalent) followed 
by taper
Monitor with liver 
function tests 
(consider weekly or 
more frequently until 
liver enzyme value 
returned to baseline or 
is stable)
Grade 3 b or 4 c
Permanently 
discontinue
Administer 
corticosteroids (initial 
dose of 1 to 2 mg/kg 
prednisone or 
equivalent) followed 
by taper
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia
New onset T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold d
Initiate insulin 
replacement 
therapy for 
participants with 
T1DM
Administer 
antihyperglycemc
in participants 
with 
hyperglycemia
Monitor participants for 
hyperglycemia or other 
signs and symptoms of 
diabetes
Hypophysitis
Grade 2
Withhold
Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated
Monitor for signs and 
symptoms of hypophysitis 
(including hypopituitarism 
and adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue d
Hyperthyroidism
Grade 2
Continue
Treat with 
nonselective beta-
blockers (eg,
propranolol) or 
thionamides as 
appropriate
Monitor for signs and 
symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
permanently 
discontinue d
Hypothyroidism
Grade 2, 3 or 4
Continue
Initiate thyroid 
replacement 
hormones (eg,
levothyroxine or 
Monitor for signs and 
symptoms of thyroid 
disorders

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liothyronine) per 
standard of care
Nephritis:
grading 
according to 
increased 
creatinine or 
acute kidney 
injury
Grade 2
Withhold
Administer 
corticosteroids 
(prednisone 
1 to 2 mg/kg or 
equivalent) followed 
by taper
Monitor changes of renal 
function
Grade 3 or 4
Permanently 
discontinue
Neurological 
Toxicities
Grade 2
Withhold
Based on severity of 
AE administer 
corticosteroids
Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 2, 3 or 4
Permanently 
discontinue
Based on severity of 
AE administer 
corticosteroids
Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes
Exfoliative 
Dermatologic 
Conditions
Suspected SJS, 
TEN, or DRESS
Withhold
Based on severity of 
AE administer 
corticosteroids
Ensure adequate 
evaluation to confirm 
etiology or exclude other 
causes
Confirmed SJS, 
TEN, or DRESS
Permanently 
discontinue
All Other irAEs
Persistent Grade 
2
Withhold
Based on severity of 
AE administer 
corticosteroids
Ensure adequate 
evaluation to confirm 
etiology or exclude other 
causes
Grade 3
Withhold or 
discontinue 
based on the 
event e
Recurrent 
Grade 3 or 
Grade 4
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; 
CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash with Eosinophilia and 
Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; 
SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; 
ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a AST/ALT: >3.0 to 5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 
to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline if baseline abnormal
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or 
treating physician. 
Grade 2, pembrolizumab may be resumed.
e Events that require discontinuation include but are not limited to: encephalitis and other clinically important 
irAEs (eg. vasculitis and sclerosing cholangitis).
5.3.6.3
Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab associated infusion 
reaction are provided in Table 4.

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Table 4. Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator.
None
Grade 2
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator.
If symptoms resolve within 1 hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion 
rate (e.g. from 100 mL/hr. to 50 mL/hr.). 
Otherwise dosing will be held until 
symptoms resolve and the participant 
should be premedicated for the next 
scheduled dose.
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further 
study drug treatment
Participant may be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
study intervention with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000
mg po (or equivalent dose of 
analgesic).
Grades 3 or 4
Grade 3:
Prolonged (i.e., not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilator 
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should 
be used immediately.
Participant is permanently discontinued from 
further study drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration. For further information, please refer to the Common 
Terminology Criteria for Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov.

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5.3.7
Other allowed dose interruption for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical or surgical events and/or unforeseen circumstances not related to study intervention. 
However, study intervention is to be restarted within 6 weeks or 42 days (for Q6W dosing) of 
the originally scheduled dose and within 84 days (for Q6W dosing) of the previously 
administered dose, unless otherwise discussed with the Sponsor. The reason for interruption 
is to be documented in the patient's study record. If pembrolizumab is interrupted after the TLT 
observation period, CyPep-1 can continue to be administered at a Q2W schedule as per 
schedule. 
5.3.8
Blinding 
Blinding is not applicable, as this is an open label trial.
5.4
Method of Assigning Subjects to Treatment
Eligible subjects (see Section 4) will receive IT CyPep-1 in this trial, as monotherapy and in 
combination with pembrolizumab. Subjects will be assigned to treatment cohorts based on 
order of enrolment. 
5.5
End of Treatment
In this trial, end of treatment will vary per subject, in view of their participation in additional 
treatment cycles with CyPep-1, for both trial phases. 
5.6
Prior and Concomitant Medication and Therapy
Medications and therapies taken specifically for the management of solid tumors during 
6 months prior to ICF signature will be recorded on the Medication History page of the eCRF.
All medications (prescription and over-the-counter drugs, vitamins and minerals) and therapies 
used during the trial, in addition to the trial intervention (CyPep-1 or pembrolizumab) will be 
considered concomitant. 
All concomitant medications and therapies will be recorded in the eCRF from time of ICF 
signature until the FU visit (or until EoT, if it occurs more than 30 days after the last CyPep-1
administration). All concomitant medications administered during SAEs or Events of Clinical 
Interest (ECIs) are to be recorded.
The following concomitant medications or therapies are of special interest:
Palliative medications 
Medication for the treatment of infections, including prophylactic or pre-emptive use of 
anti-infective medication 
Medication for the treatment of disease relapse 
Medication for the treatment of other reported AEs
Prophylactic use of immunosuppressive medication 
5.6.1
Permitted Medication and Other Treatments
If a subject uses anticoagulants, they should be stopped per Investigator discretion, according 
to local practice for invasive examinations. 

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Premedication is mandatory prior to the first IT dose of CyPep-1. Premedication is started 30-
60 minutes before the IT injection, and continues for up to 24-48 hours after the procedure was 
completed, if necessary. An antihistamine (e.g., 25 to 50 mg clemastine) is mandatory with 
optional anxiolytics if deemed appropriate by the investigator. Only for subjects experience 
pain during or after IT administration, it is recommended to provide celecoxib 400 mg as 
premedication every 6 hours for 24-48 hours. Premedication should be administered for 
subsequent CyPep-1 doses based upon clinical judgment and presence/severity of prior 
reactions. This regimen may be modified based on local treatment standards and guidelines 
as appropriate. 
However, the prophylactic use of systemic corticosteroids is not permitted. Administration of 
steroids through a route known to result in a minimal systemic exposure (topical [only on areas 
outside the injected lesions], intranasal, intro-ocular, or inhalation) is acceptable at the lowest 
possible dose. Following CyPep-1 administration, subjects must be observed for 4 hours
post-injection for potential immediate injection-related reactions.
Medications may be administered due to anticipated adverse reactions or anticipated 
emergency situations (see Appendix E: Medication for Hypersensitivity Type Reactions 
Anticipated to be Possibly Occurring Due to CyPep-1 Administration). 
At the discretion of the Investigator, any concomitant medication or therapy deemed necessary 
for the welfare of the subject during the trial, the treatment of AEs, and the treatment of disease 
relapse may be given. It is the responsibility of the Investigator to ensure that these 
medications or therapies are documented in the Concomitant Medication page of the eCRF.
5.6.2
Prohibited Medication and Other Treatments
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from study intervention or vaccination 
may be required. The investigator is to discuss prohibited medication/vaccination with the 
Sponsor’s Clinical Director. The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the participant's primary physician. However, the decision to 
continue the participant on study treatment requires the mutual agreement of the investigator, 
the Sponsor and the participant.
The following treatments must not be administered during the trial:
Immunotherapy not specified in this protocol, immunosuppressive drugs (that is, 
chemotherapy or systemic corticosteroids except for short-
allergic reactions or for the treatment of immune-related AEs), or other investigational 
agents other than CyPep-1 or pembrolizumab, with the exception that COVID-19 
treatments are allowed after consultation with the Sponsor and the Medical Monitor.
Steroids with no or minimal systemic effect are allowed. 
Chronic concurrent therapy with antibiotics is prohibited within 2 weeks before and 
during the treatment period. 
Herbal remedies with immunostimulating properties (for example, mistletoe extract) or 
known to potentially interfere with major organ function (for example, hypericin). 
Any other anti-neoplastic systemic chemotherapy, biological treatment or concurrent 
anticancer treatment or chemotherapy not specified in this protocol
Radiation therapy, with the exception of palliative short course, limited-field 
standard), which may be administered during the trial. 
Live or live attenuated vaccines, including live or live attenuated COVID-19 vaccines.

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Systemic glucocorticoids are permitted only for the following purposes:
o
To modulate symptoms of an AE that is suspected to have an immunologic 
etiology
o
As needed for the prevention of emesis
o
Premedication for IV contrast allergies
o
Short-term oral or IV use in doses >10mg/day prednisone equivalent for 
COPD exacerbations
o
For chronic systemic replacement not to exceed 10 mg/day prednisone 
equivalent
o
In addition, the following glucocorticoid use is allowed:
For topical use or ocular use
Intraarticular joint use
For inhalation in the management of asthma or chronic obstructive 
pulmonary disease. 
Concomitant medications for treatment of HIV infection and/or its complications, except 
stable ART regimen maintained for at least 4 weeks prior to study entry (exceptions 
are permissible but should be discussed with the Sponsor and medical monitor).
Note: Inhaled steroids are allowed for management of asthma.
If the investigator determines that a subject determines that a participant requires any of the 
aforementioned treatments for any reason, study intervention CyPep-1 + pembrolizumab must 
be discontinued.
5.6.3
Rescue Medications & Supportive Care
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 5.3.6 for pembrolizumab. 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. Refer to Table 3 in 
Section 5.3.6.3 for guidelines regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
5.7
Treatment Compliance
Administration of intratumoral CyPep-1 and administration of IV pembrolizumab will be done 
in a hospitalized environment by trained trial personnel. Treatment compliance will be 
accomplished by documenting in record (i.e. the drug accountability, preparation, 
administration logs, the subjects’ eCRF and medical records) information on, but not limited 
to: the batch number of CyPep-1 and of pembrolizumab used, the time point for preparation, 
the time point for administration, and signatures of designated site staff preparing and 
administering intratumoral CyPep-1 and pembrolizumab. Any deviations will be documented 
on the appropriate eCRF page.

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5.8
Pregnancy and Contraception
CyPep-1 and pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is 
not known if pembrolizumab has transient adverse effects on the composition of sperm.
Participants should be informed that taking the trial medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the trial. 
Pregnant or breastfeeding women are not allowed to participate in this trial. In women of 
childbearing potential (defined as <2 years after last menstruation or not surgically sterile), a 
serum pregnancy test has to be performed at screening and prior to trial treatment. This test 
has to be negative for a subject to participate in this trial.
Subjects must be willing and be able to adhere to the following prohibitions and restrictions 
during the course of the trial:
All male subjects with partners who are women of childbearing potential and female 
subjects of childbearing potential (as defined above) must consistently and correctly 
use a contraceptive method in accordance with the recommendation of the EU Clinical 
Trial Facilitation Group. Examples include female oral contraceptives, female 
intrauterine contraceptive device, female bilateral tubal occlusion, male vasectomy, or 
sexual abstinence. Additionally, the partners of subjects with childbearing potential are 
recommended not to donate sperm.
Contraception is to be used from screening until at least 120 days after the last dose 
of CyPep-1 or pembrolizumab. If there is any question that a participant of childbearing 
potential will not reliably comply with the requirements for contraception, that participant 
should not be entered into the trial.
Female subjects will be instructed to notify the investigator immediately if they become 
pregnant during the trial. Male subjects will be instructed to notify the investigator 
immediately if their partner becomes pregnant. If a participant inadvertently becomes 
pregnant while trial on treatment, the participant will be immediately discontinued from 
further trial treatment. The subjects will also be instructed to report pregnancies 
discovered after the last visit, if they believe that conception occurred during their 
participation in the trial. The outcome of the pregnancy will be reported to the Sponsor 
without delay and within 24 hours if the outcome is a serious adverse experience (e.g., 
death, abortion, congenital anomaly, or other disabling or life-threatening complication 
to the mother or new born). The study investigator will make every effort to obtain 
permission to follow the outcome of the pregnancy and report the condition of the fetus 
or new born to the Sponsor.
o
A pregnancy, as such, is not an adverse event (AE) unless there is a possibility 
that the IMP and / or pembrolizumab have interfered with the efficiency of any 
contraceptive measures. However, the investigator should report pregnancies 
according to the procedures and timelines described for reporting of SAEs (see 
Section 7.2.3). The pregnancy report form should be used instead of the SAE 
form.
o
The site will contact the pregnant subject or partner at least monthly and 
document the participant’s status until the pregnancy has been completed or 
terminated. Any complication during the pregnancy should preferably be 
reported as an AE. The outcome of the pregnancy must be reported (on the 
pregnancy report form) to the Sponsor without delay and within 24 hours if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or new 
born). The investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or new born to 
the Sponsor. Any spontaneous abortion, stillbirth, birth defect/congenital 

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anomaly, death, or other serious infant condition must be reported and followed 
up as a SAE.
5.8.1
Use in Nursing Women
It is unknown whether CyPep-1 or pembrolizumab are excreted in human milk. Since many 
drugs are excreted in human milk, and because of the potential for serious adverse reactions 
in the nursing infant, participants who are breastfeeding are not eligible for enrollment.
5.9
Post-trial Treatment
After participation, subjects will continue treatment in accordance with clinical practice, i.e. as 
per local guidelines and Standard of Care. 
In case of early closure or termination of the trial, eligible and benefitting patient, will have the
option to continue CyPep-1 treatment. Continued CyPep-1 treatment for eligible and 
benefitting patients will be allowed after a decision by the investigator, medical monitor and 
sponsor.
5.9.1
Continued Access pembrolizumab
Subjects who are still on study intervention at the time of study completion/termination may 
continue to receive study intervention if they are experiencing clinical benefit. The continued 
access to study intervention will end when a criterion for discontinuation is met or 18 (for Q6W 
dosing) doses of pembrolizumab have been administered.
5.10 Accountability Procedures
Cytovation will ensure that the IMP is characterized and manufactured in accordance with any 
applicable requirements of Good Manufacturing Practice (GMP) and regulatory requirements.
After the trial protocol was approved by the regulatory authorities, the trial medicinal product 
will be supplied to the investigators and trial sites together with all relevant documentation 
including a description of the storage conditions.
Cytovation will maintain records of document shipment, receipt, dispensation, return, and 
destruction of the IMP in the Trial Master File. Cytovation is responsible for the storage of 
retention samples of the IMP according to applicable laws and guidelines.
The Investigator will maintain records of IMP accountability in the ISF for the IMP provided by 
Cytovation.
After the end of the trial, the Investigator will return all used and unused IMPs to Cytovation or 
destroy used and unused IMP according to written agreement with Cytovation.

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6.
INVESTIGATIONAL PLAN
6.1
Assessment Overview
An overview of the assessments performed in the trial is provided in Table 5 below. 
Eligibility and safety of CyPep-1 (plus pembrolizumab in combination arm) will be assessed by 
means of demographics, medical and oncology history, vital signs, physical examination, 
cardiovascular function evaluation, ECOG performance status, routine laboratory tests 
(pregnancy test, hematology, clinical chemistry, urinalysis), disease assessment, concomitant 
medications, and collection of AEs.
Efficacy of CyPep-1 (plus pembrolizumab in combination arm) will be assessed by means of 
radiological assessment, local measurements of injected tumor lesions, and survival data (PFS
based on iRECIST per investigator assessments).
Additional assessments include PK, changes in the tumor microenvironment (tumor biopsy), ,
and levels of cytokines (cytokine analysis not applicable for Arm D) and selected immune cell 
markers in the peripheral blood.
Table 5. Overview of Assessments
Objective
Assessment
Specification, if any
Eligibility
Informed consent
Confirmation of written informed consent prior 
to any trial specific procedure
Eligibility check
Based on inclusion/exclusion criteria 
Demographics 
Recording of subjects’ demographics
Medical and surgical history
Recording of subjects’ complete medical 
history including details of cancer onset, prior 
surgery, cancer-related and other treatments, 
and known HIV, HCV, and HBV exposure
Tumor biopsy
Cycle 1: should be available for at least one
injected lesion(s) at screening and at Week 6; 
may be taken from non-injected lesions. 
Subsequent cycles: from any new injected 
lesion(s) before the first treatment and after 6 
weeks (not mandatory). A biopsy from lesions 
that were injected in previous cycles can be
taken (not mandatory) after 6 weeks.
Safety
Physical examination 
Physical 
examinations 
per 
institutional 
guideline.
Concomitant medications
To be assessed at screening and then at each 
visit. Will include concurrent illness.
ECG
Single 12-lead ECG recordings will be taken. 
Subjects must be supine for approximately 
10 minutes before ECG collection and 
remain supine but awake during the ECG 
collection. 
Vital signs
The following will be assessed: 
1.
Pulse rate 
2.
Systolic and diastolic blood pressure 
3.
Body temperature 

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Blood pressure and pulse rate should always 
be measured on the same arm. A time window 
of ± 5 min is allowed. 
Biochemistry
The following will be assessed: creatinine, 
alkaline 
phosphatase, 
phosphate, 
total
bilirubin, direct bilirubin (only applicable if total 
bilirubin levels > 1.5 x ULN), ALAT, ASAT,
gamma-glutamyl transferase, total protein, 
albumin, uric acid, urea, sodium, potassium, 
calcium, 
chloride, 
glucose, 
lactate 
dehydrogenase, amylase and lipase.
Hematology
The following will be assessed Hb, hematocrit, 
RBC count, WBC count with differential count 
(neutrophils, 
eosinophils, 
basophils, 
lymphocytes, monocytes), and platelet count.
Coagulation
The following will be assessed: prothrombine 
time- international normalized ratio (PT-INR) 
and activated partial thromboplastin time 
(APTT)
Urinalysis
The following will be assessed: leukocytes, 
nitrite, 
pH, 
protein, 
glucose, 
ketone, 
urobilinogen, 
bilirubin, 
blood 
(Hb 
and 
erythrocytes) (dipstick). If abnormal, sediment 
will be performed.
ECOG performance status
Using the ECOG performance status scale 
(Appendix B)
Recording (S)AEs and 
hospitalizations
To be assessed at screening and then at each 
visit, 
according 
to 
NCI-CTCAE 
v5.0 
(Appendix C)
Pregnancy test
A serum pregnancy test will be performed at 
screening. At all other occasions, a urine test 
before any study treatment is administered is 
sufficient. For the assessment of childbearing 
potential, FSH and estradiol tests may be 
required at screening.
Thyroid function 
To be evaluated at the timepoints specified in 
the schedule of assessments. 
Efficacy
Tumor biopsy
Arrangements to be made for any tumor 
material to be sent for analysis are described 
in the laboratory manual.
iRECIST (and itRECIST) 
assessment
A CT/MRI scan is the recommended modality, 
which should include chest, abdomen, pelvis 
and all other known sites of disease. For the 
case of skin lesions, measurement by clinical 
examination using calipers
and by color 
photography should be performed. Tumor 
response will be evaluated according to the 
iRECIST
using 
modified 
RECIST
1.1
(Appendix
D)
based 
on 
investigator 
assessment.
itRECIST 
will 
be 
programmatically 
calculated 
using 
data 
obtained 
from 
iRECIST 
assessments 
following the itRECIST principle summarized 
in Appendix F. itRECIST tumor response for 

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Phase I Cohort 3, Phase IIa Arms A, B and C 
will be performed retrospectively.
Local measurement of (to-be) 
injected tumor lesion(s)
For Phase I and Arms A, B, and D, local 
measurements of accessible (to-be) injected 
cutaneous/subcutaneous 
tumor 
lesion(s) 
must be done prior to each CyPep-1 injection 
by caliper and color digital photography. If 
needed, 
guidance 
with 
ultrasound 
is 
permitted. The (to-be) injected lesions under 
ultrasound control must be measured with 
ultrasound guidance before each CyPep-1
injection and only on dates of CyPep-1
injection.
Lesion mapping (Arm D only)
Will be performed during screening; a lesion 
map will be created prior to the first CyPep-1
injection
(detailed 
in 
Study 
Procedural 
Manual). Once all injectable lesions have 
been injected and the subject remains on 
treatment, a new lesion map that permits 
reprioritizing of the to-be-injected lesion sets 
will be created (details see Section 5.3.1.3)
Administration of CyPep-1
For Arms A, B and C, administration of 
CyPep-1 will be performed at Weeks 1, 3, and 
5 (Day 1 of each week). All subjects are 
planned for additional treatment cycles (Q2W
CyPep-1 administration). For Arm D, it will be 
performed 
QW 
until 
the 
second 
iRECIST/itRECIST assessment at week 16, 
followed by a Q2W dosing scheme.
Administration of pembrolizumab
Will be performed as specified in the schedule 
of assessments (at Q6W administration).
Other
PK
A time window of ± 5 min is allowed for the PK 
blood sampling.
Levels of cytokines (Arms A, B, 
and C)
 
 
Blood sampling for immune cell 
phenotyping
An additional blood sample will be taken for 
peripheral
blood phenotyping of
selected 
immune cell markers.
Note: no more peripheral blood sampling required for TCR clonality analysis (See Sections 6.2 and 8.1.6
for details). 
Abbreviations: ALAT: alanine transaminase; ANC: absolute neutrophil count; APTT: activated partial 
thromboplastin time; ASAT: aspartate transaminase; CT: computed tomography; CTCAE: Common 
terminology Criteria for Adverse Events; ECG: electrocardiogram; ECOG: Eastern Cooperative 
Oncology Group; FSH: follicle-stimulating hormone; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: 
human immunodeficiency virus; IL: interleukin; IFN: interferon; iRECIST: immune Response Evaluation 
Criteria in Solid Tumors; itRECIST: Response Criteria for Intratumoral Immunotherapy in Solid Tumors 
; MRI: magnetic resonance imaging; NCI: National Cancer Institute; OS: overall survival; PFS: 
progression-free survival; PK: pharmacokinetic; PT-INR: prothrombin time – international normalized 
ratio; RBC: red blood cell; TCR: T cell receptor; TGF: transforming growth factor; TNF: tumor necrosis 
factor; WBC: white blood cell. 

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6.2
Trial Assessment Specifications
Obtaining of written informed consent prior to any trial specific procedure (including screening 
procedures) will be performed at screening. Eligibility check, recording of subject 
demographics, past medical and surgical history (including disease under trial), and recording 
of concurrent illness and treatments will also be performed at screening or at Day 1 of Cycle 1
prior to treatment.
Eligibility
Subjects who do not meet all inclusion criteria or who meet any of the exclusion criteria are not 
eligible for trial entry. As soon as a subject is deemed ineligible during screening, all further 
trial evaluations will be cancelled for this subject.
Subjects considered suitable for the trial may only enter the trial after they have been properly 
informed and have signed the ICF.
Each subject will receive a 5-digit subject number (e.g. 01-001), which is assigned by the site 
during the screening visit and will be used throughout the trial.
Digits 1 / 2: 
trial site code
Digits 3 / 4 / 5: Individual subject number (consecutively in the order of trial entry per 
site
All subjects, including screening failures, are added to the Electronic Data Capture (EDC) 
system by site staff.
Demography and Medical and Surgical History
Demographic characteristics, obtained during screening, will include age (in years at 
screening), sex, and date of birth as described by the subject.
Each subject’s relevant medical history will focus on current or past abnormalities or diseases 
of the following systems: special senses, cardiovascular, respiratory, gastrointestinal, hepatic 
biliary, 
genitourinary/reproductive, 
renal, 
endocrine/metabolic, 
musculoskeletal, 
hematologic/lymphatic, neurologic/psychiatric, dermatologic, immunologic, and infectious 
disease, bleeding tendency, and allergy/drug sensitivity.
Disease History and Treatment
Special attention will be paid to the subject’s disease history and treatments. The disease 
information that will be documented and verified at the screening visit for each subject includes:
1.
Detailed history of the malignancy, including onset, histopathological diagnosis, 
grading, and staging at diagnosis/trial entry, and date of recurrence
2.
All therapy used for prior treatment (prior surgery, and past treatment including 
chemotherapy and/or radiation therapy) in the past two years (for therapy used for prior 
treatment > 2 years before trial initiation, only name of compound and treatment year 
need to be documented)
3.
Any other conditions that were treated with chemotherapy, radiation therapy, or 
immunotherapy
4.
Current signs and symptoms of the malignancy and AEs from current and previous 
anticancer treatments
5.
Tumor localization at trial entry
Furthermore, medical history will include details of prior HIV, HCV, and HBV exposure.

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For Arms A, C, and D: known HIV and HBV/HCV history results in ineligibility. Testing for either 
is required if mandated by local health authority. HIV+ subject is eligible when normal levels of 
CD4 are present.
For Arm B: HIV+ subjects are eligible if having controlled disease and not immune 
compromised. Details see inclusion criteria 32 (Section 4.1) and exclusion criteria 41 (Section 
4.2). 
Height, Weight, Physical Examinations
Physical examinations will be performed at several time points throughout the trial (excluding 
height determination, which will only be performed at screening; see Table 1) and may include 
as per institutional guidelines the following: head, eyes, ears, nose and throat; respiratory 
system/ chest; cardiovascular system/ heart; abdomen (including liver and spleen); skin, lymph 
nodes; extremities and (at the Investigator’s discretion) genitourinary system/ pelvis.
The assessments are to be performed prior to CyPep-1 administration or pembrolizumab (if 
pembrolizumab administration day is different from CyPep-1 scheduled day). For height and 
body weight measurements, preferably the same equipment should be used throughout the 
trial. To obtain the actual body weight, subjects must be weighed lightly clothed. Body height 
will be recorded in centimeters and body weight in kilograms.
If the investigator (or qualified designee) encounters an abnormal finding, the investigator 
should indicate whether the finding is clinically significant or not. 
Information about the physical examination must be present in the source documentation at 
the investigational site. Significant findings that are present prior to the signature of the ICF 
must be included on the Medical History eCRF. Significant findings that meet the definition of 
an AE, must be recorded on the AE eCRF.
Vital Signs
Vital signs will be assessed at regular intervals as indicated in the Table 1. The following 
variables will be measured:
1.
Systolic and diastolic blood pressure (mm/Hg)
2.
Pulse rate (beats per minute)
3.
Temperature
All blood pressure measurements require the use of completely automated device on the same 
arm. The same type of automated device is to be used at least for the same patient. The 
automated device must be calibrated annually. Body temperature will be measured in a 
consistent manner throughout the trial. Continuous oxygen monitoring will be performed if the 
subject has respiratory problems.
ECOG Performance Status
The ECOG performance status score, determined at the time points indicated in the Table 1
will be used to quantify the general well-being and activities of daily life in cancer subjects and 
uses scores as described in Appendix B. Only subjects with an ECOG Performance Status 
score of 0 or 1 are allowed to enter the trial.
The assessment is to be performed prior to CyPep-1 or pembrolizumab administration.
Cardiovascular function (ECG)
Single standard 12-lead ECGs (i.e. according to Einthoven and Goldberger as well as 
6 precordial leads according to Wilson) will be recorded using a computerized ECG device 
after at least 10 min rest in supine position (lying horizontally with the face and torso facing 

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up). ECGs should be performed prior to CyPep-1 or pembrolizumab administration and any 
scheduled vital signs measurements (see time points for ECG recordings in the Table 1).
The following parameters will be automatically calculated by the ECG device: HR, PR/PQ 
interval, QRS interval, QT interval (uncorrected).
All ECGs will be evaluated by a physician to provide immediate safety monitoring offering an
ECG diagnosis and overall assessment (including clinical relevance). Corrected QT intervals 
will be derived in addition for data evaluation.
For all safety laboratory assessments
If the time between screening and the first CyPep-1 administration is <72 hours, safety 
laboratory tests do not need to be repeated.
Hematology
At the time points indicated in the Table 1 (Table 1 a – e), blood sampling for all safety 
laboratory tests should be performed and results should be available prior to administration of 
CyPep-1 or pembrolizumab (if pembrolizumab administration day is different from CyPep-1
scheduled day).
Hematology tests will be performed at the local (institute’s) hospital. 
Parameters to be assessed include: hemoglobin, hematocrit, RBC count, WBC count with 
differential count (neutrophils, eosinophils, basophils, lymphocytes, monocytes), and platelet 
count. Further assessments may be performed up to one day prior to the visit in order to have 
the results (of at least hemoglobin, white blood cells, platelets, PT-INR, and APTT) available 
on the visit day prior to CyPep-1 administration.
The Investigator (or qualified designee) should evaluate all blood parameters either as normal 
or abnormal. If an abnormal finding is encountered, the investigator should indicate whether 
the finding is clinically significant or not. Any hematological abnormalities that are considered 
to be clinically significant need to be followed until resolution.
Biochemistry
At the time points indicated in Table 1, blood sampling for all safety laboratory tests should be 
performed and results should be available prior to administration of CyPep-1 or pembrolizumab 
(if pembrolizumab administration day is different from CyPep-1 scheduled day).
Biochemistry tests will be performed at the local (institute’s) hospital. 
Parameters to be assessed include: creatinine, total bilirubin, direct bilirubin (only applicable if 
total bilirubin levels > 1.5 x ULN), alkaline phosphatase, phosphate, ALAT, ASAT, GGT, total 
protein, albumin, uric acid, urea, sodium, potassium, calcium, chloride, glucose, LDH, amylase 
and lipase. Creatinine clearance will be estimated according to the CKD-EPI formula.
The Investigator (or qualified designee) should evaluate all clinical chemistry parameters either 
as normal or abnormal. If an abnormal finding is encountered, the Investigator should indicate 
whether the finding is clinically significant or not. Any clinical chemistry abnormalities that are 
considered to be clinically significant need to be followed until resolution.
Coagulation
Coagulation parameters will be assessed at several different time points throughout the trial
(Table 1) and include PT-INR-, and activated partial thromboplastin time (APPT) prior to 
dosing. In case there are no normal ranges available for the PT test, the international 
normalized ratio (INR) test may be used instead of PT. At screening, subjects should have an 
INR <1.5 x ULN.

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Urinalysis
At the time points indicated in Table 1a to 1e of Table 1 urinalysis is to be performed by gross 
(dipstick) urine examination. Midstream, clean-catch urine specimens will be collected for 
dipstick analysis. Parameters to be assessed include: leukocytes, nitrite, pH, protein, glucose, 
ketone, urobilinogen, bilirubin, blood (hemoglobin and erythrocytes).
If dipstick findings are abnormal according to local reference ranges, then a microscopic 
evaluation may be performed to assess the abnormal findings. Any urinalysis abnormalities 
that are considered to be clinically significant need to be followed until resolution.
Adverse Events
AEs need to be collected as soon as the subject has consented to the trial (ICF signature) until 
the FU visit (or until EoT, if it occurs more than 30 days after the last CyPep-1 or 
pembrolizumab administration). After the FU visit (or EoT visit, if it occurs more than 30 days 
after the last CyPep-1 administration or last administration of pembrolizumab in combination 
arm), only ongoing AEs or SAEs related to CyPep-1 and / or pembrolizumab administration 
will be collected.
For Arm B: All AEs meeting serious criteria, from start of treatment through 90 days following 
cessation of study treatment, or 30 days following cessation of study treatment if the 
participant initiates new anticancer therapy, whichever is earlier must be reported by the 
investigator. 
Subjects who dropped out of the trial with (S)AEs that are ongoing at the time treatment was 
withdrawn, need to visit the hospital 30 days after the last CyPep-1 or pembrolizumab 
administration for monitoring of these (S)AEs, if possible.
AEs will be assessed using CTCAE v5.0, including start and stop dates, severity, relationship 
to CyPep-1 and / or pembrolizumab, outcome and action taken. Section 7 of the protocol 
provides detailed instructions on AE reporting and definitions related to it. For more information 
on AE monitoring, please refer to Section 7.2.
Pregnancy
Women of childbearing potential must have a highly sensitive negative pregnancy test at 
screening (serum) and throughout the treatment period (Table 1a to 1e, Table 1; highly 
sensitive urine/serum). In this trial, pregnancies occurring during participation (including 
pregnancies of partners of male subjects) are not considered as an AE per se, but they must 
be reported to the sponsor using the trial Pregnancy Reporting Form, according to the rules 
described in Section 7.2.3 (Reporting of SAEs).
Concomitant and Prior Medications
All concomitant medication should be reported from ICF signature during the treatment period 
until the FU visit (or until EoT, if it occurs more than 30 days after the last CyPep-1 or 
pembrolizumab administration) in the CRF. Non-drug interventions and any changes to a 
concomitant medication or other intervention should also be recorded in the CRF. At screening, 
prior medications taken by the subject beginning 28 days prior to ICF signature are to be 
recorded in the CRF, noting the name, dose, duration and indication of each drug. 
Thyroid function
In clinical trials using pembrolizumab, the thyroid function needs to be evaluated at regular 
time intervals. For this trial, this evaluation applies for subjects in Phase IIa Arm B and should 
be performed at the timepoints specified in Table 1.
Clinical Response based on iRECIST and itRECIST assessments

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Radiological assessments are to be performed at the time points given in Table 1a to Table 1e
(depending on trial phase and treatment arm). The visit window (where applicable) is specified 
in footnote #22 of the schedule of assessments. The first on-study scan assessment should 
be performed at 8 weeks ±3 days from the date of treatment. Subsequent tumor scans should 
be performed every 8 weeks ±3 days or more frequently if clinically indicated. Scan timing 
should follow calendar days and should not be adjusted for delays in cycle starts. Scans should 
continue to be performed until disease progression is identified by the investigator. All skin 
lesions must be assessed by caliper measurement during clinical exam on the dates 
corresponding to iRECIST assessment. Documentation by color photography including a ruler 
to estimate the size of the lesion should be stored in the patient file (SoA, footnote #22).
Once a tumor lesion is documented, the target area should be recorded at every subsequent 
time point for the duration of the trial. The same type of scan should be used in a subject
throughout the study to optimize the reproducibility of the assessment of existing and new 
tumor burden and improve the accuracy of the assessment of response or progression based 
on imaging.
In order to account for the possibly delayed onset of CyPep-1 action and for subjects who are 
of acceptable clinical performance status (as deemed by the Investigator), if PD is recorded 
and provided that the tumor enlargement is smaller than 50% compared to the previous 
measurement, the subject will remain in the trial until confirmed PD and will be reassessed 
radiologically after 4 weeks. A confirmatory radiological assessment only has to be done if at 
the previous visit PD was observed with radiological assessment. If the lesion(s) continue(s) 
to enlarge, the original PD will be considered as the “first documented PD”. If lesion(s) 
remain(s) unchanged or decrease(s) in size, assessments should continue as per protocol 
(i.e., the next radiological assessment will be performed after an 8-week interval). In this case, 
the first measured PD will be disregarded. In case of unconfirmed PD, the subject should stay 
on treatment with CyPep-1 (plus pembrolizumab in the combination arm). If PD is confirmed 
4 weeks later, then the subject will be taken off-trial and move to the end of treatment visit.
Tumor response or progression on CT/MRI will be determined according to iRECIST (modified 
RECIST1.1 using up to 10 target lesions) and itRECIST [Goldmacher 2020]). A summary of 
itRECIST in comparison to iRECIST is in Appendix F.
ORR in all lesions will be evaluated based on the investigator’s assessments per iRECIST.
ORR in injected and non-injected lesions, separately, per itRECIST will be programmatically 
calculated using data obtained from iRECIST assessments.
Local measurement of tumor lesion(s)
For Phase I, and Phase IIa Arms A, B and D: Local measurements of (to-be) accessible 
injected cutaneous/subcutaneous tumor lesion(s) must be done within one day (<24h) prior to 
each CyPep-1 injection by caliper and color digital photography, using a ruler held flush to the 
skin next to the longest diameter of the lesion to indicate the size of the lesion. If needed, 
guidance with ultrasound is permitted. The (to-be) injected lesions under ultrasound control, 
must be measured with ultrasound guidance before each CyPep-1 injection only on dates of 
CyPep-1 injection. All ultrasound and color digital photography image files should be stored 
and available in the patient file). Lesion(s) that disappeared will be checked on the days of 
CyPep-1 injection.
Lesion mapping
A lesion map that will guide the preferred sequence of injection of the identified Lesion Sets
must be created prior to the first CyPep-1 injection (detailed in Study Procedural Manual). A
lesion map will contain the information as described in Section 5.3.1.3.

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Once the lesion map is created, lesion sets for sequential CyPep-1 injections will be planned 
and documented in the source. The size of the injected lesions and the lesion map should be 
updated when assessments of local measurements of tumor lesions and iRECIST and 
itRECIST assessments are performed during the treatment period. 
End of Treatment and Follow-up Tumor Imaging (Arm B)
If subjects discontinue study treatment, tumor scans should be performed at the time of 
discontinuation (±4-week window) unless previous scans were obtained within 4 weeks of 
discontinuation. Subjects who are clinically stable and treated past radiographic progression 
may continue to be assessed until progression is confirmed according to the rules of iRECIST, 
when clinically appropriate. 
If subjects discontinue study treatment without documented disease progression, every effort 
should be made to monitor disease status by acquiring tumor scans using the same schedule 
used while on treatment (every 8 weeks in Year 1 or every 12 weeks after Year 1). Scans are 
to be continued until one of the following conditions are met:
Disease progression as defined by iRECIST
The start of a new anticancer treatment
Pregnancy
Death
Withdrawal of consent
The end of the study
Survival
PFS 
PFS is defined as the time from enrolment until disease relapse or disease progression (based 
on iRECIST per the investigator’s assessments), death due to any cause, withdrawal of 
consent, loss to follow-up, or until the end of the trial whichever occurs first and will be
evaluated at the time points defined in Table 1.
Once a tumor lesion is documented, the target area should be recorded at every subsequent 
time point for the duration of the trial. For subjects who leave the trial early and do not receive 
any other anti-cancer therapy or any other investigational therapy, PFS visits should continue 
to be performed every 8 weeks (from C1D1) until occurrence of confirmed progressive disease
or until start of any further line of anti-cancer treatment. In the case of PD or start of any further 
line of anticancer treatment, the next FU will be OS-FU (Schedule of Assessments).
OS
Every three months after the confirmation of PD and until the end of the trial, a phone call for 
survival status (OS) will be done. Additionally, any next line of anti-cancer therapies, ORR and 
duration of response to next line anti-cancer therapies, and additional relevant information will 
be recorded. If necessary, patients may be contacted occasionally outside of this FU window,
and data regarding next line anti-cancer therapies can be collected retrospectively.
Additional efficacy assessments
Pharmacokinetics 

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Blood samples for PK determination will be collected from the first 9 subjects of Phase I, all
subjects of Arm C, and the first 12 subjects of Arm D receiving CyPep-1 at the time points 
given in Table 1a. All relevant sample collection and analysis will be performed according to 
qualified and/ or Good Laboratory Practice (GLP) methods, as appropriate. Details of the 
sampling and processing procedures, storage, and transportation will be provided in a 
separate laboratory manual.
Peripheral Cytokines (Arms A, B, and C)
Levels of blood cytokines will be determined at a central laboratory at the time points specified 
in Table 1 by enzyme-linked immunosorbent assay (ELISA). 
Changes in the Tumor Microenvironment (Tumor Biopsy)
Primary (archival only for screening) tumor material of all subjects will be used for analysis 
(see Table 1a to Table 1e for time points of when tumor biopsies will be taken).
Immunohistochemistry/immunofluorescent staining of paraffin-embedded samples will be 
conducted at a central laboratory. Tumor samples will be processed according to laboratory 
standards. Tumor tissue will be stained using immunohistochemistry/immunofluorescence in 
order to determine T-cell infiltration and characteristics of tumor tissue. 
No biopsy is to be taken if tumor is inaccessible, biopsy not in subject’s best interest or thought 
to be dangerous or if subject declines to consent to biopsy.
Tumor tissue staining will be performed provided there is access to sufficient tissue (formalin-
fixed paraffin-embedded), post-hoc, batch-wise during the trial or at the end of the trial and 
from the most recent available tissue. 
Additional analysis (as for example tumor mutational burden) might be performed according to 
the investigator’s or sponsor’s decision.
Stainings will be performed for the following:
1.
Immune cell infiltrates:
CD3, CD4, CD8 (T cells)
CD80, CD86 (dendritic cells)
2.
Immune-suppressive cell markers: 
)
3.
Immune markers:
PD-1
PD-L1
Additional stainings for other factors based on emerging scientific understanding of the 
intratumoral CyPep-1 therapy may also be performed.
TCR Clonality
The change in T-cell receptor (TCR) clonality levels will be assessed in the available peripheral 
blood samples. To assess the hypothesis that CyPep-1 increases the TCR clonality 

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systematically, which suggests that T-cells are targeting the tumor, the clonality metric will be 
computed for all subjects providing peripheral blood samples at screening and/or Week 6 of 
every CyPep-1 treatment cycle. 
TCR sequencing might be performed on the available remaining tumor biopsy material from 
the analyses of changes in the tumor microenvironment. Overlaps of T cell clones in respect 
to expansion and breadth of T cell clonality before and after intratumoral injection with CyPep-
1, as monotherapy and in combination with pembrolizumab (central analysis) will be analyzed.
Peripheral blood phenotyping
A peripheral blood sample will be collected at the time points specified in the Table 1.
PBMCs will be isolated, stored and analyzed at a central laboratory. Subjects will be asked to 
provide consent for these additional samples. 
 

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7.
ADVERSE EVENTS
All AEs in this trial will be collected and processed in accordance with ICH-GCP and national 
and local laws and regulations. In line with these regulations, the investigator is responsible 
for reporting SAEs to Allucent, the sponsor’s designee, within the appropriate timelines (see 
below). If required, the investigator is also responsible for notifying the appropriate local ethics 
committee of SAEs per the guidelines of the Institution and in accordance with aforementioned 
laws and regulations.
All AEs involving injection site reactions and dermatological reactions must be documented 
with color digital photography in addition to standard documentation methods.
7.1
Definitions
7.1.1
Adverse Event (AE)
An AE is defined as any untoward medical occurrence in a clinical trial subject administered 
with a medicinal product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
IMP, whether or not considered related to the IMP. All AEs reported by the subject or observed 
by the investigator or his staff will be recorded. 
7.1.2
Treatment-Emergent Adverse Event (TEAE)
All AEs reported from the start of the trial (Day 1) are considered TEAEs. 
7.1.3
Adverse Drug Reaction (ADR)
All noxious and unintended responses to the CyPep-1 and / or to the pembrolizumab medicinal 
product, related to any dose, should be considered as adverse drug reactions (ADRs). The 
phrase “responses to medicinal product” means that a causal relationship between the
medicinal product and an AE is at least a reasonable possibility, i.e., a relationship cannot be 
ruled out. ADRs are also referred to as toxicity.
7.1.3.1
Tumor lysis syndrome (TLS)
A possible risk associated with CyPep-1 intratumoral administration, considering the mode of 
action of CyPep-1, or of pembrolizumab, is TLS, which needs to be mitigated, especially for 
the frail elderly patients. TLS can be mitigated by starting therapy at a low dose of CyPep-1
(as planned for the first cohort of subjects enrolled in Phase I of the trial), by slow dose ramp-up 
(as planned for cohorts in Phase I of the trial), and by staggered approach in Phase II 
combination arm (initial dosing of 3 subjects at RP2D in combination with pembrolizumab 
before enrolling all subjects) and by appropriate preventive measures. Measures to prevent 
TLS include TLS risk assessment, prophylactic hydration and medication prior to initial dosing 
with careful monitoring during the first 4 hours after dosing for metabolic or clinical signs of 
impending TLS, according to institutional standards.
To ensure prophylactic hydration, subjects should consume 2 L of fluid intake per day, starting 
For patients 
who have difficulty to maintain adequate oral hydration, intravenous hydration is 
recommended, at an infusion rate of 150-200 mL/hr (i.e., 2-3 L per day) for initial dosing; for 
following dose escalations, an intravenous hydration with 1.5-2 L per day is advisable. 

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Prophylactic medications for TLS include uric acid reducers such as allopurinol (300 mg orally 
after the last dose 
escalation). 
7.1.4
Unexpected Adverse Drug Reaction
An unexpected adverse drug reaction is an adverse drug reaction of which the nature or 
severity is not consistent with the available product information, e.g. the IB for an unapproved 
investigational product. ADRs that are more specific or more severe than described in the 
investigator’s brochure should also be considered unexpected.
7.1.5
Serious Adverse Event (SAE)
Any untoward medicinal occurrence or effect that at any dose:
Results in death (not due to disease progression); 
Is life-threatening (the subject was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were more severe); 
Requires hospitalization or prolongation of existing hospitalization; 
Results in persistent or significant disability or incapacity; 
Is a congenital anomaly or birth defect.
The following are not considered (and do not need to be reported) as SAEs:
Hospitalization due to a social indication
Elective pre-planned hospitalizations for treatment of an existing condition prior to 
entering the trial
Hospitalizations due to tumor-related symptoms or tumor progression
Any event that does not meet the above criteria may also be considered by the investigator to 
be a SAE, based on appropriate medical and scientific judgment. This includes important 
medical events that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the subject or may require intervention to prevent one of the other 
outcomes listed in the definition above. For example, allergic bronchospasm requiring 
intensive treatment in an emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency.
7.1.6
Suspected Unexpected Serious Adverse Reaction (SUSAR)
SUSARs are SAEs that are at a minimum possibly related to the study agent and are 
unexpected (i.e., not listed in the investigator brochure). SUSARs will be collected and 
expeditiously reported to CAs and IECs according to applicable regulatory requirements.
7.1.7
Toxic Death
Any death to which drug toxicity is thought to have made a contribution should be notified to 
at once. 
will notify the DEC and sponsor immediately.
7.1.8
Pregnancy
In this trial, pregnancies occurring during participation (including pregnancies of partners of 
male subjects) are not considered as an AE per se, but they must be reported to the sponsor 
using the trial Pregnancy Reporting Form, according to the rules described in Section 7.2.3.

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The CA and IEC will be informed on these pregnancies.
Pregnancies must be followed-up to determine outcome (including spontaneous miscarriage, 
elective termination, normal birth, or congenital abnormality) and status of mother and child, 
even if the subject was discontinued from the trial. Pregnancy complications, elective 
terminations for medical reasons and spontaneous miscarriages must be reported as SAEs.
7.2
Monitoring, Reporting, and Documentation of Adverse Events (AEs) 
7.2.1
Monitoring of AEs
Subjects will be monitored for AEs and Events of Clinical Interest (ECIs) from the time of ICF 
signature until the FU visit (or until EoT, if it occurs more than 30 days after the last CyPep-1
administration for Phase I and Arms A and C and D; for Arm B refer to Section 7.2.1.3). After 
the FU visit (or EoT visit, if it occurs more than 30 days after the last CyPep-1 administration),
only ongoing AEs or SAEs related to CyPep-1 administration will be collected. 
For all phases and arms, AEs will be assessed using CTCAE v5.0 (Appendix C), assessments 
will include start and stop dates, severity, relationship to CyPep-1 and / or pembrolizumab,
outcome and action taken.
At every trial visit, subjects will be asked whether they have experienced or are experiencing 
any medically related changes in their health. They will also be asked if they have been 
hospitalized, had any accidents, used any new medications/therapies, or changed concomitant 
medication regimens (both prescription and over the counter medications).
In addition, for all subjects with any remaining CyPep-1 and / or pembrolizumab-related AEs
at the last follow-up visit after the last CyPep-1 intratumoral administration, AE information 
needs to be collected until: 
The symptom subsides or stabilizes; 
Any clinically relevant abnormal laboratory value has returned to baseline; 
There is a satisfactory explanation other than the trial medication for the change(s) 
observed; or
Death, in which case an autopsy report should be supplied to 
, if performed.
7.2.1.1
Events of Clinical Interest (Arm B)
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be reported to the Sponsor within 24 h of awareness.
Events of clinical interest for this trial include: 
1.
an overdose of Sponsor's product, as defined in Section 7.2.1.2
2.
an elevated AST or ALT lab value that is greater than or equal to 3X the upper 
limit of normal and an elevated total bilirubin lab value that is greater than or 
equal to 2X the upper limit of normal and, at the same time, an alkaline 
phosphatase lab value that is less than 2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents. The purpose of the criteria is to 
specify a threshold of abnormal hepatic tests that may require an additional evaluation for an underlying etiology. 
The trial site guidance for assessment and follow up of these criteria can be made available. It may also be 
appropriate to conduct additional evaluation for an underlying etiology in the setting of abnormalities of liver blood 
tests including AST, ALT, bilirubin, and alkaline phosphatase that do not meet the criteria noted above. In these 
cases, the decision to proceed with additional evaluation will be made through consultation between the study 
investigators and the Sponsor Clinical Director. However, abnormalities of liver blood tests that do not meet the 
criteria noted above are not ECIs for this trial.

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7.2.1.2
Treatment of Overdose (Arm B)
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater. 
No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the subject should be observed closely for signs of toxicity. Appropriate 
supportive treatment should be provided if clinically indicated.
7.2.1.3
Time Period and Frequency for Collecting AE, SAE and Other Reportable 
Safety Event Information (Arm B)
Specific considerations on safety reporting for Arm B are summarized below:
All AEs, SAEs and other reportable safety events that occur after the consent form is 
signed but before treatment /allocation must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event cause the 
participant to be excluded from the study, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, 
diet, or a procedure. 
All AEs or ECIs (Events of Clinical Interest) from the time of treatment/ allocation 
through 30 days following cessation of study treatment must be reported by the 
investigator. 
All AEs meeting serious criteria, from the time of treatment/ allocation through 90 days 
following cessation of study treatment, or 30 days following cessation of study 
treatment if the participant initiates new anticancer therapy, whichever is earlier must 
be reported by the investigator. 
All pregnancies and exposure during breastfeeding, from the time of treatment/ 
allocation through 120 days following cessation of study treatment, or 30 days following 
cessation of study treatment if the participant initiates new anticancer therapy must be 
reported by the investigator. 
Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately to the Sponsor if the 
event is considered to be drug-related.
7.2.2
Documentation of AEs
All AEs are to be evaluated for duration, intensity, and relationship to (associated with) the trial 
treatment or due to other causes including underlying disease.
All AEs (problems, complaints, signs, and symptoms and clinically relevant laboratory 
abnormalities), both those observed by trial site personnel and those spontaneously reported 
by the trial subjects, must be recorded on the AE page in the eCRF, as well as in the subject’s 
medical record using standard medical terminology regardless of causality. If an AE occurred 
after signing the ICF, but the subject withdraws from the trial before receiving any trial 
treatment, the AE should be recorded in the eCRF. 
Each event should be recorded as a single diagnosis. Accompanying signs (including 
abnormal laboratory values, physical examination findings, pulmonary or cardiovascular 
function tests) or symptoms should not be recorded as additional AEs. However, if the 
diagnosis is unknown or uncertain, signs and symptoms must be recorded. As soon as the 
diagnosis causing the signs and symptoms is known, the event terms will be adjusted to the 
final diagnosis.

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For each AE, a minimum required information should be reported, which includes:
The type of AE,
An estimate of its severity (using NCI-CTCAE version 5.0, see Appendix C),
Date and time of occurrence, 
Date of resolution, 
Actions required, 
An assessment of its causal relationship to trial medication (using the WHO system 
for standardized case causality assessment, provided separately in the investigator 
File). 
AEs resulting from disease relapse/ progression themselves are not considered to be an AE. 
Likewise, any medical condition that is present at the Screening Visit will be considered as 
baseline and will not be reported as an AE but as medical history. However, if the condition 
changes at any time during the trial, it will be recorded as an AE. Investigators should ensure 
that the event term recorded captures the change in the condition (e.g., “worsening of...”).
7.2.2.1
Severity of AEs
Each AE is to be classified and graded according to CTCAE v5.0 criteria (see Appendix C). 
Dates of onset and resolution, including dates at which the grade of an AE changes, are to be 
recorded in the subject file. 
If no CTCAE grading is available, the severity of an AE is to be graded as follows:
Mild (Grade 1): the event causes discomfort without disruption of normal daily activities.
Moderate (Grade 2): the event causes discomfort that affects normal daily activities.
Severe (Grade 3): the event makes the subject unable to perform normal daily activities 
or significantly affects his/her clinical status.
Life-threatening (Grade 4): the subject was at risk of death at the time of the event or the 
event caused death.
Death (Grade 5): death related to an AE.
7.2.2.2
Relationship to Trial Treatment
The investigator should use medical judgment to determine whether there is a reasonable 
causal relationship, including all relevant factors such as temporal course and latency, pattern 
of the reaction, known pharmacological properties of the product, and alternative explanations 
(e.g., other drugs, medical history, and concomitant diseases). The expression “reasonable 
causal relationship” means to convey in general that there is evidence or argument to suggest 
a causal relationship. The relationship of an AE to trial medication will be recorded on the 
eCRF and defined as follows: 
Not Related: An AE that does not follow a reasonable temporal sequence related to IMP 
and / or pembrolizumab and is likely to have been produced by the patient’s clinical state, 
other modes of therapy or other known etiology.
Unlikely Related: An AE that follows such a temporal sequence from administration of the 
study medication (IMP and / or pembrolizumab) that a relationship is not likely, and is likely 

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to be due to a cause such as (known characteristics of) the patient’s clinical state or other 
treatment.
Possibly Related: AE that has a reasonable possibility that the event may have been 
caused by IMP and / or pembrolizumab. The AE has a timely relationship to the IMP and / 
or pembrolizumab; however, the pattern of response is untypical, and an alternative cause 
seems more likely or there is significant uncertainty about the cause of the event.
Probably Related: An AE that has a reasonable possibility that the event is likely to have 
been caused by IMP and / or pembrolizumab. The AE has a timely relationship and follows 
a known pattern of response, but a potential alternative cause may be present. 
Definitively Related: There is a reasonable possibility that the event may have been 
caused by IMP and / or pembrolizumab. A certain event has a strong temporal relationship 
and an alternative cause is unlikely.
Ultimately, at the time of data analysis, the relationship to the AE will be categorized as either 
“unrelated” (including, unlikely or not related) or “related” (including definitely, probably or 
possibly related).
7.2.3
Reporting of SAEs
Information on SAEs will be collected from the time of ICF signature until the FU visit (or until 
EoT, if it occurs more than 30 days after the last CyPep-1 or pembrolizumab administration).
After the FU visit (or EoT visit, if it occurs more than 30 days after the last CyPep-1 or 
pembrolizumab administration), only ongoing AEs or SAEs related to CyPep-1 and / or 
pembrolizumab administration will be collected.
Specific timing for Arm B is provided in Section 7.2.1.3.
All AEs that meet the criteria for SAE require the completion of a trial specific SAE Form (or
Additional Safety Information [ASI]) Form), including an assessment of the relationship to the 
trial drug. This applies to all SAEs, whether or not they were considered to be related to the 
trial treatment. 
The investigator must report all SAEs to 
immediately, i.e. within 24 hours (by fax or e-
mail) of learning of its occurrence. For this reporting, a SAE Form (provided in the investigator 
File) needs to be completed in English. The original SAE report form, together with the fax 
confirmation sheet (if applicable) or e-mail, must be kept at the study site. Follow-up
information about a previously reported SAE must also be reported to 
within 24 hours 
of receiving the information. This follow-up data must be provided on an ASI Form or an 
updated SAE form. The SAE report should provide a detailed description of the AE and should 
include anonymized copies of hospital records and other relevant documents. Autopsy results, 
if applicable, should also be sent to 
as soon as they become available. Copies of each 
report will be kept in the investigator File. 
All SAEs will need to be followed actively until resolution or stabilization. The above is also 
applicable to follow-up SAE information.
7.2.4
SUSARs
 on behalf of Cytovation, is required by law to report to the health authorities in a 
written safety report: 1) all fatal or life-threatening SUSARs within seven (7) calendar days of 
initial notification; and 2) all other SUSARs within fifteen (15) calendar days of initial notification. 

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All investigators in the trial will be informed about SUSARs that have occurred 
 on 
behalf of Cytovation.
7.2.5
Pharmacovigilance Contact for Reporting SAEs
Stationsplein Noord-Oost 438 1117 CL Schiphol
The Netherlands
Tel: 31 (0)20 4350581
Fax: 31 (0)20 4350589

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8.
STATISTICAL METHODS
8.1
Statistical Analytical Plan
A statistical analysis plan (SAP) will be written in which the details of the statistical methods 
will be described. The SAP will be finalized before database lock. Any deviations from the 
originally planned statistical analysis or SAP will be described and justified in the clinical trial 
report. Changes known at the time of SAP preparation will also be described in the SAP.
A data review meeting will be held before database hard lock. Protocol deviations will be 
reviewed during the data review meeting. Furthermore, assignment of subjects to the analysis 
sets will be performed.
Data of subjects who did not meet the entry criteria (screening failures) and data of subjects 
who received no investigational product (e.g., due to withdrawal) entered in the clinical 
database will only be listed. Minimal information will include date of ICF signed, demography, 
screen failure details and eligibility criteria, end of study form, SAEs if applicable. These data 
will be entered into the eCRF. These data will not be included in the evaluation of any analysis 
population.
8.1.1
Data Sets to be Analyzed
The analysis population sets are defined as follows:
All Screened Set (SCR): All subjects who were screened for the study and signed informed 
consent. This analysis set will be used for subject disposition table and for creation of listings.
Safety Analysis Set (SAF): All subjects who received at least one dose of trial drug (CyPep-1
or pembrolizumab in the combination arm). All analyses (except for PK) will be based on this 
analysis set.
CyPep-1 PK Analysis Set: The first 9 subjects of Phase I, all subjects of Phase IIa Arm C,
and the first 12 subjects of Phase IIa Arm D who received at least one dose of CyPep-1, have 
no clinically important protocol deviations or important events considered affecting PK, and 
have provided at least one evaluable pre-dose and post-dose PK blood sample. All PK 
analyses will be based on this analysis set. 
8.1.2
Summary Statistics 
In general, data will be summarized by means of summary statistics. All data collected in this 
trial will be documented with the help of subject data listings, summary tables, and figures. 
Data will be summarized with respect to population for analysis, sub-grouped by dose level of 
CyPep-1 and extension arms, regarding demographic and baseline characteristics, PK 
measurements, clinical efficacy observations and measurements, safety observations and 
measurements. Continuous variables will be summarised using descriptive statistics 
(arithmetic mean and/or geometric mean, standard deviation and/or coefficient of variation,
median, minimum, and maximum). Categorical variables will be summarised using counts and 
percentages. All individual subject data will be listed.
8.1.3
Adverse Events
Analyses of AEs will be based on the SAF set. AEs will be coded according to CTCAE v5.0 
(for severity) and the Medical Dictionary for Regulatory Activities (MedDRA).
The total number/incidence of AEs will be summarized, including the number of subjects with 
at least one AE and the number of unique AEs per cohort and overall. The number of AEs per 

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severity (CTCAE) and relation to trial drug will also be included and summarized per cohort 
and overall. Additionally, listings of AEs leading to treatment discontinuation, resulting in death, 
and according to maximum severity will be tabulated. The incidence DLT/TLTs will also be 
evaluated for each dose level, and for all subjects combined. SAEs will be summarized in a 
similar manner.
The number of subjects and the number of AEs will be tabulated by MedDRA system organ 
class and preferred term. AEs will also be tabulated versus worst severity and worst 
relationship to treatment. In this table, subjects with AEs will be identified by their subject 
number.
Vital signs and body weight, 12-lead ECG parameters, laboratory data (hematology, 
biochemistry, coagulation, urinalysis) will be summarized using descriptive statistics. Shift 
tables showing changes from baseline will be generated where appropriate. 
Pre-treatment events occurring between first assessment at screening and first dose of 
CyPep-1 will be summarized separately.
8.1.4
Efficacy Analyses 
The efficacy endpoints are defined in relation to the trial objectives. Efficacy endpoints will be 
evaluated using the SAF. Further analyses will be defined in the SAP.
Efficacy will be determined from the number of subjects with CR, PR, SD or PD, according to 
iRECIST based on the investigator’s assessments. PFS (percentage of subjects alive and 
progression-free after trial treatment start) will also be determined. These clinical response 
data will be summarized. 
ORR (proportion of subjects with a best overall response of PR or, CR) will be evaluated
based on iRECIST.
For Phase I Cohort 3 and all Phase IIa arms, ORR (proportion of subjects with a best overall 
response of PR or, CR) will be evaluated by two additional approaches based on itRECIST:
Injected response: considering only the targeted-injected lesions.
Non-injected response: considering only the targeted-non-injected lesions. 
8.1.5
Pharmacokinetic Analysis (PK)
The first 9 subjects of Phase I,all subjects of Arm C, and the first 12 subjects of Arm D who 
have received CyPep-1 and have provided one evaluable pre-dose and at least one post-dose 
PK blood sample will be evaluable for PK (CyPep-1 PK Analysis Set).
PK analysis is planned via the determination of the plasma concentration time profile of 
CyPep-1 and, if detectable plasma drug levels are identified, the derived PK parameters will 
be assessed. These include area under the curve (AUC), peak plasma concentration (Cmax), 
time to reach Cmax (tmax), systemic clearance (CL), elimination half-life (t1/2) and volume of 
distribution (VD).
8.1.6
Immunological Analysis
This analysis will be performed on the SAF.
The relative change in intratumoral CD8+ T-cell infiltration (CD8+ expression) in the biopsied 
injected, and whenever available, non-injected lesions between screening and Week 6 will be 
assessed.
The association between the relative changes in CD8+ T-cell infiltration and response rate in 
the injected lesions (per itRECIST) and all lesions (per iRECIST) will be assessed.

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The change in T-cell receptor (TCR) clonality levels will be assessed in the available peripheral 
blood samples. To assess the hypothesis that CyPep-1 increases TCR clonality systematically,
which suggests that T-cells are targeting the tumor, the clonality diversity metric will be 
computed for all subjects providing peripheral blood samples at screening and/or Week 6 of 
every CyPep-1 treatment cycle. Based on preliminary on file data of TCR clonality analysis in 
peripheral blood dated Nov 2022, the dataset collected is sufficient for the intended analysis 
and further sampling will provide no additional insights.
Uncertainty about the 
representativeness of data generated with blood samples regarding TCR changes in the tumor 
microenvironment has lead Cytovation to reconsider this scientific relevance of this assay. 
Therefore, Cytovation decided to stop collecting blood samples for TCR clonality analysis. TCR 
sequencing might be performed on the available remaining tumor biopsy material from the 
analyses of changes in the tumor microenvironment. Overlaps of T cell clones in respect to 
expansion and breadth of T cell clonality before and after intratumoral injection with CyPep-1, 
as monotherapy and in combination with pembrolizumab (central analysis) will be analyzed.
The change in tumor microenvironment will be examined via the expression of selected 
candidate immune markers by immunohistochemistry:
 
 
 
 
 
 
 
 
 
 
 
 
 For each marker, a difference in expression will be explored.
Changes in cytokine levels (only for Arms A, B, and C) and in frequency of various immune 
cell types in peripheral blood (immunophenotyping) will be explored. 
8.1.7
Concomitant Treatment
Concomitant medication and concomitant therapy will be summarized as number of subjects 
being treated with each type of medication/therapy classified according to Anatomical
Therapeutic Chemical (ATC) level 2 and World Health Organization (WHO) Drug Dictionary 
preferred term. The SAF will be used for this presentation.
8.1.8
Tabulation of Individual Participant Data
Individual participant data will be listed by measure and time point.
8.1.9
Exploratory Analyses
Exploratory analyses will be specified in the SAP. A separate analysis of subjects having 
received weekly vs Q2W CyPep-1 administration is planned as sub-group analysis.
8.2
Determination of Sample Size 
This is a proof-of-concept trial and the number of subjects chosen is based on clinical 
considerations and not on a formal statistical power calculation. 
The exact number will be dependent on the number of dose cohorts investigated and the 
number of subjects enrolled in each dose cohort in Phase I (dose escalation), based on the 
toxicity encountered. 
Phase I (dose escalation): It is anticipated that 12 subjects will be included in this phase of the 
trial (Figure 2) at 3 dose levels, with the last dose level including three additional subjects for 
further confirmation of RP2D. 
Phase IIa (dose expansion Arm A): It is planned that 9 subjects will be enrolled in this phase
of the trial for further evaluation of CyPep-1 in monotherapy arm (Figure 2). 

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Formal assessment of response will be based on the first 12 evaluable subjects as follows: in 
case of no responders in 12 subjects, the likelihood of a 20% ORR is 6.9%; in case of one 
responder in 12 subjects, the likelihood of a 20% ORR is 26.5%. Assuming stable disease to 
occur in 30% of subjects, in case no subject has stable disease in the first 12 evaluated 
subjects, the likelihood is 1.4%; in case one subject has stable disease in the first 12 evaluated 
subjects, this becomes 8.5%, while with two subjects having stable disease, this becomes 
25.2%. Therefore, in case of either one of 12 subjects having an objective response or two of 
12 subjects having stable disease, the number of subjects in Arm A may be increased to a 
total of 24 subjects (meaning 18 subjects in Arm A; based on the total number of subjects at 
RP2D during dose escalation plus the number of subjects at RP2D in Arm A). In case, these 
outcomes are not observed, Arm A will enrol the planned 9 subjects.
In the current trial, the ORR assessment is based on sum of diamter of all target lesions and
SD decision is based on the duration >16 weeks of SD from onset.
Phase IIa (combination Arm B): The safety and tolerability of CyPep-1 in combination with 
pembrolizumab will be evaluated in an arm of 15 subjects in total (Figure 2).
Phase IIa (liver metastasis, Arm C): For Arm C, a total of 9 subjects is planned to be enrolled 
to evaluate at least two dose levels of CyPep-1 based on results of Phase I.
Phase IIa (dose expansion melanoma, Arm D): The sample size for Phase IIa Arm D is based 
on a desired precision by which preliminary clinical efficacy (ORR for injected lesions) may be 
evaluated. Using 90% 1-sided Clopper-Pearson exact confidence intervals, lower bounds 
identified in the Table 6 would apply.
Table 6. 90% 1-sided Confidence Intervals for the Number of Responders in N=30
Subjects
Number or 
Responders
Observed 
ORR
One-sided 
90% Lower 
Bound
1
3.3%
0.4%
2
6.7%
1.8%
3
10.0%
3.7%
4
13.3%
5.9%
5
16.7%
8.3%
6
20.0%
10.9%
7
23.3%
13.5%
8
26.7%
16.2%
9
30.0%
19.0%
For example, the lower bound for an observed ORR of 13.3% when there are 4 responders 
would be higher than 5% (i.e. 5.9%); the lower bound if 6 responders are observed would be 
10.9%, which is greater than 10%, allowing for a sufficient sample to review preliminary 
effectiveness of CyPep-1 monotherapy for Arm D subjects.

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8.3
Disposition, Demographic and Other Baseline Characteristics 
A subject disposition will be made including the number of subjects included, exposed to trial 
drug, and completing or withdrawing from trial (including reason for withdrawal). The number 
of subjects in each analysis set will be included. The subject disposition will be made 
separately by cohort and overall.
Demographic, medical history, and other baseline data will be presented using summary 
statistics based on the SAF overall and split by cohort.
8.4
Procedures for Reporting any Deviation(s) from the Original Statistical Analysis 
Plan
Any deviation(s) from the original SAP will be described and justified in a protocol amendment 
and/or in a revised SAP and/or in the final report, as appropriate.
8.5
Exposure to Treatment
All details collected in relation to CyPep-1, as monotherapy and in combination with 
pembrolizumab, will be listed and tabulated if applicable. Exposure data for CyPep-1 and / or 
pembrolizumab use will be listed per cohort and overall. Number of doses and total treatment 
length will be summarized using descriptive statistics. 
8.6
Safety Analysis for Dose Selection
Following completion of Phase I of the trial, a safety analysis (dose escalation analysis) will be 
performed for RP2D dose selection. All subjects having participated in Phase I of the trial will 
be part of this analysis to evaluate treatment safety. The DEC will issue a recommendation for 
the continuation of the trial based on safety and will confirm the MTD or RP2D (in case the 
MTD is not reached).
8.7
Follow-up Analysis of Post-Trial Survival Data 
Survival data will be analyzed post-treatment end as described in Section 8.1.4 and presented 
as addendum(s) to the final trial report. Time-point(s) for analysis will be confirmed when 
considered justified by Cytovation and the investigator.

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9.
DATA MANAGEMENT AND MONITORING
9.1
Data Collection, Validation, and Handling
Data management and handling of data will be conducted according to the trial specific Data 
Management Plan and 
standard operating procedures (SOPs).
Data for this trial will be captured using eCRFs. Data collection and entry into the eCRF is the
responsibility of the clinical trial staff at the investigational site under the supervision of the 
investigator. The data will be subjected to validation according to the Data Validation and 
Medical Review Plans in order to ensure the information in the eCRF is complete, consistent, 
and accurate. The clinical trial site staff are responsible for resolving data queries issued by 
Clinical Research Associates (CRAs), Medical Monitor(s) and Data Management team. A 
system audit trail will maintain a record of initial entries and changes made; reasons for 
change; time and date of entry; and username of trial personnel authorizing entry or change. 
Prior to the database lock, the eCRF must be completed and electronically signed by the 
principal investigator or authorized delegate from the clinical trial site staff. A complete eCRF 
package will be transferred to sponsor and the investigator will receive a copy at the end of the 
trial.
All external data will be electronically transferred to 
for further data handling.
9.2
Data Review
This trial will be monitored by appropriate staff from 
and may be also 
audited/inspected by 
the sponsor, or by an independent body and/or authority. By 
agreeing to this Protocol, the investigator agrees to cooperate with compliance checks by 
allowing access for authorized individuals to all relevant trial documents.
CRAs will conduct regular monitoring visits. A representative of the sponsor may accompany 
the CRA on that occasion. Amongst others, the following will be reviewed at those visits:
Trial progress;
Compliance with the Protocol;
Consent procedures, including date of consent and signatures;
Completion of eCRFs and verification of data against the source data;
Adverse events reporting;
Storage, dispensing and accountability of trial medication;
Archiving of trial documentation.
It is the investigator’s responsibility to assure that adequate time for these visits will be made
available by him/her and other study personnel.
It is a prerequisite of the investigator’s participation in this trial that the CRA has direct access 
to source data for data verification. All information on eCRFs must be traceable to these source 
documents in the subject's file (permission will be sought from the subject as part of the 
consent process). Direct access to source documents will also be required for representatives 
of the sponsor and for competent authorities. 
In addition, participation and personal information is treated as strictly confidential to the extent 
the applicable law permits and not publicly available. The audit or inspection may include, for 
example, a review of all source documents, drug records, original clinical medical notes, some 
or all of the facilities used in the trial.

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9.3
Medical Coding
Coding of prior and concomitant medications will be performed using WHO Drug Dictionary. 
AEs and medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA, version to be specified in the data management plan) and CTCAE, version 5.0:
Appendix C).
9.4
Health Economics Data Collection
Not applicable. 

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10. ADMINISTRATIVE ASPECTS
10.1 Quality Control and Quality Assurance
The sponsor or its designee will perform the quality assurance and quality control activities of 
this trial. However, responsibility for the accuracy, completeness, and reliability of the trial data 
presented to the sponsor lies with the principal or qualified investigator generating the data.
10.2 Maintenance of Subject Records
The investigator will maintain adequate records, including flow sheets, laboratory reports, 
signed subject consent forms, drug disposition records, and information on AEs, subject 
treatment discontinuation and reasons for treatment discontinuation. All records will be signed 
and dated by the investigators. All records are to be retained for a period of 25 years following 
the date the entire clinical investigation is completed, terminated or discontinued.
10.3 Investigator Site File (ISF)
At trial initiation, each investigator will be provided with an Investigator Site File (ISF) containing 
information as specified in Section 8.2-4 of ICH GCP.
Among others, the following documents will be provided in that file: 
Trial Protocol
Site-specific ICF
IB for the trial medication
Subject registration forms and instructions
Subject screening and enrolment logs
Curricula Vitae (CVs)
Template institute signature sheet
Template training log
Medical/ laboratory/ technical documentation
Documents regarding trial medicinal products shipment, receipt, preparation, 
administration, and accountability
Safety Handling Manual and SAE Forms
NCI-CTCAE criteria (version 5.0, see Appendix C)
Subject insurance
Synopsis Clinical Trial Protocol
In addition, the investigator will be instructed to keep in the file institute-specific documents, 
among others those regarding:
Agreements 
Site Insurance 
Protocol deviations/ notes to file 
Site submission and approval 
The original subject informed consent (a copy is provided to the subject) 
Site personnel qualifications (CVs) 
Laboratory accreditation/quality assurance and normal ranges 
Correspondence with 
and Cytovation
It is the investigator's responsibility to keep the ISF up to date.

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10.4 Handling of Investigational Product(s)
The trial medication must be received by a designated person at the trial site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator, 
Pharmacist, and designated assistants have access. Upon receipt of the trial medication, all 
supplies should be stored according to the instructions specified on the drug labels.
Medication labels will comply with the legal requirements of the country. In addition, they will 
include storage conditions for the drug but no information about the trial. For drug 
accountability, the investigator must maintain an accurate record of the shipment and 
dispensing of trial drug. The trial medication must be used only as directed in the Protocol and 
for subjects enrolled in this trial only. For more information, see Sections 5.1 to 5.4.
10.5 Drug Accountability
Each time the trial medication is dispensed to a subject this must be recorded on a drug 
dispensing/accountability log. Copies of this form will be supplied in the ISF. 
At regular intervals, the CRA(s) will perform a ‘drug reconciliation visit’, verifying if all trial 
medication that has been shipped to the institute can be accounted for by records of receipt, 
dispensing, and destruction. 
Unused IMP that is not dispensed may only be destroyed following authorisation by a 
representative of 
and destruction is fully documented. Alternatively, the IMP may be 
returned to the sponsor.
At the end of the trial, it must be possible to reconcile delivery records with records of usage 
and destroyed or returned stock. It is essential that the investigator or institute account for all 
trial treatment, and that any discrepancies are explained and documented.
10.6 Procedures for Protocol Amendments
Should any change be required to the approved Protocol, a Protocol amendment must be 
prepared. Any amendment is to be approved by the same persons approving the original 
Protocol. Upon approval, the final Protocol amendment will be incorporated into the Protocol. 
In case of a substantial Protocol amendment, this must be submitted to the IEC and competent 
authorities, detailing the reasons necessitating the amendment. Approval by an IEC and 
competent authorities is required for all substantial amendments, in accordance with 
international and local regulations. Notwithstanding the need for approval before 
implementation of formal Protocol amendments, the investigator is expected to take any 
immediate action required for the safety of any subject included in this trial, even if this action 
represents a deviation from the Protocol. 
10.7 Protocol Deviations
A protocol deviation is any non-compliance with the clinical trial protocol, GCP, or requirements 
in other procedures. The non-compliance may be either on the part of the participant, the
investigator, or the study site staff. Because of deviations, corrective actions are to be 
developed by the site and implemented promptly. These practices are consistent with ICH E6: 
4.5 Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3 
5.1 Quality Assurance and Quality Control, Section 5.1.1 
5.20 Non-compliance, Sections 5.20.1 and 5.20.2. 

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Major protocol deviations are any deviations that might significantly affect the completeness, 
accuracy, and/or reliability of the trial data or that might significantly affect a subject's rights, 
safety, or well-being. This includes deviations related to subject eligibility, informed consent, 
IMP dosing errors, or failing to perform assessments required to interpret the primary endpoint. 
Additional categories may be identified as deemed necessary by the Medical Monitor. 
All protocol deviations will be reported by the CRAs or other trial-involved personnel, such as 
data manager and statisticians. The protocol deviations will be reviewed by the Medical 
Monitor. The Medical Monitor determines whether a deviation is major or not. Major deviations 
are reported to the sponsor as part of the regular reporting. Important protocol deviations will 
be summarized in the clinical trial report. In accordance with applicable competent authority 
mandates, the investigator is responsible for reporting protocol deviations to the IEC.
In case of a deviation, the investigator enters a comment in the source documents and the 
non-compliance will be documented in a Monitoring Visit Report by the CRA. All 
non-compliance will be followed up and reported to CA and IEC as per local regulations. In 
parallel, corrective and/or preventive actions will be undertaken and documented, including 
any retraining of the investigator and site staff. No waivers for inclusion or exclusion criteria 
will be given.
10.8 Clinical Trial Report
A clinical trial report according to ICH Guideline "Note for Guidance on Structure and Content 
of Clinical Trial Reports" will be issued. A summary of the trial results will be provided to the 
IEC and the competent authority within one year after end of trial.

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11. ETHICAL AND LEGAL CONSIDERATIONS
The investigator will ensure that this trial is conducted in full conformance with the Protocol, 
the principles of the “Declaration of Helsinki” (64th WMA General Assembly, Fortaleza, Brazil, 
October 2013) or with the laws and regulations of the country in which the research is 
conducted, whichever affords the greater protection to the individual. The trial must fully adhere 
to the principles outlined in “Guideline for Good Clinical Practice” ICH Tripartite Guidelines for 
Good Clinical Practice or with local law if it affords greater protection to the subject. As this trial 
is conducted in the EU/ European Economic Area (EEA) countries, the investigator will ensure 
compliance with the EU Clinical Trial Directive [2001/20/EC].
11.1 Competent Authority / Independent Ethics Committees 
The protocol and any accompanying material provided to the subject (such as subject 
information sheets or descriptions of the trial used to obtain informed consent as well as any 
recruitment materials or compensation given to the subject) will be submitted to the CA and 
IEC. 
Approval from the committee must be obtained before starting the trial and should be
documented in a letter to the investigator specifying the date on which the committee met and 
granted the approval. 
Any modifications made to the protocol after receipt of the CA/IEC approval must be 
re-submitted in the EEA member states in accordance with local procedures and regulatory 
requirements.
11.2 Site Review
The investigator will submit this protocol, the site-specific ICF, and any required documents for 
site review and approval. A letter confirming approval must be forwarded to 
prior to 
initiation of this trial at each Investigational site. 
Prior to trial start, the investigator is required to sign a Protocol Signature Page confirming 
his/her agreement to conduct the trial 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 CRAs, auditors, and competent authorities as required. Investigators ascertain they 
will apply due diligence to avoid protocol deviations.
The investigator will make appropriate reports on the progress of this trial to 
in 
accordance with applicable government regulations and their agreement with 
.
11.3 Informed Consent
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH-GCP, 
the Data Protection Directive (Directive 95/46/EC), and local regulations. The investigator will 
prepare the ICF and provide the documents to the RA and IEC for approval. Informed consent 
must be obtained before any trial specific procedures (including screening procedures) are 
performed. The process of obtaining informed consent should be documented in the subject 
source documents.
Before enrolment in the trial, the investigator or an authorized member of the investigational 
staff must explain to potential trial subjects and/or his/her legal representative the aims, 
methods, reasonably anticipated benefits, and potential hazards of the trial, and any discomfort 
participation in the trial may entail. Subjects will be informed that their participation is voluntary,

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and they may withdraw consent to participate at any time. They will be informed that choosing 
not to participate will not affect the care that the subject will receive for the treatment of his or 
her disease. Subjects will be told that alternative treatments are available if they refuse to take 
part and that such refusal will not prejudice future treatments. By signing the ICF, the subject 
agrees to allow his or her trial physician to re-contact the subject for obtaining consent for 
additional safety evaluations if needed, or to obtain information about his or her vital status. 
The subject will be given sufficient time to read the ICF and the opportunity to ask questions. 
After this explanation and before entry into the trial, consent should be appropriately recorded 
by means of the subject’s personally dated signature and authorized trial staff’s personally 
dated signature. After obtaining the consent, a copy of the ICF must be given to the subject. 
If the subject is unable to read or write, an impartial witness should be present for the entire 
ICF process (which includes reading and explaining all written information) and should 
personally date and sign the ICF after the oral consent of the subject is obtained.
The investigator shall provide a copy of the signed ICF to the subject and the signed original 
shall be maintained in the ISF. The original of the signed ICF must be filed in the subject’s 
source file. If new safety information results in significant changes in the risk/benefit 
assessment, the ICF should be reviewed and updated if necessary. All subjects should be 
informed of the new information and give their consent to continue the trial.
All changes to the consent form will be IEC-approved; a determination will be made regarding 
whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form.
11.4 Trial Discontinuation and Closure
This trial may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable 
cause. 
Written 
notification, 
documenting 
the 
reason 
for 
trial 
suspension/termination, will be provided by the sponsor to the investigators and CAs. If the 
trial is prematurely terminated/suspended, the principal investigator will promptly inform the 
IEC and will provide the reason(s) for termination/suspension. 
Circumstances that may warrant termination/suspension include, but are not limited to: 
Determination of unexpected, significant, or unacceptable risk to participants 
Demonstration of efficacy that would warrant stopping 
Insufficient compliance to protocol requirements 
Data that are not sufficiently complete and/or evaluable 
Determination of futility 
The trial may resume once concerns about safety, protocol compliance and/or data quality are 
addressed and satisfy the sponsor, IEC and/or the CAs.
11.5 Confidentiality
By conducting this trial, the investigator affirms to 
that all information regarding this 
trial and CyPep-1 will be maintained in strict confidence. Such information can be 
communicated to the investigator's local review and approval authority under an appropriate 
understanding of confidentiality. Updated General Data Protection Regulations (GDPR) 
procedures are covered in the ICF and in site agreements. 
Every effort will be made to maintain the anonymity and confidentiality of subjects during this 
clinical trial. However, because of the experimental nature of this treatment, the investigator 
agrees to allow representatives of 
 the sponsor, and authorized employees of the CAs

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to inspect the facilities used in this trial as well as to review, for purposes of verification, the
hospital or clinic records of all subjects enrolled into this trial. A statement to this effect is to be 
included in the subject consent form.
11.6 Financing and Insurance
Financial aspects of the trial are addressed in a separate clinical trial agreement.
The investigator/ institution is required to have adequate current insurance to cover claims for 
negligence and/ or malpractice according to applicable national regulations. The sponsor will 
provide insurance coverage for the clinical trial as required by applicable national regulations.
Trial subjects will not be paid for their participation. Any trial-related travel expenses made by 
the subject or the accompanying person will be reimbursed based on actual cost as proven by 
original or copies of receipts, or an allowance per kilometre travelled.
11.7 Statement of Compliance
This study will be conducted in accordance with International Council for Harmonisation GCP
(ICH GCP E6[R2]), and applicable local laws and regulations. The principal investigator will 
assure that no deviation from, or changes to the protocol will take place without prior 
agreement from the sponsor and documented approval from the IEC, except where necessary 
to eliminate an immediate hazard to the study participants. All relevant personnel involved in 
the conduct of this study have completed ICH-GCP training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IEC for review and approval. Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled. 
11.8
Publication Policy
The sites and the principal investigator shall have the right to publish and present results of 
the study following submission to Cytovation for review of the manuscript, abstract or 
presentation intended for publication or presentation at least 70 days prior to the date of 
submission for publication or presentation. Regard shall be given to the sponsor's legitimate 
interests, e.g., containing optimal patent protection, coordination of submissions to health 
authorities or with other ongoing studies in the same therapeutic field, protection of confidential 
data, and information, etc. Cytovation shall complete its review within 60 days of receipt of the 
submitted manuscript, abstract or presentation. Cytovation may request that the principal 
investigator or the sites delete from the manuscript, abstract or presentation any confidential 
information. At the end of the 60-day period, the sites and the principal investigator will have 
the right to publish and present the material, abstract or presentation. 
The above-described procedure also applies to information on prematurely discontinued and 
other non-completed studies.
Results from investigations shall not be made available to any third parties by the investigating 
team outside the publication procedure as set out above.
The sponsor will not quote from publications by investigators in its scientific information and/or 
promotional material without full acknowledgement of the source (i.e., author and reference).

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11.9
Conflict of Interest Policy
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this study will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will 
be required to have such conflicts managed in a way that is appropriate to their participation 
in the study.

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12. REFERENCE LIST 
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MA, Puzanov I, Santomasso BD, Shanbhag SP, Sharma R, Skondra D, Sosman JA, Turner 
M, Ernstoff MS. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on 
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Jun;9(6):e002435. doi: 10.1136/jitc-2021-002435.
Chemnitz, Jens M., Parry, Richard V., Nichols, Kim E., June, Carl H., Riley, James L., SHP-1
and SHP-2 Associate with Immunoreceptor Tyrosine-Based Switch Motif of Programmed 
Death 1 upon Primary Human T Cell Stimulation, but Only Receptor Ligation Prevents T Cell 
Activation. The Journal of Immunology.2004, 173: 945–954.
Curran, M.A., et al., PD-1 and CTLA-4 combination blockade expands infiltrating T cells and 
reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S 
A, 2010. 107(9): p. 4275-80.
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13. APPENDICES
Appendix A: List of Non-clinical Studies Mentioned in the Protocol
Study number
Study name
506066
A Combined Single Dose and 7 Day Dose Range Finding Study of CyPep-1 by 
Intravenous Injection (Bolus) in Rats
506092
A 4 Week Study of CyPep-1 by Intravenous Injection (Bolus) in Rats with a 4 
Week Recovery Period
507379
A Combined Single Dose Maximum Tolerated Dose and 14 Day Dose Range 
Finding Study of CyPep-1 by Intravenous Injection (Bolus) in Dogs
614716
Respiratory Effects following Single Intravenous Injection (Bolus) Administration 
in Male Han Wistar Rats
614721
Effects in the Irwin Screen after Single Intravenous Injection (Bolus) 
Administration in Male Han Wistar Rats
01027002
Salmonella-E. Coli Mammalian Microsome Reverse Mutation Assay
01027003
In Vitro Micronucleus Assay in TK6 Cells
AB22310
A 14-Day Range-Finding Toxicity Study of CyPep-1 by the Dermal Route in the 
Göttingen Minipig
AB22311
A 04-week Toxicity Study of 1% CyPep-1 Cream by the Dermal Route in the 
Göttingen Minipig with a 04-week Recovery Period
614700
Effect of CyPep-1 by Intravenous Injection (Bolus) on Cardiovascular Parameters 
in Conscious Telemetered Beagle Dogs
B-02852
Pharmacokinetic profile of CyPep-1 after a single intravenous (bolus) or 
subcutaneous administration in Sprague-Dawley rats

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Appendix B: Eastern Cooperative Oncology Group Performance Status Scoring (Oken 
MM et al, 1982)
Grade 
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair
5
Dead

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Appendix C: Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
CTCAE term (AE description) and grade: The descriptions and grading scales found in the 
revised NCI-CTCAE version 5.0 will be utilized for AE reporting. All appropriate treatment areas 
should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can 
be 
downloaded 
from 
the 
CTEP 
web 
site: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
Quick Reference 
The NCI-CTCAE is a descriptive terminology, which can be utilized for Adverse Event (AE) 
reporting. A grading (severity) scale is provided for each AE term. 
Components and Organization 
System Organ Class (SOC), the highest level of the Medical Dictionary for Regulatory Activities 
(MedDRA) hierarchy, is identified by anatomical or physiological system, etiology, or purpose 
(e.g. SOC Investigations for laboratory test results). CTCAE terms are grouped by MedDRA 
Primary SOCs. Within each SOC, AEs are listed and accompanied by descriptions of severity 
(Grade). 
CTCAE Terms 
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medical treatment or procedure 
that may or may not be considered related to the medical treatment or procedure. An AE is a 
term that is a unique representation of a specific event used for medical documentation and 
scientific analyses. Each CTCAE v 5.0 term is a MedDRA LLT (Lowest Level Term). 
Definitions 
A brief definition is provided to clarify the meaning of each AE term. 
Grades 
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique 
clinical descriptions of severity for each AE based on this general guideline: 
Grade 1 Mild: asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2 Moderate: minimal, local or non-invasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living.
Grade 3 Severe or medically significant but not immediately life-threatening: 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL. 
Grade 4 Life-threatening consequences: urgent intervention indicated. 
Grade 5 Death: related to AE.

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Appendix D: Description of the iRECIST Process for Assessment of Disease 
Progression
iRECIST is based on RECIST 1.1 but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor 
response and progression, and to guide decisions about changes in management.
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic disease progression based on modified RECIST 1.1, there is no distinct 
iRECIST assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show radiological PD by RECIST 1.1, the Investigator will decide whether 
to continue a participant on study treatment until repeat scans are obtained, as described in 
Section 14. 
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:
mm from nadir
o
Note: The iRECIST publication uses the terminology “sum of measurements”, 
but “sum of diameters” will be used in this protocol, consistent with the original 
RECIST 1.1 terminology.
Unequivocal progression of non-target lesion(s) identified at baseline
Development of new lesion(s)
iRECIST defines new response categories, including iUPD (unconfirmed progressive disease) 
and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, the first 
visit showing progression according to RECIST 1.1 will be assigned a visit (overall) response 
of iUPD, regardless of which factors caused the progression.
At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be assessed 
as usual.
New lesions will be classified as measurable or non-measurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 10 lesions total (up to 2 per organ), may be selected as New Lesions – Target.
The sum of diameters of these lesions will be calculated and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively as 
New Lesions – Non-target.
Assessment at the Confirmatory Scans
On the confirmatory scans, the participant will be classified as progression confirmed (with an 
overall response of iCPD), or as showing persistent unconfirmed progression (with an overall 
response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).

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Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:
Any of the factors that were the basis for the initial iUPD show worsening
o
mm, 
compared to any prior iUPD time point
o
For non-target lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the “unequivocal” 
standard of RECIST 1.1
o
For new lesions, worsening is any of these:
mm from a prior iUPD 
time point 
Visible growth of new non-target lesions 
The appearance of additional new lesions
Any new factor appears that would have triggered PD by RECIST 1.1
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:
None of the progression-confirming factors identified above occurs AND
The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
Additional scans for confirmation are to be scheduled 4 to 8 weeks from the scans on which 
iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation scan proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:
None of the progression-confirming factors identified above occurs, AND
The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudoprogression, and the level of suspicion 
for progression is “reset”. This means that the next visit that shows radiographic progression, 
whenever it occurs, is again classified as iUPD by iRECIST, and the confirmation process is 
repeated before a response of iCPD can be assigned.

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Management Following the Confirmatory Scan
If repeat scans do not confirm PD per iRECIST, as assessed by the Investigator, and the 
participant continues to be clinically stable, study intervention is to continue and the regular 
scan schedule is to be followed. If PD is confirmed, participants may be discontinued from 
study intervention.
NOTE: If a participant has confirmed radiographic progression (iCPD) and clinically meaningful 
study intervention may be continued after consultation with the Sponsor. In this case, if study 
treatment is continued, tumor imaging should continue to be performed following the intervals 
as outlined in Section 14.
Detection of Progression at Visits After Pseudoprogression Resolves
After resolution of pseudoprogression (ie., after iSD/iPR/iCR), another instance of progression 
(another iUPD) is indicated by any of the following events:
Target lesions
o
mm increase from 
nadir) either for the first time, or after resolution of previous pseudoprogression. 
The nadir is always the smallest sum of diameters seen during the entire trial, 
either before or after an instance of pseudoprogression.
Non-target lesions
o
If non-target lesions have never shown unequivocal progression, their doing so 
for the first time results in iUPD.
o
If non-target lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth 
of non-target lesions, taken as a whole.
New lesions
o
New lesions appear for the first time
o
Additional new lesions appear
o
5 mm in the new 
lesion sum of diameters, from the nadir value of that sum
o
Previously identified non-target lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory scan above) is repeated. Progression 
must be confirmed before iCPD can occur.
The decision process on the subsequent iUPD is identical to the iUPD confirmation process 
for the initial PD, with one exception, which can occur if new lesions had occurred at a prior 
instance of iUPD, had not resolved, then worsened (increase in size or number) leading to the 
second iUPD. If new lesion worsening has not resolved at the confirmatory scan then iUPD 
cannot resolve to iSD or iPR. It will remain iUPD until either a decrease in the new lesion 
burden allows resolution to iSD or iPR, or until new or worsening causes of progression 
indicates iCPD.
Additional details about iRECIST are provided in the iRECIST publication (Seymour 2017).

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Appendix E: Medication for Hypersensitivity Type Reactions Anticipated to be Possibly 
Occurring Due to CyPep-1 Administration
Anaphylactic reactions are usually categorized into the following stages:
Stage 
Extent and type of reactions 
0
Locally confined skin reaction 
I 
Mild systemic reaction: 
- Disseminated skin reactions: flushing, pruritus, generalized urticaria 
- Mucosal reactions (nose, conjunctiva) 
- General reactions: restlessness, headache 
II 
Profound systemic reactions: 
- Cardiovascular dysregulation: changes in blood pressure and pulse rate 
- Difficulty in breathing: mild dyspnea, slight bronchospasm 
- Urinary and fecal urgency 
III 
Life threatening systemic reaction: s
- Shock 
- Dyspnea, bronchospasm 
- Loss of consciousness (possibly with urinary and fecal incontinence) 
IV 
Vital insufficiency: 
- Cardiac and/or respiratory arrest 
Depending on severity and type of the AEs, the following treatments are suggested and may 
be changed at the discretion of the investigator and local standards: 
Fever, anaphylaxis 
Paracetamol (acetaminophen) 1000 mg orally and/or metamizole (dipyrone) 1000 mg slowly 
i.v. infusion of physiological electrolyte solutions, adrenaline, anti-histamine H1- and H2-
receptor antagonists, parenteral glucocorticoids. 
Blood pressure instability, hypotension 
Therapy according to the local best standard treatment options (e.g., catecholamines, plasma 
expanders [colloids, cristalloids], oxygen, etc.). 
Bronchospasm, dyspnea
-sympathomimetics such as fenoterol by inhalation of two 
puffs as often as required, parenteral glucocorticoids (theophylline 200–400 mg i.v. 
additionally, if necessary).
Antibiotic therapy
Infection with Salmonella typhi can be treated effectively with fluoroquinolones, including 
ciprofloxacin or ofloxacin.

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Appendix F: High-level Summary of itRECIST and the Comparison of itRECIST with 
iRECIST 
Current oncology response criteria, such as Response Evaluation Criteria in Solid Tumors 
version 1.1 (RECIST 1.1) and guidelines for immunotherapeutic trials (iRECIST), were 
designed to assess response to systemic therapy and does not allow separate response 
assessment in injected and non-injected lesions. As intratumoral (IT) immunotherapy applies 
focal intervention, the ability to assess treatment response of injected and non-injected lesions 
is critical for IT immunotherapy trials.
Goldmacher et al proposed a modified RECIST 1.1 for intratumoral immunotherapy (itRECIST) 
with the goal to create guidelines for capturing data and assessing response in IT 
immunotherapy trials (Goldmacher 2020). 
itRECIST is designed to address the unique needs of IT immunotherapy trials but, where 
possible, aligns with RECIST 1.1 and iRECIST. It does not dictate which lesions to inject at 
each visit, but rather provides guidelines for assessing responses as treatment evolves.
A high level summary of the difference between itRECIST and iRECIST are provided below: 
Table 1 presents the general difference between itRECIST and iRECIST, while Table 2 
presents the difference in response assessment between the two.
Table 1. General difference between itRECIST and iRECIST
General Difference
itRECIST
iRECIST
Capture of systemic 
and/or local effects of 
immunotherapy
Capture both systemic and local effects
Only capture systemic effects
Lesion Measurement
Should be performed per RECIST 1.1, 
with the except of permitting ultrasound 
measurement for subcutaneous if no 
other lesions are available for quantitative 
assessment.
Recommendations for imaging 
procedures:
1.
Same operator should perform the 
ultrasound at all visits using the same 
equipment and acquisition 
parameters, capturing lesion images 
in a similar orientation, with anatomic 
landmarks to align with preceding 
scans.
2.
The same imaging technique is used 
for a given target lesion at each 
assessment to evaluate changes over 
time.
Does not allow ultrasound for 
lesion measurement due to 
operator dependence and 
difficulty with standardization
Evaluable lesions
1. Treatment response in injected lesions 
can be evaluate separately from non-
injected lesions 
2. Injected lesions remain evaluable for 
overall response assessment even after 
termination of local procedures.
3. Excisional tumor biopsy renders a 
lesion non-evaluable. (Core needle 
biopsy would not render a lesion non-
evaluable but its use is discouraged for 
target lesions). When feasible, biopsies 
should be restricted to non-target lesions.
Treatment response is 
evaluated as a combination 
of injected and non-injected 
lesions.

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Reclassification of 
Lesions After 
Baseline 
Injected lesions may change to non-
injected lesions and vice versa based on 
individual circumstances judged per 
investigators, as long as target lesions 
always remain target and nontarget 
lesions remain non-target. However, once 
any T-NI lesion is injected, the non-
injected response becomes non-
evaluable.
Note: Lesions designated T-NI at baseline 
should remain non-injected for as long as 
possible to allow assessment of maximal 
systemic response to IT therapy in non-
injected lesions.
Reclassification not allowed.
Table 2. Difference in Response Assessment between itRECIST and iRECIST
Difference in 
Response 
Assessment
itRECIST
iRECIST
Overall Response
Similar to RECIST 1.1, with the difference 
only in allowing more target lesions, in 
injected lesions nob becoming non-
evaluable, and allowing ulatrasound 
assessment.
Per RECIST 1.1
Injected Response 
and Non-injected 
Response 
Injected response is based entirely on 
the changes in the sum of diameters 
(SOD) of the targeted-injected (T-I) 
lesions
Non-injected response is based entirely 
on the changes in the SOD of the
targeted-non-injected (T-NI) lesions. 
Response from non-targeted lesions 
are not taken into account (See Figure 
1)
Per RECIST 1.1, Target 
lesion response is based on 
the combination response of 
T-I and T-NI lesions, while 
nontarget lesion response is 
based on the combination 
response of NT-I and NT-NI.
Response Definition
until disease 
progression
Target lesion response is based on the 
changes in the SOD of all target lesions 
together.
Nontarget lesion response is the 
qualitative assessment of all target 
lesions together.
The evaluation for possible new lesions 
The Overall response is the sum of the 
target lesion response, nontarget lesion 
response and new lesion response per 
RECIST 1.1
Response by lesion category is 
summarized in Table 3.
Per RECIST 1.1 
Decisions at 
REICIST progression
Same as per iRECIST (Appendix D)
(Appendix D)
Response 
Assessment After 
RECIST Progression
Similar as per iRECIST (Appendix D), 
except injected response and non-
injected response should follow the rule 
of “Injected Response and Non-injected 
Response”
(Appendix D)
Interval to 
Confirmatory
Reassessment
4 to 12 weeks
4 to 8 weeks

Clinical Trial Protocol 
Sponsor: Cytovation
Version: 10.0
Trial Code: CyPep-1
Date: 30Jan2023
EudraCT: 2019-003317-33
Confidential
Page 134 of 136
Treatment response calculation per itRECIST is summarized in Figure 1.
Definition of response by lesion category per itRECIST is presented in Table 3.
Figure 1. Calculation of Responses in itRECIST
Adopted from Figure 2 in Goldmacher 2020.
Abbreviations: NT-I = Non-Target-Injected; NT-NT = Non-Target-Non-Injected; T-I = Target-Injected; 
T-NI = Target Non-Injected.
Table 3. Definition of Response by Lesion Category in itRECIST
Adopted from Table 1 in Goldmacher 2020.

Clinical Trial Protocol 
Sponsor: Cytovation
Version: 10.0
Trial Code: CyPep-1
Date: 30Jan2023
EudraCT: 2019-003317-33
Confidential
Page 135 of 136
Abbreviations: CR = complete response; NE = non-evaluable; PD = progressive disease ; PR = partial 
response ; SD = stable disease ; SOD = sum of diameters; T-I = Target-Injected; T-NI = Target Non-
Injected.
An simplified example of iterative assessment of injected lesion response during treatment can 
be found in Figure 3 of Goldmacher 2020. More detailed guidance on the lesion mapping and 
sequence of CyPep-1 injection are detailed in the Study Procedural Manual. 

Clinical Trial Protocol 
Sponsor: Cytovation
Version: 10.0
Trial Code: CyPep-1
Date: 30Jan2023
EudraCT: 2019-003317-33
Confidential
Page 136 of 136