A Phase II Multi-Arm (Basket) Trial Investigating the Safety and Efficacy of IO102-IO103 in Combination With Pembrolizumab, as First-Line Treatment for Patients With Metastatic NSCLC, SCCHN, or Metastatic mUBC
Phase: PHASE2
Conditions: Lung Cancer Non Small Cell, Head and Neck Squamous Cell Carcinoma, Urothelial Carcinoma Bladder
Sponsor: IO Biotech

  
 
 
 
 
 
 
Clinical Trial Protocol  
IO102-IO103-022 (IOB-022) 
MK3475-D38 (KN-D38) 
A Phase II Multi-Arm (basket) Trial Investigating the Safety and Efficacy of 
IO102-IO103 in Combination with Pembrolizumab, as First-line Treatment for 
Patients with Metastatic Non-Small Cell Lung Cancer (NSCLC), Squamous Cell 
Carcinoma of Head and Neck (SCCHN), or Metastatic Urothelial Bladder Cancer 
(mUBC) 
 
 
Sponsor: 
IO Biotech ApS 
Ole Maaløes Vej 3 
DK-2200 Copenhagen N, 
Denmark  
 
 
Trial ID: 
IO102-IO103-022 
(IOB-022)/ MK3475-D38 
(KN-D38) 
 
EU Trial No: 
2024-511561-10-00 
 
IND No: 
Not applicable 
 
Version: 
8.0 
 
Date: 
 
21-Jun-2024 
 
 
 
 
 
 
 
 
 
 
This confidential document is the property of IO Biotech ApS. No unpublished information 
contained herein may be disclosed without prior written approval from IO Biotech ApS. Access to 
this document must be restricted to relevant parties 

Trial ID: IO102-IO103-022/ 
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1 
Clinical Trial Protocol Statement  
1.1 
Sponsor’s Approval of Clinical Trial Protocol  
This clinical trial will be conducted in compliance with the clinical trial protocol, ICH-GCP and the 
applicable regulatory requirements,including Regulation (EU) No 536/2014 of the European Parliament and 
of the Council of 16 April 2014. 
 

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1.2 
Co-ordinating Investigator’s Approval of Clinical Trial Protocol  
I have read and agree to the IO102-IO103-022 (IOB-022)/MK3475-D38 (KN-D38) clinical trial “A Phase II 
Multi-Arm (basket) Trial Investigating the Safety and Efficacy of IO102-IO103 in Combination with 
Pembrolizumab, as First-Line Treatment for Patients with Metastatic Non-Small Cell Lung Cancer 
(NSCLC), Squamous Cell Carcinoma of Head and Neck (SCCHN), or Metastatic Urothelial Bladder Cancer 
(mUBC)”. I am aware of my responsibilities as the Co-ordinating Investigator under the guidelines of Good 
Clinical Practice (GCP, 2001), local regulations (as applicable) and the trial protocol. I agree to conduct this 
clinical trial according to these guidelines and to appropriately direct and assist the staff under my control, 
who will be involved in this clinical trial. 
 
 
 
Jonathan Riess 
International Coordinating Investigator 
 
 
 

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1.3 
Acknowledgement Statement Investigators  
I have read and agree to the IO102-IO103-022 (IOB-022)/MK3475-D38 (KN-D38) clinical trial “A Phase II 
Multi-Arm (basket) Trial Investigating the Safety and Efficacy of IO102-IO103 in Combination with 
Pembrolizumab, as First-line Treatment for Patients with Metastatic Non-Small Cell Lung Cancer (NSCLC), 
Squamous Cell Carcinoma of Head and Neck (SCCHN), or Metastatic Urothelial Bladder Cancer (mUBC)”. 
I am aware of my responsibilities as an Investigator under the guidelines of Good Clinical Practice (GCP, 
2001), local regulations (as applicable) and the trial protocol. I agree to conduct this clinical trial according 
to these guidelines and to appropriately direct and assist the staff under my control, who will be involved in 
this clinical trial. 
 
 
Signature: 
 
     Date of Signature: 
 
 
 
Name:  
 
 
 

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Table of Contents  
1 
CLINICAL TRIAL PROTOCOL STATEMENT ............................................................................................... 2 
1.1 
SPONSOR’S APPROVAL OF CLINICAL TRIAL PROTOCOL ........................................................................................ 2 
1.2 
CO-ORDINATING INVESTIGATOR’S APPROVAL OF CLINICAL TRIAL PROTOCOL .................................................... 3 
1.3 
ACKNOWLEDGEMENT STATEMENT INVESTIGATORS ............................................................................................. 4 
TABLE OF CONTENTS ................................................................................................................................................. 5 
LIST OF ABBREVIATIONS AND ACRONYMS ...................................................................................................... 10 
2 
PROTOCOL SUMMARY .................................................................................................................................... 13 
3 
TRIAL PROCEDURES ........................................................................................................................................ 22 
4 
TRIAL DESIGN .................................................................................................................................................... 27 
4.1 
TRIAL DESIGN ..................................................................................................................................................... 27 
5 
TRIAL OBJECTIVES .......................................................................................................................................... 28 
5.1 
PRIMARY OBJECTIVE ........................................................................................................................................... 28 
5.2 
SECONDARY OBJECTIVES .................................................................................................................................... 28 
5.3 
EXPLORATORY OBJECTIVES ................................................................................................................................ 29 
6 
TRIAL ENDPOINTS ............................................................................................................................................ 29 
6.1 
PRIMARY ENDPOINT ............................................................................................................................................ 29 
6.2 
SECONDARY ENDPOINTS ..................................................................................................................................... 29 
6.3 
EXPLORATORY ENDPOINTS ................................................................................................................................. 29 
7 
BACKGROUND ................................................................................................................................................... 30 
7.1 
THERAPEUTIC BACKGROUND .............................................................................................................................. 30 
7.1.1 
NSCLC Background .................................................................................................................................. 30 
7.1.2 
SCCHN Background ................................................................................................................................. 32 
7.1.3 
mUBC Background ................................................................................................................................... 34 
7.2 
IDO AND PD-L1 ANTIGENS AS TARGETS ............................................................................................................ 35 
7.3 
PHARMACEUTICAL BACKGROUND ...................................................................................................................... 36 
7.3.1 
IO102 and IO103 ...................................................................................................................................... 36 
7.3.2 
Pembrolizumab ......................................................................................................................................... 36 
7.4 
NONCLINICAL AND CLINICAL TRIALS ................................................................................................................. 37 
7.4.1 
Pembrolizumab Pre Clinical and Clinical Trials ..................................................................................... 37 
7.4.2 
IO102 Pre-Clinical ................................................................................................................................... 37 
7.4.3 
IO102 Clinical Trials ................................................................................................................................ 38 
7.4.4 
IO103 Pre-Clinical Studies ....................................................................................................................... 38 
7.4.5 
IO103 Clinical Trials ................................................................................................................................ 39 
7.4.6 
IO102-IO103 – Clinical Trial ................................................................................................................... 39 
8 
RATIONALES ...................................................................................................................................................... 40 
8.1 
RATIONALE FOR PEMBROLIZUMAB DOSE AND SCHEDULE .................................................................................. 40 
8.2 
RATIONALE FOR IO102-IO103 DOSE AND SCHEDULE ......................................................................................... 41 
8.3 
RATIONALE FOR TRIAL POPULATION .................................................................................................................. 42 
8.3.1 
Rationale for Trial Population - NSCLC .................................................................................................. 42 
8.3.2 
Rationale for Trial Population - SCCHN.................................................................................................. 43 
8.3.3 
Rationale for Trial Population - mUBC.................................................................................................... 43 
8.4 
OVERALL RISK/BENEFIT ASSESSMENT ............................................................................................................... 44 
9 
TRIAL POPULATION......................................................................................................................................... 45 
9.1 
ENTRY CRITERIA ................................................................................................................................................. 45 
9.1.1 
Diagnosis/Condition for Entry into the Trial ............................................................................................ 45 
9.1.2 
Patient Inclusion Criteria ......................................................................................................................... 45 

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9.2 
PATIENT EXCLUSION CRITERIA ........................................................................................................................... 48 
9.3 
PATIENT WITHDRAWAL FROM TRIAL TREATMENT AND WITHDRAWAL FROM TRIAL PARTICIPATION ................ 50 
9.3.1 
Withdrawal from Trial Treatment ............................................................................................................. 50 
9.3.2 
Patient Withdrawal from Trial Participation ........................................................................................... 51 
10 
TRIAL DESIGN .................................................................................................................................................... 51 
10.1 OVERALL TRIAL DESIGN ..................................................................................................................................... 51 
10.2 RANDOMISATION OR TREATMENT ALLOCATION ................................................................................................. 51 
10.2.1 
Stratification of Patients ........................................................................................................................... 51 
10.3 SAMPLE SIZE ....................................................................................................................................................... 52 
10.4 TRIAL DESIGN FLOW DIAGRAM .......................................................................................................................... 52 
10.5 TRIAL DURATION AND PARTICIPATING CENTRES ................................................................................................ 52 
10.6 SCHEDULE OF EVENTS ........................................................................................................................................ 53 
10.6.1 
Screening Assessments and Procedures.................................................................................................... 53 
10.6.2 
Trial Treatment Period ............................................................................................................................. 54 
10.6.3 
Post Trial Treatment Period ..................................................................................................................... 56 
11 
TRIAL TREATMENT ......................................................................................................................................... 57 
11.1 INVESTIGATIONAL MEDICINAL PRODUCTS .......................................................................................................... 57 
11.2 PACKAGING AND LABELING ................................................................................................................................ 57 
11.2.1 
Storage and Preparation of Trial Treatment ............................................................................................ 58 
11.2.2 
Preparation and Storage of Pembrolizumab ............................................................................................ 58 
11.3 TREATMENT AND DOSE SCHEDULE ..................................................................................................................... 58 
11.3.1 
Timing of Trial Treatment Administration ................................................................................................ 58 
11.3.2 
Dose Modification and Toxicity Management Guidelines ........................................................................ 59 
11.3.3 
Dose Modification and Toxicity Management of Infusion-Reactions Related to Pembrolizumab ............ 65 
11.3.4 
Other Allowed Dose Interruption for IO102-IO103 and Pembrolizumab ................................................ 67 
11.4 COMPLIANCE CHECK AND DRUG ACCOUNTABILITY ........................................................................................... 67 
11.4.1 
IO102-IO103 ............................................................................................................................................. 67 
11.4.2 
Pembrolizumab ......................................................................................................................................... 67 
11.5 UNBLINDING PROCEDURES ................................................................................................................................. 67 
11.6 CONCOMITANT MEDICATIONS AND VACCINATIONS (ALLOWED AND PROHIBITED) ............................................ 68 
11.6.1 
Allowed Medication and Procedures ........................................................................................................ 68 
11.6.2 
Disallowed Medication and Procedures ................................................................................................... 68 
11.6.3 
Diet/Contraception and Other Considerations ......................................................................................... 69 
12 
CLINICAL ASSESSMENTS ............................................................................................................................... 70 
12.1 EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE SCALE .................................................................. 70 
12.2 EFFICACY ASSESSMENTS..................................................................................................................................... 70 
12.2.1 
Tumor (Disease) Evaluation ..................................................................................................................... 70 
12.2.2 
Response Evaluation ................................................................................................................................. 72 
12.2.3 
Overall Survival ........................................................................................................................................ 72 
12.2.4 
Biomarker Assessments ............................................................................................................................. 72 
12.3 SAFETY ASSESSMENT .......................................................................................................................................... 73 
12.3.1 
Adverse Events .......................................................................................................................................... 73 
12.3.2 
Physical Examination ............................................................................................................................... 74 
12.3.3 
Vital Signs ................................................................................................................................................. 74 
12.3.4 
12-Lead Electrocardiogram ...................................................................................................................... 74 
12.3.5 
Eastern Cooperative Oncology Group Performance Scale ...................................................................... 74 
12.3.6 
Safety Laboratory Parameters .................................................................................................................. 74 
12.3.7 
Demographics and Other Baseline Characteristics.................................................................................. 75 
12.3.8 
Medical History and Concomitant Illness................................................................................................. 75 
12.3.9 
Echocardiogram/Multi-Gated Acquisition Scan ....................................................................................... 76 
12.3.10 Body Weight and Height ........................................................................................................................... 76 
12.3.11 Pregnancy Test ......................................................................................................................................... 76 
12.4 PHARMACOKINETIC ASSESSMENT ....................................................................................................................... 76 

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13 
ADVERSE EVENTS ............................................................................................................................................. 76 
13.1 ADVERSE EVENT DEFINITIONS ............................................................................................................................ 76 
13.2 ADVERSE EVENT ASSESSMENT DEFINITIONS ...................................................................................................... 77 
13.2.1 
Severity ..................................................................................................................................................... 77 
13.2.2 
Relationship to Trial Treatment ................................................................................................................ 77 
13.2.3 
Outcome .................................................................................................................................................... 78 
13.3 REPORTING OF ADVERSE EVENTS ....................................................................................................................... 78 
13.4 FOLLOW-UP ON ADVERSE EVENTS ...................................................................................................................... 79 
13.5 SPONSOR RESPONSIBILITY FOR REPORTING SAES .............................................................................................. 79 
13.6 DEFINITION OF AN OVERDOSE AND REPORTING OF AN OVERDOSE ..................................................................... 79 
13.7 EVENTS OF CLINICAL INTEREST .......................................................................................................................... 79 
13.8 REPORTING OF PREGNANCIES ............................................................................................................................. 80 
14 
CHANGES TO TRIAL CONDUCT .................................................................................................................... 80 
14.1 PROTOCOL AMENDMENTS ................................................................................................................................... 80 
14.2 CLINICAL TRIAL PAUSING ................................................................................................................................... 80 
14.3 PREMATURE TERMINATION OF THE TRIAL .......................................................................................................... 80 
14.4 PREMATURE TERMINATION OF A TRIAL SITE ...................................................................................................... 81 
15 
DATA HANDLING AND RETENTION OF DOCUMENTS ........................................................................... 81 
15.1 SOURCE DATA ..................................................................................................................................................... 81 
15.2 CODING OF DATA ................................................................................................................................................ 81 
16 
RETENTION OF DOCUMENTS ....................................................................................................................... 81 
17 
STATISTICAL METHODS ................................................................................................................................. 82 
17.1 TIMING OF ANALYSES ......................................................................................................................................... 82 
17.2 SAMPLE SIZE AND POWER CONSIDERATIONS ...................................................................................................... 82 
17.3 APPROACH TO ENDPOINT ANALYSES .................................................................................................................. 83 
17.3.1 
Primary endpoint ...................................................................................................................................... 83 
17.3.2 
Other endpoints ......................................................................................................................................... 83 
17.4 ANALYSIS DATA SETS ......................................................................................................................................... 83 
17.5 DEFINITION OF EFFICACY ENDPOINTS ................................................................................................................. 84 
17.5.1 
Primary Endpoints .................................................................................................................................... 84 
17.5.2 
Secondary Endpoints ................................................................................................................................ 84 
17.5.3 
Progression Free Survival (PFS) .............................................................................................................. 84 
17.5.4 
Progression Free Survival according to iRECIST (iPFS) ........................................................................ 84 
17.5.5 
Duration of Response (DoR) ..................................................................................................................... 84 
17.5.6 
Complete Response Rate (CRR) and Disease Control Rate (DCR) .......................................................... 85 
17.5.7 
Overall Survival (OS) ............................................................................................................................... 85 
17.5.8 
Time to Response (TTR) ............................................................................................................................ 85 
17.5.9 
ECOG Performance Status ....................................................................................................................... 85 
17.5.10 Exploratory Endpoints .............................................................................................................................. 85 
17.6 STATISTICAL/ANALYTICAL ISSUES ..................................................................................................................... 85 
17.6.1 
Missing Data ............................................................................................................................................. 85 
17.6.2 
Examination of Subgroups ........................................................................................................................ 85 
17.7 SAFETY ANALYSIS .............................................................................................................................................. 85 
17.7.1 
Adverse Events .......................................................................................................................................... 86 
17.7.2 
Electrocardiogram .................................................................................................................................... 86 
17.7.3 
Vital Signs ................................................................................................................................................. 86 
17.7.4 
Laboratory Safety Assessments ................................................................................................................. 86 
17.8 PHARMACOKINETIC ANALYSIS ............................................................................................................................ 86 
18 
GOOD CLINICAL PRACTICE .......................................................................................................................... 86 
19 
ETHICS.................................................................................................................................................................. 87 
19.1 INDEPENDENT ETHICS COMMITTEES / COMPETENT AUTHORITIES ...................................................................... 87 

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19.2 INFORMED CONSENT ........................................................................................................................................... 87 
20 
AUDITS AND INSPECTIONS ............................................................................................................................ 87 
21 
MONITORING ..................................................................................................................................................... 87 
22 
REPORTING OF RESULTS ............................................................................................................................... 88 
22.1 INTEGRATED CLINICAL TRIAL REPORT ............................................................................................................... 88 
22.2 USE OF INFORMATION ......................................................................................................................................... 88 
22.3 PUBLICATION OF RESULTS .................................................................................................................................. 88 
23 
INSURANCE AND LIABILITY ......................................................................................................................... 88 
24 
REFERENCES ...................................................................................................................................................... 90 
25 
APPENDICES ....................................................................................................................................................... 96 
APPENDIX I - EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE SCORE ........ 96 
APPENDIX II - DISEASE ASSESSMENT BY RECIST V. 1.1 AND PROGRESSIVE DISEASE ASSESSMENT 
BY IRECIST ................................................................................................................................................................... 97 
APPENDIX III - MANAGEMENT OF PATIENTS DURING THE CORONAVIRUS DISEASE 2019 (COVID-
19) PANDEMIC .............................................................................................................................................................. 99 
 
LIST OF TABLES 
Table 1 Schedule of Trial Procedures (Year 1) .................................................................................. 22 
Table 2 Schedule of Trial Procedures (Year 2 and/or end of trial treatment) ..................................... 24 
Table 3 Assessments and Procedures in Screening ............................................................................ 53 
Table 4 Assessments and Procedures during Trial Treatment Period ................................................ 55 
Table 5 Assessments and Procedures after Discontinuation of Trial Treatments .............................. 56 
Table 6 Investigational Medicinal Products Summary ...................................................................... 57 
Table 7 IO102-IO103 and Pembrolizumab Dose and Schedule ........................................................ 57 
Table 8 Dose Modification and Toxicity Management Guidelines for Immune-related AEs 
Associated with Pembrolizumab ................................................................................ 60 
Table 9 Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines............... 66 
Table 10 Tumor Tissue Testing and Requirements (All Patients) ...................................................... 73 
Table 11 Laboratory Tests .................................................................................................................. 75 
 
 
 

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LIST OF FIGURES 
Figure 1 Trial Diagram .................................................................................................................... 27 
Figure 2 Trial Flow Diagram ............................................................................................................. 52 

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List of Abbreviations and Acronyms  
Abbreviation  
Definition   
5-FU 
5-Fluorouracil 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event   
AEOSI 
Adverse Events of Special Interest  
ALK 
Anaplastic Lymphoma Kinase  
ALT 
Alanine Aminotransferase  
APC 
Antigen Presenting Cells 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransperase  
β-hCG 
Beta-Human Chorionic Gonadotropin 
BCC 
Basal Cell Carcinoma 
BCG 
Bacillus Calmette–Guérin 
BRAF  
Proto-oncogene B-Raf 
CI  
Confidence Interval 
CIT 
Cancer Immunotherapy 
CNS 
Central Nervous System 
CPS  
Combined Positive Score 
CR 
Complete Response 
CrCl 
Calculated Creatinine Clearance 
CRF 
Case Report Form 
CRO 
Clinical Research Organisation 
CRR 
Complete Response Rate  
CT  
Computed Tomography 
CTCAE  
Common Terminology Criteria for Adverse Event 
CTFG 
Clinical Trials Facilitation and Coordination Group 
CTLA-4 
Cytotoxic T-Lymphocyte Associated Protein 4 
DCR 
Disease Control Rate  
DoR 
Duration of Response  
EBV 
Epstein-Barr Virus 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECI 
Events of Clinical Interest  
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EDC 
Electronic Data Capture 
EGFR  
Epidermal Growth Factor Receptor 
EMA 
European Medicines Agency 
EOT 
End of Treatment  
ESMO 
European Society for Medical Oncology 
FDA 
Food and Drug Administration 
FFPE 
Formalin Fixed Paraffin Embedded 
FSH 
Follicle Stimulating Hormone 
FU 
Follow Up 
GCP 
Good Clinical Practice  
GDPR 
General Data Protection Regulation 
GFR 
Glomerular Filtration Rate 
GLP 
Good Laboratory Practise 
HbsAg 
Hepatitis B Surface Antigen 
HCP 
Health Care Professional 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus  

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HLA 
Human Leucocyte Antigen 
HMA 
European Union Heads of Medicines Agencies 
HPV  
Human Papillomavirus 
HR 
Hazard Ratio 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICI 
Immune Checkpoint Inhibitor  
ICH 
International Conference on Harmonization 
iCPD  
Confirmed Progressive Disease according to iRECIST 
IDO 
Indoleamine 2,3-dioxygenase 
IEC  
Independent Ethics Committees 
IgG4 
Humanized Immunoglobulin G4 
IHC 
Immunohistochemistry  
IIT 
Investigator Initiated Trials 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
iPFS 
Immune-Related Progression-Free Survival 
irAE 
Immune-Related AE 
IRB 
Institutional Review Board 
iRECIST 
Immune-Related Response Evaluation Criteria In Solid Tumors 
IUD 
Intrauterine Device 
iUPD  
Unconfirmed Progressive Disease according to iRECIST 
IUS 
Intrauterine Hormone-releasing System 
IV 
Intravenous 
KRAS 
Kirsten Rat Sarcoma viral oncogene homolog 
LDH 
Lactate Dehydrogenase 
M 
Metastatic  
MCBS 
Magnitude of Clinical Benefit Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHC 
Major Histocompatability Complex 
MM 
Multiple Myeloma  
MRI 
Magnetic Resonance Imaging 
mUBC  
Metastatic Urothelial Bladder Cancer  
MUGA 
Multi-Gated Acquisition 
N 
Nonmissing data 
NE 
Not Evaluable 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
OTC 
Over The Counter 
PBMC  
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PD-1 
Programmed Cell Death 1 
PD-L1  
Programmed Death Ligand 1 
PD-L2 
Programmed Cell Death Ligand 2 
PFR 
Progression-Free Rate  
PBPK 
Physiologically-based PK 
PFS 
Progression-Free Survival 
PoC 
Proof of Concept 
PK 
Pharmacokinetic 
PR 
Partial Response 

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PT 
Prothrombin Time 
PV 
Pharmacovigilance 
Q2W 
Every 2 Weeks 
Q3W 
Every 3 Weeks  
QOL 
Quality Of Life 
R 
Recurrence  
RECIST  
Response Evaluation Criteria In Solid Tumors 
RNA 
Ribonucleic Acid  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan  
SC  
Subcutaneously  
SCCHN  
Squamous Cell Carcinoma of Head and Neck 
SD 
Stable Disease 
SEER 
Surveillance, Epidemiology, and End Results 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedures 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected, Unexpected Serious Adverse Reaction 
TC 
Tumor Cell 
TCC 
Transitional Cell Carcinoma 
TCR 
T Cell Receptor 
TEAE 
Treatment Emergent Adverse Events  
TIL 
Tumor Infiltrating Lymphocytes 
TL 
Target Lesion  
TPS 
Tumor Proportion Score 
TSH 
Thyroid Stimulating Hormone 
TTR 
Time to Response   
UBC 
Urothelial Bladder Cancer  
UC 
Urothelial Carcinoma  
UCC 
Urothelial Cell Carcinoma 
ULN 
Upper Limit of Normal 
VGPR 
Very Good Partial Response 
WFI 
Water for Injection  
WOCBP 
Woman Of Childbearing Potential 
WT 
Wild Type 
 
 
 
 
 
 
 
 
 
 
 

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2 
Protocol Summary  
Short Protocol Title 
A Phase II Multi-Arm (basket) Trial Investigating the Safety and Efficacy of 
IO102-IO103 in Combination with Pembrolizumab, as First-Line Treatment 
for Patients with Metastatic Non-Small Cell Lung Cancer (NSCLC), 
Squamous Cell Carcinoma of Head or Neck (SCCHN), or Metastatic 
Urothelial Bladder Cancer (mUBC) 
Trial No 
IOB-022/MK3475-D38 (KN-D38)  
Protocol Date and Version 
Version 7.0; 24-Apr-2023  
Trial Phase  
II 
Sponsor 
IO Biotech ApS 
Ole Maaløes Vej 3, DK-2200 Copenhagen N 
Denmark 
Background information 
Naturally occurring indoleamine 2,3-dioxygenase (IDO)/programmed death ligand 
1 (PD-L1) specific T cells recognize MHC-bound IDO/PD-L1 peptides, and are 
able to eliminate IDO expressing or PD-L1 expressing immunoregulatory cells and 
cancer cells. Activation of IDO or PD-L1 specific T cells through injection with 
the IDO and PD-L1 peptides will boost natural killing of cancer cells and 
counteract immunoregulatory mechanisms in the tumor microenvironment.  
 
Thus, IDO/PD-L1 specific T cells may both directly support anti-cancer immunity 
by killing target T cells but also indirectly by releasing pro-inflammatory 
cytokines in the microenvironment to boost additional anti-cancer immunity. 
 
Both IDO and PD-L1 represent two key checkpoint molecules in the context of anti-
tumor immunity. Mouse surrogate IDO peptide (for IO102) and PD-L1 peptide (for 
IO103) have both shown anti-tumor therapeutic effect in murine cancer models and 
synergy of the two peptide injections has been observed in a cancer model where 
IDO and PD-L1 expression was confirmed in different cell populations within tumor 
microenvironment. The dual-antigen approach addresses the known heterogeneity 
of IDO and PD-L1 expression in human cancers (where cell populations 
overexpressing these molecules do not necessarily overlap) and therefore 
heterogeneity in immune resistance mechanisms in individual patients. A CT26 
cancer model demonstrated that IDO peptide injection in combination with an 
anti-PD-1 works in a synergistic manner, leading to complete response. The overall 
immune modulation induced by the 
peptide injection 
renders 
tumor 
microenvironment more inflamed, thus enhancing the therapeutic action of the 
anti-PD-1 antibody. 
An ongoing investigator sponsored Phase I/II trial (MM1636) of IO102-IO103 
plus nivolumab have shown highly encouraging efficacy and a favorable safety 
profile in the cohort of anti PD-1 naïve patients with metastatic melanoma 
(NCT 03047928).  
 
Preliminary data from an ongoing randomized Phase I/II trial (Study No. IO102-
012/KN-764, NCT03562871) in a cohort with PD-L1 Tumor Proportion 
Score (TPS) ≥50% treated with IO102 + pembrolizumab demonstrated that 
patients with metastatic NSCLC and a PD-L1 TPS ≥50%  receiving IO102 plus 
pembrolizumab stayed longer on treatment compared to patients receiving 
pembrolizumab monotherapy and without adding new safety signals.  
 

Trial ID: IO102-IO103-022/ 
MK3475-D38 (KN-D38)  
Date: 21-Jun-2024 
Version: 8.0 Final 
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Based on above, it is hypothesized that dual antigen therapy with IO102-IO103 plus 
pembrolizumab will improve the efficacy of anti PD-1 antibody in patients with a 
PD-L1 TPS of ≥50% 
 
There is therefore a strong rationale for investigation of the dual antigen 
(IO102-IO103) in combination with PD-1 in the first line setting of patients with 
metastatic NSCLC and in other solid tumor indications such as SCCHN or mUBC. 
 
Identifying patients who would respond to the combination of IO102-IO103 and 
pembrolizumab is key to successful management of patients with mUBC and 
SCCHN. For these two indications, although both TPS and Combined Positive 
Scores (CPS) will be collected,  patient inclusion will be based on CPS as this has 
been identified as most relevant and likely indicator to response and therefore 
provide benefit from the trial treatment. Further rationale is provided in Section 7. 
Trial Objectives 
Primary objective: 
The primary objective is to investigate the efficacy of IO102-IO103 in 
combination with pembrolizumab in the frontline treatment of each of the different 
solid tumor indications (NSCLC adenocarcinoma PD-L1 TPS ≥50%, SCCHN PD-
L1 CPS ≥20, or metastatic UBC PD-L1 CPS ≥10) with the intent to expand a 
specific cohort if a clinically relevant signal is observed. 
Secondary objective: 
The secondary objective is to investigate the safety of IO102-IO103 in combination 
with pembrolizumab in each of the 3 disease indications. 
Exploratory objectives: 
Analysis of tumour tissue and blood samples will be undertaken to evaluate 
biomarkers that inform regarding trial drug activity or may predict response to 
treatment.  
Trial Endpoints 
Primary endpoint 
Overall objective response rate (ORR) according to RECIST v. 1.1 
 
Secondary endpoints 
• 
Progression-Free Survival (PFS) according to RECIST v. 1.1 
• 
Duration of response (DOR) 
• 
Complete response rate (CRR) 
• 
Disease control rate (DCR) 
• 
Time to response (TTR) 
• 
Safety 
Exploratory endpoints  
• 
Overall survival (OS) 
• 
PFS according to iRECIST (iPFS) 
• 
Analysis of the tumor microenvironment for IDO and PD-L1 expression 
and lymphocyte infiltration 
• 
Circulating tumor DNA as a surrogate measure of tumor burden 
• 
Assessment of peripheral immune cell function and treatment-specific T 
cell responses 
• 
ORR and PFS according to independent central review, if applicable 
Diagnosis/population 
A. NSCLC adenocarcinoma (metastatic disease) with PD-L1 expression TPS 
≥50%. 
B. SCCHN (recurrent or metastatic disease) with  PD-L1 CPS ≥ 20. 
C. UBC (metastatic disease) with PD-L1 CPS ≥ 10. 
 

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Date: 21-Jun-2024 
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Inclusion Criteria 
1. Patients with histologically or cytologically confirmed: 
Metastatic NSCLC (adenocarcinoma) (Cohort A), who have not received prior 
systemic treatment for their metastatic disease and who have:  
• No known sensitizing genetic aberrations where there are approved 
therapies (such as ALK, ROS1, EGFR, BRAF V600E, MET skipping 
mutations, and RET mutations or rearrangements) 
or 
SCCHN (Cohort B) with no prior systemic therapy administered in the 
recurrent or metastatic setting (with the exception of systemic therapy 
completed >6 months prior if given as part of multimodal treatment for locally 
advanced disease) and who have: 
• SCCHN considered incurable by local therapies. Tumors of 
nasopharyngeal origin (any histology) are excluded 
• Documented results of p16/HPV status for oropharyngeal cancer (per 
institution standard) 
or 
Metastatic UBC (Cohort C) with no prior therapy and not eligible for any 
platinum-containing chemotherapy: 
• Urothelial cancer of the renal pelvis, ureter, bladder or urethra 
(transitional cell and mixed transitional/non transitional cell histologies 
permitted but transitional cell histology must be the dominant histology) 
For all cohorts, any solitary metastases must be biopsied to confirm diagnosis 
of metastases from primary indication. 
 
2. PD-L1 TPS or PD-L1 CPS (as confirmed prior to enrolment using the PD-L1 
IHC DAKO 22C3 PharmDx assay, using local or central services): 
• Cohort A (NSCLC adenocarcinoma): PD-L1 TPS ≥50% 
• Cohort B (SCCHN): PD-L1 CPS ≥20; HPV +/- 
• Cohort C (mUBC): PD-L1 CPS ≥10 
3. A female participant is eligible to participate if she is not pregnant not 
breastfeeding, and at least one of the following conditions applies:  
• Not a woman of childbearing potential (WOCBP) 
• A WOCBP who agrees to follow contraceptive guidance starting with 
the screening visit and through 120 days after last dose of 
pembrolizumab or 180 days after last dose of chemotherapy.  
Note: A WOCBP, i.e., fertile, following menarche and until becoming 
post-menopausal unless permanently sterile. Permanent sterilisation 
methods include hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy. Tubal ligation is not a method of permanent sterilisation. 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 
 

Trial ID: IO102-IO103-022/ 
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4. The participant (or legally acceptable representative if applicable) provides 
written informed consent for the trial in accordance with International 
Conference on Harmonization Good Clinical Practice Guideline (ICH-GCP) 
and local legislation prior to admission to the trial.  
5. At least 18 years of age on day of signing informed consent. 
6. Have measurable disease per RECIST v. 1.1 as assessed by local site 
investigator/radiologist. Lesions situated in a previously irradiated area are 
considered measurable if progression has been demonstrated in such lesions. 
7. Have provided archival tumor tissue sample or newly obtained core or 
excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, 
paraffin embedded (FFPE) tissue blocks are preferred to slides.  
8. Have an ECOG performance status of 0 to 1. 
9. If participant received major surgery, they must have recovered adequately 
from the adverse events and/or complications from the intervention prior to 
starting trial treatment. 
10. Have adequate organ function as defined below. Specimens must be collected 
within 10 days prior to the start of trial treatment. 
Adequate organ function as defined by: 
• 
Haematology: 
Absolute neutrophil count ≥1500/µL or ≥1.5 × 109/L 
Platelets ≥100,000/µL or ≥100 × 109/L 
Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L. Criteria must be met without 
packed red blood cell transfusion within the prior 2 weeks. Participants 
can be on stable dose of erythropoietin (≥ approximately 3 months) 
• 
Renal: 
Creatinine ≤1.5 × upper limit of normal (ULN), or 
Measured or calculated creatinine clearance (CrCl) ≥50 mL/min for 
patients with creatinine levels >1.5 × institutional ULN;  
GFR can also be used in place of creatinine or CrCl 
• 
Hepatic: 
Total bilirubin ≤1.5 × ULN or direct bilirubin ≤ ULN for patients with 
total bilirubin levels >1.5 × ULN 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤2.5 × ULN (≤5 × ULN for patients with liver metastases) 
Alkaline phosphatase ≤2.5 × ULN 

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• 
Endocrine: 
No uncontrolled endocrinopathies 
• 
Coagulation: 
International normalised ratio or prothrombin time (PT) and activated 
partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless patient is 
receiving anticoagulant therapy as long as PT or aPTT is within 
therapeutic range of intended use of anticoagulants 
11. Patients who are hepatitis B surface antigen (HBsAg)  positive are eligible if 
they have received hepatitis B virus (HBV) antiviral therapy for at least 
4 weeks and have undetectable HBV viral load prior to treatment initiation. 
Note: Patients should remain on anti-viral therapy throughout trial 
treatment and follow local guidelines for HBV anti-viral therapy after 
completion of trial treatment. Hepatitis B screening tests are not required 
unless:  
  a.  Known history of HBV infection 
  b.  As mandated by local health authority 
12. Patients with history of hepatitis C virus (HCV) infection are eligible if HCV 
viral load is undetectable at screening. 
Note: Patients must have completed curative anti-viral therapy at least 
4 weeks before treatment initiation. Hepatitis C screening tests are not 
required unless: 
  a.  Known history of HCV infection  
  b.  As mandated by local health authority 
Exclusion Criteria 
Cohorts A, B, and C: 
 
1. A WOCBP who has a positive urine pregnancy test (within 72 hours) prior to 
treatment. If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required. 
2. 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 immune-related AE (irAE). 
3. Has received prior systemic anti-cancer therapy in the first line setting for the 
participant’s metastatic disease (treatment with chemotherapy and/or radiation 
as part of neoadjuvant/adjuvant therapy is allowed as long as completed at 
least 6 months prior to diagnosis of metastatic disease). 
4. Has not recovered from all AEs due to previous therapies to ≤ Grade 1 or 
baseline. Participants with ≤ Grade 2 neuropathy are eligible. 
5. Has received any prior radiotherapy, with the exception of palliative 
radiotherapy to non-target lesions, within 2 weeks prior to the start of trial 

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treatment or radiotherapy to the lung >30 Gy within 6 months of start of trial 
treatment. Participants must have recovered from all radiation-related adverse 
events and not have had radiation pneumonitis requiring corticosteroids.   
6. Have a life expectancy of <3 months and/or rapidly progressing disease.  
7. Have received a live or live attenuated vaccine within 30 days prior to the first 
dose of trial treatment. Examples of live vaccines include, but are not limited 
to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), 
yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. 
Administration of killed vaccines, mRNA based (e.g., covid-19) and vector 
based vaccines are allowed. Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed; however, intranasal influenza 
vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.  
8. Is currently participating in or has participated in a study of an investigational 
agent or has used an investigational device within 4 weeks prior to the first 
dose of study treatment. Note: Participants who have entered the follow-up 
phase of an investigational study may participate as long as it has been 4 
weeks after the last dose of the previous investigational agent. 
9. Has a diagnosis of immunodeficiency 
10. Received any of the following medications or procedures within 2 weeks prior 
to first dose of trial treatment: chronic systemic steroid therapy (in dosing 
exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy 
11. Has a known additional malignancy that is progressing or has required active 
treatment within the past 2 years.  
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. 
12. Has CNS metastases and/or carcinomatous meningitis. Participants in Cohort 
A (NSCLC) with previously treated brain metastases may participate provided 
they are clinically stable and without requirement of steroid treatment for at 
least 14 days prior to first dose of trial treatment.  
13. Has severe hypersensitivity (≥ Grade 3) to IO102 or IO103, pembrolizumab 
and/or any of their excipients. 
14. 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. 
15. Has a history of (non-infectious) pneumonitis that required steroids or has 
current pneumonitis/insterstitial lung disease. 
16. Has an active infection requiring systemic therapy. 

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17. Has a known history of human immunodeficiency virus (HIV) infection. No 
HIV testing is required unless mandated by local health authority. 
18. Known adrenal insufficiency function (that is basal cortisol level <140nmol/L 
or <5 μg/dL). 
19. Has known active Hepatitis B virus (defined as Hepatitis B surface antigen 
[HBsAg] reactive and/or detectable HBV DNA) or known active Hepatitis C 
virus (HCV) (defined as anti-HCV Ab positive and detectable HCV 
ribonucleic acid [RNA] [qualitative]) infection.  
Note: No testing for Hepatitis B and Hepatitis C is required unless  
  a.  Known history of HBV or HCV infection 
  b.  Mandated by local health authority. 
Patients who have a history of hepatitis will be screened using serology to 
confirm status. 
20. Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the 
patient’s participation for the full duration of the trial, or is not in the best 
interest of the patient to participate, in the opinion of the treating investigator. 
21. Has known psychiatric or substance abuse disorders that would interfere with 
the patient’s ability to cooperate with the requirements of the trial. 
22. Is pregnant or breastfeeding or expecting to conceive within the projected 
duration of the trial, starting with the screening visit through 180 days after 
last dose of trial treatment. 
23. Has had an allogeneic tissue/solid organ transplant. 
24. Has progressive disease (PD) within six months of completion of curatively 
intended systemic treatment for locoregionally advanced SCCHN. 
Number of patients 
1. Cohort A (NSCLC adenocarcinoma). Approximately 30 patients will be 
enrolled and treated. 
2. Cohort B (SCCHN). Approximately 30 patients will be enrolled and treated. 
3. Cohort C (mUBC). Approximately 30 patients will be enrolled and treated. 
Number of countries and 
sites 
3 to 5 countries (UK, Spain, USA plus additional) with approximately 25 sites 
Estimated total duration of 
trial and timing of statistical 
analyses 
Screening phase: up to 28 days 
Treatment period up to 2 years  
 
Each patient will receive treatment for up to 2 years. Following completion of trial 
treatment, patients will be followed until the last patient has been treated for 35 
cycles plus 30 days follow-up or until death, withdrawal of consent, or lost-to-
follow-up. 
 
After the end of trial treatment each patient will be followed for a minimum of 30 
days for adverse event (AE) monitoring. Serious adverse events (SAE) and Events 
of Clinical Interest (ECI) will be collected for up to 90 days following cessation of 
treatment or 30 days following cessation of treatment if the patient initiates new 
anticancer therapy, whichever is earlier. 

Trial ID: IO102-IO103-022/ 
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This is an open label trial therefore analysis of each cohort will occur 
independently of the others. For each treatment cohort, the primary analysis will 
be performed 6 months after the last patient started treatment.  
 
Investigational and 
concomitant products, route 
of administration, dose and 
schedule 
Investigational agents: 
IO102-IO103 is an immunotherapeutic targeting the immunoregulatory enzymes 
IDO and PD-L1 emulsified with adjuvant (Montanide ISA 51 VG). 
Pembrolizumab is a potent humanized monoclonal immunoglobulin G4 (IgG4) 
with high specificity of binding to the PD-1 receptor. 
Route of administration and dose: 
IO102-IO103: SC administration (IO102 85µg SC and IO103 85µg SC every 3 
weeks (Q3W) in combination with pembrolizumab (IV administration 200 mg 
Q3W). 
 
Schedule: 
IO102-IO103: 
- 
Induction period: SC administrations of  IO102-IO103 will be given on 
days 1 and 8 of cycles 1 and 2. In total, 4 doses of each will be 
administered during the first 2 cycles. 
- 
Maintenance period: from cycle 3, SC administrations will be given on 
day 1 of each 3 week cycle for a max of 33 cycles.  
- 
A total of 37 administrations during 2 years.  
 
Pembrolizumab: 
- 
Day 1 of each 3 week cycle for a max of 35 cycles (2 years) 
- 
A total of 35 administrations during 2 years. 
 
During the COVID-19 pandemic: 
To minimize or eliminate immediate hazards and to protect the life and well-being 
of research participants (e.g. to limit exposure to COVID-19) it is advised to assess 
and manage the risk of COVID-19 to the patient, taking into consideration prior 
exposure to the SARS-COV2 virus, vaccination status, age and co-morbitities. 
Scheduled visits are advised to be delayed as appropriate in the situation of a 
patient who has a positive COVID-19 test or where an outbreak occurs at the 
investigational hospital. See Appendix III for further details. All COVID-19 
related deviations from the protocol will be recorded as COVID-19 deviations. 
 
Selection of doses in the trial 
IO102-IO103 will be used as add-on therapy to pembrolizumab. The dose of 
IO102-IO103 planned to be studied in this trial is 85 µg of each peptide 
administered as an emulsion for SC injection. The dose is based on previous 
experience in clinical trials and is expected to achieve both immunological and 
clinical responses. No dose selection is applied in the trial.  
Statistical Methods 
ORR, CRR and DCR, will be assessed and 95% confidence intervals will be 
calculated using the Clopper-Pearson exact methodology. 
 
PFS rate (PFR) at 6 months as well as the endpoint duration of response with 
corresponding 95% intervals, will be estimated using Kaplan-Meier methods. 
 
The trial will assess the opportunity for a positive risk benefit in three indications 
(NSCLC adenocarcinoma, SCCHN and mUBC) based on ORR for each 
indication; if a clinically meaningful signal is observed based on the primary 
endpoint, then there will be an opportunity to consider expanding that particular 
indication beyond proof of concept, either by adding in more patients or cohorts. 
 

Trial ID: IO102-IO103-022/ 
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Interim analyses for each cohort will be considered after 15 patients are treated 
with ≥2 cycles in the cohort and have either completed at least 2 post-baseline 
tumor assessments or have discontinued. Details of the interim analyses will be 
defined in the Statistical Analysis Plan. 
 
Sample Size Calculation 
This is an exploratory study and all calculations are done using a 1-side 15% 
significance level based on 30 patients in each cohort to be enrolled and treated. 
 
Cohort A (NSCLC adenocarcinoma PD-L1 TPS ≥50%) 
For patients with PD-L1 ≥50% treated with pembrolizumab, the ORR is estimated 
to be 39% (Mok et al., 2019).  
If the true ORR for IO102-IO103 plus pembrolizumab is 55% there is a power of 
77% to detect a difference between 39% and 55% with 30 patients. If there are 17 
responders from the 30 patients, the ORR point estimate will be 57% and the 95% 
Clopper-Pearson confidence interval will be 37% - 75%. 
 
Cohort B (SCCHN, PD-L1 CPS ≥ 20) 
For patients with CPS ≥20 treated with pembrolizumab, the ORR is estimated to 
23% (Burtness et al., 2019). 
If the true ORR for IO102-IO103 plus pembrolizumab is 35% there is a power of 
68% to detect a difference between 23% and 35% with 30 patients. If there are 11 
responders from the 30 patients, the ORR point estimate will be 37% and the 95% 
Clopper-Pearson confidence interval will be 20% - 56%. 
 
Cohort C (mUBC, PD-L1 CPS ≥ 10) 
Patients with CPS ≥10 treated with pembrolizumab, the ORR is estimated to 47% 
(Vuky et al., 2020). 
If the true ORR for IO102-IO103 plus pembrolizumab is 60% there is a power of 
65% to detect a difference between 47% and 60% with 30 patients. If there are 18 
responders from the 30 patients, the ORR point estimate will be 60% and the 95% 
Clopper-Pearson confidence interval will be 41% - 77%. 
 
Efficacy Assessments 
Efficacy will be assessed by imaging tumors using CT scans and per RECIST v. 1.1. 
A baseline scan will be performed at screening, every 9 weeks the first year of 
treatment and thereafter every 12 weeks until patient end treatment, either by 
completion of treatment or withdrawal. 
 
 

 
 
Trial ID: IO102-IO103-022/ MK3475-D38 (KN-D38)  
Date: 21-Jun-2024 
Version: 8.0 Final 
Page 22 of 99 
 
 
CONFIDENTIAL 
 
3 
Trial Procedures  
Table 1 Schedule of Trial Procedures (Year 1)  
 
Screening 
Trial treatment period – Year 1 
Trial Treatment Period Week 
Number 
(+/- 3 days) 
-4 wk 
to D-1 
-1 wk 
to D-1 
1 
2 
4 
5 
7 
10 
13 
16 
19 
22 
25 
28 
31 
34 
37 
40 
43 
46 
49 
Day 
D-28 
to D-1 
D-7 
to D-1 
1 
8 
 
29 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab Cycle Number: 
 
 
P1 
 
P2 
 
P3 
P4 
P5 
P6 
P7 
P8 
P9 
P10 
P11 
P12 
P13 
P14 
P15 
P16 
P17 
Visit number: 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Informed consent main and 
biomarker 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Stage (NSCLC, UBC or 
SCCHN, previous treatment)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In-/exclusion criteria check 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiogram or MUGA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test2 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Tumor imaging3  
X3a,b 
 
 
 
 
 
 
X3c,
e 
 
 
X3c,
e 
 
 
X3c,
e 
 
 
X3c,
e 
 
 
X3c,
e 
 
Clinical disease Assessment 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Tumor tissue biopsy or archival 
tissue sample4 
X 
 
 
 
 
 
 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker blood sampling 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
PD-L1 status (DAKO 22C3)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical chemistry5 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Haematology6 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pembrolizumab (200 mg IV) 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

 
 
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Date: 21-Jun-2024 
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Page 23 of 99 
 
 
CONFIDENTIAL 
 
Table 1 Schedule of Trial Procedures (Year 1)  
 
Screening 
Trial treatment period – Year 1 
Trial Treatment Period Week 
Number 
(+/- 3 days) 
-4 wk 
to D-1 
-1 wk 
to D-1 
1 
2 
4 
5 
7 
10 
13 
16 
19 
22 
25 
28 
31 
34 
37 
40 
43 
46 
49 
Day 
D-28 
to D-1 
D-7 
to D-1 
1 
8 
 
29 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab Cycle Number: 
 
 
P1 
 
P2 
 
P3 
P4 
P5 
P6 
P7 
P8 
P9 
P10 
P11 
P12 
P13 
P14 
P15 
P16 
P17 
Visit number: 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
IO102 (85µg SC) and IO103 (85µg 
SC) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis7 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Thyroid function tests8 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Coagulation Tests9 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Vital signs10 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination11  
(full or directed) 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
12-lead ECG12 
X 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Adverse events 
 
X13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic blood sampling17 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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CONFIDENTIAL 
 
Table 2 Schedule of Trial Procedures (Year 2 and/or end of trial treatment)  
 
Trial treatment period – Year 2 Trial treatment 
EoT 
Post Trial 
treatment 
(Endpoint 
FUP) 
Week number 
(+/- 3 days) 
52 
55 
58 
61 
64 
67 
70 
73 
76 
79 
82 
85 
88 
91 
94 
97 
100 
103 
EoT14 
or 107 
Every 
12 wk15 
Pembrolizumab Cycle Number: 
P18 
P19 
P20 
P21 
P22 
P23 
P24 
P25 
P26 
P27 
P28 
P29 
P30 
P31 
P32 
P33 
P34 
P35 
 
 
Visit number: 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
 
Pregnancy test2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG PS 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Tumor imaging3  
 
 
X3c
,e 
 
 
 
X3c
,e 
 
 
 
X3c
,e 
 
 
 
X3c
,e 
 
 
 
X3c,d,e 
X3d,e 
Clinical disease Assessment 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Pembrolizumab (200mg IV) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
IO102 (85µg SC) and IO103 (85µg SC)
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Clinical chemistry5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Haematology6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis7 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Thyroid function tests8 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Coagulation Tests9 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Vital signs10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical examination11 (full or directed)
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
12-lead ECG12 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X18 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Subsequent anti-cancer treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Date of death/Survival follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 

 
 
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General instructions: 
• 
X denotes an assessment for all patients. 
• 
(X) denotes an optional assessment for all patients. 
• 
EOT – end of treatment visit occurs after cessation of all Trial treatment or completion of 24 months (last treatment at 96 weeks) trial therapy. If cessation of Trial treatment is caused by reasons other than 
Disease Progression, Tumor Imaging and Disease Assessments will continue until Disease Progression. 
• 
P# represents the pembrolizumab cycle number.  
Footnotes: 
1. 
Demography includes: gender, ethnic origin, race, year of birth. 
2. 
A urine pregnancy test is mandatory for female patients of childbearing potential within 72 hours prior to start of treatment. Repeat every 3 weeks during the treatment period, as well as at the end of 
relevant systemic exposure, i.e. 120 days after last dose of pembrolizumab. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test (β-hCG) will be required. 
3. 
Tumor (radiological) imaging: CT scans of abdomen, chest and pelvis. A MRI scan can be used if CT contrast is contra-indicated. The same radiographic procedure must be used throughout the trial. Assess 
disease response according to RECIST v. 1.1. After PD or response per iRECIST, repeat imaging for confirmation is required. Repeat imaging at between 4 and 8 weeks to confirm PD; and repeat imaging 
at >4 weeks to confirm response. 
a. 
Imaging must be done before administration of trial treatment. 
b. 
At screening, include a brain scan to exclude active metastases or leptomeningeal metastases.  
c. 
Pseudo progression should be considered if progression observed in the absence of clinical deterioration, and if suspected, tumor assessments can continue until progression is confirmed (iRECIST). 
d. 
For patients who discontinue trial treatment, tumor imaging should be performed at the time of treatment discontinuation (±4 week window). If previous imaging was obtained within 4 weeks prior to 
the date of discontinuation, then imaging at treatment discontinuation is not mandatory. Continue tumor imaging every 12 weeks until progression. 
e. 
+/-7 days 
4. 
Two samples of tumor tissue are required to be provided at screening and these can be either archival (within 3 months, and in absence of adjuvant or neo-adjuvant treatment) or newly acquired biopsy 
tissue. Use of archival tissue >3 months old, may be considered after communication with and agreement by the Sponsor. One of the samples (FFPE block or slides) is for PD-L1 status which will be 
assessed prior to enrolment using the DAKO 22C3 assay. The PD-L1 status can be assessed locally for eligibility and enrollment but one sample (FFPE block or slides) is required for central 
confirmation. Tissue sampling for biomarkers at week 10 is optional and contingent on patient signing biomarker consent form and depends on the presence of a suitable lesion.  
5. 
Clinical chemistry includes: albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransperase (AST), lactate dehydrogenase (LDH), , uric acid, calcium, glucose, phosphorus, 
potassium, sodium, magnesium, total bilirubin, direct bilirubin if total bilirubin is >ULN, total protein, urea. In addition, troponin (per institutional standard) will be measured at Screening. 
6. 
Haematology includes:, hemoglobin, platelet count, white blood cell (total and differential). 
7. 
Urinanalysis will be performed at screening, trial treatment and every 6 weeks during trial treatment and as clinically indicated and includes: blood, glucose, protein, specific gravity, microscopic examination 
(if abnormal results noted), creatinine (plasma or serum) or measured or calculated creatinine clearance (CrCl). GFR can be used instead of creatinine or CrCl. 
8. 
Thyroid function testing (TSH, T3 or FT3, FT4) at screening, start of trial treatment and every 6 weeks during trial treatment, and as clinically indicated.  
9. 
Coagulation Tests includes: prothrombin time (PT INR), partial thromboplastin time (activated) aPTT 
10. Vital Signs include blood pressure, heart rate, respiration rate, weight and temperature. Height will be measured at screening only. 
11. Physical examination:  
a. 
Full examination at Screening and every 12 weeks. Check and describe any significant abnormal physical examinations or findings: heart, lung, general, skin (other than the melanoma), oral cavity, 
chest, lymph nodes. 
b. 
Directed examination at other timepoints or as clinically indicated to include: symptom driven examination. 
12. 12-lead ECG is performed at screening, at the start of the trial treatment, and every 12 weeks during trial treatment and as clinically indicated.  
13. AEs occurring after informed consent to be recorded 
14. End of Treatment visit has to be conducted for all patients at the timepoint of permanent discontinuation of trial treatment. 

 
 
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15. Patients are to be followed-up post trial treatment every 12 weeks for survival status until the last patient in has been treated for 35 cycles plus 30 days follow up or until disease progression, death, 
withdrawing consent, or becoming lost to follow-up. If a patient cannot be contacted for survival follow  up, information may also be obtained by other means in accordance with local regulations, e.g., 
contact with patients’ health care providers, public sources, e.g. death registry, obituary listing, etc. when it is available and verifiable. 
16. For female patients of childbearing potential a urine pregnancy test is mandatory at 120 days after last dose of pembrolizumab. If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test (β-hCG) will be required. 
17. Pharmacokinetic blood sampling will be performed in a subset of up to 10 patients. See Section 12.4 for details. 
18. AEs to be recorded until at least 100 days after the last administration of trial treatment. 
 
 

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4 
Trial Design  
4.1 
Trial Design  
This is a non comparative, open label, multi-cohort (basket) trial of IO102-IO103 in combination with 
pembrolizumab in three indications: non-small cell lung cancer (NSCLC) adenocarcinoma, squamous 
cell carcinoma of the head and neck (SCCHN) or metastatic urothelial bladder carcinoma (mUBC).  
The primary objective of the trial is to investigate the efficacy of IO102-IO103 in combination with 
pembolizumab in the frontline treatment in each of the different solid tumor indications with the 
intent to expand a specific cohort if a clinically meaningful signal is observed based on primary 
endpoint as defined in Section 17.  
 
The primary endpoint is ORR according to RECIST v. 1.1. Disease evaluation by CT scan or MRI 
will be done locally for all patients based on RECIST v. 1.1 prior to administration of trial treatment, 
every 9 weeks post baseline the first year of treatment followed by every 12 weeks until disease 
progression. A copy of the CT scan or MRI will be provided to the sponsor. The same modality of 
radiological examination must be used throughout the trial.  
 
The clinical trial is unblinded and will consist of 3 cohorts: 
• 
Cohort A: Patients with NSCLC adenocarcinoma (metastatic disease) and programmed cell 
death ligand 1 (PD-L1) expression TPS  ≥50%. 
• 
Cohort B: Patients with SCCHN (recurrent or metastatic disease) and PD-L1 CPS ≥20 
• 
Cohort C: Patients with mUBC (metastatic disease) and PD-L1 CPS ≥10  
 
  Figure 1 Trial Diagram  
 
 
Approximately 90 patients will be enrolled and treated; approximately 30 patients in each cohort. 
 

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All eligible patients will receive treatment for up to 2 years with IO102-IO103 (IO102 85µg and 
IO103 85µg) subcutaneously (SC) every 3 weeks (Q3W) in combination with pembrolizumab 
intravenously (IV) 200mg Q3W.  
 
IO102-IO103 will be administered one hour prior to pembrolizumab as follows:  
• 
Induction period: On Day 1 and 8 of the first 2 cycles. In total 4 administrations will be provided 
during the first 2 cycles. 
• 
Maintenance period: On Day 1 of each subsequent 3 week cycle for a maximum of 33 cycles 
starting from cycle 3.  
A maximum of 37 administrations will be provided for each patient during the trial.  
 
Pembrolizumab will be administered on Day 1 of each 3 week cycle in accordance with standard of 
care for a maximum of 35 cycles (2 years). A maximum of 35 administrations will be provided for 
each patient during the trial.  
 
Patients will be followed-up post-treatment every 12 weeks for disease status, including initiating a 
non-trial cancer treatment, until the last patient in has been treated for 35 cycles plus 30 days follow 
up or until disease progression, death, withdrawing consent, start new anti cancer treatment or 
becoming lost to follow-up. End of trial is defined as last patient last visit. 
 
Adverse events (AEs) will be assessed using CTCAE v. 5.0. A steering committee will be established 
by the Sponsor to oversee the study conduct and perform reviews of safety data after approximately 
5 patients have received the first cycle of study treatment and then after 25% (approximately 22 of the 
90 patients planned) have received the first cycle of study treatment. Thereafter, safety data will be 
monitored periodically and according to the steering committee charter throughout the trial. Steering 
committee members will include Sponsor representatives, Investigators and, when required, other 
external experts. 
 
AEs will be monitored for a minimum of 30 days after patients discontinue trial treatment. SAE and 
Adverse Events of special interest (AEOSI) data will be collected for up to 90 days following 
discontinuation of trial treatment or 30 days following discontinuation of trial treatment if the patient 
initiates new anticancer therapy, whichever is earlier.  
 
Specific procedures to be performed during the trial, as well as their prescribed times and associated 
visit windows, will be outlined in the Trial Procedures Table 1 and  Table 2. Details of each 
procedure will be provided in Trial Procedures, Section 10.6 and Section 12.  
5 
Trial Objectives  
5.1 
Primary Objective  
The primary objective is to investigate the efficacy of IO102-IO103 in combination with 
pembolizumab in the frontline treatment of each of the different solid tumor indications (NSCLC 
adenocarcinoma PD-L1 TPS ≥50%, SCCHN PD-L1 CPS ≥20 , or mUBC CPS ≥10) with the intent to 
expand a specific cohort if a significant clinically relevant signal is observed. 
5.2 
Secondary Objectives  
The secondary objective is to investigate the safety of IO102-IO103 in combination with 
pembrolizumab in each of the 3 disease indications. 

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5.3 
Exploratory Objectives  
The exploratory objectives are to evaluate biomarkers that inform regarding trial drug activity or may 
predict response to treatment. 
Biomarkers, will be measured in tumor tissue and blood (whole, serum or plasma) provided during 
screening and on-treatment. Specific objectives are: 
• 
To evaluate and establish the pharmacodynamic activity of IO102 and IO103 on T cells, the 
tumor microenvironment, and IDO activity in cellular and/or molecular assays 
• 
To evaluate biomarkers that may predict response to IO102 and IO103 including pretreatment 
IDO and PD-L1 expression, the composition of tumor infiltrating lymphocytes, tumor 
mutational burden, and HLA type 
6 
Trial Endpoints  
6.1 
Primary Endpoint  
The primary endpoint is ORR according to RECIST v. 1.1. 
 
6.2 
Secondary Endpoints  
The Key secondary endpoints are the following:  
• 
Progression-free survival (PFS) according to RECIST v. 1.1 
• 
Duration of response (DOR) 
• 
Complete response rate (CRR) 
• 
Disease control rate (DCR) 
• 
Time to response (TTR) 
 
Safety endpoints:  
• 
Incidence of participants with AEs [ Up to 3 years ] 
• 
Incidence of participants with SAEs [ Time Frame: Up to 3 years ] 
• 
Incidence of treatment-related AEs [ Time Frame: Up to 3 years ] 
• 
Incidence of treatment-related SAEs [ Time Frame: Up to 3 years ] 
• 
Incidence of AEs causing discontinuation of trial treatment 
 
6.3 
Exploratory Endpoints  
• 
Overall survival (OS) 
• 
PFS according to iRECIST (iPFS) 
• 
Analysis of the tumor microenvironment for IDO and PD-L1 expression and lymphocyte 
infiltration 
• 
Circulating tumor DNA as a surrogate measure of tumor burden 
• 
Assessment of peripheral immune cell function and treatment-specific T cell responses 
• 
ORR and PFS according to independent central review, if applicable 

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7 
Background  
7.1 
Therapeutic Background  
7.1.1 
NSCLC Background  
7.1.1.1 
Epidemiology  
Lung cancer remains the leading cause of cancer deaths worldwide, accounting for approximately 
12% of all new cancers in 2018 (Bray et al., 2018). In 2021 in the United States, it is estimated that 
there are 235,760 new cases of lung cancer (119,100 in men and 116,660 in women) and 131,880 
lung cancer deaths (Siegel et al., 2021). Similar data from Europe estimate that in 2018 there were 
387,900 lung cancer deaths (267,300 in men and 120,600 in women) (Ferlay et al., 2019).  
 
NSCLC is the predominant subtype, accounting for approximately 85% of all cases (Molina et al., 
2008; Howlader et al., 2014). NSCLC can be divided into two major histologic types: 
adenocarcinoma and squamous cell carcinoma (Travis et al., 2011). Adenocarcinoma histology 
accounts for more than half of all NSCLC, while squamous cell histology accounts for approximately 
25% of NSCLC (Langer et al., 2010). The remaining cases of NSCLC are represented by large-cell 
carcinoma, neuroendocrine tumors, sarcomatoid carcinoma, and poorly differentiated histology. 
 
Genetic changes that have prognostic and/or predictive significance in NSCLC include mutations in 
the epidermal growth factor receptor (EGFR) gene, rearrangements in the anaplastic lymphoma 
kinase (ALK) gene, and mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene. 
The rates of these mutations differ between adenocarcinoma and squamous cell carcinoma. For 
example, EGFR kinase domain mutations have been reported in 10%-40% of patients with 
adenocarcinoma NSCLC but are infrequently observed in patients with squamous NSCLC (Herbst, 
Heymach and Lippman, 2008). The ALK fusion oncogene, recognized as a driver of lung 
tumorigenesis, is observed in approximately 7% of patients with adenocarcinoma but is rare in 
squamous histology (Herbst, Heymach and Lippman, 2008; Langer et al., 2010). In addition, KRAS 
mutations can be observed in up to 30% of adenocarcinoma NSCLC, while they are rare in squamous 
NSCLC (Travis et al. 2011). 
7.1.1.2 
First-Line Immunotherapy as Monotherapy for Advanced NSCLC with 
high (≥ 50%) PD-L1 Expression  
Chemotherapy-based regimens are associated with substantial toxicities and are generally poorly 
tolerated by elderly patients and by patients with poor performance status. Therefore, novel therapies 
that deliver an improved therapeutic index are needed for NSCLC. Pursuing personalized cancer 
immunotherapy (CIT), several Phase III trials have been conducted to investigate chemotherapy-free 
regimens involving anti-PD-L1/PD-1 inhibitors versus standard cytotoxic chemotherapy in treatment-
naive patients with PD-L1-positive NSCLC without an activating EGFR mutation or ALK gene 
rearrangement. These randomized trials have demonstrated that a high level of programmed cell death 
ligand 1 (PD-L1) expression predicts response to pembrolizumab, atezolizumab and cemiplimab. This 
level of PD-L1 expression may be seen in approximately 30 % of advanced NSCLCs (Reck et al., 
2016).  
 
The KEYNOTE-024 trial demonstrated significant improvement in survival with pembrolizumab 
monotherapy over standard platinum-based doublets in advanced NSCLC with high PD-L1 
expression (tumor proportion score [TPS] ≥50% assessed using the PD-L1 immunohistochemistry 

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[IHC] 22C3 pharmDx assay), with OS HR = 0.63 (95% CI: 0.44% to 0.91%), p <0.002, median OS 
30.0 versus 14.2 months; and PFS HR = 0.50, p <0.001, median PFS 10.3 versus 6.0 months (Reck et 
al., 2016, 2019).  
 
In KEYNOTE-042 trial, patients with a tumor proportion score (TPS) ≥1% (determined using the PD-
L1 IHC 22C3 pharmDx assay) were enrolled, survival outcomes of pembrolizumab compared with 
chemotherapy doublets in the two primary patient populations with a TPS ≥50% and a TPS ≥1% were 
OS HR = 0.69, p <0.0003, median OS: 20.0 versus 12.2 months, and OS HR = 0.81, p <0.0018, 
median OS: 16.7 versus 12.1 months, respectively. However, patients in a prespecified exploratory 
subgroup with TPS 1%-49% appeared to have similar OS in the two arms: HR = 0.92, median OS 
13.4 versus 12.1 months; 95% CI: 0.77 to 1.11 months (Mok et al., 2019). Based on results from 
these studies, pembrolizumab is approved for the the first line treatment of patients with metastatic 
NSCLC without an activating EGFR mutation or ALK gene rearrangement, whose tumors express 
PD-L1 (TPS ≥1%) in the United States and in patients whose tumors express high PD-L1 (TPS 
≥50%) in the European Union. 
 
Recently, atezolizumab monotherapy has also demonstrated a statistically significant and clinically 
meaningful improvement in OS compared with platinum-based doublet chemotherapy as first line 
treatment of metastatic NSCLC that expresses high PD-L1 in the IMpower110 trial (Herbst et al., 
2020). IMpower110 is a Phase III, randomized, open-label trial evaluating the efficacy and safety of 
atezolizumab monotherapy compared with platinum-based doublet chemotherapy in PD-L1-selected, 
chemotherapy-naive patients with advanced non-squamous or squamous NSCLC without EGFR or 
ALK mutations (wild type [WT]).  
 
Only patients whose tumors expressed PD-L1 (defined as tumor cell [TC]1/2/3 or immune cell 
[IC]1/2/3, as determined by the VENTANA® SP142 IHC Assay) were eligible. A total of 572 patients 
were enrolled and were randomized in a 1:1 ratio to receive atezolizumab monotherapy, cisplatin, or 
carboplatin (per investigator discretion) combined with either pemetrexed (non-squamous) or 
gemcitabine (squamous), followed by maintenance therapy with pemetrexed alone (non-squamous) or 
best supportive care (squamous). The trial enrolled patients with an EGFR mutation or ALK 
translocation who had disease progression or intolerable toxicity to treatment with a tyrosine kinase 
inhibitor; these patients were excluded from the analysis population, which included WT patients 
only (554 WT patients). The primary efficacy endpoint was OS by PD-L1 subgroup (TC3/IC3-WT; 
TC2/3 IC2/3-WT; and TC1/2/3 IC1/2/3-WT), as determined using the VENTANA PD-L1 SP142 
IHC assay. Key secondary endpoints included investigator-assessed PFS, ORR, and DOR.  
 
At the time of the interim OS analysis (clinical cutoff date: 10 September 2018), atezolizumab 
monotherapy showed a statistically significant and clinically meaningful improvement in OS 
compared with chemotherapy in patients with high PD-L1 expression (TC3/IC3-WT) with a stratified 
HR (95% CI) of 0.595 (0.398 to 0.890), p <0.0106, median OS 20.2 months versus 13.1 months (see 
Table 1). Because the OS statistical testing boundary was not crossed in the TC2/3 or IC2/3-WT or 
TC1/2/3 or IC1/2/3-WT subgroups at this interim analysis, the trial will continue to the OS final 
analysis for these subgroups.  
 
IMpower110 also demonstrated a clinically meaningful improvement in investigator-assessed PFS for 
atezolizumab in patients with high PD-L1 expression (TC3/IC3-WT) with a stratified HR (95% CI) of 
0.630 (0.449 to 0.884) and median PFS of 8.1 months versus 5.0 months. Atezolizumab monotherapy 
was also associated with improved ORR in the TC3/IC3-WT subgroup, with durable responses 
compared to chemotherapy. 

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More recently, cemiplimab, a PD-1 inhibitor, improved OS and PFS compared with chemotherapy in 
patients with advanced NSCLC with PD-L1 of ≥50 % without an EGFR, ROS1, or ALK genetic 
aberration (Sezer et al., 2021), and has the Food and Drug Administration (FDA) approval for this 
indication.  
 
In the EMPOWER-Lung 1 trial, among 563 patients with advanced NSCLC with PD-L1 of ≥50 %, 
cemiplimab 350 mg every three weeks improved OS relative to platinum-doublet chemotherapy 
(median, not reached versus 14.2 months, respectively; HR 0.57, 95% CI 0.42-0.77), as well as PFS 
(8.2 versus 5.7 months; HR 0.54, 95% CI 0.43-0.68) (Sezer et al., 2021). OS and PFS were also 
improved in the intention-to-treat population of 710 patients (which additionally included patients 
with PD-L1 expression that had not been confirmed or had been established as <50 %), despite 74 % 
crossover. Grade ≥3 toxicities were 28 % with cemiplimab and 39 % with chemotherapy. 
 
Overall, chemotherapy-free options with first line immunotherapy offers patients with advanced 
NSCLC expressing PD-L1 significant survival benefits as well as a more tolerable toxicity profile. 
Despite improvements and benefits with PD-L1/PD-1-targeting agents, nearly all patients experience 
disease progression. Consequently, new molecules and combinations, including novel 
immunotherapy combinations, are needed to address this unmet medical need. 
 
7.1.2 
SCCHN Background  
7.1.2.1 
Epidemiology  
SCCHN develop from the mucosal epithelium in the oral cavity, pharynx and larynx and are the most 
common malignancies that arise in the head and neck. The burden of SCCHN varies across countries 
and regions and has generally been correlated with exposure to tobacco-derived carcinogens, 
excessive alcohol consumption, or both. Increasingly, tumors that arise in the oropharynx are linked 
to prior infection with oncogenic strains of HPV, primarily HPV-16, and, to a lesser extent, HPV-18 
and other strains (Isayeva et al., 2012; Michaud et al., 2014; Stein et al., 2015). HPV-positive 
SCCHN generally has a more favourable prognosis than HPV-negative SCCHN (Johnson et al., 
2020). 
 
Median age of diagnosis for non-virally associated SCCHN is 66 years, whereas the median age of 
diagnosis for HPV-associated oropharyngeal cancer and Epstein-Barr virus (EBV)-associated 
nasopharyngeal cancer is ~53 years and ~50 years, respectively (Windon et al., 2018). The survival 
for SCCHN has improved modestly over the past three decades; for example, the 5-year survival 
increased from 55% during the period 1992-1996 to 66% during the period 2002-2006 when analysed 
across all age groups and anatomical sites within the Surveillance, Epidemiology, and End Results 
(SEER) registry (Pulte and Brenner, 2010).  
 
7.1.2.2 
 Frontline treatment options for locoregional recurrence and metastatic 
SCCHN  
Patients with locoregional recurrence (R) who are not amenable to surgery and/or radiotherapy as 
well as those with metastatic (M) disease are eligible for systemic treatment (Machiels et al., 2021). 
Standard of care has for more than a decade been platinum base chemotherapy plus cetuximab based 
on results from the  EXTEREME trial (Vermorken et al., 2008). Addition of cetuximab to cisplatin-5-
fluorouracil (5-FU) increased OS from 7.4 months with platinum-5-FU to 10.1 months with platinum, 

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5-FU and cetuximab. In the EXTREME trial, the corresponding ORR increased from 20 to 30% and 
the PFS increased from 3.3 to 5.6 weeks. The EXTREME regimen is associated with a 82% 
frequency of Grade 3/4 toxicities. Paclitaxel or docetaxel-based regimens are also used, but have yet 
to be compared head-to-head with the EXTREME regimen. Recent studies showed that the median 
OS of the EXTREME regimen may be prolonged (approximately 11 months) than that seen in 
original studies which showed a median OS published in 2008 of approximately 10 months 
(Vermorken et al., 2014; Bossi et al., 2017; Ferris et al., 2018). 
Since R/M first line patients have somewhat heterogeneous characteristics, National Comprehensive 
Cancer Network (NCCN 2021) guidelines (Guidelines Detail (nccn.org)) highlight the importance of 
considering individualized systemic therapies based on patient characteristics, given the toxicity of 
the EXTREME regimen. NCCN guidelines offer consideration of the use of alternative combination 
regimens including platinum plus taxane, cisplatin plus cetuximab and cisplatin plus 5-FU, or the use 
of these agents as monotherapies.  
According to the guidelines of the European Society for Medical Oncology (ESMO), in the first-line 
treatment of recurrent SCCHN, EXTREME is standard of care for patients with contraindications to 
anti-PD-1 inhibitors and in patients with a tumor not expressing PD-L1. EXTREME can also be 
considered as second-line treatment after progression on an immune checkpoint inhibitor in fit 
patients considered eligible for platinum-based chemotherapy (Machiels et al., 2021).  
7.1.2.3 
 Pembrolizumab in frontline SCCHN  
The standard of care first-line therapy for recurrent and/or metastatic disease has changed recently. 
The KEYNOTE-048 trial showed that the combination of platinum based chemotherapy plus 
pembrolizumab significantly improved OS compared with the EXTREME regimen (cisplatin or 
carboplatin plus 5-FU plus cetuximab): median OS 13.0 versus 10.7 months (p=0.0034) (Burtness et 
al., 2019). Objective response rate (ORR) and PFS were similar between the chemotherapy plus 
cetuximab and chemotherapy plus pembrolizumab arms [ORR 35.6% and 36.3%, PFS 4.9 and 5.1 
months, Grade 3-5 adverse events (AEs) 85.1% versus 83.3%, respectively]. 
 
Pembrolizumab monotherapy also improved median OS in patients with PD-L1-expressing SSCHN: 
14.9 versus 10.7 months in the CPS ≥20 subgroup and 12.3 versus 10.3 months in the CPS ≥1 
subgroup. As expected, pembrolizumab monotherapy was better tolerated than the EXTREME 
regimen (Grade 3-5 AEs 54.7% versus 83.3%, respectively). However, PFS with pembrolizumab 
monotherapy was not significant compared with EXTREME: 3.4 versus 5.0 months in CPS ≥20 and 
3.2 versus 5.0 months in CPS ≥1. Similarly, ORR for pembrolizumab monotherapy versus 
EXTREME regimen was 23.3% versus 36.1% and 19.1% versus 34.9% in the CPS ≥20 and CPS ≥1 
groups, respectively.The 6 month estimates for PFS in patients with CPS >20 was 32% in the 
pembrolizumab alone arm and 45% in the cetuximab plus chemotherapy arm. 
 
Therefore, based on the KEYNOTE-048 results, two different approaches are validated for patients 
with locoregional relapse not amenable to locoregional salvage treatment and/or with distant 
metastases (Machiels et al., 2021). A ‘chemo-free’ approach with pembrolizumab monotherapy in 
patients with CPS ≥1 SCCHN should be considered, especially when a rapid tumor shrinkage is not 
needed. A second option, independent of PD-L1 status, is the combination of pembrolizumab and 
chemotherapy (cisplatin or carboplatin plus 5-FU), particularly in symptomatic patients or when a 
rapid tumor shrinkage is needed (Machiels et al., 2021).  
 

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The FDA recently approved pembrolizumab in combination with chemotherapy as first-line treatment 
regardless of PD-L1 expression and pembrolizumab alone for patients with PD-L1-expressing tumors 
(CPS ≥1). In contrast, the European Medicines Agency (EMA) has approved pembrolizumab with or 
without chemotherapy only for patients with a CPS ≥1 [I, A; ESMO-Magnitude of Clinical Benefit 
Scale (ESMO-MCBS) v1.1 score: 4] (Machiels et al., 2021). 
7.1.3 
mUBC Background  
7.1.3.1 
Epidemiology  
Urothelial carcinoma (UC, also termed transitional cell carcinoma [TCC], urothelial bladder cancer or 
urothelial cell carcinoma [UCC] of the urinary tract) describes a range of tumors that arise from the 
urothelial endothelium, which includes the bladder, renal pelvis, ureter, and urethra. The worldwide 
incidence of bladder cancer exceeds 300,000 cases annually, ranking it as the seventh most common 
cancer worldwide (Jemal et al., 2011). TCC is the most common histologic subtype associated with 
bladder cancer and accounts for greater than 90% of all urothelial carcinoma cases in the 
industrialized world, whereas non-urothelial subtypes, including squamous cell, adenocarcinoma, and 
small cell carcinoma, are more frequent in other areas of the world (Chalasani, Chin and Izawa, 
2009).  
7.1.3.2 
Frontline treatment options for mUBC  
Cisplatin-based combination chemotherapy is the preferred standard first-line treatment for medically 
fit patients patients with previously untreated metastatic urothelial bladder carcinoma based on 
randomized trials (Logothetis et al., 1990; Loehrer et al., 1992; Saxman et al., 1997; Von der Maase 
et al., 2000; Von Der Maase et al., 2005; Sternberg et al., 2006; Galsky, Hahn, Rosenberg, Sonpavde, 
Hutson, Oh, Dreicer, Vogelzang, C. Sternberg, et al., 2011). The median survival with these regimens 
is 13 to 15 months, and 5% to 15% of patients attain long-term survival. However, the presence of 
pre-existing co morbidities such as renal dysfunction, poor performance status, neuropathy and heart 
failure usually confers cisplatin ineligibility (Dash et al., 2006; Galsky, Hahn, Rosenberg, Sonpavde, 
Hutson, Oh, Dreicer, Vogelzang, C. N. Sternberg, et al., 2011; Galsky, Hahn, Rosenberg, Sonpavde, 
Hutson, Oh, Dreicer, Vogelzang, C. Sternberg, et al., 2011) and up to 50% of patients are ineligible 
for a cisplatin based regimen. 
 
Immune checkpoint inhibitors have revolutionized the field of oncology, providing a novel 
mechanism for anticancer therapy. PD-1-targeting antibodies pembrolizumab and nivolumab and PD-
L1-targeting antibodies atezolizumab and avelumab have been approved for use in advanced 
urothelial cancer in the post-platinum setting or in the upfront setting in platinum-ineligible patients. 
While this represents a significant step forward in management of urothelial cancers, most patients do 
not have an objective response to these therapies. PD-L1 expression is not a consistently predictive 
biomarker, but is recommended for checkpoint utilization in select circumstances. 
 
In addition to approval for patients who progress following platinum-based chemotherapy, 
atezolizumab and pembrolizumab are approved in the first-line setting for mUBC. Both agents were 
initially approved as first-line treatment for cisplatin-ineligible patients on the basis of the Phase II 
IMvigor210 (Balar, Galsky, et al., 2017) and KEYNOTE-052 (Balar, Castellano, et al., 2017) trials. 
Subsequently, the randomized phase III IMvigor130 trial of atezolizumab and KEYNOTE-361 trial of 
pembrolizumab enrolled platinum-eligible patients with locally advanced/metastatic UC and no prior 
systemic therapy to receive atezolizumab/pembrolizumab with or without platinum-based 
chemotherapy versus platinum-based chemotherapy alone (Suzman et al., 2019). In June 2018, 
interim analyses of these two trials showed that patients with low PD-L1 expression receiving 
atezolizumab or pembrolizumab monotherapy had decreased survival compared with patients with 

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low PD-L1 expression who received platinum-based chemotherapy, leading to a change in drug 
approval (Suzman et al., 2019). Currently, atezolizumab and pembrolizumab are indicated as first-
line treatment for locally advanced /metastatic UC patients who are cisplatin-ineligible and whose 
tumors express PD-L1 or patients who are not eligible for any platinum therapy regardless of PD-L1 
status.  
 
There is also growing evidence to suggest that the clinical benefit of the combination of immune 
checkpoint inhibitors with chemotherapy in the first-line setting may be limited. Results from 
IMvigor130 evaluating the combination of atezolizumab plus chemotherapy demonstrated a PFS 
benefit over chemotherapy alone (8.2 versus 6.3 months; HR 0.82, 95% CI 0.70–0.96) but this benefit 
was small and of questionable clinical significance (Grande et al., 2019). Thus, there remains a 
significant unmet medical need for well-tolerated active therapies in this population. 
7.1.3.3 
Pembrolizumab in mUBC  
The phase II KEYNOTE-052 trial studied pembrolizumab as first-line treatment for 370 cisplatin-
ineligible patients with metastatic urothelial carcinoma (Balar, Castellano, et al., 2017) ORR was 
24% in all patients who received at least one dose of pembrolizumab. The ORR was higher (38%) in 
patients with a CPS of 10 or more. The ongoing Phase III KEYNOTE-361 trial (NCT02853305) is 
randomizing treatment-naive metastatic urothelial cancer patients 1:1:1 to receive pembrolizumab, 
pembrolizumab plus investigator’s choice of chemotherapy (containing cisplatin), or chemotherapy 
alone. Patients who are cisplatin-ineligible are randomized to a carboplatin-based regimen. The 
indication label for pembrolizumab includes cisplatin-ineligible patients, as long as they have a CPS 
≥10 by an FDA-approved test or patients who are not eligible for any platinum-containing 
chemotherapy regardless of PD-L1 status.  
7.2 
IDO and PD-L1 Antigens as Targets  
Cancer cells are naturally attacked by cells of the immune system, including cytotoxic T cells. Cancer 
cells can induce a state of tolerance whereby they can escape this immune system response. This 
effect is brought about by many different mechanisms; some of the most important are through 
overexpression of the PD-1, PD-L1 molecules and the metabolic enzyme IDO. The PD-1 receptor is 
expressed on various cells, including T cells. The blocking of PD-1 on T cells by PD-1 blocking 
antibodies protects the T cells from the inactivation signal from PD-L1 expressed by cancer cells or 
immune regulatory cells. Pembrolizumab is a PD-1 blocking antibody that has been shown to provide 
an objective clinical response rate in 45% of the patients with melanoma (Pedoeem et al., 2014) 39% 
of patients with NSCLCwith TPS ≥50% (Mok et al. 2019), 23% of patients with SCCHN CPS ≥20 
(Burtness et al. 2019) and 32% of patients with mUBC CPS ≥10 (Powles et al. 2021) 
The expression of the metabolic enzyme IDO is induced on various host cells and tumor cells upon 
exposure to IFN-γ. Activation of IDO inhibits cytotoxic T cells by depleting the microenvironment of 
amino acids crucial to the function of lymphocytes (Van Allen et al., 2014). 
Spontaneous T cell reactivity against IDO and PD-L1 in the tumor microenvironment and in the 
peripheral blood of various cancer patients and healthy donors has been identified (Søorensen et al., 
2009; Sørensen et al., 2011; S. Munir et al., 2013; Shamaila Munir, Andersen, Met, et al., 2013; 
Shamaila Munir, Andersen, Svane, et al., 2013; Ahmad et al., 2016). The IDO reactive CD8+ T cells 
were cytotoxic and could kill both cancer cells and immune regulatory dendritic cells in vitro. The 
PD-L1 reactive CD8+ T cells were also cytotoxic and were able to kill cancer cells and myeloid 
derived suppressor cells (MDSCs). Therefore, boosting specific T cells that recognize immune 
regulatory proteins, such as IDO and PD-L1, may directly modulate immune regulation (Sørensen et 
al., 2009; Sørensen et al., 2011; S. Munir et al., 2013; Shamaila Munir, Andersen, Met, et al., 2013; 

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Shamaila Munir, Andersen, Svane, et al., 2013; Ahmad et al., 2016). Due to the distinctive 
mechanisms of action, the combination of treatment with a monoclonal antibody targeting PD-1 and 
PD-L1 and IDO peptides are expected to have synergistic effects. There is nothing to suggest that 
combining pembrolizumab with the experimental IDO and PD-L1 peptide injection should be more 
toxic than treatment with pembrolizumab alone. The PD-L1 peptide (PD-L19-27; IO103) and IDO 
peptide (IDO194-214; IO102) both contain CD8+ T cell epitopes as well as CD4+ T cell epitopes. 
IO102-IO103 consisting of IDO and PD-L1 peptides boosts the natural immunity mediated by IDO 
and PD-L1 specific T cells. These can attack and kill regulatory immune cells and cancer cells as well 
as support additional anti-cancer immunity by the release of helper cytokines.  
7.3 
Pharmaceutical Background  
7.3.1 
IO102 and IO103  
IO102 is an immunotherapeutic targeting the immunoregulatory enzyme IDO, a critical endogenous 
cellular factor that contributes to immune suppression and tumor immune escape. IDO activity 
constitutes a counter regulatory mechanism induced by proinflammatory signals, which is a crucial 
mechanism in cancer. Patients with cancer may exhibit increased IDO expression, which can be 
detected both in immune cells and tumor cells. IDO is involved in the regulation of the immune 
response by suppressing T-cell function as well as enabling local tumor immune escape. In cancer, 
IDO can either be expressed directly by the tumor cells themselves or induced indirectly in the host 
antigen presenting cells by the tumor. In these settings, IDO mediates an acquired immune tolerance 
towards tumors, allowing tumors to evade immune responses by the host. Furthermore, high IDO 
expression has been shown to be correlated with a poor prognosis and shorter OS in various 
malignancies. Therefore, IDO is an attractive target in therapeutic interventions aimed at restoring the 
immune response towards the tumor and may serve as a widely applicable target for a therapeutic 
cancer immunotherapeutic.  
IO103 is an immunotherapeutic targeting the PD-L1 antigen. It is a single PD-L1-derived peptide 
designed to engage and activate PD-L1–specific T-cells. IO103 consists of a 19-amino acid peptide 
from the signal peptide of PD-L1.  
Refer to the most recent versions of the Investigator’s Brochure (IB) for IO102-IO103 for detailed 
information on the trial treatments and full pre-clinical and clinical data.  
7.3.2 
Pembrolizumab  
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody with high 
specificity of binding to the PD-1 receptor, thus inhibiting its interaction with 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 IV immunotherapy for advanced malignancies. Pembrolizumab is 
indicated for the treatment of patients across a number of indications. For more details on specific 
indications, refer to the IB for pembrolizumab. 
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 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). 

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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 to the dephosphorylation of effector molecules such as 
CD3 zeta (CD3ζ), protein kinase C-theta (PKCθ), and zeta-chain-associated protein kinase 
(ZAP70), which are involved in the CD3 T-cell signaling cascade (Okazaki et al., 2001; Chemnitz et 
al., 2004). 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 
(Francisco et al., 2010). As a consequence, the PD-1/PD-L1 pathway is an attractive target for 
therapeutic intervention in NSCL, SCCHN and mUBC.  
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as an IV 
immunotherapy for advanced malignancies. Pembrolizumab is indicated for the treatment of patients 
across a number of indications. For more details on specific indications refer to the IB for 
pembrolizumab. 
 
7.4 
Nonclinical and Clinical Trials  
7.4.1 
Pembrolizumab Pre-Clinical and Clinical Trials  
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 et al., 
2005; Blank et al., 2004; Curran et al., 2010; Pilon et al., 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 (Curran et al., 
2010; Pilon et al., 2010; Zhang et al., 2004). In such studies, tumor infiltration by CD8+ T cells and 
increased IFN-γ, granzyme B and perforin expression were observed, 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 for pembrolizumab). 
7.4.2 
IO102 Pre-Clinical  
In summary, ex vivo proof-of-concept (PoC) studies demonstrate that the IO102 IDO peptide 
injection:  
• 
has the ability to bind stably to human leucocyte antigen (HLA) to allow efficient antigen 
presentation by antigen presenting cells (APC);  
• 
is recognised by the peptide-specific T cells, leading to activation of IDO-specific T cells;  
• 
can activate IDO-specific T cells to differentiate into effector T cells and demonstrate 
cytotoxicity in the case of CD8+ T cells.  
In addition, in vivo PoC studies in syngeneic mouse tumor models reveal that IDO-targeting vaccine 
induces expansion of IDO-specific T cells in mice, leading to demonstrable anti-tumor therapeutic 
responses accompanied by reduction of IDO+immune suppressive cells in the tumor. In addition, 
efficacy of IDO peptide injection in a syngeneic mouse colon carcinoma model, CT26, is further 

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improved by co-administration of anti-PD-1 antibody.  
Two repeat dose toxicology studies (one Good Laboratory Practise (GLP)-compliant) with IO102 in 
mice applying doses up to 50 μg SC weekly for 8 weeks have shown that IO102 peptide injection was 
well tolerated without causing any dermal reactions at the injection sites or any systemic toxicity.  
7.4.3 IO102 Clinical Trials  
IO102 and its predecessor, IO101 have been studied in humans in the following clinical trials: 
The first immune modulating peptide to be investigated was a short peptide IO101. This was a 9-
amino acid peptide, which was investigated in a Phase I trial in patients with metastatic NSCLC. The 
IO101 peptide is an HLA-A2-restricted, IDO-derived CD8+ T-cell epitope. IO101 comprises only the 
MHC class I-restricted CD8+ T-cell epitope that is entirely contained within a longer peptide, the 
IO102. The IO102 comprises of both CD8+ T-cell epitopes and CD4+ T-cell epitopes.  
Fifteen HLA-A2 positive patients with Stage III-IV NSCLC in disease stabilization after standard 
chemotherapy (at least 28 days after last dose of chemotherapy) were treated with the IO101 IDO 
peptide, 85 μg once every 2 weeks (Q2W) for 12 weeks and subsequently once Q4W until disease 
progression or death. 
The IO101 peptide injection was well tolerated with no treatment related AEs of CTCAE Grade >2. 
In terms of longer follow-up (>5 years), the IO101 was well tolerated with no severe AEs for 
administration up to 5 years (Iversen et al., 2014, Kjeldsen et al., 2018). Two of 15 patients were 
long-term survivors with ongoing clinical response 6 years after the first treatment and with presence 
of IDO-specific T cells in the blood at several time points.  
IO102 was studied in a first in human trial (Bjoern et al., 2016) in combination with ipilumumab in 
patients with malignant melanoma (MM1304). Ten patients with histologically verified unresectable 
Stage III or IV malignant melanoma were treated with IO102 at a dose of 250 μg once weekly for 4 
weeks and subsequently once Q2W for a total of 7 administrations. In addition, the patients received 
ipilimumab administered IV at a dose of 3 mg/kg bodyweight. In total, four series of ipilimumab were 
given, 3 weeks apart.  
All 10 patients received at least 5 administrations of the IO102 peptide injection. One patient had 
received IFN-α in an adjuvant setting before entering the trial. None of the patients had received any 
prior systemic therapy for metastatic disease. At the first evaluation at 12 weeks, 5/10 treated patients 
were in stable disease, 1 of whom had an unconfirmed PR with a 44% reduction of target lesion (TL) 
diameter. Five patients progressed and were referred to other treatments. Two of the 5 patients with 
SD at the first evaluation were confirmed, 2 progressed by the second evaluation, and 1 patient died 
between the first and second evaluations. The death was considered unrelated to IO102.  
Future trials will evaluate the safety and efficacy of IO102-IO103 in a range of tumors including 
melanoma and HNSCC (NCT: 04445064). Please refer to current IO102-IO103 IB. 
Review of the ipilimumab safety data only revealed findings already known for the compound. 
IO102 was well tolerated with no associated CTCAE Grade 3/4 AEs reported.  
7.4.4 
IO103 Pre-Clinical Studies  
In summary: ex-vivo/in vitro PoC studies demonstrate that the IO103 PD-L1 peptide: 
• 
has the ability to bind stably to HLA to allow efficient antigen presentation by APC; 
• 
is recognized by PD-L1-specific T cells, leading to activation of PD-L1-specific T cells; 
• 
can activate PD-L1-specific T cells to differentiate into effector T cells that demonstrate 

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(MacKie et al., 2009) cytotoxicity in the case of CD8+ T cells and (Schadendorf et al., 2018) 
enhancement of activity of other effector T cells. 
In addition, in vivo PoC studies reveal that PD-L1 peptide treatment IO103  induces expansion of PD-
L1-specific T cells in mice, leading to demonstrable anti-tumor activity in a syngeneic mouse tumor 
model (CT26). In addition, in the same model, administration of IDO- and PD-L1 peptides together 
leads to additive anti-tumor therapeutic response.  
7.4.5 
IO103 Clinical Trials  
IO103 monotherapy has been studied in 2 investigator-initiated trials – 1 in multiple myeloma (MM) 
and 1 in basal cell carcinoma (BCC). 
The multiple myeloma trial (NCT03042793, MY0001) has been completed and was a first in human, 
open-label, single-center trial investigating safety, immunological response, and clinical response of 
treatment with PD-L1 peptide emulsified with Montanide adjuvant in patients with multiple myeloma 
(MM) after high-dose chemotherapy with stem cell support (Jørgensen et al., 2020). Patients received 
IO103 every 2 weeks (Q2W) for the first 10 weeks and thereafter monthly for 9 months e.g. 15 
administrations in total. Before treatment, 4 patients were in CR or better, and 5 patients were in very 
good partial response (VGPR). Following treatment, 3 patients showed an improved depth of 
response during therapy, and a further patient exhibited spontaneous basal cell carcinoma (BCC) 
clearance and was macroscopically complete. The rate of relapses was as expected for the population. 
Grade I/II self-limiting injection site reactions (itching, tenderness and redness), were reported in 9/10 
patients. During treatment, a total of 9 Grade 3 AEs were reported and none have been deemed 
related to the treatment with IO103. The level of infections and other AEs were as expected in the 
period after high-dose chemotherapy and autologous stem cell transplantations. No Grade 4 or 5 
toxicities were reported. 
IO103 was tested as monotherapy in patients with resectable BCC based on the regression of 2 BCCs 
seen in the myeloma trial. The aim of the trial was to assess the safety and efficacy IO103 therapy in 
10 patients with BCC. Patients were treated with IO103 together with Montanide as adjuvant up to 9 
times during 6 months. Regression in tumor size of at least 30% was seen in 5 of 18 tumors, 2 of 
which showed complete regression of individual tumors but not all tumors in single individuals. 
Treatments resulted in immune responses against the therapy in blood samples from 9/10 patients and 
in skin samples from 5/9 patients. The monotherapy of IO103 was well tolerated as the most frequent 
AEs were local injection site reactions which were easily manageable (Jørgensen et al., 2020). 
See the IB for further clinical trial details. 
7.4.6 
IO102-IO103 – Clinical Trial  
Currently, 1 ongoing trial investigates IO102-IO103 in combination with nivolumab standard of care 
in patients with melanoma.  
The clinical trial is a Phase I/II trial and includes 30 patients with metastatic melanoma in a first line 
setting (NCT03047928, MM1636). This ongoing open-label, single-center trial started in October 
2017 and is investigating safety and efficacy of combination therapy with nivolumab and the 
IDO/PD-L1 (IO102-IO103) antigen. The IO102-IO103 antigen is administered from the start of 
nivolumab treatment, i.e., bi-weekly for the first 6 administrations and thereafter every 4th week for 
up to 1 year. 
Baseline characteristics of the 30 patients are representative of a typical trial population of metastatic 
melanoma. Of note, 13 (43%) patients had PD-L1 negative tumors (PD-L1<1%) and 18 (60%) had 
visceral metastatic/M1c disease. Additionally, 19 (63%) patients’ tumors were BRAF WT and 11 

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(37%) carried a BRAF mutation. Twenty-four patients (80.0%) had an objective response, and 22 of 
these patients have a radiologically confirmed objective response (73.3%) assessed by RECIST v. 1.1 
at least 4 weeks after the first response observation. Of the 17 patients with PD-L1 positive disease, 
15 obtained a confirmed objective response (88.2%) while in the 13 patients with PD-L1 negative 
disease, 7 obtained a confirmed objective response (53.8%). Complete responses were seen in 8 
patients with M1c disease and four of these patients had a PD-L1-negative tumor. Of the 22 patients 
with a confirmed objective response, 14 patients had disease progression. Overall, 8 patients died, 1 
due to AEs considered unrelated to IO102-IO103 treatment; the remaining patients discontinued due 
to progression and died. Median PFS was 25.3 months. The 85 μg doses were well tolerated in 
combination with nivolumab, with no DLTs. Based on the similarities between nivolumab and 
pembrolizumab, the doses are expected to be well tolerated with pembrolizumab, with no need for a 
safety run-in. 
A summary is included in the most recent IO102-IO103 IB. Results have been published (Kjeldsen et 
al., 2021) and presented at ESMO (Svane, 2020) and AACR (Kjeldsen et al., 2022).  
 
8 
Rationales  
8.1 
Rationale for Pembrolizumab Dose and Schedule  
The planned dose of pembrolizumab for this trial is 200 mg every Q3W. Based on the totality of data 
generated in the Keytruda development program, 200 mg Q3W is an appropriate dose of 
pembrolizumab for adults across all indications. As outlined below, this dose is justified by: 
• 
Clinical data from 8 randomized studies in melanoma and NSCLC indications demonstrating 
flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 Q2W 
representing an approximate 5 to 7.5 fold exposure range (refer to the IB for pembrolizumab)  
• 
Population pharmacokinetic (PK) analysis showing that both fixed dosing and weight-based 
dosing provides similar control of PK variability with considerable overlap in the 
distributions of exposures, supporting suitability of 200 mg Q3W 
• 
Clinical data showing meaningful improvement in benefit-risk including overall survival at 
200 mg Q3W across multiple indications, and 
• 
Pharmacology data showing full target saturation in both systemic circulation (inferred from 
PK data) and tumor (inferred from physiologically-based PK [PBPK] analysis) at 200 mg 
Q3W. 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled with 
melanoma and non-small cell lung cancer (NSCLC), covering different disease settings (treatment 
naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment settings 
(monotherapy and in combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 
10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies 
compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and 
KN006). All of these studies demonstrated flat dose- and exposure-response relationships across the 
doses studied representing an approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg (or 200 
mg fixed-dose) Q3W provided similar responses to the highest doses studied. Subsequently, flat dose-
exposure-response relationships were also observed in other tumor types including head and neck 
cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 200 mg Q3W as 
the appropriate dose independent of the tumor type. These findings are consistent with the mechanism 

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of action of pembrolizumab, which acts by interaction with immune cells, and not via direct binding 
to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data in 
KN001 evaluating target-mediated drug disposition conclusively demonstrated saturation of PD-1 in 
systemic circulation at doses much lower than 200 mg Q3W. Second, a PBPK analysis was conducted 
to predict tumor PD-1 saturation over a wide range of tumor penetration and PD-1 expression. This 
evaluation concluded that pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both 
blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body weight 
and other participant covariates on exposure, has shown that the fixed-dosing provides similar control 
of PK variability as weight-based dosing, with considerable overlap in the distribution of exposures 
from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. Supported by these PK characteristics and 
given that fixed-dose has advantages of reduced dosing complexity and reduced potential of dosing 
errors, the 200 mg Q3W fixed-dose was selected for evaluation across all pembrolizumab protocols. 
8.2 
Rationale for IO102-IO103 Dose and Schedule  
IDO is a cytosolic enzyme responsible for tryptophan catabolism and conversion of tryptophan into 
kynurenine. It is overexpressed by a variety of tumor cell types and antigen-presenting cells and plays 
an important role in immunosuppression mainly through suppression of cytotoxic T-
lymphocyte activation; tryptophan depletion inhibits T-lymphocyte proliferation and activation and 
suppresses the immune system. PD-L1 is overexpressed on many human cancer cell types, including 
malignant melanoma. PD-L1 binding to its cognate receptor PD-1 on T-cells suppresses the immune 
system and results in increased immune evasion and decreased cytotoxic T-lymphocyte activation.  
IO102 and IO103 stimulate activation of human T-cells against IDO and PD-L1 expressing 
cells, respectively, and they have been demonstrated to activate proinflammatory immune responses 
and cytotoxic killing of immunosuppressive cells in vitro. Thus, treatment with IDO and PD-L1 
peptides in patients with cancer may activate the immune system to eradicate IDO- and 
PDL1expressing tumor and immune cells in the tumor microenvironment (TME), facilitating the 
activation and proliferation of effector T-cells against tumor cells.  
Data from murine preclinical tumor models directly support this notion, where the antitumor activity 
of both IDO and PD-L1 targeting antigen immunotherapeutic has been demonstrated. Importantly, 
treatment with IDO and PD-L1 peptides demonstrates combinational antitumor response in a tumor 
model where IDO and PD-L1 molecules are expressed by different cell types within the TME.  
As noted above, both IDO and PD-L1 represent key checkpoint molecules in the context of antitumor 
immunity. While both molecules are regulated and induced by IFNγ secreted by 
lymphocytes (Spranger et al., 2013) and could be expressed by both myeloid cells and tumor cells in 
the TME, their expression does not necessarily overlap in the same cells. 
A trial by Krähenbühl confirmed that the expression profile of IDO and PD-L1 was nonoverlapping 
in melanoma biopsies before and after targeted therapy versus immune therapy (Krähenbühl et al., 
2018).   
In summary, IO102-IO103 targets two separate, but interlinked key cancer immune resistance 
pathways (IDO and PD-L1, respectively). Thus, treatment with IO102 and IO103 results in 
targeting 2 separate escape mechanisms that are not confined in the same cell populations. Further, an 
attack on either or both IDO-positive and PD-L1–positive target cells in the TME would lead 
to IFNγ secretion by activated T-cells, resulting in elevation of IDO/PD-L1 expression in the 

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surrounding cells, rendering them sensible prone to further for attack by IO102-IO103 dual-
antigen treatment induced T cells.  
The proposed doses of IO102 and IO103 to be studied in this trial are 85 μg. The 85 μg doses were 
well tolerated in combination with nivolumab, with no DLTs. Based on the similarities between 
nivolumab and pembrolizumab, the doses are expected to be well tolerated with pembrolizumab, with 
no need for a safety run-in (Svane, 2020). This dose is aligned with the net peptide administered to 
patients with advanced melanoma in trial MM1636, which corresponds to the gross weight of the 
peptide administered (100 μg). The formulations for IO102 and IO103 are comparable to those used 
previously in clinical trials (NCT03562871 and NCT03047928 for IO102; NCT03714529 for IO103) 
and can be expected to achieve both immunological and clinical responses.  
No dose selection is applied in the trial. Identifying the maximum tolerated dose has been challenging 
for cancer vaccines. The sponsor’s clinical experience is that with administration of 100 μg or 250 μg 
of IO102, an expected immunological response measured by analyzing induced dual-antigen 
immunotherapeutic specific cellular response in the treated patients is generated (Iversen et al., 2014, 
Bjoern et al., 2016). Especially relevant in these settings is the finding that close to 100% of all 
treated patients in the MM1636 trial (please refer to section 7.4.6) have demonstrated induction of 
dual-antigen immunotherapeutic specific T cell response (measured by IFNγ enzyme-linked 
immunospot assay). As the expression of both PD-L1 and IDO are induced strongly by IFNγ, and as 
both are immunotherapeutics, both IO102 and IO103 are expected to have a similar mode of action. It 
is the sponsor’s conclusion that the dose regimen of IO102-IO103 chosen for the proposed trial is 
relevant to achieve both immunological and clinical responses.  
The schedule selected is driven by the expected synergy with pembrolizumab, evidence from 
MM1636 and other trials (data on file), and convenience for the patient to avoid unnecessary visits (as 
well as administrations). The schedule includes an induction period where 2 additional 
administrations of the dual-antigen are given on Day 8 of cycles 1 and 2 to ensure expansion of dual-
antigen specific T-cells. 
8.3 
Rationale for Trial Population  
8.3.1 
Rationale for Trial Population - NSCLC  
Pembrolizumab has shown significant clinical benefit in patients with metastatic NSCLC independent 
of histology.  
 
Use of pembrolizumab for patients with PD-L1 expression ≥50 % is supported by the phase III 
KEYNOTE-024 trial, in which 305 treatment-naïve patients with advanced NSCLC having at least 
50 % tumor cell PD-L1 staining were randomly assigned to pembrolizumab monotherapy (200 mg IV 
Q3W) versus standard platinum-doublet chemotherapy (Reck et al., 2016). At a median follow-up of 
11.2 months, PFS, the primary endpoint, was prolonged with pembrolizumab compared with 
platinum-doublet chemotherapy (median PFS, 10.3 versus 6 months; HR 0.50, 95% CI 0.37-0.68), 
and ORRs were improved (45 versus 28 %). The median duration of response was not reached in the 
pembrolizumab group and was 6.3 months in the chemotherapy group. Severe (≥ Grade 3) treatment-
related adverse effects were lower among patients receiving pembrolizumab (27 versus 53 %). Any-
grade pneumonitis was reported in 5.8 % of patients treated with pembrolizumab, with severe 
pneumonitis in 2.6 %. Although PFS was prolonged, there is still a significant unmet need in this 
population for more durable responses. 
 
In the Phase III KEYNOTE-042 trial of patients with treatment-naïve, advanced, EGFR/ALK WT 
NSCLC and at least 1% tumor PD-L1 expression, pembrolizumab monotherapy is being compared 

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with platinum-doublet chemotherapy, chosen according to histology. Of note, this trial did not permit 
crossover. At a median follow-up of 12.8 months, results are as follows (Mok et al., 2019). OS, the 
primary endpoint, was prolonged among patients receiving pembrolizumab compared with those 
receiving chemotherapy as follows: 
 
• 
TPS ≥50 % (599 patients), 20 versus 12 months (HR 0.69, 95% CI 0.56-0.85) 
There was no statistically significant PFS benefit among patients receiving pembrolizumab compared 
with those receiving chemotherapy, except for those with the highest level of PD-L1 expression (TPS 
≥50 %; median PFS, 7.1 versus 6.4 months [HR 0.81, 95% CI 0.67-0.99]). As in KEYNOTE-024, 
pembrolizumab was better tolerated than chemotherapy, with grade 3 to 5 adverse events occurring in 
18% of those receiving pembrolizumab and 41 % of those receiving chemotherapy. 
 
Pembrolizumab is approved by the FDA for the front-line treatment of patients with advanced 
EGFR/ALK wild-type NSCLC whose tumors have ≥1 % PD-L1 expression based on the 22C3 
pharmDx test (Merck and Corp., 2020).  
 
The RR results obtained in this trial will be compared to an historical RR of 40%. A 40% RR is at the 
average of RRs observed with existing agents as monotherapy - especially immune checkpoint 
inhibitors - tested in the first line setting in metastatic NSCLC patients . Considering the effect of 
pembrolizumab on duration of response and the population being studied, a RR of 55% is considered 
clinically important for the combination of pembrolizumab with IO102-IO103. 
8.3.2 
Rationale for Trial Population - SCCHN  
A large number of patients with head and neck cancer initially present with locally advanced, Stage 
III/IV disease that is initially treated with combinations of chemotherapy, radiation and/or surgery. 
This initial treatment is generally designated as “definitive” therapy, which typically combines 
chemoradiation and surgery and can result in disease control rates ranging between 33 and 86% of 
patients. Patients who progress after initial definitive therapy require subsequent treatment for 
recurrent (R) disease. Patients who initially present with metastatic (M) disease generally receive the 
same therapy as those with recurrent disease after definitive treatment. 
 
Despite the recent progress with immune-checkpoint inhibitors in R/M SCCHN, only about 30% of 
patients respond to current therapy regimens, with a median OS of 15 months, even when combined 
with chemotherapy (Vermorken et al., 2008; Burtness et al., 2019). Hence, there remains a high 
unmet need in R/M SCCHN for regimens with a more favorable therapeutic index, to improve 
treatment efficacy and decrease treatment-related toxicity. A 6-month estimate of PFS in patients with 
a CPS ≥20 would be estimated to be 39% in patients treated with IO102-IO103 plus pembrolizumab. 
8.3.3 
Rationale for Trial Population - mUBC  
Inoperable locally-advanced/metastatic urothelial bladder carcinoma has an extremely poor prognosis 
with a high unmet medical need. Platinum-based chemotherapy is the current standard of care for 
patients with previously untreated mUBC. Systemic chemotherapy in mUBC is, however, 
characterized by significant toxicity with poor OS and low response rates and limited durability in a 
frail population of advancing age and multiple co-morbidities.  
 
Many patients are not eligible to receive treatment with cisplatin-based chemotherapy due to their 
poor health status  and need more effective therapeutic options. 
 

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Immunotherapy in mUBC has shown significant promise. Frontline treatment with pembrolizumab in 
patients who are ineligible to receive cisplatin has demonstrated durable responses (Rosenberg et al., 
2016; Balar, Castellano, et al., 2017). However, response rates and overall survival remain poor. 
8.4 
Overall Risk/Benefit Assessment  
Pembrolizumab has a positive benefit-risk profile and is well tolerated in the approved indications. 
The most common pembrolizumab adverse reactions (reported in ≥20% of patients) include pruritus, 
diarrhea, and cough. In the pembrolizumab monotherapy trials, the incidence of Grade 3-5 drug-
related AEs across studies is 13.8%. Pembrolizumab immune-mediated Adverse Events of Special 
Interest (AEOSIs) are relatively uncommon. The most frequently reported AEOSI is hypothyroidism, 
with an overall incidence of 8.5%. Furthermore, most AEOSIs are mild to moderate in severity, and 
are generally readily manageable with appropriate care in the clinical setting.  
 
Pembrolizumab has been generally well-tolerated; adverse events with potentially immune-mediated 
causes that are consistent with an immunotherapeutic agent, including rash, hypothyroidism, 
hepatitis/elevated transaminases, colitis, and myasthenia gravis, have been observed in ongoing 
studies of pembrolizumab. To date, these events have been amenable to monitoring and treatment. 
Details of the pembrolizumab risks are highlighted in the IB for pembrolizumab. 
 
A clinical trial (MM1636) evaluated IO102-IO103 in combination with nivolumab in the intended 
advanced melanoma patient population at the intended dose, and has demonstrated clinically relevant 
improvements in the ORR, including sub-groups of patients and in terms of the complete response 
rate and the duration of response. Details are included in the most recent IO102-IO103 IB.   
It is considered a high risk that the patients get injections site reactions, but they are manageable and 
reversible by use of local treatment with steroid ointments and or antihistamines. The AEs reported in 
the MM1636 trial included injection site reactions (in 76.7% patients, the majority were Grade 1 or 
2), and the remaining AEs were related to anti-PD-1 monotherapy. The safety profile of the IO102-
IO103 dual-antigen immunotherapeutic is considered favorable. 
Apart from injection site reactions AEs, there is a potential risk for a small increase in radiation 
exposure during the assessment of disease with radiological scans and tumor tissue biopsies. The 
imaging schedule of every 3 months used in this trial is usually considered standard intervals for 
tumor assessments with standard of care treatment.  
At screening, it is possible for patients to utilize archival samples (obtained within 3 months and 
without previous exposure to anticancer therapy). Archival tissue that is obtained more than 3 months 
from screening, may be considered on after communication with and agreement by the Sponsor. 
Acquisition of on-trial repeat biopsies is largely dependent on a suitable lesion being available and the 
willingness of the patient. Patients have a risk of bleeding, infection, and pain during a biopsy and 
will be informed about these risks. Patients will be carefully selected if they are suitable for a re-
biopsy. 
 
As described in detail above, the combination of the IDO/PD-L1 antigen IO102-IO103 and the 
immune checkpoint inhibitor (ICI) nivolumab is safe with encouraging early efficacy data: an ORR of 
73.3% was reached and 46.7% achieved a complete response in patients with melanoma. The safety 
profiles for nivolumab and pembrolizumab are similar and therefore the combination with IO102-
IO103 with pembrolizumab  will likely yield a similar safety profile to that of combining with 
nivolumab. Hence, treatment with IO102-IO103 may offer potential benefits compared to ICIs such 

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as pembrolizumab alone, as preliminary evidence suggests that treatment with IO102-IO103 may 
result in a better antitumor response with ICIs. Except for local reactions at injection site, toxicity was 
comparable to patients receiving nivolumab monotherapy. Additional details regarding specific 
benefits and risks for patients participating in this clinical trial may be found in the patient 
information sheet. 
 
In summary, treatment with pembrolizumab in combination with IO102-IO103 offers the potential for 
clinical benefit in previously untreated patients with solid tumors. Given the promising efficacy and 
good safety profile of immune checkpoint inhibitors such as nivolumab in combination with IO102-
IO103 treatment, the benefit-risk assessment for this basket trial in combination with pembrolizumab 
is regarded as positive. 
 
AEs will be assessed using CTCAE v. 5.0. 
 
To minimize or eliminate immediate hazards and to protect the life and well-being of research 
participants (e.g., to limit exposure to COVID-19) it is advised to assess and manage the risk of 
COVID-19 to the patient, taking into consideration prior exposure to the SARS-COV2 virus, 
vaccination status, age and co-morbitities. Scheduled visits are advised to be delayed as appropriate in 
the situation of a patient who has a positive COVID-19 test or where an outbreak occurs at the 
investigational hospital. See Appendix III for further details. All COVID-19 related deviations from 
the protocol will be recorded as COVID-19 deviations. Patients most at risk of rapidly progressing 
disease are excluded, and all patients are required to have a life expectancy of at least 3 months. 
 
9 
Trial Population  
9.1 
Entry Criteria  
9.1.1 
Diagnosis/Condition for Entry into the Trial  
• 
Cohort A. NSCLC adenocarcinoma (metastatic disease) with PD-L1 expression TPS ≥50%. 
• 
Cohort B. SCCHN (recurrent or metastatic disease) with  PD-L1 CPS ≥20. 
• 
Cohort C. mUBC (metstatic disease) with PD-L1 CPS ≥10 
9.1.2 
Patient Inclusion Criteria  
1. Patients with histologically or cytologically confirmed: 
Metastatic NSCLC (adenocarcinoma) (Cohort A), who have not received prior systemic 
treatment for their metastatic disease and who have:  
• 
No known sensitizing genetic aberrations where there are approved therapies (such as 
ALK, ROS1, EGFR, BRAF V600E, MET skipping mutations, and RET mutations or 
rearrangements) 
or 
 
 SCCHN (Cohort B) with no prior systemic therapy administered in the recurrent or 
metastatic setting (with the exception of systemic therapy completed >6 months prior if given 
as part of multimodal treatment for locally advanced disease) and who have: 
• 
SCCHN considered incurable by local therapies. Tumors of nasophyngeal origin (any 
histology) are excluded 

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• 
Documented results of p16/HPV status for oropharyngeal cancer (per institution 
standard) 
 
or 
 
Metastatic UBC (Cohort C) with no prior therapy and not eligible for any platinum-
containing chemotherapy: 
• 
Urothelial cancer of the renal pelvis, ureter, bladder or urethra (transitional cell and  
mixed transitional/non transitional cell histologies permitted but transitional cell 
histology must be the dominant histology) 
 
For all cohorts, any solitary metastases must be biopsied to confirm diagnosis of metastases 
from primary indication. 
 
2. PD-L1 TPS or PD-L1 CPS (as confirmed prior to enrolment using the PD-L1 IHC DAKO 22C3 
pharmDx assay, using local or central services): 
• 
Cohort A (NSCLC adenocarcinoma): PD-L1 TPS ≥ 50% 
• 
Cohort B (SCCHN): PD-L1 CPS ≥20; HPV +/- 
• 
Cohort C (mUBC): PD-L1 CPS ≥10 
3. A female participant is eligible to participate if she is not pregnant not breastfeeding, and at 
least one of the following conditions applies:  
• Not a woman of childbearing potential (WOCBP) 
• A WOCBP who agrees to follow contraceptive guidance starting with the screening visit and 
through 120 days after last dose of pembrolizumab or 180 days after last dose of 
chemotherapy.  
Note: A WOCBP, i.e., fertile, following menarche and until becoming post-menopausal 
unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. Tubal ligation is not a method of permanent 
sterilisation. A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 
 
4. The participant (or legally acceptable representative if applicable) provides written informed 
consent for the trial in accordance with ICH-GCP and local legislation prior to admission to 
the trial.  
5. At least 18 years of age on day of signing informed consent. 
6. Have measurable disease per RECIST v. 1.1 as assessed by local site investigator/radiologist. 
Lesions situated in a previously irradiated area are considered measurable if progression has 
been demonstrated in such lesions. 

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7. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a 
tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue 
blocks are preferred to slides.  
8. Have an ECOG performance status of 0 to 1. 
9. If participant received major surgery, they must have recovered adequately from the adverse 
events and/or complications from the intervention prior to starting trial treatment. 
10. Have adequate organ function as defined below. Specimens must be collected within 10 days 
prior to the start of trial treatment. 
Adequate organ function as defined by: 
• 
Haematology: 
Absolute neutrophil count ≥1500/µL or ≥1.5 × 109/L 
Platelets ≥ 100,000/µL or ≥ 100 × 109/L 
Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L. Criteria must be met without packed red blood 
cell transfusion within the prior 2 weeks. Participants can be on stable dose of 
erythropoietin (≥ approximately 3 months). 
• 
Renal: 
Creatinine ≤1.5 × ULN, or 
Measured or calculated creatinine clearance (CrCl) ≥50 mL/min for patients with 
creatinine levels >1.5 × institutional ULN;  
GFR can also be used in place of creatinine or CrCl 
• 
Hepatic: 
Total bilirubin ≤1.5 × ULN or direct bilirubin ≤ ULN for patients with total bilirubin 
levels >1.5 × ULN 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN (≤5 
× ULN for patients with liver metastases) 
Alkaline Phosphatase ≤2.5 × ULN 
• 
Endocrine: 
No uncontrolled endocrinopathies 
• 
Coagulation: 

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International normalised ratio (INR) or prothrombin time (PT) and activated partial 
thromboplastin time (aPTT) ≤1.5 × ULN unless patient is receiving anticoagulant therapy 
as long as PT or aPTT is within therapeutic range of intended use of anticoagulants 
11. Patients who are hepatitis B surface antigen (HBsAg)  positive are eligible if they have 
received hepatitis B virus (HBV)  antiviral therapy for at least 4 weeks and have undetectable 
HBV viral load prior to treatment initiation. 
Note: Patients should remain on anti-viral therapy throughout trial treatment and follow local 
guidelines for HBV anti-viral therapy after completion of trial treatment. Hepatitis B 
screening tests are not required unless:  
  a.  Known history of HBV infection 
  b.  As mandated by local health authority 
12. Patients with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is 
undetectable at screening. 
Note: Patients must have completed curative anti-viral therapy at least 4 weeks before 
treatment initiation. Hepatitis C screening tests are not required unless: 
  a.  Known history of HCV infection  
  b.  As mandated by local health authority 
9.2 
Patient Exclusion Criteria  
Cohorts A, B, and C: 
 
1. A WOCBP who has a positive urine pregnancy test (within 72 hours) prior to treatment. If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
2. 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 immune-related AE 
(irAE). 
3. Has received prior systemic anti-cancer therapy in the first line setting for the participant's 
metastatic disease (treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant 
therapy is allowed as long as completed at least 6 months prior to diagnosis of metastatic 
disease). 
4. Has not recovered from all AEs due to previous therapies to ≤ Grade 1 or baseline. Participants 
with ≤ Grade 2 neuropathy are eligible. 
5. Has received any prior radiotherapy, with the exception of palliative radiotherapy to non-target 
lesions, within 2 weeks prior to start of trial treatment or radiotherapy to the lung >30 Gy within 6 
months of start of trial treatment. Participants must have recovered from all radiation-related 
adverse events and not have had radiation pneumonitis requiring corticosteroids.  
6. Have a life expectancy of <3 months and/or rapidly progressing disease.  

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7. Have received a live or live attenuated vaccine within 30 days prior to the first dose of trial 
treatment. Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin 
(BCG), and typhoid vaccine. Administration of killed vaccines, mRNA based (e.g., covid-19) and 
vector based vaccines are allowed. Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live 
attenuated vaccines and are not allowed. 
8. Is currently participating in or has participated in a study of an investigational agent or has used 
an investigational device within 4 weeks prior to the first dose of study treatment. Note: 
Participants who have entered the follow-up phase of an investigational study may participate as 
long as it has been 4 weeks after the last dose of the previous investigational agent. 
9. Has a diagnosis of immunodeficiency 
10. Received any of the following medications or procedures within 2 weeks prior to first dose of 
trial treatment: chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone 
equivalent) or any other form of immunosuppressive therapy.  
11. Has a known additional malignancy that is progressing or has required active treatment within the 
past 2 years.  
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. 
12. Has CNS metastases and/or carcinomatous meningitis. Participants in Cohort A (NSCLC) with 
previously treated brain metastases may participate provided they are clinically stable and without 
requirement of steroid treatment for at least 14 days prior to first dose of trial treatment.  
13. Has severe hypersensitivity (≥ Grade 3) to IO102 or IO103, pembrolizumab and/or any of their 
excipients. 
14. 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. 
15. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis / 
insterstitial lung disease. 
16. Has an active infection requiring systemic therapy. 
17. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is 
required unless mandated by local health authority. 
18. Known adrenal insufficiency function (that is basal cortisol level <140nmol/L or <5 μg/dL). 

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19. Has known active Hepatitis B virus (defined as Hepatitis B surface antigen [HBsAg] reactive 
and/or detectable HBV DNA) or known active Hepatitis C virus (HCV) (defined as anti-HCV Ab 
positive and detectable HCV ribonucleic acid [RNA] [qualitative]) infection.  
Note: No testing for Hepatitis B and Hepatitis C is required unless  
  a.  Known history of HBV or HCV infection  
  b.  Mandated by local health authority. 
Patients who have a history of hepatitis will be screened using serology to confirm status. 
20. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the trial, interfere with the patient's participation for the full duration of 
the trial, or is not in the best interest of the patient to participate, in the opinion of the treating 
investigator. 
21. Has known psychiatric or substance abuse disorders that would interfere with the patient’s ability 
to cooperate with the requirements of the trial. 
22. Is pregnant or breastfeeding or expecting to conceive within the projected duration of the trial, 
starting with the screening visit through 180 days after last dose of trial treatment. 
23. Has had an allogeneic tissue/solid organ transplant. 
24. Has progressive disease (PD) within six months of completion of curatively intended systemic 
treatment for locoregionally advanced SCCHN. 
9.3 
Patient Withdrawal from Trial Treatment and Withdrawal from Trial Participation  
9.3.1 
Withdrawal from Trial Treatment  
Discontinuation of trial treatment does not represent withdrawal from the trial. See Section 9.3.2 for 
guidance on withdrawal from trial.   
 
A patient must be discontinued from IO102-IO103 and pembrolizumab but may continue to be 
monitored in the trial for any of the following reasons: 
 
• 
Disease progression according to iRECIST.  
NOTE: If the participant is achieving a clinically meaningful benefit, an exemption to continue 
trial treatment may be considered following consultation with the Sponsor. In this case, if trial 
treatment is continued, tumor imaging should continue to be performed following the intervals as 
outlined in schedule of assessments 
• 
The patient becomes pregnant 
• 
Initiation of new anti-cancer treatment  
• 
The patient withdraws consent to further interventional treatment. 
• 
Completion of 35 cycles of administration of trial treatments 

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During the 2-year treatment period, a patient may be withdrawn from IO102-IO103 and 
pembrolizumab, or may continue treatment with pembrolizumab alone or IO102-IO103 alone if the 
investigator considers there is clinical benefit: 
 
• 
The Investigator believes that for safety reasons it is in the best interest of the patient discontinue 
dosing 
• 
The patient is not in compliance with trial treatment administration 
• 
Significant AEs based on the Investigator or Sponsor’s medical director judgment.  
• 
Need for concomitant medication that is not permitted during this trial (see Section 11.7.2) 
• 
The patient wishes to discontinue trial treatment 
• 
Discontinuation of trial treatment may be considered for patients who have attained a confirmed 
CR and have been treated for at least 8 cycles (at least 24 weeks).  
 
Patients are not permitted to be withdrawn from only one of IO102 or IO103 for any reason. 
 
9.3.2 
Patient Withdrawal from Trial Participation  
In accordance with the Declaration of Helsinki (in accordance with the applicable country’s 
acceptance), each patient is free to withdraw from the trial at any time. The Investigator also has the 
right to withdraw a patient from the trial due to non compliance with trial requirements.   
Patients withdrawn from the trial should perform the EOT assessments and post-trial treatment 
(Endpoint FUP) assessments as defined in Table 1 and Table 2. 
 
The primary reason for trial withdrawal should be recorded in the electronic case report form (eCRF). 
Withdrawal due to AEs should be distinguished from withdrawal due to insufficient response.  
Patients withdrawn from the clinical trial due to pregnancy are required to follow the instructions as 
outlined in Section 13.8. 
10 
 Trial Design   
10.1 
Overall Trial Design  
Non comparative, open label, multi-cohort (basket) trial of IO102-IO103 in combination with 
pembrolizumab in 3 indications (NSCLC adenocarcinoma, SCCHN, and mUBC). A clinically 
meaningful efficacy signal will allow  expansion as appropriate. For more details, please refer to 
Section 4.1. 
10.2 
Randomisation or Treatment Allocation  
Not applicable as there is no randomization in the trial. 
10.2.1 Stratification of Patients  
There will be no stratification of patients 

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10.3 
Sample Size  
Approximately 90 patients will be enrolled and treated; approximately 30 patients in each cohort. 
Assuming a screen failure rate of 30%, approximately 130 patients are expected to enter screening. 
10.4 
 Trial Design Flow Diagram   
Figure 2 Trial Flow Diagram  
 
10.5 
Trial Duration and Participating Centres  
The duration of the trial will include a screening phase lasting up to 28 days, a treatment period of 24 
months and a follow-up period lasting until the last patient in has completed the trial treatment plus 
30 days follow up or until PD, death, withdrawal of consent or lost-to-follow-up.  
 
The trial will require approximately 3 years from the time the first patient signs the ICF until the last 
patient last visit.   
 
Approximately 25 sites in 3 to 5 countries are planned to participate in the trial.  
 
The end of trial is defined as the date of last patient last visit. 
 

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10.6 
Schedule of Events  
10.6.1 Screening Assessments and Procedures  
Table 3 Assessments and Procedures in Screening  
Informed Consent 
The patient must be fully informed about the trial and sign the Main 
Informed Consent Form (ICF). The ICF must be signed before any trial 
specific assessments or procedures are conducted. 
 
Demographics 
• Year of birth is to be recorded in the eCRF (date of birth can be recorded 
on samples, vials etc. to facilitate the identification of patient samples). 
• Gender 
• Ethnic origin and race 
• Height (cm) and weight (kg) 
Medical history 
Details of all previous or concomitant conditions or surgical procedures. 
Disease Stage (NSCLC 
adenocarcinoma, UBC or 
SCCHN, previous treatment)  
• Tumor classification 
• Date of first diagnosis  
• Prior treatments, including all surgical or chemotherapy/targeted or 
immunotherapy interventions; date of start/stop, regimen 
administered and response to treatment. 
Pregnancy test 
For WOCBP, a urine pregnancy test must be conducted within 72 hours 
prior to administration of trial treatment. 
If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test (β-hCG) will be required. 
ECOG PS 
ECOG performance status. See Appendix I.  
Tumor imaging 
CT scans of abdomen, chest and pelvis must be done prior to administration 
of trial treatment. A MRI scan can be used if CT contrast is contra-
indicated.  
The same radiographic procedure must be used throughout the trial. 
At screening, a brain scan must be included to exclude active metastases or 
leptomeningeal metastases.  
Clinical disease Assessment 
Disease response is assessed according to RECIST v. 1.1.  
After PD or response per iRECIST, repeat imaging for confirmation is 
required. Repeat imaging between 4 and 8 weeks to confirm PD; and repeat 
imaging at >4 weeks to confirm response 
Tumor tissue biopsy or 
archival tissue sample 
Blood sample and archival tumor tissue sample or newly obtained core or 
excisional biopsy of a tumor lesion not previously irradiated. Formalin-
fixed, paraffin embedded tissue blocks are preferred to slides. 
Used for analysis of PD-L1 (clone 22C3) and immunomodulatory markers 
by multiplexed IHC, immune gene signature, and tumor mutational burden. 
Biomarker blood sampling 
A blood sample for the purpose of assessing biomarkers. 

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PD-L1 status (DAKO 22C3)  
The PD-L1 status of the patient must be evaluated using the PD-L1 IHC 
pharmDx assay. See Section 12.2.4.1. 
Clinical chemistry 
Clinical chemistry parameters to be collected are described in Table 11. All 
screening laboratory assessments must be performed or repeated within 7 
days prior to treatment initiation. 
Haematology 
Haematology parameters to be collected are described in Table 11. All 
screening laboratory assessments must be performed or repeated within 7 
days prior to treatment initiation. 
Urinalysis 
Urinalysis parameters to be collected are described in Table 11.  
Thyroid function tests 
Thyroid Function Test parameters to be collected are described in Table 11.  
Coagulation Tests 
Coagulation Test parameters to be collected are described in Table 11. 
Vital signs 
• Blood pressure (suprine systolic and diastolic) 
• Heart rate 
• Respiration rate 
• Weight 
• Body temperature 
• Height 
Physical examination 
(full) 
A full physical examination of heart, lung, general, skin, oral 
cavity, chest, lymph nodes.  
Any abnormalities should be provided on the Medical History 
record. 
12-lead electrocardiogram 
(ECG) 
Date and time of ECG and interpretation are collected 
Echocardiogram or multi-
gated acquisition (MUGA) 
scan 
Date and time of echocardiogram/MUGA and interpretation are collected 
Concomitant medication 
If the patient is receiving any medication for conditions mentioned on the 
Medical History page, details need to be recorded on the Concomitant 
therapies record. 
Adverse Events 
Record any AEs that have occurred since the date of informed consent, 
including AEs following procedures such as tumor biopsy or blood 
sampling. These AEs will not be considered drug related. 
 
10.6.2 Trial Treatment Period  
The following assessments must be completed during the trial treatment period or at the End of 
Treatment (EoT) visit. 

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Table 4 Assessments and Procedures during Trial Treatment Period  
Assessment  or procedure: 
Trial Treament Period: 
ECOG PS 
Every 9 weeks during the first year of treatment and then every 12 
weeks  
Tumor imaging 
Every 9 weeks during the first year of treatment and then every 12 
weeks for the second year of treatment 
Clinical disease Assessment 
Every 9 weeks during the first year of treatment and then every 12 
weeks for the second year of treatment  
After PD or response per iRECIST 1.1, repeat imaging for 
confirmation is required. Repeat imaging between 4 and 8 weeks to 
confirm PD; and repeat imaging at >4 weeks to confirm response 
Tumor tissue biopsy or archival 
tissue sample 
At week 10 if a suitable lesion is available and patient has consented 
Biomarker blood sampling 
At week 4, 10 and 19 
Clinical chemistry 
All visits except visits 2 and 5 
Laboratory samples can be collected up to 48 hours prior to treatment 
administration and must be known and acceptable prior to dosing. 
Haematology 
At all visits except visits 2 and 5 
Laboratory samples can be collected up to 48 hours prior to treatment 
administration and must be known and acceptable prior to dosing. 
Pembrolizumab (200 mg IV) 
Pembrolizumab will be administered on Day 1 of each 3 week cycle in 
accordance with standard of care 
IO102 (85µg SC) and IO103 (85µg 
SC) 
IO102-IO103 will be administered on Day 1 of each 3 week cycle and 
additionally on day 8 and 29 during the first 2 cycles.  
Urinalysis 
Every 6 weeks before trial treatment 
administration. 
Thyroid function tests 
Every 6 weeks before trial treatment administration. 
Coagulation Tests 
Every 6 weeks before trial treatment administration. 
Vital signs 
• Blood pressure (suprine systolic and diastolic) 
• Heart rate 
• Respiration rate 
• Weight 
• Body temperature  
At all visits except visits 2 and 5. Vital signs must be assessed before 
trial treatment administration. 

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Physical examination 
(full or directed) 
Full physical examination is performed every 12 weeks of heart, 
lung, general, skin, oral cavity, chest, lymph nodes. 
 
Directed physical examination is performed at visit 1, 4, 6 and 12 and 
as clinically indicated to include symptom driven examination. 
12-lead ECG 
Every 12 weeks before trial treatment administration. 
Adverse events 
Any new AEs or changes to existing AEs must be recorded at all 
visits  
Concomitant medication 
Any new concomitant medication or changes to existing concomitant 
medication must be recorded at all visits  
Pregnancy test 
Urine pregnancy tests to be repeated every 3 weeks during the 
treatment period, as well as at EOT.  
If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test (β-hCG) will be required 
Pharmacokinetic blood sampling 
(only applicable to patients who 
have consented to PK blood 
sampling) 
Blood samples for the purpose of measuring drug concentration. 
 
10.6.3 
Post-Trial Treatment Period  
The following assessments and procedures are required every 12 weeks after permanent discontinuation 
of the trial treatments (that is discontinuation of IO102-IO103 and pembrolizumab). 
Table 5 Assessments and Procedures after Discontinuation of Trial Treatments  
Assessment or Procedure: 
Frequency 
Tumor imaging 
Every 12 weeks until disease progression (iRECIST) or death, 
withdrawal of consent, start of new anticancer therapy or end of 
trial 
Clinical disease Assessment 
Every 12 weeks until disease progression (iRECIST) or death 
withdrawal of consent, start of new anticancer therapy or end of 
trial 
Adverse events 
Every 12 weeks 
Subsequent anti-cancer treatment 
Every 12 weeks 
Date of death/Survival follow-up 
Every 12 weeks 
Pregnancy test 
For female patients of childbearing potential a urine pregnancy test is 
mandatory at 120 days after last dose of pembrolizumab.  
If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test (β-hCG) will be required. 
 

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11 
 Trial Treatment   
The trial treatments are IO102-IO103 dual-antigen immunotherapeutic and pembrolizumab. 
 
Pembrolizumab is available as a 100 mg/4 mL solution for injection and may be obtained from 
commercial supplies (and reimbursed by IO Biotech) or provided by IO Biotech. Clinical supplies of 
pembrolizumab provided by Merck Sharp & Dohme, LLC, Rahway, NJ, USA may also be used. The 
contents of the label will be in accordance with all applicable regulatory requirements.  
11.1 
Investigational Medicinal Products  
The investigational medicinal products (IMPs) are outlined in Table 6 and Table 7. Trial treatments 
will be administered after all baseline procedures and assessments have been completed and the 
patients have been confirmed eligible for the trial.  
Table 6 Investigational Medicinal Products Summary  
Product Name & Potency 
Dosage Form 
IO102 
 
Powder for solution for injection 
IO103 
Powder for solution for injection 
Pembrolizumab (MK-3475) 100 mg/vial 
Solution for injection 
Table 7 IO102-IO103 and Pembrolizumab Dose and Schedule  
Drug 
Dose Frequency 
Route of 
Administration 
Regimen 
IO102-IO103  
Day 1 Q3W, with 
additional 
administration on day  
8 during the first 2 
cycles. 
Subcutaneous 
Induction period: Day 1 of each 3 week cycle. 
Additional IO102-IO103 administrations on day 
8 during the first 2 cycles.  
In total 4 injections during the first 2 cycles. 
 
Maintenance period: SC administrations on day 1 
of each 3 week cycle for a max of 33 cycles.  
A total of 37 administrations. 
IO102-IO103 will be administered 1 hour +/- 15 
minutes prior to pembrolizumab. IO102-IO103 
are administered separately in any order. 
Pembrolizumab 
Q3W 
IV infusion 
Day 1 of each 3 week cycle for a max of 35 
cycles (2 years) 
11.2 
Packaging and Labeling  
Labeling will be in accordance with all applicable regulatory requirements. 
 

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11.3 
Storage and Preparation of Trial Treatment  
11.3.1 Storage and Preparation of IO102  
The IO102 drug product is a freeze-dried powder and must be stored according to the instructions in 
the IB. Storage temperature must be monitored.  
IO102 in the form of a freeze-dried powder consists of powder for solution for injection. Before 
administration, IO102 must be reconstituted with water for injection (WFI) and subsequently 
emulsified with an adjuvant Montanide ISA 51 VG (Seppic, France).  
IO102, WFI and adjuvant (Montanide) will be supplied by the Sponsors. Instructions for preparing and 
administering IO102 will be provided in a separate Pharmacy Manual.  
11.3.2 Storage and Preparation of IO103  
The IO103 drug product is a freeze-dried powder and must be stored according to the instructions in 
the IB. Storage temperature must be monitored. 
IO103 in the form of freeze-dried powder consists of powder for solution for injection.  Before 
administration, IO103 must be reconstituted with WFI and subsequently emulsified with the adjuvant 
Montanide ISA 51 VG (Seppic, France).  
IO103, WFI and adjuvant (Montanide) will be supplied by the Sponsor. Instructions for preparing and 
administering IO103 will be provided in a separate Pharmacy Manual.  
11.3.3 
Preparation and Storage of Pembrolizumab  
Refer to the Pharmacy Manual for storage and preparation of pembrolizumab.  
11.4 
Treatment and Dose Schedule  
The trial treatments will be administered after all procedures and assessments have been completed.  
Patients will receive their trial treatment Q3W as described in Table 7. Patients will additionally receive 
IO102-IO103 on day 8 and 29 during the first 2 cycles.  
IO102-IO103 will be administered by SC injection at a dose of 85µg each dose. The injection is made 
by SC administration in the upper arm of the patient (single location, 5 cm [2 inches] apart). Abdomen 
can alternatively be used as injection site in case the patient has reactions from previous injections. 
Pembrolizumab will be administered using IV infusion on Day 1 of each 3-week treatment cycle after 
all procedures and assessments have been completed. Pembrolizumab will be administered as a dose 
of 200 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 and administration of the trial 
treatments. 
11.4.1 
Timing of Trial Treatment Administration  
IO103-IO102 will be administered as two separate SC injections, one hour +/- 15 minutes prior to 
pembrolizumab. IO102-IO103 injections can be administered in any order, however both must be given 
to constitute complete treatment with IO102-IO103. 

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11.4.2 Dose Modification and Toxicity Management Guidelines  
11.4.2.1 
IO102-IO103  
There is currently no information about dose modification or dose delay requirements for IO102-IO103. 
In the situation of toxicity considered related to, or possibly related to IO102-IO103, the investigation 
can consider whether to stop the IO102-IO103 treatment. 
In case of Grade ≥ 3 injection site reactions such as ulceration or necrosis, administration of IO102-
IO103 will stop and no further administration will occur. With the Sponsor’s agreement, the patient can 
continue to receive pembrolizumab if the injection site reaction has improved and there is evidence of 
clinical benefit. 
Treatment with IO102-IO103 or pembrolizumab cannot be re-started once the decision is taken to 
permanently withdraw the patient from trial treatment. 
Management of Injection Site Reactions Associated with IO102-IO103 
Injection site reactions have been experienced by the majority of patients who have received 
treatment with IO102-IO103 (melanoma trial: MM1636; 23/30 [77%] patients), IO102 as 
monotherapy (melanoma trial: MM1304; 6/10 [60%] patients) and IO103 as monotherapy (basal cell 
carcinoma trial: BB1801; 10/10 [100%] patients and myeloma trial: MY0001; 9/10 [90%] patients).  
The majority of the injection site reactions were Grade 1 or 2 in severity, short-term and local at the 
injection site (e.g., injection site tenderness, redness, swelling, itching and granulomas). One patient 
treated with IO102-IO103 experienced a Grade 3 granuloma that required resection. 
Injection site reactions that typically manifested as transient adverse events and in most cases, 
symptoms responded to oral antihistamines, and symptoms remitted after completion of treatment. 
Injection site reactions ≥Grade 2 associated with IO102-IO103 will be documented in the eCRF. Any 
pathology report of a biopsy should be available as a source document. 
It is recommended that oral antihistamines are used to manage local injection site reactions associated 
with IO102-IO103. Local corticosteroid treatment is allowed in the presence of symptoms lasting 
≥48 hours after the IO102-IO103 injection. The medical need to use local corticosteroids over several 
cycles should be discussed with the Sponsor.  
11.4.2.2 
Pembrolizumab   
Immune-related AEs Associated with Pembrolizumab  
Events of special interest include immune related adverse events and infusion reactions. Adverse events 
associated with pembrolizumab exposure may represent an immunologic etiology. These 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 
appropriate treatment is critical to reduce complications.  Based on existing clinical trial data, most 
irAEs were reversible and managed with interruptions of pembrolizumab, administration of 
corticosteroids and/or other supportive care. For suspected irAEs, the investigator will be required to 
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, the investigator may choose to withhold or permanently discontinue pembrolizumab, 

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or administer corticosteroids. Dose modification and toxicity management guidelines for irAEs 
associated with pembrolizumab are provided in the respective SmPC. 
 
Dose Modification and Toxicity Management of Infusion Reactions Related to Pembrolizumab 
AEs associated with pembrolizumab combination exposure, including coadministration with additional 
compounds may represent an immune-related response. These irAEs may occur shortly after the first 
dose or several months after the last dose of pembrolizumab combination 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 trial data, most irAEs were reversible and 
could be managed with interruptions of pembrolizumab combination treatment, 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. Dose modification and toxicity 
management guidelines for irAEs associated with pembrolizumab are provided in Table 8. 
 
Attribution of Toxicity:  
When trial interventions are administered in combination, attribution of an adverse event to a single 
component is likely to be difficult. Therefore, while the investigator may attribute a toxicity event to 
the combination, to IO102-IO103 alone, or to pembrolizumab alone, for adverse events listed in Table 
8, both interventions must be held according to the criteria in Table 8 Dose Modification and Toxicity 
Management Guidelines for Immune-related AEs Associated with Pembrolizumab.  
 
Holding Trial Interventions:  
When trial interventions are administered in combination, if the AE is considered immune-related, both 
interventions should be held according to recommended dose modifications. 
 
Restarting Trial Interventions:  
Participants may not have any dose modifications (no change in dose or schedule) of pembrolizumab 
in this trial, as described in Table 8.  
 
If the toxicity does not resolve or the criteria for resuming treatment are not met, the participant must 
be discontinued from all trial interventions.  
 
If the toxicities do resolve and conditions are aligned with what is defined in Table 8, the combination 
of IO102-IO103 and pembrolizumab may be restarted at the discretion of the investigator. In these 
cases where the toxicity is attributed to the combination or to IO102-IO103 alone, re-initiation of 
pembrolizumab as a monotherapy may be considered after communication with and agreement by the 
Sponsor. 
Table 8 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 dose is not 
≤10 mg/day within 12 weeks of the last pembrolizumab treatment.  
3. 
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 

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4. 
If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to ≤ Grade 1 after 
corticosteroid taper. 

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irAEs 
Toxicity grade 
(CTCAE v. 5.0) 
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 in 
stool with or without 
fever) and of bowel 
perforation (ie. 
peritoneal signs and 
ileus) 
Participants with ≥Grade 2 
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 
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue 
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 

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Type 1 diabetes 
mellitus (T1DM) or 
Hyperglycemia 
New onset T1DM 
or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of b-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 
liothyronine) per 
standard of care 
Monitor for signs and 
symptoms of thyroid 
disorders 
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  

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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. If control achieved or ≤ 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). 

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11.4.3 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 9. 
 

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Table 9 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 for 
≤24 hrs. 
• 
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 trial treatment 
Participant may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of trial 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 trial 
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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11.4.4 Other Allowed Dose Interruption for IO102-IO103 and Pembrolizumab  
IO102-IO103 and pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical or surgical events and/or unforeseen circumstances not related to trial intervention. However, trial 
intervention is to be restarted within 21 days of the originally scheduled dose and within 42 days of the 
previously administered dose, unless otherwise discussed with the Sponsor. The reason for interruption is to 
be documented in the patient's trial record.  
 
11.5 
Compliance Check and Drug Accountability  
11.5.1 IO102-IO103  
The Investigator must ensure that a designated person at the trial site/pharmacy receives the trial treatments 
from the Sponsor and that all such deliveries are: 
• 
Recorded 
• 
Handled and stored safely and properly 
• 
Only dispensed to trial patients according to the protocol 
• 
Returned to distributor if unused. 
The Investigator or designee must keep an inventory and accountability logs for the trial treatments, including 
all IO102-IO103 components. The inventory must include details of receipt and dispensing to the patient, batch 
and identification numbers. Accounting must be made of any treatments deliberately or accidently destroyed. 
Discrepancies between the number of vials received and dispensed must be reconciled and documented. 
Empty, Used Vials 
After completion of accountability logs for the trial treatments, used/partially used vials may be discarded 
locally in accordance with site specific procedures 
 
Unused Vials 
All unused vials must be kept and returned to the storage facility identified by the Sponsor after the 
reconciliation of delivery records with accountability logs by the Site Monitor, unless specific written 
agreement with the Sponsor or designee is in place for local destruction of unused vials. 
All trial supplies are to be accounted for on an accountability log. It is essential that all used and unused 
supplies are retained for verification (by the Sponsor or Sponsor’s representative). The Investigator should 
ensure adequate records are maintained via the accountability log. 
11.5.2 Pembrolizumab  
The Investigator must ensure that a designated person at the trial site/pharmacy handles drug accountability of 
pembrolizumab according to institutional standard operating procedures and policies.. 
11.6 
Unblinding Procedures  
Not applicable as the trial is unblinded. 

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11.7 
Concomitant Medications and Vaccinations (Allowed and Prohibited)  
11.7.1 Allowed Medication and Procedures  
All treatments that the investigator considers necessary for a participant’s welfare may be administered at the 
discretion of the investigator provided they meet the permitted medications criteria (not supplied by the 
sponsor) in keeping with the community standards of medical care.  
 
All concomitant medication will be recorded on the eCRF including all prescription, over-the-counter (OTC) 
products, herbal supplements, and IV medications and fluids. If changes occur during the trial period, 
documentation of drug dosage, frequency, route, and date should also be included on the eCRF. 
All concomitant medications received within 28 days prior to the first dose of trial treatment and up to 30 
days after the last dose of trial treatment should be recorded. Concomitant medications administered beyond 
30 days after the last dose of trial treatment should only be recorded for SAEs and ECIs as defined in Section 
13.3 and 13.7.   
11.7.2 Disallowed Medication and Procedures  
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 trial treatment requires the mutual agreement of the 
investigator, the Sponsor and the participant.  
 
Listed below are specific restrictions for concomitant therapy or vaccination during the course of the trial: 
• 
Antineoplastic systemic chemotherapy or biological therapy  
• 
Immunotherapy not specified in this protocol 
• 
Chemotherapy not specified in this protocol 
• 
Investigational agents other than IO102, IO103 
• 
Radiation therapy, with the following exception: Palliative radiation to non-target lesions is 
permitted.  
• 
Live vaccines within 30 days prior to the first dose of trial treatment and while participating in the 
trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza 
vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal 
influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. COVID-19 
vaccines, in general are not live or attenuated vaccines, and in most cases are permitted. 
Systemic glucocorticoids for any purpose other than to modulate symptoms from an AE that is 
suspected to have an immunologic etiology. The use of physiologic doses of corticosteroids may be 
approved after consultation with the Sponsor. 
Note: Inhaled steroids are allowed for management of asthma.  
Patients who, in the assessment by the investigator, require the use of any of the aforementioned treatments 
for clinical management must be discontinued. 
 

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The Exclusion Criteria describes other medications that are prohibited in this trial. 
 
11.7.3 Diet/Contraception and Other Considerations  
11.7.3.1 
Diet  
Patients should maintain a normal diet unless modifications are required to manage an AE such as diarrhea, 
nausea or vomiting.   
11.7.3.2 
Contraception  
IO102-IO103 and pembrolizumab may have adverse effects on a fetus in utero.    
Participants should be informed that taking the study medication may involve unknown risks to the fetus 
(unborn baby) if pregnancy were to occur during the study. In order to participate in the study, participants of 
childbearing potential must adhere to the contraception requirement from the day of study medication initiation 
(or 14 days prior to the initiation of study medication for oral contraception) throughout the study period up to 
at least 120 days after the last dose of study medication. 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 study.  
According to the Recommendations related to contraception and pregnancy testing in clinical trials v.1.1 dated 
21 Septemeber 2020, developed by the Clinical Trials Facilitation and Coordination Group (CTFG) of 
European Union Heads of Medicines Agencies (HMA), the following definitions and recommendations related 
to contraception and pregnancy testing in clinical trials are used: 
• 
WOCBP: 
Woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming 
post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, 
bilateral salpingectomy and bilateral oophorectomy. 
• 
Postmenopausal state is defined as:  
12 months with no menses without alternative medical cause  
High follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a 
post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. 
However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 
Postmenopausal women and females who are permanently sterilised (bilateral oophorectomy or hysterectomy 
confirmed with medical records of the actual procedure or confirmed by an ultrasound, bilateral salpingectomy, 
vasectomy) do not need to use contraception to be eligible for the trial. 
Based on the recommendations of the Clinical Trials Facilitation and Coordination Group related to 
contraception and pregnancy testing in clinical trials (CTFG, 2020) a WOCBP must use a highly effective 
contraception method. Highly effective contraception have a failure rate of <1% per year and include the 
following: 
• 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulation: 
o Oral 
o Intravaginal 
o Transdermal 

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• 
Progestogen-only hormonal contraception, associated with inhibition of ovulation: 
o Oral 
o Injectable 
o Implantable 
• 
intrauterine device (IUD) 
• 
intrauterine hormone-releasing system (IUS) 
• 
bilateral tubal occlusion. 
• 
vasectomised partner (provided that partner is the sole sexual partner of the WOCBP trial patient and that 
the vasectomised partner has received medical assessment of the surgical success) 
• 
true sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the trial treatments). 
Male patients do not need to use contraception during the trial. 
11.7.3.3 
Use in Pregnancy and Lactating Women  
If a patient inadvertently becomes pregnant while on trial treatment, the patient will be immediately 
discontinued from trial treatment. The site will contact the patient at least monthly and document the patient’s 
status until the pregnancy has been completed or terminated. 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 newborn). 
The trial investigator will make every effort to obtain permission to follow the outcome of the pregnancy and 
report the condition of the fetus or newborn to the sponsor. 
It is unknown whether any of the trial treatments 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, patients who 
are breast-feeding are not eligible for enrollment. 
12 
 Clinical Assessments   
The following sections describe the methods of assessments and list the type of data to be recorded in the CRF. 
A detailed schedule for the different assessments is given in Table 1 and Table 2 (Schedule of Trial 
Procedures). 
12.1 
Eastern Cooperative Oncology Group Performance Scale  
Eastern Cooperative Oncology Group (ECOG) Performance Scale will be recorded at times indicated in 
Table 1 and Table 2. The ECOG Performance Scale is provided in Appendix I. 
 
12.2 
Efficacy Assessments  
12.2.1 Tumor (Disease) Evaluation  
Tumor imaging is strongly preferred to be acquired by computed tomography (CT). Contrast-enhanced 
magnetic resonance imaging (MRI) may be used when CT with iodinated contrast is contraindicated, or 
when mandated by local practice.   
The same imaging technique regarding modality, ideally the same scanner, and the use of contrast should be 
used in a patient throughout the trial 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.  

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Imaging should include at least the chest, abdomen, and pelvis; however, other sites may be imaged at the 
recommendation of the investigator, if clinically applicable. 
 
Tumor images must be sent to the central imaging vendor for collect and hold purposes. A central read of 
images may be performed if a signal of interest is detected in one or more cohorts.  
 
Confirmation of measurable disease based on RECIST v. 1.1 at Screening will be used to determine patient 
eligibility (RECIST 1.1 is detailed in Appendix II). 
All scheduled and unscheduled scans must be submitted to the central imaging vendor for potential external 
independent assessment.     
12.2.1.1 
Initial Tumor Imaging  
Initial tumor imaging at Screening must be performed within 28 days prior to the date of planned first dose 
of trial treatment.  The site trial team must review screening images to confirm the patient has measurable 
disease per RECIST v. 1.1. 
Tumor imaging performed as part of routine clinical management is acceptable for use as screening tumor 
imaging if it is of diagnostic quality and performed within 28 days prior to the date of planned first dose of 
trial treatment 
12.2.1.2 
Tumor Imaging During the Trial Treatment Period  
The first post-baseline imaging assessment should be performed at 9 weeks (±7 days) from the date of first 
dose of trial treatment. Subsequent tumor imaging should be performed every 9 weeks (±7 days) for first 
year on treatment followed by every 12 weeks (±7 days) during the second year on treatment until End of 
Trial or more frequently if clinically indicated. After End of Trial, imaging will continue to be performed 
every 12 weeks (±7 days) until the last patient in has completed 35 treatment cycles or has confirmed disease 
progresssion.  
Imaging timing should follow calendar days and should not be adjusted for delays in cycle starts.  Imaging 
should continue to be performed until disease progression is identified by the investigator.  Imaging should 
not be delayed due to interruptions or delays in the delivery of each cycle or in the event of the extension of 
pembrolizumab cycle intervals.  
Objective response should be confirmed by a repeat imaging assessment. Tumor imaging to confirm PR or 
CR should be performed at least 4 weeks after the first indication of a response is observed. Patients will 
then return to regular scheduled imaging, starting with the next scheduled imaging time point. Patients who 
receive additional imaging for confirmation do not need to undergo the next scheduled tumor imaging if it is 
less than 4 weeks later; tumor imaging may resume at the subsequent scheduled imaging time point.   
Per iRECIST disease progression should be confirmed by the site 4 to 8 weeks after site-assessed first 
radiologic evidence of PD (iUPD) in clinically stable patients. Patients who have unconfirmed disease 
progression may continue on treatment at the discretion of the investigator until progression is confirmed by 
the site, provided they have met the conditions detailed in Section 12.2.3. Patients who receive confirmatory 
imaging do not need to undergo the next scheduled tumor imaging if it is less than 4 weeks later; tumor 
imaging may resume at the subsequent scheduled imaging time point, if clinically stable. Patients who have 
confirmed disease progression by iRECIST, as assessed by the site, will discontinue trial treatment. 
Exceptions are detailed in Section 12.2.3. 

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12.2.1.3 
Tumor Imaging after Discontinuation of Trial Treatment(s)  
For patients who discontinue trial treatment, tumor imaging should be performed at the time of treatment 
discontinuation (±4 week window). If previous imaging was obtained within 4 weeks prior to the date of 
discontinuation, then imaging at treatment discontinuation is not mandatory. For patients who discontinue 
trial treatment due to documented disease progression, this is the final required tumor imaging if the 
investigator elects not to implement iRECIST. 
 
For patients who discontinue trial treatment without documented disease progression, every effort should be 
made to continue monitoring disease status by tumor imaging every 12 weeks until the start of a new 
anticancer treatment, disease progression, pregnancy, death, withdrawal of consent, or the end of the trial, 
whichever occurs first. 
12.2.2 Response Evaluation  
RECIST v. 1.1 will be used to assess 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 progression, and make treatment decisions. Patients are expected to continue 
with the trial treatment until the progressive disease or for another reason as described in Section 9.3.1, such 
as toxicity or completion of trial treatment, etc. This allowance to continue treatment despite initial disease 
progression takes into account the observation that some patients can have a transient tumor flare in the first 
few months after the start of immunotherapy, and then experience subsequent disease response. 
 
If repeat imaging does not confirm disease progression per iRECIST, as assessed by the Investigator, and the 
patient continues to be clinically stable, the regular imaging schedule should be maintained and trial 
treatment may continue. 
 
If repeat imaging confirms disease progression per iRECIST, trial treatment should be discontinued (Section 
9.3.1); however, if the patient is achieving a clinically meaningful benefit, an exception to continue trial 
treatment may be considered following consultation with the Sponsor. In this case, if trial treatment is 
continued, tumor imaging should continue to be performed following the intervals as outlined in Table 1 and 
Table 2. 
12.2.3 Overall Survival  
OS is defined as the duration of time from date of enrollment to death from any cause. After disease 
progression, all patients are expected to be followed every 12 weeks to confirm their survival status. These 
follow-up visits/contacts continue until the last planned overall survival analysis. 
12.2.4 Biomarker Assessments  
12.2.4.1 
Tumor Tissue  
Samples should be obtained and processed according to the Laboratory Manual. 
Samples of formalin-fixed paraffin embedded (FFPE) tumor tissue are required to be provided at screening 
and these can be either archival (within 3 months prior to signing the informed consent form, and in absence 
of adjuvant or neoadjuvant treatment) or newly acquired core, incisional, or excisional biopsy of a tumor 
lesion that was not previously irradiated. Use of archival tissue >3 months old may be considered after 
communication with, and agreement by, the Sponsor. 
FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archival tissue. If 
submitting unstained cut slides, newly cut slides should be submitted to the testing laboratory within 14 days 
from the date slides are cut (details pertaining to tumor tissue submission can be found in the Laboratory 
Manual). 
Biomarkers will be measured from the sample(s) of tumor tissue provided. They will include (but are not 
limited to) biomarkers applicable to all patients (see Table 10). 

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The PD-L1 status can be assessed locally for eligibility and enrollment in the study, but samples (FFPE 
block or slides) are required for central confirmation. Tissue sampling for biomarkers at Week 10 is optional 
and contingent on patient signing biomarker consent form and depends on the presence of a suitable lesion 
Subsequent tissue sampling for biomarkers (Week 10) is voluntary and depends on the presence of a suitable 
lesion. Provision of tissue at this timepoint is not a prerequisite for participation in the trial, however 
sequential biopsies are highly encouraged. 
Table 10 Tumor Tissue Testing and Requirements (All Patients)  
Test 
Local/central 
laboratory 
Number 
of slides 
Schedule 
PD-L1 expression (Dako 22c3 PharmDx) 
Local and central 
confirmation 
3 
Screening 
Analysis of the tumor microenvironment by 
multiplexed analysis of target expression and 
lymphocyte infiltration 
Central 
8 
Screening and 
Week 10 
Tumor Mutational Burden 
Central 
5 
Screening 
 
12.2.4.2 
Blood Biomarkers  
Biomarkers will be analyzed centrally from blood samples and derivatives (whole, serum, plasma, PBMC) 
collected at the timepoints indicated in Table 1. Local PBMC preparation is required unless explicitly 
exempted by Sponsor. Blood biomarkers will include: 
• 
Assessment of peripheral immune cell function (PBMC) and treatment-specific T-cell responses 
• 
Analysis of circulating tumor DNA 
• 
IDO activity (serum/plasma) including kynurenine/tryptophan (Kyn/Trp) ratio.  
• 
HLA typing 
For these assessments, blood sample(s) totaling approximately 60-70 mL will be obtained at Screening and 
Week 4, Week 10 and Week 19, and sent for analysis at a central laboratory. 
Except for PD-L1 analysis used for eligibility and enrollment, all other molecular and cellular analyses are 
for scientific research use only and will not be included in the clinical trial report.  
12.3 
Safety Assessment  
AEs will be assessed using CTCAE v. 5.0. 
12.3.1 Adverse Events  
An AE is the development of an undesirable medical condition or the deterioration of a pre-existing medical 
condition following or during exposure to a pharmaceutical product, whether or not considered causally 
related to the trial treatment. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), 
signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, 
electrocardiogram).  In clinical trials an AE can include an undesirable medical condition occurring at any 
time, including run in or washout periods, even if no investigational medicinal product has been 
administered.  
Adverse events will be monitored from the time that the patient provides written informed consent and 

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throughout the trial duration, until 30 days post last dose of trial treatment and will be elicited by direct, non 
leading questioning or by spontaneous reports.  
Adverse event will be graded and recorded throughout the trial and during the follow-up period according to 
NCI CTCAE (Version 5.0). 
Further details for AE reporting can be found in Section 13. 
12.3.2 Physical Examination  
Full physical examinations will be conducted at times indicated in Table 1 and Table 2. Any clinically 
significant physical examination findings (abnormalities) observed during the screening period should be 
recorded under medical history (if resolved).  Any clinical significant physical examination findings 
observed after the first trial treatment dose will be reported as AEs. Any physical examination findings 
(abnormalities) persisting at the end of the trial will be followed by the Investigator until resolution or until 
reaching a clinically stable endpoint. 
Directed physical examinations will be conducted for cycles that do not require a full physical examination 
as indicated in Table 1 and Table 2 the Investigator or qualified designee will perform a directed physical 
examination as clinically indicated. 
12.3.3 Vital Signs  
Vital Signs include blood pressure, heart rate, respiration rate, weight and temperature. Height will be 
measured at screening only. Vitals signs will be recorded at times indicated in Table 1 and Table 2. The 
method of vital signs assessment must be kept consistent throughout the trial. 
12.3.4 12-Lead Electrocardiogram  
A standard 12-lead ECG will be performed using local standard procedures at times indicated in Table 1 and 
Table 2. Any clinically significant findings at screening should be recorded in medical history. 
12.3.5 Eastern Cooperative Oncology Group Performance Scale  
Eastern Cooperative Oncology Group (ECOG) Performance Scale will be recorded at times indicated in 
Table 1 and Table 2. The ECOG Performance Scale is provided in Appendix I. 
12.3.6 Safety Laboratory Parameters  
12.3.6.1 
Biochemistry, Hematology and Urinalysis  
All safety laboratory analysis will be performed at a laboratory facility local to the trial site. 
Laboratory tests for hematology, biochemistry and urinalysis are specified in Table 11 and the timing is 
specified in Table 1 and Table 2. 
 
All safety screening laboratory evaluations should be performed or repeated within 7 days prior 
to treatment initiation; all other screening assessments are performed within 28 days.  
 
Rescreening is permitted, if applicable and after discussion with the Sponsor. 
 
Laboratory samples can be collected up to 48 hours prior to the scheduled trial treatment and results must be 
known and acceptable prior to dosing.  
 

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12.3.6.2 
Thyriod Function Tests and Coagulation Tests  
Thyroid Function and coagulation tests will be performed locally and are specificed in Table 11, and the 
timing is specified in Table 1 and Table 2.  
 
Laboratory samples can be collected up to 48 hours prior to the scheduled trial treatment and results must be 
known and acceptable prior to dosing.  
 
Table 11 Laboratory Tests  
Hematology 
Chemistry 
Urinalysis 
Other 
Hemoglobin 
Platelet count 
White blood cell (total 
and differential) 
Albumin 
Alkaline phosphatase 
ALT 
AST 
LDH 
Uric acid 
Calcium 
Glucose 
Phosphorus 
Potassium 
Sodium 
Magnesium 
Total bilirubin 
Direct bilirubin if total bilirubin 
is >ULN 
Total protein 
Creatinine+++ 
Urea 
Troponin (Screening only)# 
Blood 
Glucose 
Protein 
Specific gravity 
Microscopic examination (if 
abnormal results noted) 
Creatinine or measured or 
calculated creatinine 
clearance (CrCl) +++ 
 
Urine pregnancy test† 
TSH 
T3 or FT3 
FT4 
Prothrombin time 
(PT INR) 
Partial thromboplastin 
time (activated) aPTT 
Serum β-hCG † 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum 
pregnancy test will be required.   
# Per institutional standard.  
+++ Creatinine can be measured in plasma or serum. Measured or calculated creatinine clearance (CrCl). CrCl should be calculated 
per institutional standard. If no local guideline is available, CrCl should be calculated using the Cockcroft-Gault Method. GFR 
can also be used in place of creatinine or CrCl. 
 
12.3.7 Demographics and Other Baseline Characteristics  
The following will be collected:  
• 
Year of birth  
• 
Age 
• 
Race and ethnic origin 
• 
Gender 
 
12.3.8 Medical History and Concomitant Illness  
The medical history for each patients that has provided written informed consent will be obtained.  Medical 
history will include all active conditions and previous conditions within the last 10 years that are considered 
relevant or clinically significant by the Investigator. 

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12.3.9 Echocardiogram/Multi-Gated Acquisition Scan  
An echocardiogram or MUGA scan will be performed within 7 days prior to treatment initiation. Clinically 
significant findings will recorded as medical history. 
12.3.10 Body Weight and Height  
The trial patients’ body weight and height will be collected.  
12.3.11 Pregnancy Test  
Urine pregnancy test will be collected within 72 hours prior to trial treatment, every 3 weeks during the trial 
treatment, at the End of Treatment, as well at 120 days after the last dose of pembrolizumab. If the urine test 
is positive or cannot be confirmed as negative, a serum pregnancy test (β-hCG) will be required. Women 
with childbearing potential must be willing to use adequate birth control starting from the screening visit and 
through 120 days after last dose of pembrolizumab or 180 days after last dose of treatment with IO102-
IO103.  
12.4 
Pharmacokinetic Assessment  
PK samples will be taken from up to 10 patients at the following timepoints on Day 1 of the first cycle: 
Pre-dose and the following times after IO102-IO103 peptide administration: 15 minutes, 1 hour, 2 hours and 
4 hours post-dose. A separate ICF will be used for this sub-study. Plasma samples will be analyzed using 
liquid chromatography tandem mass spectrometry (LC-MS/MS). 
13 
 Adverse Events   
13.1 
Adverse Event Definitions  
An Adverse Event (AE), an Adverse Drug Reaction (ADR) and a Serious Adverse Event (SAE) are defined 
according to ICH Guideline E2A. AEs will be assessed using CTCAE v. 5.0. 
An AE is any untoward medical occurrence in a patient administered the Trial treatment(s) and which does 
not necessarily have to have a causal relationship with this Trial treatments(s). An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), for example, symptom, or 
disease temporally associated with the use of the Trial treatment(s), whether or not considered related to the 
Trial treatment(s). 
Progression of the cancer under study is not considered an adverse event unless it results in hospitalization or 
death. 
An ADR is any noxious and unintended response to a Trial treatment(s) at least possibly related to any dose 
of the Trial treatment(s).  
An SAE is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening (this refers to an event in which the patient 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 was more severe) 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 

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• 
Is judged medically important (this refers to an event that may not be immediately life-threatening or 
result in death or hospitalization, but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed) 
A non-SAE is any AE that does not meet the definition of an SAE. 
The following will not be considered an AE: 
• 
Pre-planned procedure (documented at Visit 1) unless the condition for which the procedure was 
planned has worsened from the first trial related activity after the patient has signed the informed 
consent form 
• 
Symptoms and events associated with diease progression will not be reported as an adverse event. 
• 
Concomitant illness identified as a result of screening procedures. However, if symptoms are 
worsened and/or become serious, this must be reported as a SAE. 
• 
Hospital admissions for social reasons such as pre-planned cosmetic surgery not associated with the 
underlying disease. 
 
13.2 
Adverse Event Assessment Definitions  
13.2.1 Severity  
The investigator should assess the severity of all AEs according to the following definitions: 
 
Grade 1. Mild: Discomfort noticed, but no disruption of normal daily activity. Prescription drug not ordinarily 
needed for relief of symptom but may be given because of personality of patient. 
Grade 2. Moderate: Discomfort sufficient to reduce or affect normal daily activity. Patient is able to continue 
in study; treatment for symptom may be needed. 
Grade 3. Severe: Incapacitating, severe discomfort with inability to work or to perform normal daily activity. 
Severity may cause cessation of treatment with test drug; treatment for symptom may be given and/or patient 
hospitalized. 
Grade 4. Life-Threatening: Symptom(s) place the patient at immediate risk of death from the reaction as it 
occurred; it does not include a reaction that, had it occurred in a more serious from, might have caused death. 
Grade 5. Fatal: Event caused the death of the patient. 
Note the distinction between seriousness and severity: The term severe is used to describe the intensity of the 
event and a severe event is not necessarily serious. CTCAE v. 5.0 (or later versions if updated) will be used to 
define severity. The seriousness criteria serve as a guide for defining regulatory reporting obligations see 
Section 13.1. 
 
13.2.2 Relationship to Trial Treatment  
Assessment of causality is based on the following considerations: associative connections (time and/or place), 
pharmacological explanations, previous knowledge of the drug, presence of characteristic clinical or 
pathological phenomena, exclusion of other causes, and/or absence of alternative explanations. 
The investigator will be asked to assess causal relationship to each of the trial treatments (pembrolizumab, 
IO102-IO103) according to the following classifications: 
• 
Probably related 
• 
Possibly related 

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• 
Unlikely related 
13.2.3 Outcome  
The investigator will be asked to record the most appropriate outcome of the following: 
• 
Recovered/resolved 
• 
Recovering/resolving 
• 
Not recovered/not resolved 
• 
Recovered with sequelae 
• 
Fatal 
• 
Unknown 
13.3 
Reporting of Adverse Events  
At each visit the patient will be asked about AEs in an objective manner, e.g.: “Have you experienced any 
problems since the last visit?” 
Only medically qualified personnel (investigators) must assess AEs. 
AEs will be assessed according to CTCAE v. 5.0 (or later) and must be reported on the AE form. The diagnosis 
should be recorded, if available. If no diagnosis is available each sign and symptom should be recorded as 
individual AEs. 
All other relevant documents supporting the reported SAE (e.g. diagnostic procedures, hospital records, 
autopsy reports) must be sent using the same method as the reported SAE.  
• 
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. 
The independent ethics committees and regulatory authorities will be notified by the Sponsor or Sponor’s 
delegate of SAEs according to current regulation and local requirements. 
All Suspected, Unexpected Serious Adverse Reactions (SUSARs) are subject to expedited reporting to 
regulatory authorities by the Sponsor or Sponsor’s pharmacovigilance vendor. 

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13.4 
Follow-up on Adverse Events  
All AEs should be followed until they are resolved or stable the patient’s participation in the trial ends, 
whichever comes first. 
SAEs and severe, non-serious AEs considered related to trial drug should be followed on a regular basis 
according to the investigator’s clinical judgment until a final outcome has been established. 
13.5 
Sponsor Responsibility for Reporting SAEs  
The Sponsor is responsible for the ongoing safety evaluation of the trial treatment. 
The sponsor is responsible for the prompt notification to all concerned investigators, the ECs/Institutional 
Review Boards (IRBs) and Competent Authorities where IO102 and/or IO103 studies are ongoing, of 
findings that affect the health of the patients, impact on the conduct of the study or alter the Competent 
Authority’s authorisation to continue the study in accordance with Directive CTR 536/2014 or local law as 
applicable. 
The sponsor has to keep detailed records of all AEs reported to him by the investigators and to perform an 
evaluation with respect to seriousness, causality and expectedness. These records shall be submitted to the 
Competent Authorities in the countries where the clinical study is being conducted, if they so request. 
Each individual AE should be evaluated by the Sponsor, with regard to its seriousness and causal relationship 
to the IMP. The sponsor will assess whether or not the AE is unexpected. 
13.6 
Definition of an Overdose and Reporting of an Overdose  
Overdose will is defined as ≥1,000 mg (5 times the approved dose) of pembrolizumab. 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. 
 
Overdose with IO102-IO103 is unlikely, due to the SC route of administration. There is no information 
available regarding overdose with IO102-IO103. 
13.7 
Events of Clinical Interest  
Selected non-serious and serious adverse events are also known as ECI and must be reported to the Sponsor 
within 24 hours of awareness. 
Events of clinical interest for this trial include:  
• 
An overdose of Sponsor's product, as defined in Section 13.6 that is not associated with clinical 
symptoms or abnormal laboratory results. 
• 
An elevated AST or ALT lab value that is greater than or equal to 3× the upper limit of normal and an 
elevated total bilirubin lab value that is greater than or equal to 2× the upper limit of normal and, at 
the same time, an alkaline phosphatase lab value that is less than 2× 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 trial investigators 

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and the sponsor. However, abnormalities of liver blood tests that do not meet the criteria noted above 
are not ECIs for this trial. 
 
13.8 
Reporting of Pregnancies  
If a participant inadvertently becomes pregnant while on treatment with IO102-IO103 and/or 
pembrolizumab, the participant will be immediately discontinued from study treatment. The site will contact 
the participant at least monthly and document the participant’s status until the pregnancy has been completed 
or terminated. 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 newborn). 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 
newborn to the Sponsor. 
In addition, the investigator must attempt to collect pregnancy information on any female partners of male 
trial patients who become pregnant while the patient is enrolled in the trial. Pregnancy information must be 
reported to sponsor as described above. 
All pregnancies and exposure during breastfeeding, from the time of treatment through 120 days following 
cessation of trial treatment, or 30 days following cessation of trial treatment if the participant initiates new 
anticancer therapy whichever is earlier. 
14 
 Changes to Trial Conduct   
14.1 
 Protocol Amendments   
Before implementation of substantial protocol changes, approval/favorable opinion must be obtained from 
the appropriate national Competent Authority(ies) and IRBs/IECs, unless the amendment is considered an 
urgent safety measure in which case, the amendment will be implemented immediately and before approval. 
Amendments considered administrative or logistical may be implemented without IRBs/IECs or national 
Competent Authority(ies) approval. 
14.2 
Clinical Trial Pausing  
The clinical trial may be paused for reasons considered to change the risk of patients to be entered or already 
entered to the trial. Conditions that may warrant pausing of the clinical trial include, but are not limited to the 
following: 
• 
The death (other than death related to disease progression) of a patient within 30 days of receiving 
trial treatment that is considered at least possibly related to trial treatment. 
14.3 
Premature Termination of the Trial  
In case of premature termination of the trial, Competent Authorities and independent ethics committees will 
be notified in writing, including the reason for premature termination. 
Conditions that may warrant premature termination of the trial include, but are not limited to the following: 
• 
The discovery of an unexpected and significant or unacceptable risk to the patients enrolled in the 
trial 
• 
Failure of the investigators to enroll patients at an acceptable rate in the trial as a whole 
• 
A decision of the sponsor to discontinue development of the IO102-IO103 combination or one of the 
two components of the combination. 

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14.4 
 Premature Termination of a Cohort or Trial Site   
The sponsor can decide to prematurely terminate single cohorts and/or sites. Conditions that may warrant 
termination include, but are not limited to the following: 
• 
Insufficient adherence to protocol requirements 
• 
Failure to enroll patients at an acceptable rate and/or with steering committee agreement 
15 
 Data Handling and Retention of Documents   
15.1 
Source Data  
For all data recorded, the source document must be defined in a source document agreement or similar 
document at each trial site. There must only be one source defined at any time for any data elements. 
Source data should as a general rule be recorded in the patients’s medical record or other defined document 
normally used at the trial site. Source data not normally collected as a routine part of the clinical practice at 
the site may be entered on a worksheet. Clinical assessments/safety evaluations must be signed by medically 
qualified investigators.  
If the worksheet does not become part of the patient’s medical record, the following should as a minimum be 
added to the patient’s medical record: 
• 
Date(s) of conducting the informed consent process (date of enrolment) including date of 
provision of patient information 
• 
A statement from the investigator to verify that each of the eligibility criteria are met for each 
patient 
• 
Patient ID  
• 
Randomisation code number (if applicable) 
• 
The fact that the patient is participating in a clinical trial in NSCLC adenocarcinoma, SCCHN, 
and mUBC including treatment with IO102-IO103 and pembrolizumab for up to 24 months 
• 
Other relevant medical information 
The trial monitor will check the CRFs for accuracy and completeness by verifying data recorded in the CRF 
against source data to ensure such records are consistent.   
15.2 
Coding of Data  
Medical history and AEs will be coded using the most current version of Medical Dictionary for Regulatory 
Activities (MedDRA). 
Concomitant medication will be coded using most current version of WHO Drug Reference List. 
16 
 Retention of Documents   
The monitor will instruct the investigator to maintain source documents and the signed informed consent 
form for each patient. 
Furthermore, the monitor will instruct the investigator to archive essential documents for the duration 
defined in the ICH Guideline E6 (Note for Guidance on Good Clinical Practice) or for 15 years, whichever 
comes first. 
The duration of archiving defined in the ICH Guideline E6 is as follows: 
Essential documents should be retained until at least 2 years after the last approval of a marketing application 
in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational 

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product. These documents should be retained for a longer period however if required by the applicable 
regulatory requirements or by an agreement with the sponsor. 
The sponsor will notify the investigator when retention of the trial-related records is no longer required. 
17 
 Statistical Methods   
All output will be generated for each cohort (NSCLC adenocarcinoma, SCCHN and mUBC). 
The data will be summarized in tables, as appropriate, showing the number of patients with nonmissing data 
(N), mean, standard deviaton, median, minimum and maximum for continous data and showing counts and 
percentage for the categorical data. Data will also be listed as deemed appropriate. 
The Statistical Analysis Plan (SAP) will describe in detail the analyses presented below. 
ORR, CRR and DCR, will be assessed and 95% confidence intervals will be calculated using the Clopper-
Pearson exact methodology. 
PFS rate (PFR) at 6 months as well as the endpoint duration of response with corresponding 95% intervals, 
will be estimated using Kaplan-Meier methods using the treated patient population. 
17.1 
Timing of Analyses  
For each treatment cohort, the primary analysis will be performed 6 months after the last patient started 
treatment. 
Interim analyses for each cohort will be considered after 15 patients are treated with ≥2 cycles in the cohort 
and have either completed at least 2 post-baseline tumor assessments or have discontinued. Details of the 
interim analyses will be defined in the SAP. 
17.2 
Sample Size and Power Considerations  
A minimum of 2 cycles of vaccination is considered necessary to induce benefit over monotherapy 
pembrolizumab; additional patients may be enrolled to ensure at least 30 patients are treated for 2 cycles and 
more. This is an exploratory study and for all 3 cohorts a 1-side 15% significance level is used and sample 
sizes have been considered. 
Cohort A (NSCLC adenocarcinoma PD-L1 TPS ≥50%) 
For patients with PD-L1 TPS ≥ 50% with pembrolizumab, ORR is estimated to be 39% (Mok et al., 2019).  
If the true ORR for IO102-IO103+pembrolizumab is 55% there is a power of 77% to detect a difference 
between 39% and 55% with 30 patients. If there are 17 responders from the 30 patients, the ORR point 
estimate will be 57% and the 95% Clopper-Pearson confidence interval will be 37% - 75%. 
Cohort B (SCCHN, PD-L1 CPS ≥20) 
 
For patients with CPS ≥20 with pembrolizumab, ORR is estimated to 23% (Burtness et al., 2019). 
If the true ORR for IO102-IO103+pembrolizumab is 35% there is a power of 68% to detect a difference 
between 23% and 35% with 30 patients. If there are 11 responders from the 30 patients, the ORR point 
estimate will be 37% and the 95% Clopper-Pearson confidence interval will be 20% - 56%. 
  
Cohort C (mUBC, PD-L1 CPS ≥10) 
 
Patients with CPS ≥10 with pembrolizumab, ORR is estimated to 47% (Vuky et al., 2020). 

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If the true ORR for IO102-IO103+pembrolizumab is 60%  there is a power of 65% to detect a difference 
between 47% and 60% with 30 patients. If there are 18 responders from the 30 patients, the ORR point 
estimate will be 60%, and the 95% Clopper-Pearson confidence interval will be 41% - 77%.  
17.3 
Approach to Endpoint Analyses  
Statistical analyses will be performed on the treated set, including all patients that receive at least one dose of 
IMP, and the minimum exposure set, including all patients that receive at least 2 cycles of IO102-IO103. A 
per-protocol set may be defined prior to database lock for sensitivity analysis of efficacy endpoints. 
17.3.1 Primary endpoint  
The primary endpoint is ORR according to RECIST v. 1.1. 
ORR will be assessed and 95% confidence intervals will be calculated using the Clopper-Pearson exact 
methodology. 
The primary analysis will be based on the treated patient population, but supported with analysis of the 
minimum exposure patient population. 
17.3.2 Other endpoints  
The endpoint of the PFS will be estimated using Kaplan-Meier methods. 
DCR and CRR will be assessed and 95% confidence intervals will be calculated using the Clopper-Pearson 
exact methodology. 
For overall survival the percentage of patients who are alive at 6 monthly intervals after first dose will be 
presented based on the Kaplan-Meier estimates. 
DOR and iPFS will be illustrated using Kaplan-Meier plots with time to censoring marked on the curves. 
Median time of response/median progreesion free time with corresponding 95% CI will be estimated  using 
Kaplan-Meier methods. 
TTR will be presented in a cumulative plot i.e. inverted Kaplan-Meier plot. Time to censoring will be 
marked on the curves and median time to response will be estimated if applicable using Kaplan-Meier 
methods. 
17.4 
Analysis Data Sets  
The following 2 analysis sets will be defined:  
• 
Treated set: patients who receive at least one dose of any study medication.  
• 
Minimum exposure set: all treated patients who did not discontinue IO102-IO103 treatment 
prior to the second dose of Cycle 2 (Day 8 of Cycle 2 administration).  
Additional analysis sets may be defined in the SAP. 
Patients enrolled but not treated will be included in listings and patient profiles only. 

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17.5 
Definition of Efficacy Endpoints  
17.5.1 Primary Endpoints  
ORR is based on disease evaluation done locally for all patients in accordance with RECIST v. 1.1 prior to 
administration of trial treatment and every 9 weeks post baseline the first year of treatment followed by every 
12 weeks until disease progression and is the percentage of patients that has a complete or partial response.  
Response (complete response or partial response) should be confirmed by a repeat imaging assessment. 
Tumor imaging to confirm PR or CR should be performed at least 4 weeks after the first indication of a 
response is observed.   
17.5.2 Secondary Endpoints  
The list of secondary efficacy endpoints evaluated in the trial is 
• 
PFS according to RECIST v. 1.1 
• 
DoR 
• 
CRR 
• 
DCR 
• 
OS 
• 
TTR 
 
17.5.3 Progression Free Survival (PFS)  
PFS is defined as the time from first treatment with IMP to the first documented disease progression (based 
on disease evaluation done locally for all patients in accordance with RECIST v. 1.1) or death from any 
cause. If a patient is not known to have progressed or died then they will be censored at the date of the last 
disease assessment. If a patient progresses after they have 2 or more consecutively missed disease 
assessment visits then they will be censored at the date of the last non missing disease assessment. 
17.5.4 Progression Free Survival according to iRECIST (iPFS)  
PFS is defined as the time from first treatment with IMP to the first documented disease progression (based 
on iRECIST) or death from any cause.  
Per iRECIST disease progression should be confirmed by the site 4 to 8 weeks after site-assessed first 
radiologic evidence of PD (iUPD). The event date used for calculation for progression free survival should 
be the first date when the progression criterion is met (iUPD) providing that progression is confirmed at the 
next assessment (see Appendix II).  
If a patient is not known to have progressed or died then they will be consored at the date of the last disease 
assessment. If a patient progresses after they have 2 or more consecutively missed disease assessment visits 
then they will be censored at the date of the last non missing disease assessment. 
17.5.5 Duration of Response (DoR)  
Duration of response will be measured from the date of first observed objective response until disease 
progression or death (whichever is earlier). Date of progression and censoring will be handled in the same 
way as for PFS (evaluation done locally for all patients in accordance with RECIST v. 1.1). The time of the 
initial response will be defined as the latest of the dates contributing towards the first visit response of PR or 
CR. 

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If a patient does not progress following a response, then their duration of response will use the PFS censoring 
time. 
17.5.6 Complete Response Rate (CRR) and Disease Control Rate (DCR)  
CRR is defined as the number (%) of patients with a visit response of CR. Evaluation of response will be 
done locally for all patients in accordance with RECIST v. 1.1. 
DCR is defined as the number (%) of patients with a visit response of PR or CR or SD. Evaluation of 
response will be done locally for all patients in accordance with RECIST v. 1.1. 
17.5.7 Overall Survival (OS)  
Overall survival is defined as the time from first dose of IMP until death from any cause. Patients not known 
to have died will be censored at the date last known to be alive. After disease progression, all patients are 
expected to be followed every 12 weeks to confirm their survival status. These follow-up visits/contacts 
continue until the last planned overall survival analysis. 
17.5.8 Time to Response (TTR)  
In the subset of responding patients, TTR is defined as the time from first dose of IMP until the date of the 
first observed partial or complete response. Evaluation of response will be done locally for all patients in 
accordance with RECIST v. 1.1. 
17.5.9 ECOG Performance Status  
ECOG performance status is a scale measuring the disease impacts a patient’s daily living abilities. The scale 
takes on the values 0, 1, 2, 3, 4 and 5 and measures the impact from from fully active (equals 0) to dead 
(equals 5). 
17.5.10 Exploratory Endpoints  
Exploratory endpoints are biomarkers, measures of immune markers, Progression Free Survival according to 
iRECIST (iPFS), and ORR and PFS according to independent central review, if applicable. 
 
The presentation of the exploratory endpoints will be described in detail in the statistical analysis plan.  
17.6 
Statistical/Analytical Issues  
17.6.1 Missing Data  
For the assessment of ORR, CRR and DCR, a patient without sufficient tumor assessment data (Not 
Evaluable [NE] as disease response) will be considered as a non-responder. 
Procedures for dealing with missing data will be described in detail in the statistical analysis plan. 
17.6.2 Examination of Subgroups  
Important demographic and baseline value-defined subgroups will be examined and the results presented, 
e.g., comparison of effects by smoking status, age, sex and baseline value. A detailed description will be 
provided in the statistical analysis plan 
17.7 
Safety Analysis  
All safety output will be based on the treated set. 

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17.7.1 Adverse Events  
A treatment emergent adverse events (TEAE) is defined as any event which is not present prior to exposure 
to study medication, and starts no later than 30 days after last trial treatment for non-serious events and no 
later than 90 days after last trial treatment for serious events, or any event already present that worsens in 
either intensity or frequency following exposure to IMP. 
An overview of all AEs including severity, relationship to IMP, serious AEs (SAEs) and AEs leading to 
withdrawals or death will be presented. 
TEAEs will be summarized by system organ class (according to MedDRA current version) and preferred 
term (according to MedDRA current version) displaying number of patients, number and percentage of 
patients having the AE as well as number of AEs. Furthermore, AEs will be summarized according to 
severity, relationship, outcome and seriousness. AEs causing discontinuation of trial treatment will be 
summarized by SOC and preferred term. 
Summaries will be done across all cycles. 
SAEs and AEs leading to withdrawal will be listed and tabulated, if appropriate. 
All data will be listed. 
17.7.2 Electrocardiogram  
ECG assessments will be summarized by visit. 
17.7.3 Vital Signs  
Blood pressure, pulse, temperature and body weight will be summarized by visit. 
17.7.4 Laboratory Safety Assessments  
Laboratory parameters will be graded according to CTCAE grading. CTCAE changes in laboratory 
parameters will be presented by shift tables showing baseline values against values at treatment visits.  
Mean changes from baseline over time will also be summarized and plots produced for each laboratory 
parameter. Plots will show mean and error bars (+/- SE). 
A liver related scatterplot (eDISH plot - part 1) of alanine aminotransferase by bilirubin will be presented. 
All patients with alanine aminotransferase ≥ 3 × ULN and bilirubin ≥ 2 × ULN (eDISH plot - part 2 – 
patients in Hy’s law range, if any) will have their liver parameters presented in a plot by visit and patient. 
17.8 
Pharmacokinetic Analysis  
PK data (drug concentration) will be summarized descriptively. 
18 
 Good Clinical Practice   
This trial will be carried out in compliance with the protocol, GCP, Standard Operating Procedures (SOPs) of 
the CROs and applicable regulatory requirements. 
The investigator agrees, when signing this protocol, to adhere to the instructions and procedures described in 
it, to the principles of Good Clinical Practice and to applicable regulatory requirements. 
 

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19 
 Ethics   
19.1 
Independent Ethics Committees / Competent Authorities  
Before implementing this trial, the protocol, the proposed patient information and patient consent form, and 
other documents as required, will be reviewed by properly constituted Independent Ethics Committees (IECs) 
and by the national Competent Authorities. 
A signed and dated statement that the protocol and patient information and patient consent form have been 
approved by the IECs and regulatory authorities will be obtained before trial initiation. 
For each individual IEC the name and occupation of the chairman and the members of the IEC will be collected 
as well as a statement that the IEC works in accordance with ICH GCP. 
IECs will receive updates on trial progress according to local regulations. 
19.2 
Informed Consent  
The patient’s signed and dated informed consent to participate in the trial will be obtained prior to any trial 
related procedure being carried out. 
Before any trial related procedure the investigator will explain to the potential patient the aims, methods, 
reasonably expected benefits and potential hazards of the trial and any discomfort participation in the trial may 
entail. Patient will be informed that participation in the trial is voluntary and that the patient may withdraw 
from the trial at any time and for any reason. Patient will be informed that if they choose not to participate, 
this will not affect the care the patient will receive for the treatment of his or her disease. Finally, patients will 
be informed that their records may be accessed by health authorities and authorized sponsor staff without 
violating the confidentiality of the patient, to the extent permitted by the applicable laws or regulations. 
All patients will be given opportunity to ask questions and will be given sufficient time to consider before 
consenting. The patients may choose to be accompanied, e.g. by a family member, during the information 
process. After having consented, a copy of the informed consent form will be given to the patient. 
All patients will be asked to consent to the genomic analyses which include at least the following analyses:  
• 
Tumor mutational burden 
• 
Immune gene signatures 
• 
T-cell receptor sequencing  
Patients participating in the PK blood sampling will be required to sign a separate consent form. 
20 
 Audits and Inspections   
A representative of the sponsor may visit the trial sites at any time during the trial or after completion of the 
trial to conduct an audit of the trial. These audits will require access to all trial records, including source 
documents, for inspection and comparison with the CRFs. Patient privacy will, however, be respected. The 
investigator and other trial personnel will be responsible for being present and available for consultation during 
routinely scheduled site audit visits conducted by the sponsor’s representative. 
Similar auditing procedures (inspections) may also be conducted by agents of regulatory health authorities, 
either as part of a national GCP compliance program or to review the results of this trial in support of a 
regulatory submission. The investigator should notify the sponsor’s representative or sponsor immediately, if 
he/she has been contacted by a regulatory agency concerning an upcoming inspection. 
21 
 Monitoring   
Before trial initiation a monitor from sponsor’s representative will review the protocol and the CRF with the 
investigators and their trial personnel. During the trial the monitor will visit the trial site regularly to check the 
completeness of patient records, the accuracy of entries in CRFs, the adherence to the protocol and to GCP, 

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the progress of enrolment and the handling and accounting of the trial treatments. Key trial personnel must be 
available to assist the monitor during these visits. 
The investigator must give the monitor direct access to source data/documents (e.g. relevant hospital or medical 
records) to confirm their consistency with the entries in eCRFs. No information in these records about the 
identity of the patients must leave the trial site. 
If there are institutional restrictions on visitors remote monitoring may be necessary. The procedures associated 
with remote monitoring are discussed in the Monitoring Plan. 
22 
 Reporting of Results   
22.1 
Integrated Clinical Trial Report  
Data will be reported in an integrated clinical trial report in compliance with the requirements of the current 
version of ICH E3: Structure and Content of Clinical Study Report. 
The signatory investigator will review and sign the integrated clinical trial report. 
22.2 
Use of Information  
All unpublished information relating to this trial and/or to the trial drug is considered confidential by the 
sponsor and shall remain the sole property of the sponsor. 
The investigator must accept that the sponsor may use the information from this clinical trial in connection 
with the development of the IMP(s), and therefore, may disclose it as required to other investigators, to 
government licensing authorities, to regulatory agencies of other governments, stock exchange market, and 
commercial partners. 
22.3 
Publication of Results  
Basic information of this trial will be posted by the Sponsor on the website: www.clinicaltrials.gov before the 
first patient enters the trial. 
The sponsor is committed to publishing the trial results, whether positive or negative, in a peer-reviewed 
journal.  
The criteria for authorship as set out by the Committee of Medical Journal Editors (www.icmje.org) will be 
applied. 
The contributorship model will be applied and contributors who do not meet the criteria for authorship will be 
listed in an acknowledgments section with descriptions of the role of each contributor in order to ensure 
indexation in the National Library of Medicine. 
Publications are subject to the following conditions: 
• 
Data are the property of the Sponsor and cannot be published without prior authorization from the 
Sponsor. 
• 
Publications should be drafted with protection of individual privacy, intellectual property and contract 
rights in mind, and also conform to legislation and current national practices in patent and other laws. 
• 
The primary publication (i.e. the results from all centers) should be published before, or in parallel with, 
any secondary publications.  
• 
Publications shall not disclose any Sponsor confidential information or property. 
23 
 Insurance and Liability   
The sponsor has subscribed to an insurance policy covering, in its terms and provision, its legal liability for 
injuries caused to participating patients and arising out of trial procedures performed in accordance this 

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protocol, in accordance with applicable law and with the ICH Guideline E6 (Note for Guidance on Good 
Clinical Practice). 
 
 
 

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24 
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25 
Appendices  
 
APPENDIX I - Eastern Cooperative Oncology Group (ECOG) Performance Score  
Grade 
ECOG Performance status 
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 II - Disease Assessment by RECIST v. 1.1 and Progressive Disease 
Assessment by iRECIST  
RECIST v. 1.1 evaluation and definitions of disease response 
Complete Response (CR) 
Disappearance of all TLs since baseline. Any pathological lymph 
nodes selected as TLs must have a reduction in short axis to <10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of TLs, taking as 
reference the baseline sum of diameters 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD 
Progression of disease (PD) 
At least a 20% increase in the sum of diameters of TLs and an 
absolute increase of at least 5 mm, taking as reference the smallest 
sum on study (this includes the baseline sum if that is the smallest on 
study). 
Not Evaluable (NE) 
Only relevant if any of the TLs were not assessed or not evaluable or 
had a lesion intervention at this visit. Note: if the sum of diameters 
meets the progressive disease criteria, progressive disease overrides 
not evaluable as a TL response 
 
Assessment at Screening and Prior to Disease Progression by RECIST v. 1.1 
Until radiographic disease progression based on RECIST v. 1.1, there is no distinct iRECIST assessment. 
 
Overall visit response algorithm 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No or NE 
CR 
CR 
NA 
No or NE 
CR 
CR 
Non CR/Non PD 
No or NE 
PR 
CR 
NE 
No or NE 
PR 
PR 
Non PD or NE or NA 
No or NE 
PR 
SD 
Non PD or NE or NA 
No or NE 
SD 
NE 
Non PD or NE or NA 
No or NE 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
RECIST v. 1.1 and iRECIST defined disease progression 
Assessment and Decision at RECIST v. 1.1 Progression 
For patientes who show evidence of radiological PD by RECIST v. 1.1 as determined by the Investigator, the 
Investigator may continue the patient on trial treatment until repeat imaging is obtained as described in the 
Table below (that is, using iRECIST for patient management). This decision by the Investigator should be 
based on the patients’s overall clinical condition.  
 

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Disease 
assessment: 
Definition of 
Response 
criteria  
Timing of 
radiological 
assessment 
Key criteria to be met  
At progressive 
disease 
RECIST v. 1.1 Timing 
according to 
the 
radiological 
scan schedule 
At least a 20% increase in the sum of diameters of 
TLs and an absolute increase of at least 5 mm, taking 
as reference the smallest sum on study (this includes 
the baseline sum if that is the smallest on study). New 
lesions and/or unequivocal increase in non-target 
lesions will also contribute. 
 
This is referred to as iUPD (unconfirmed progressive 
disease according to iRECIST) 
At 
confirmation 
progressive 
disease  
 
iRECIST 
At least 4 
weeks, but 
not more than 
8 weeks after 
iUPD 
iCPD (confirmed progressive disease according to 
iRECIST): continued increase in tumor burden where 
RECIST v. 1.1 definitions of progression has been 
met in target, non-target or new lesions. Progression 
in target disease worsens with an increase of at 
least 5mm in the absolute sum and/or unequivocal 
increase in non-target tumor burden and/or 
increase in previously identified new lesions and/or 
further new lesions. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Trial ID: IO102-IO103-022/ 
MK3475-D38 (KN-D38) 
Date: 21-Jun-2024 
Version: 8.0 Final 
Page 99 of 99 
 
 
 
APPENDIX III - Management of Patients During the Coronavirus Disease 2019 
(COVID-19) Pandemic  
The safety and protection of patients from the SARS-CoV-2 virus which causes COVID-19 is a priority.  
 
In general, the risk of COVID-19 for fully SARS-CoV-2 vaccinated patients is considered less than the risk 
of not treating the patient for advanced cancer.  
 
During the COVID-19 pandemic, it is recommended that: 
• 
the overall risk of COVID-19 to the patient is considered (taking into consideration age, vaccination 
status, co-morbidities etc.); 
• 
all patients have a negative PCR or lateral flow test before consent (that is - before starting the 28 
day screening period prior to treatment initiation);  
• 
patients continue to confirm their negative status using either lateral flow or PCR before each 
clinical trial related hospital visit. The Sponsor will reimburse reasonable costs for COVID-19 tests. 
 
Patients who have not yet consented to enter the clinical trial. 
It is recommended to delay patient consent to enter the trial in the situation where either the patient has a 
positive PCR test for COVID-19, or if there is considered to be a COVID-19 outbreak at the hospital site or 
institution. The duration of delay is at the discretion of the investigator or in accordance with the institution’s 
policy, but should be at least 2 weeks. 
 
Patients who have consented to participate in the clinical trial. 
It is recommended that scheduled visit to the hospital and/or administration of IO102-IO103 and/or 
pembrolizumab be delayed for 2 weeks in the situation where a patient reports a positive lateral flow or PCR 
test.  
 
In the situation of a hospital specific COVID-19 outbreak, the visit to the hospital should be delayed until the 
outbreak is curtailed and contingency plans implemented as necessary.  
 
Contingency plans are designed to protect the patient, their family and hospital staff in the situation of a 
COVID-19 outbreak at the hospital and the delay to the scheduled visit likely to be more than 2 weeks. 
Contingency plans can include, but are not limited to: 
• 
Home visits by health care professional(s) (HCP) able to administer IO102-IO103 and conduct 
physical examination and take blood, as per the protocol schedule. 
• 
Telephone contact to discuss AEs and other relevant clinical discussion. 
 
Patients should be asked to return to the hospital for their trial treatment administration and trial specific 
procedures at the earliest opportunity, in accordance with the institution’s policy.  
Reimbursement of reasonable taxi fares and other unplanned expenses will be made by the Sponsor in order 
to avoid public transportation. 
 
For these patients, the delay to the scheduled visit, or home visit by HCP must be documented in the 
patient’s medical notes and identified as a COVID-19 protocol deviation. 
 
Activities such as remote monitoring and remote source data verification (SDV) and maintenance of General 
Data Protection Regulation (UK/EU GDPR) during the COVID-19 pandemic are documented in the 
Monitoring Manual or Monitoring Plan. 

Signature Page for IO102-IO103-022 Protocol Version 8.0 v1.0