Conditions: SCC - Squamous Cell Carcinoma of Skin
Keywords: cSCC metastatic locally advanced
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 30
Healthy volunteers: no

Brief summary:
This is an open-label, "non comparative", non-randomized, Phase II study. Patients will be enrolled in 2 treatment arms

Detailed description:
This is an open-label, non-randomized, Phase II study. Patients will be enrolled in 2 treatment arms (Arm A: Vilobelimab monotherapy; Arm B: Vilobelimab + pembrolizumab combination therapy), both consisting of 2 stages whereas Arm B starts with a safety run in portion. Enrollment follows an optimal Simon's 2-stage design with an interim analysis of treatment response after Stage 1 prior to patient enrollment into Stage 2.

Arm B will start after ≥3 patients have been treated in Arm A and no toxicity concerns have emerged. In a safety run-in part of Arm B, escalating doses of Vilobelimab will be investigated in combination with pembrolizumab in order to identify the maximum tolerated dose (MTD) or recommended Phase II dose (RP2D). Patients will be treated until progression, occurrence of unacceptable toxicity, or treatment discontinuation for any other reason.

Arms:
arm 1: Vilobelimab monotherapy; Vilobelimab monotherapy was administered as a 30-minute (-5 / +10 minutes) intravenous infusion as follows: 800 mg on Days 1, 4, 8, and 15, followed by 1600 mg Q2W starting on Day 22 of Cycle 1 until end of treatment (EOT) arm 2: Vilobelimab + pembrolizumab combination therapy; Vilobelimab was administered as a 30-minute (-5/+10 minutes) intravenous infusion as follows: 400 mg on Days 1, 4, 8, and 15, followed by 800 mg Q2W starting on Day 22 of Cycle 1 until EOT. Vilobelimab treatment was combined with pembrolizumab, administered as a 30-minute (-5/+10 minutes) intravenous infusion at a dose of 400 mg starting at Day 8 of Cycle 1 and then Q6W on Day 1 of each treatment cycle arm 3: Vilobelimab + pembrolizumab combination therapy; Vilobelimab was administered as a 30-minute (-5/+10 minutes) intravenous infusion as follows: 600 mg on Days 1, 4, 8, and 15, followed by 1200 mg Q2W starting on Day 22 of Cycle 1 until EOT. Vilobelimab treatment was combined with pembrolizumab, administered as a 30-minute (-5/+10 minutes) intravenous infusion at a dose of 400 mg starting at Day 8 of Cycle 1 and then Q6W on Day 1 of each treatment cycle arm 4: Vilobelimab + pembrolizumab combination therapy; Vilobelimab was administered as a 30-minute (-5/+10 minutes) intravenous infusion as follows: 800 mg on Days 1, 4, 8, and 15, followed by 1600 mg Q2W starting on Day 22 of Cycle 1 until EOT. Vilobelimab treatment was combined with pembrolizumab, administered as a 30-minute (-5/+10 minutes) intravenous infusion at a dose of 400 mg starting at Day 8 of Cycle 1 and then Q6W on Day 1 of each treatment cycle

Interventions: intervention 1: Vilobelimab intervention 2: Vilobelimab + pembrolizumab combination therapy
Intervention descriptions: intervention 1: Vilobelimab Monotherapy intervention 2: Vilobelimab + pembrolizumab combination therapy

Protocol document:
Prot_SAP_000.pdf: 
 
 
The information contained in this document is confidential and the proprietary property of 
InflaRx. Any unauthorized use or disclosure of such information without the prior written 
authorization of InflaRx is expressly prohibited. 
 
CLINICAL STUDY PROTOCOL 
 
OPEN LABEL, MULTICENTER PHASE II STUDY OF THE C5A-ANTIBODY 
IFX-1 ALONE OR IFX-1 + PEMBROLIZUMAB IN PATIENTS WITH PD-1- OR 
PD-L1-RESISTANT/REFRACTORY LOCALLY ADVANCED OR METASTATIC 
CUTANEOUS SQUAMOUS CELL CARCINOMA (CSCC) 
 
Protocol Number: 
IFX-1-P2.8 
Compound:  
IFX-1 
Phase: 
II 
Indication: 
Locally advanced or metastatic cutaneous squamous 
cell carcinoma (cSCC) 
IND Number: 
EudraCT Number: 
144632 
2020-000864-42 
Sponsor Name and Address: 
InflaRx GmbH 
Winzerlaer Strasse 2 
07745 Jena, Germany 
Version and Date: 
Version 4.0, 12 May 2021 
 
  
 






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Signature of National Coordinating Investigator (if applicable) 
 
Protocol Number: 
IFX-1-P2.8 
Title: 
Open label, multicenter phase II study of the C5a antibody IFX-1 
alone or IFX-1 + pembrolizumab in patients with PD-1 or PD-L1 
resistant/refractory locally advanced or metastatic cutaneous 
squamous cell carcinoma (cSCC) 
 
 
 
Date 
Name: 
 
 
____________________________________________ 
 
 
 
National Coordinating Investigator 
 
 
 
 


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Investigator Protocol Signature Page 
 
Protocol Number: 
IFX-1-P2.8 
Title: 
Open label, multicenter phase II study of the C5a antibody IFX-1 
alone or IFX-1 + pembrolizumab in patients with PD-1 or PD-L1 
resistant/refractory locally advanced or metastatic cutaneous 
squamous cell carcinoma (cSCC) 
 
I have read this protocol and agree that it contains all necessary details for carrying out this study. 
I will conduct the study as outlined herein and will complete the study within the time designated, 
in accordance with all stipulations of the protocol and in accordance with Good Clinical Practice, 
local regulatory requirements, and the Declaration of Helsinki. 
 
 
 
Date 
 
 
 
Name: 
 
___________________________________________ 
 
 
 
Principal Investigator 
 
 


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TABLE OF CONTENTS 
ABBREVIATIONS AND DEFINITIONS OF TERMS ...........................................................11 
1. 
SYNOPSIS ............................................................................................................................14 
2. 
SCHEDULE OF ASSESSMENTS .....................................................................................23 
3. 
INTRODUCTION AND BACKGROUND INFORMATION ........................................26 
3.1. 
Background ........................................................................................................................26 
3.2. 
Study Rationale ..................................................................................................................29 
3.2.1. 
Drug Profiles ...................................................................................................................29 
3.2.1.1. 
IFX-1 ............................................................................................................................29 
3.2.1.2. 
Pembrolizumab ............................................................................................................29 
3.2.2. 
Non-clinical and Therapeutic Studies .............................................................................29 
3.2.2.1. 
IFX-1 ............................................................................................................................29 
3.2.2.2. 
Pembrolizumab ............................................................................................................30 
3.2.3. 
Experience in Humans ....................................................................................................30 
3.2.3.1. 
IFX-1 ............................................................................................................................30 
3.2.3.2. 
Pembrolizumab ............................................................................................................31 
3.2.4. 
Scientific Rationale for the Study ...................................................................................31 
3.2.5. 
Justification for Dose ......................................................................................................32 
3.2.5.1. 
IFX-1 ............................................................................................................................32 
3.2.5.2. 
Pembrolizumab ............................................................................................................34 
3.3. 
Benefit/Risk Assessment ...................................................................................................34 
4. 
OBJECTIVES AND ENDPOINTS ....................................................................................36 
4.1. 
Study Objectives ................................................................................................................36 
4.1.1. 
Monotherapy Arm A .......................................................................................................36 
4.1.2. 
Combination Therapy Arm B .........................................................................................36 
4.2. 
Study Endpoints .................................................................................................................37 
4.2.1. 
Primary Endpoints ..........................................................................................................37 
4.2.1.1. 
Monotherapy Arm A ....................................................................................................37 
4.2.1.2. 
Combination Therapy Arm B ......................................................................................37 
4.2.2. 
Secondary Endpoints ......................................................................................................38 
4.2.2.1. 
Monotherapy Arm A ....................................................................................................38 
4.2.2.2. 
Combination Therapy Arm B ......................................................................................38 
4.2.3. 
Explorative Endpoints.....................................................................................................38 
5. 
STUDY DESIGN .................................................................................................................39 
5.1. 
Overall Design ...................................................................................................................39 
5.1.1. 
Method of Treatment Assignment ..................................................................................41 
5.1.2. 
Blinding ..........................................................................................................................41 
5.2. 
Patient Enrollment .............................................................................................................41 
5.2.1. 
Monotherapy Arm A .......................................................................................................41 
5.2.2. 
Combination Therapy Arm B .........................................................................................42 
5.2.2.1. 
Safety Run-In ...............................................................................................................42 
5.2.2.2. 
Arm B Phase II Portion ................................................................................................42 


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5.3. 
Steering Committee ...........................................................................................................42 
5.3.1. 
Monotherapy Arm A .......................................................................................................43 
5.3.2. 
Combination Therapy Arm B .........................................................................................43 
5.4. 
Patient and Study Completion ...........................................................................................44 
5.4.1. 
End of Treatment Definition ...........................................................................................44 
5.4.2. 
Follow-Up .......................................................................................................................45 
5.4.3. 
End of Study Definition ..................................................................................................45 
5.4.4. 
Consent Withdrawal/Discontinuation of Study Participation .........................................45 
5.4.5. 
Lost to Follow-Up ...........................................................................................................46 
6. 
STUDY POPULATION ......................................................................................................46 
6.1. 
Inclusion Criteria ...............................................................................................................46 
6.2. 
Exclusion Criteria ..............................................................................................................50 
6.3. 
Screening Failures ..............................................................................................................52 
6.4. 
Meals and Dietary Restrictions ..........................................................................................52 
7. 
STUDY DRUG(S) AND ADMINISTRATION .................................................................52 
7.1. 
Investigational Medicinal Product .....................................................................................52 
7.1.1. 
IFX-1 ...............................................................................................................................53 
7.1.1.1. 
Packaging and Labelling of Investigational Medicinal Product ..................................53 
7.1.1.2. 
Storage, Handling, and Accountability ........................................................................53 
7.1.1.3. 
Drug Preparation and Administration Instructions ......................................................54 
7.1.1.4. 
Recall of Investigational Medicinal Product................................................................54 
7.1.2. 
Pembrolizumab ...............................................................................................................54 
7.1.2.1. 
Packaging and Labelling of Investigational Medicinal Product ..................................54 
7.1.2.2. 
Storage, Handling, and Accountability ........................................................................54 
7.1.2.3. 
Drug Preparation and Administration Instructions ......................................................55 
7.1.2.4. 
Recall of Investigational Medicinal Product................................................................55 
7.2. 
Administration and Dosage ................................................................................................56 
7.2.1. 
Treatment Administered .................................................................................................56 
7.2.1.1. 
Monotherapy Arm A ....................................................................................................56 
7.2.1.2. 
Combination Therapy Arm B ......................................................................................57 
7.2.2. 
Treatment Modification ..................................................................................................58 
7.2.2.1. 
Monotherapy Arm A ....................................................................................................59 
7.2.2.2. 
Combination Therapy Arm B ......................................................................................59 
7.2.2.2.1. 
Immune-Related Adverse Events .............................................................................59 
7.2.2.2.2. 
Infusion-Related Reactions .......................................................................................60 
7.2.2.2.3. 
Dose-Limiting Toxicities ..........................................................................................60 
7.2.2.2.4. 
Maximum Tolerated Dose ........................................................................................61 
7.2.3. 
Re-Dosing Criteria ..........................................................................................................62 
7.2.4. 
Treatment Discontinuation Criteria ................................................................................62 
7.2.4.1. 
Monotherapy Arm A ....................................................................................................62 
7.2.4.2. 
Combination Therapy Arm B ......................................................................................63 
7.3. 
Premedication and Postmedication ....................................................................................63 
7.4. 
Concomitant Medication/Treatments.................................................................................64 
7.4.1. 
Prohibited Concomitant Medication/Treatment .............................................................64 
7.5. 
Rescue Medications and Supportive Care .........................................................................65 


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7.6. 
Treatment of Overdose ......................................................................................................65 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..............................................................65 
8.1. 
Baseline Assessments ........................................................................................................66 
8.1.1. 
Medical History (Except cSCC History) ........................................................................67 
8.1.2. 
cSCC (Disease) History ..................................................................................................67 
8.1.3. 
Concomitant Disease ......................................................................................................67 
8.1.4. 
Prior and Concomitant Medication/Treatments ..............................................................67 
8.2. 
Efficacy Assessments.........................................................................................................67 
8.2.1. 
Imaging Requirements ....................................................................................................68 
8.2.2. 
Evaluation of Overall Response .....................................................................................68 
8.3. 
Safety Assessments ............................................................................................................68 
8.3.1. 
Adverse Events Assessments ..........................................................................................68 
8.3.2. 
Clinical Safety Laboratory Assessments ........................................................................69 
8.3.3. 
Vital Signs.......................................................................................................................69 
8.3.4. 
Electrocardiograms .........................................................................................................70 
8.3.5. 
Physical Examination .....................................................................................................70 
8.3.6. 
Immunogenicity ..............................................................................................................70 
8.3.7. 
Survival Status ................................................................................................................70 
8.3.8. 
Antineoplastic Therapies ................................................................................................70 
8.4. 
Pharmacokinetics ...............................................................................................................71 
8.5. 
Pharmacodynamics ............................................................................................................71 
8.6. 
Explorative Biomarkers .....................................................................................................71 
8.7. 
Genetics..............................................................................................................................72 
8.8. 
Quality of Life (EORTC-QLQ-C30) .................................................................................72 
8.9. 
Health Economics ..............................................................................................................72 
9. 
ADVERSE EVENT COLLECTION AND REPORTING ..............................................72 
9.1. 
Duration of Adverse Event Collection and Reporting .......................................................73 
9.1.1. 
Non-serious Adverse Events ...........................................................................................73 
9.1.2. 
Adverse Events of Special Interest (AESI).....................................................................73 
9.1.3. 
Serious Adverse Events ..................................................................................................74 
9.1.4. 
Pregnancies .....................................................................................................................74 
9.1.5. 
Breastfeeding ..................................................................................................................74 
9.2. 
Serious Adverse Event Reporting and Timelines ..............................................................74 
9.2.1. 
Initial Reporting of Serious Adverse Events ..................................................................74 
9.2.2. 
Follow-Up Reporting of Serious Adverse Events ..........................................................75 
9.3. 
Determination of Relationship ...........................................................................................75 
9.4. 
Death Reporting .................................................................................................................76 
9.5. 
Abnormal Laboratory Values/Vital Signs/Electrocardiogram/Physical 
Examination ...........................................................................................................77 
9.6. 
Events to be Handled as Serious Adverse Events ..............................................................77 
9.6.1. 
Overdose Reporting ........................................................................................................77 
9.6.2. 
Pregnancy and Breastfeeding Reporting.........................................................................78 
9.6.3. 
Drug-Induced Liver Injury..............................................................................................78 
9.6.4. 
Suspected Transmission of an Infectious Agent via Study Drug ...................................79 
9.7. 
Adverse Events of Special Interest ....................................................................................79 


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9.7.1. 
IFX-1 ...............................................................................................................................79 
9.7.2. 
Pembrolizumab ...............................................................................................................80 
9.8. 
Reporting to Competent Authorities and Ethics Committees ............................................81 
10. STATISTICAL CONSIDERATIONS ...............................................................................81 
10.1. Sample Size Determination................................................................................................81 
10.2. Analysis Sets ......................................................................................................................81 
10.3. Statistical Analyses ............................................................................................................82 
10.3.1. 
Efficacy Analyses ...........................................................................................................82 
10.3.2. 
Safety Analyses...............................................................................................................84 
10.3.3. 
Exploratory Analyses ......................................................................................................84 
10.3.3.1. Pharmacokinetic Analyses ...........................................................................................84 
10.3.3.2. Immunogenicity Analyses ...........................................................................................85 
10.3.3.3. Quality of Life Analyses ..............................................................................................85 
10.3.3.4. Pharmacodynamic Analyses ........................................................................................85 
10.3.4. 
Interim Analyses .............................................................................................................85 
10.3.4.1. Formal Interim Analysis Based on Simon’s 2-Stage Design.......................................85 
10.3.4.2. Safety Run-In Based on 3+3 Design (Combination Therapy Arm B) .........................85 
11. REFERENCES ....................................................................................................................87 
12. APPENDICES ......................................................................................................................91 
Appendix 1 
Visit Procedures .....................................................................................................92 
Appendix 2 
Clinical Laboratory Tests .......................................................................................96 
Appendix 3 
RECIST ..................................................................................................................97 
Appendix 4 
iRECIST ...............................................................................................................108 
Appendix 5 
Regulatory and Ethical Considerations ................................................................113 
I. 
Regulatory and Ethical Considerations ............................................................................113 
II. 
Financial Disclosure.........................................................................................................113 
III. 
Informed Consent Process ...............................................................................................113 
IV. 
Data Protection.................................................................................................................114 
V. 
Administrative and Committees Structure .......................................................................115 
VI. 
Publication Policy ............................................................................................................115 
VII. 
Dissemination of Clinical Study Information ..................................................................115 
VIII. 
Data Quality Assurance ...................................................................................................116 
IX. 
Source Documents ...........................................................................................................116 
X. 
Study and Site Closure .....................................................................................................116 
Appendix 6 
Adverse Events: Definitions and Procedures .......................................................118 
I. 
Definitions........................................................................................................................118 
II. 
Recording, Evaluation, Follow-Up, and Reporting of an AE, Including AESIs and 
SAEs .....................................................................................................................120 
Appendix 7 
Contraceptive Guidance and Collections of Pregnancy Information ...................123 
Appendix 8 
Treatment Modification Guidelines .....................................................................127 
Appendix 9 
Eastern Cooperative Oncology Group .................................................................131 
Appendix 10 List of Vendors .....................................................................................................132 
 


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LIST OF TABLES 
Table 1 
Schedule of Assessments ..............................................................................................23 
Table 2 
Protocol-Required Safety Laboratory Assessments ......................................................96 
Table 3 
Highly Effective Contraceptive Methods....................................................................124 
Table 4 
Dose Modification and Toxicity Management Guidelines for Immune-Related 
Adverse Events Associated with Pembrolizumab.......................................................127 
Table 5 
Dose Modification and Toxicity Management Guidelines for Infusion-Related 
Reactions Associated with Pembrolizumab or IFX-1 .................................................130 
 
LIST OF FIGURES 
Figure 1 Study Design .................................................................................................................40 
Figure 2 Patient Calendar: Arm A (IFX-1 Monotherapy) ...........................................................57 
Figure 3 Patient Calendar: Combination Arm B (IFX-1 + Pembrolizumab) ..............................58 
 


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ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
Antidrug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
C5aR 
C5a receptor 
CFR 
Code of Federal Regulations 
Cmax 
Peak concentrations 
CR 
Complete response 
cSCC 
Cutaneous squamous cell carcinoma 
CT 
Computed tomography 
Ctrough 
Trough concentrations 
DLT 
Dose-limiting toxicity 
ECG 
Electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group performance status 
eCRF 
Electronic case report form 
EORTC 
European Organisation for Research and Treatment of Cancer 
EOS 
End of study 
EOT 
End of treatment 
FAS 
Full analyses set 
FDG 
Fluorodeoxyglucose 
H0 
Beginning of IFX-1 administration 
HS 
Hidradenitis suppurativa 
IB 
Investigator Brochure 
iCPD 
Confirmed progressive disease 
iCR 
Complete response according to iRECIST 
IEC 
Independent Ethic Committee 
IgG4 
Immunoglobulin G4 
IL 
Interleukin 
IMP 
Investigational medicinal product 
IND 
Investigational new drug 
iPR 
Partial response according to iRECIST 
irAE 
Immune related- adverse event 
IRB 
Independent Review Board 


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iRECIST 
Response evaluation criteria in solid tumors for immune-based 
therapeutics 
iSD 
Stable disease according to iRECIST 
iUPD 
Unconfirmed progressive disease according to iRECIST 
IWRS 
Interactive Web Response System 
Km 
Michaelis constant (substrate concentration at which the reaction rate is 
half of its maximal value; indicates the affinity of an enzyme for a given 
substrate) 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI CTCAE 
National Cancer Institute common terminology criteria for adverse 
events 
NMSC 
Non-melanoma skin cancer 
NOAEL 
No Observed Adverse Effect Level (Highest dose at which there is no 
toxic or adverse effect observed) 
NSCLC 
Non-small cell lung cancer 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PD-1 
Programmed cell death 1 protein 
PD-L1(2) 
Programmed cell death ligand 1 (2) 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PR 
Partial response 
Q2W 
Bi-weekly 
Q3W 
Every 3 weeks 
Q4W 
Every 4 weeks 
Q6W 
Every 6 weeks 
QLQ 
Quality of life questionnaire 
QoL 
Quality of life 
QW 
Weekly 
RECIST 
Response evaluation criteria in solid tumors 
RNA 
Ribonucleic acid 


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RP2D 
Recommended Phase II dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Safety analysis set 
SCC 
Squamous cell carcinoma 
SD 
Stable disease 
SoA 
Schedule of assessments 
TEAE 
Treatment-emergent adverse event 
TME 
Tumor microenvironment 
ULN 
Upper limit of normal 
UV 
Ultraviolet 
uPA 
Urokinase plasminogen activator 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 
 
 


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1. 
SYNOPSIS 
Title of Study:  
Open label, multicenter Phase II study of the C5a-antibody IFX-1 alone or IFX-1 + 
pembrolizumab in patients with PD-1- or PD-L1-resistant/refractory locally advanced or 
metastatic cutaneous squamous cell carcinoma (cSCC) 
Protocol/Study Number: IFX-1-P2.8 
EudraCT Number: 2020-000864-42 
Type of Study: 
Proof of Concept Study 
Indication:  
Locally 
advanced 
or 
metastatic 
cutaneous 
squamous cell carcinoma (cSCC) 
Sponsor: InflaRx GmbH, Winzerlaer Strasse 2, 07745 Jena, Germany 
Study Site(s): 
Approximately 32 sites in approximately 6 countries 
Phase of Development: II 
Objectives: 
Primary Objectives: 
Arm A: 
• 
To assess the antitumor activity of IFX-1 
Arm B: 
• 
To determine the maximum tolerated dose (MTD) or recommended Phase II dose (RP2D) 
• 
To assess the antitumor activity of IFX-1 + pembrolizumab 
• 
To assess the safety profile of IFX-1 + pembrolizumab 
Secondary Objectives: 
Arm A: 
• 
To further assess efficacy of IFX-1 
• 
To assess the safety profile of IFX-1  
• 
To assess the pharmacokinetics (PK) of IFX-1 
• 
To monitor the immunogenicity of IFX-1 
• 
To assess the impact of IFX-1 on quality of life (QoL) 
Arm B: 
• 
To further assess efficacy of IFX-1 
• 
To assess the PK of IFX-1 


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• 
To monitor the immunogenicity of IFX-1 
• 
To assess the impact of IFX-1 + pembrolizumab on QoL 
Methodology:  
This is an open-label, non-randomized, Phase II study. Patients will be enrolled in 2 treatment 
arms (Arm A: IFX-1 monotherapy; Arm B: IFX-1 + pembrolizumab combination therapy), both 
consisting of 2 stages. Enrollment follows an optimal Simon’s 2-stage design with an interim 
analysis of treatment response after Stage 1 prior to patient enrollment into Stage 2. 
Arm B will start after ≥3 patients have been treated in Arm A and no toxicity concerns have 
emerged. In a safety run-in part of Arm B with 3 dose cohorts, escalating doses of IFX-1 will 
be investigated in combination with 400 mg pembrolizumab every 6 weeks [Q6W], in order to 
identify the MTD or RP2D. The MTD or RP2D will be explored in a Phase II portion of Arm B. 
Patients will be treated until progression, occurrence of unacceptable toxicity, or treatment 
discontinuation for any other reason. 
Number of Patients: 
Up to approximately 70 patients 
Study Population: 
Patients must meet all the following criteria at screening and at inclusion to participate in 
the study: 
1. 
At least 18 years of age on day of signing informed consent 
2. 
Patients with biopsy-proven, histologically or cytologically confirmed (a.) locally 
advanced cSCC not amenable for curative treatment or (b.) metastatic cSCC. Patients 
must have been treated with all approved therapies for (a.) inoperable locally advanced 
cSCC contraindicated for radiation therapy or (b.) metastatic cSCC.  
Note: More details defining eligibility of locally advanced cSCC or metastatic cSCC can 
be found in the body text. 
3. 
Patients must have progressed on treatment with an anti-PD1/L1 monoclonal antibody 
(mAb) administered either as monotherapy or in combination with other checkpoint 
inhibitors or other therapies. PD-1 treatment progression is defined by meeting all of the 
following criteria: 
a) Has received ≥2 doses of an anti-PD1/L1 mAb that has been approved for 
treatment of cSCC or any solid tumor 
b) Has demonstrated progressive disease (PD)/confirmed PD (iCPD) after PD-1/L1 
inhibitor treatment as defined by modified response evaluation criteria in solid 
tumors (RECIST) version 1.1/RECIST for immune-based therapeutics 
(iRECIST). The initial evidence of PD is to be confirmed by a second assessment 


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≥4 weeks from the date of the first documented PD, unless there is rapid clinical 
progression. 
c) Disease progression has been documented within 12 weeks from the last dose of 
anti-PD-1/L1 mAb. 
4. 
The PD-1-/PDL1 infusion must have been the most recent treatment for locally advanced 
or metastatic cSCC. 
5. 
Patients must consent to undergo the following biopsies (at each time point a punch 
biopsy of externally visible cSCC lesions or a biopsy of material from accessible 
metastases) for biomarker assessments:  
 
a. 
At baseline, prior to the first administration of the investigational therapy and if 
possible, within 7 days prior to initiation of study treatment administration 
(mandatory for all patients) 
b. For Stage 2 patients only: on Cycle 2 Day 1 (±3 days) (mandatory) 
c. 
For Stage 2 patients only: at the time of CR/iCR/PR/iPR (optional, to be conducted 
only if the investigator considers this biopsy as clinically possible and potentially 
informative)  
d. For Stage 2 patients only: At the time of tumor progression (optional, to be 
conducted only if the investigator considers this biopsy as clinically possible and 
potentially informative).  
For all biopsies intended to analyze biomarkers, it is important to obtain sufficient material 
to conduct the biomarker program, which needs to be the equivalent to a 4 mm x 4 mm 
punch biopsy. If biopsies for biomarkers are not feasible due to the complete absence of 
any suitable cutaneous or metastatic lesions, then this is not an exclusion criterium. 
However, this needs to be documented and confirmed by the investigator.  
The biopsied lesion is not considered a target lesion. 
6. 
Patients must have the following minimum washout before first study treatment 
administration from previous treatments: 
• ≥4 weeks for mAbs, systemic cytotoxic anticancer therapy, treatment with other 
anticancer investigational agents 
• ≥3 weeks for local radiation therapy 
Note: Patients must have recovered from all radiation-related toxicities, not require 
corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted 
for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system 
disease. 
7. 
Eastern Cooperative Oncology Group performance status (ECOG PS) status of ≤1 
Adequate organ function: 
 
 


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System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count 
≥1 500/µL 
Platelets 
≥100 000/µL 
Hemoglobin 
≥9.0 g/dL or ≥5.6 mmol/La 
Renal 
 
Creatinine OR 
Measured or calculatedb creatinine clearance 
(GFR can also be used in place of creatinine 
or CrCl) 
≤1.5 × ULN OR 
≥30 mL/min for patient with creatinine 
levels >1.5 × institutional ULN 
Hepatic 
 
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
patients with total bilirubin levels 
>1.5 × ULN 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN (≤5 × ULN for patients with 
liver metastases) 
Coagulation 
 
International normalized ratio OR PT 
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 
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); 
aPTT=activated partial thromboplastin time; AST (SGOT)=aspartate aminotransferase 
(serum glutamic oxaloacetic transaminase); CrCL=creatinine clearance; GFR=glomerular 
filtration rate; PT=prothrombin time; ULN=upper limit of normal. 
a Note hematology test should be obtained without transfusion or receipt of stimulating 
factors within 2 weeks before obtaining screening blood sample.:  
b CrCl should be calculated per institutional standard. 
8. 
Patient (or legally acceptable representative if applicable) provides written informed 
consent for the study. 
Patients who fulfil any of the following criteria at screening are not eligible to participate 
in the study: 
1. 
Patients with limited cSCC, who do not require systemic therapy 
2. 
Has known active central nervous system metastases and/or carcinomatous meningitis. 
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radiologically stable, i.e., without evidence of progression for ≥4 weeks by repeat 
imaging (note that the repeat imaging should be performed during study screening), 
clinically stable, and without requirement of steroid treatment for ≥14 days prior to first 
dose of study treatment. 
3. 
Has a diagnosis of immunodeficiency or autoimmune disease, or is receiving chronic 
systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or 
any other form of immunosuppressive therapy within 3 weeks prior the first dose of 
study treatment 
4. 
Patients who have a history of (non-infectious) pneumonitis that required steroids or 
have current pneumonitis 
5. 
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., 
cytotoxic -T-lymphocyte-associated antigen 4, OX 40, CD137) and was discontinued 
from that treatment due to a ≥Grade 3 immune-related adverse event (irAE) 
6. 
Has severe hypersensitivity (≥Grade 3) to pembrolizumab or IFX-1 and/or any of their 
excipients or had a severe (≥Grade 3) infusion-related reaction to treatments with other 
mAbs 
7. 
Patients who fulfil inclusion criterion 6 (washout times) but who have not recovered 
from side effects of such therapies 
8. 
Has received a live vaccine within 30 days prior to the first dose of study treatment 
9. 
Patients who have undergone major surgery <4 weeks prior to starting study treatment 
10. 
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: Patients 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. 
11. 
Patients with known ≥Grade 3 (per National Cancer Institute common terminology 
criteria for adverse events [NCI CTCAE] v5.0 criteria) active systemic or cutaneous 
viral, bacterial, or fungal infection 
12. 
Patients with known history of Hepatitis B or C infections or known to be positive for 
Hepatitis B antigen (HBsAg)/ Hepatitis B virus (HBV) DNA or Hepatitis C Antibody or 
RNA.  
13. 
Patients who have a history of human immunodeficiency virus infection 


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14. 
Patients who have a history of interstitial lung disease 
15. 
Patients who have had an allogeneic tissue/solid organ transplant 
16. 
Patients with a history of other malignancies during the past 5 years. Note: The following 
are exempt from the 5-year limit: curatively resected basal cell carcinoma, or carcinoma 
in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially 
curative therapy. 
17. 
Patients who are pregnant or breastfeeding or expecting to conceive or father children 
within the projected duration of the study, starting with the screening visit through 
after the last dose of IFX-1 or 120 days after the last dose of pembrolizumab 
18. 
Women of childbearing potential (WOCBP) who have a positive serum pregnancy test 
result within 7 days before treatment. Note: Post-menopausal women must be 
amenorrheic for ≥12 months to be considered not WOCBP. 
19. 
Male patients and WOCBP who do not agree to practice an effective method of 
contraception during study and
after last dose of IFX-1 or 120 days after 
last dose of pembrolizumab 
20. 
Patients with congestive heart failure, Class III or IV, by New York Heart Association 
criteria 
21. 
Patients with any serious underlying medical condition that would impair their ability to 
receive or tolerate the planned treatment 
22. 
Patients with dementia or altered mental status that would preclude understanding and 
rendering of informed consent document 
Test Product, Dose, and Mode of Administration: 
In treatment Arm A, IFX-1 monotherapy will be administered as a 30-minute (-5/+10 minutes) 
intravenous infusion as follows: 800 mg on Days 1, 4, 8, and 15, followed by 1600 mg Q2W  
starting on Day 22 of Cycle 1 until end of treatment (EOT). 
In treatment Arm B, IFX-1 will be administered as a 30-minute (-5/+10 minutes) intravenous 
infusion as follows: 400 mg (regimen 1), 600 mg (regimen 2), or 800 mg (regimen 3) on Days 1, 
4, 8, and 15, followed by 800 mg Q2W (regimen 1), 1200 mg Q2W (regimen 2), or 1600 mg 
Q2W (regimen 3) starting on Day 22 of Cycle 1 until EOT. IFX-1 treatment will be combined 
with pembrolizumab, administered as a 30-minute (-5/+10 minutes) intravenous infusion at a 
dose of 400 mg starting at Day 8 of Cycle 1 and then Q6W on Day 1 of each treatment cycle. 
IFX-1 infusion will start 60 minutes (±10 minutes) after the pembrolizumab-infusion has been 
finished.  
For those patients receiving less than 1600 mg IFX-1 Q2W (regimen 1 and 2) the dose of IFX-
1 may be increased to 1600 mg Q2W at the discretion of the investigator and after consultation 


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with the sponsor as soon as the safety of this dose will have been confirmed in at least 3 patients 
receiving 1600 mg Q2W (regimen 3). 
Treatment will be continued until either disease progression is diagnosed, unacceptable toxicity 
occurred, or treatment has been administered for approximately 2 years. 
Reference Therapy, Dose, and Mode of Administration: 
NA 
Study Duration: 
The expected duration of the study from “first patient first visit” to “last patient last follow-up 
visit” is 3 years. 
 
Criteria for Evaluation 
Primary Endpoint: 
Arm A: 
• 
Investigator assessed best overall response rate (ORR) for IFX-1, with response being 
defined as best response of CR/confirmed CR (iCR) or PR/confirmed PR (iPR) per 
modified RECIST v1.1/iRECIST 
Arm B: 
• 
Frequency of dose-limiting toxicities (DLTs) by dose cohort 
• 
Investigator assessed best ORR for IFX-1 + pembrolizumab, with response being defined 
as best response of CR/confirmed CR (iCR) or PR/confirmed PR (iPR) per modified 
RECIST v1.1/iRECIST 
• 
Frequency, severity, and investigational new drug (IND) attribution of treatment-emergent 
adverse events (TEAEs) and serious adverse events (SAEs) according to Medical 
Dictionary for Regulatory Activities (MedDRA) coding (version valid at time of reporting) 
and the NCI CTCAE grading system (version 5.0, 27 November 2017) 
Secondary Endpoints: 
Arm A: 
• 
Response (CR/iCR/PR/iPR) and stable disease (SD) duration 
• 
Disease control rate (CR/iCR+PR/iPR+SD) 
• 
Progression-free survival (PFS) 
• 
Overall survival (OS) 
• 
Frequency, severity, and IND attribution of TEAEs and SAEs according to MedDRA 
coding (version valid at time of reporting) and the NCI CTCAE grading system v5.0 
• 
Post infusion maximum (Cmax) and trough concentration (Ctrough) of IFX-1 
• 
Development of human antidrug antibodies (ADAs) against IFX-1 


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• 
Changes in QoL as per the European Organisation for Research and Treatment of Cancer 
(EORTC)-QoL questionnaire (QLQ)-C30 total score 
Arm B: 
• 
Response (CR/iCR/PR/iPR) and SD duration 
• 
Disease control rate (CR/iCR+PR/iPR+SD) 
• 
PFS 
• 
OS 
• 
Cmax, and Ctrough of IFX-1 
• 
Development of human ADAs against IFX-1 
• 
Changes in QoL as per the EORTC-QLQ-C30 total score 
Statistical Methods: 
Efficacy: All efficacy analyses will be performed on the full analysis set. All analyses will be 
conducted separately by treatment arm. Patients will be analyzed descriptively and stratified by 
locally advanced or metastatic cSCC. The 2 treatment arms will be compared descriptively. 
For investigator assessed- ORR (primary efficacy variable), number and percentage of 
responders will be displayed per treatment arm along with its 95% confidence interval according 
to Clopper-Pearson. 
Statistical inference will be based on the thresholds defined by the Simon’s 2-stage design. At 
the final analysis, the null hypothesis of an ORR of ≤5% will be rejected if >3 patients out of a 
total of 29 patients respond (CR/iCR/PR/iPR). In the case of dropouts, appropriate statistical 
methods will be applied to correct for the deviation from the planned sample size.  
Number and percentage of patients per RECIST tumor response category will be displayed for 
each scheduled tumor assessment time point.  
Safety: All safety analyses will be performed on the safety analysis set. 
Number of TEAEs, SAEs, and adverse events of special interest (AESIs) with a MedDRA 
System Organ Class and Preferred Term will be assessed. Number and percentage of patients 
with a TEAE, SAE, or AESI for IFX-1 (Arm A) and for IFX-1 and pembrolizumab (Arm B) 
will be assessed. 
Where adverse events (AEs) are grouped by NCI CTCAE grade or relationship, the maximum 
grade/relationship per patient and class of AE will be considered. Analyses will be performed 
for the treatment period and the follow-up period separately.  
Safety laboratory, vital signs, and 12-lead electrocardiogram parameters will be analyzed by 
summary statistics for absolute values and changes from baseline by visit. Shift tables 
comparing baseline and the worst post-baseline assessment will be prepared if applicable. 
Categorical safety parameters will be summarized by absolute and relative frequencies by time 
point. 


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Pharmacokinetics and pharmacodynamics: Actual PK sampling times will be determined, and 
IFX-1 plasma concentration assessed by time point. Summary statistics will be provided for the 
PK concentrations of IFX-1 at all measured time points including the geometric mean and its 
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(1) 
Screening: ≤4 weeks prior to the first administration of IFX-1. 
(2) 
End of treatment (EOT) Visit to be performed 30 days after the last IFX-1 or pembrolizumab administration or before the patient starts on another antineoplastic therapy, whichever occurs earlier. 
(3) 
Locally advanced cSCC patient to provide archived or newly obtained tumor material for central pathology review for confirmation of diagnosis of cSCC. 
(4) 
Disease/Response assessment according to modified response evaluation criteria in solid tumors (RECIST) version 1.1/RECIST for immune related therapeutics (iRECIST) (magnetic resonance 
imaging, computed tomography (CT), or CT scan with contrast, of chest, abdomen, pelvis (and other regions where metastases are suspected). Standardized medical photography of ≥1 index skin 
tumor must be added. Re-assessments must be made with the same imaging technique as used at baseline. Imaging will also be performed at time of complete response (CR) confirmation. 
Response assessments to be performed ±7 days. In case patients experience a partial response (PR)/confirmed PR (iPR) or CR/confirmed CR (iCR) that lasts ≥1 year, imaging frequency can be 
decreased to every other cycle. 
(5) 
IFX-1 administration by intravenous route as 30-minute (-5/+10 minutes) infusion, followed by at least 60 minutes of observation. Start of administration should be seen as “H0”. 
(6) 
Pembrolizumab administration ends 60 minutes (±10 minutes) before IFX-1 infusion start. Pembrolizumab by intravenous route as 30-minute (-5/+10 minutes) infusion, followed by at least 60 
minutes of observation.  
(7) 
Vital signs: heart rate, blood pressure (diastolic and systolic), body temperature, and respiratory rate to be performed at each visit, at pre-dose, and H0+1h (±5 minutes) on the days of administration 
and whenever medically indicated 
(8) 
FU every 3 months until 12 months after EOT Visit. All adverse events (AEs) with onset during treatment until EOT Visit will have to be followed until the outcome of the event is “recovering” (for 
chronic conditions) or until the end of study (EOS = last FU), and until all queries related to these AEs have been resolved. New related serious adverse events (SAEs) with onset during the follow 
up period (from the EOT Visit until the EOS) will have to be collected. FU visits may occur by telephone contact, if applicable. 
(9) 
12-lead electrocardiogram (ECG): at screening, on C1D1 pre-dose and at H0+1 (±5 minutes), on C2D1 at H0+1 (±5 minutes), and at the EOT Visit 
(10) Hematology: red blood cells (RBC), white blood cells (WBC) with differential count, platelet count, hemoglobin, mean corpuscular volume (MCV) and hematocrit 
(11) Biochemistry: sodium, potassium, calcium, magnesium, alkaline phosphatase (ALP), total bilirubin, lactate dehydrogenase (LDH), aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase (AST [SGOT]), alanine aminotransferase (serum glutamic pyruvic transaminase) (ALT [SGPT]), glucose, total proteins, albumin, urea, uric acid, creatinine, and C reactive protein 
(CRP). 
(12) Coagulation: activated partial thromboplastin time (aPTT), prothrombin time (PT). 
(13) Urine analysis: PH, glucose, leucocytes, proteins, blood.  
(14) Preferably Total T3, Free T4 should be analyzed, or other T3/T4 fractions (depending on local standards). 
(15) Pregnancy testing (WOCBP: women of childbearing potential only): During screening: serum beta-human chorionic gonadotropin test within 72 hours before first drug administration. During 
treatment period: urine pregnancy test. During FU urine pregnancy test on the first FU visit for Arm A, on the first FU visit and 120 days after the last dose of pembrolizumab for Arm B 
(16) Complement: C5a to be performed at pre-dose during treatment period.C3a to be performed only at C1D1 [pre-dose] 
(17) Antidrug antibodies (ADAs) against IFX-1 to be performed at pre-dose during treatment period.  
(18) Pharmacokinetics: To be performed at pre-dose during treatment period and in addition at the end of infusion H0+0.5h (-5/+10 minutes, but not before the end of IFX-1 administration) on Cycle 1 
Days 1 and 22. 
(19) Punch biopsies (skin lesion, whenever possible) and biopsy of a metastasis (only if punch biopsy of a skin lesion is not possible) are to be obtained at screening (all patients) and at C2D1 (+/- 2 
days; only patients in Stage 2). Sampling must be obtained at minimal clinical risk from an area that has not been previously irradiated. Additional optional biopsies should be obtained from patients 
enrolled in Stage 2 at the time of CR/iCR/PR/iPR and/or Progressive Disease is diagnosed.    


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3. 
INTRODUCTION AND BACKGROUND INFORMATION 
3.1. 
Background 
Non-melanoma skin cancer (NMSC) is the most frequent malignant neoplasm in white 
populations, with dramatically increasing incidence rates over the last decades (Eigentler et al., 
2017).  
A systematic analysis for the global burden of disease study revealed 7.7 million (95% uncertainty 
interval, 5.3-10.6 million) incident cancer cases of NMSC worldwide with 65,000 cancer deaths 
in 2017. Among cases of NMSC, 1.8 million were identified worldwide cases of squamous cell 
carcinoma (SCC; Fitzmaurice et al., 2019). 
Cutaneous SCC (cSCC) is a common skin cancer characterized by the malignant proliferation of 
keratinizing cells of the epidermis or its appendages. cSCC usually arises from precursor lesions 
such as actinic keratosis, and Bowen’s disease (SCC in situ) but can also grow de novo or on 
irradiated skin with or without manifestations of chronic radio dermatitis, or on chronically 
inflamed skin such as in chronic wounds or chronic inflammatory skin disorders (Stratigos et al., 
2015). 
The pathogenesis of cSCC is multifactorial and includes many extrinsic and intrinsic factors. The 
most important extrinsic factor is generally recognized to be ultraviolet (UV) sunlight exposure. 
As lifetime UV exposure increases, so does the incidence of cSCC. Other extrinsic factors that are 
related to the development of cSCC are industrial carcinogens, such as pitch, tar, or fuel oil 
(Shulstad and Proper 2010). Some targeted anticancer therapies, such as inhibitors of B-raf protein, 
can promote eruptive cSCC via other mechanisms, i.e., by boosting the effect of pre-existing 
mutations in chronically sun-exposed areas (Boussemart et al., 2013). Intrinsic factors associated 
with cSCC include age, lighter skin pigmentation, scars, dermatoses associated with 
photosensitivity (chronic cutaneous lupus), ulcerations, and lichen planus (Shulstad and Proper 
2010). cSCC is rare under the age of 45, its incidence dramatically increasing with age (Stratigos 
et al., 2015). It is also very prevalent in patients who are immunosuppressed and these patients 
experience higher recurrence rates and decreased survival (Manyam et al., 2017). 
In contrast to basal cell carcinoma, which very rarely metastasizes, cSCC has the potential to 
metastasize initially to regional lymph nodes and subsequently to distant sites. The rate of 
metastasis in cSCC has been estimated to range from 2% to 5%. While its distant metastatic 
potential is comparatively low, the presence of distant metastasis is associated with a dismal 
prognosis and a median survival of less than 2 years. Thus, it is crucial to preserve the general high 
chances of cure of cSCCs by a careful evaluation and proper early management of all cases. The 
potential aggressiveness of this tumor should not be underestimated (Stratigos et al., 2015). 


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Clinical Presentation and Prognosis 
The most common clinical appearance of invasive cSCC is an actinic keratosis that becomes 
hyperkeratotic or its base becomes infiltrated, or else becomes tender or ulcerated (Stratigos et al., 
2015). While most cSCCs will arise in the context of actinic keratosis, the rate of transformation 
of actinic keratosis into invasive cSCC is apparently low, at least in a few years period of follow-
up (<1/1000 cases per year during a 5-year follow-up) (Marks et al., 1988; Werner et al., 2013). 
Notably, the progression appears to be more frequent in actinic keratosis harboring persistent beta 
papilloma virus infections (Stratigos et al., 2015). 
When the tumor arises de novo or the early keratosis phase is lacking, cSCC can present as an 
asymptomatic small plaque or nodule that enlarges over time. It can become crateriform 
(‘keratoacanthoma-like’), ulcerated, necrotic, or botryomycotic. Alternatively, patients may 
present with a flat ulcer with a raised border (Stratigos et al., 2015). 
The potential for local recurrence or metastasis of cSCC varies with the pathologic variant, 
localization of the primary lesion, perineural invasiveness, and differentiation grade (verrucous, 
spindle, desmoplastic, acantholytic, or adenosquamous) (National Comprehensive Cancer 
Network [NCCN] Guideline on Squamous Cell Skin Cancer version 1.0, 2020; Stratigos et al., 
2015). 
Overall, advanced SCC has a dismal prognosis and 10-year survival rates are less than 20% for 
patients with regional lymph node involvement and less than 10% for patients with distant 
metastases (Hillen et al., 2018). Patients with distant metastases have median survival of less than 
2 years (Stratigos et al., 2015). 
Treatment of the Disease 
The goals of primary treatment of cSCC are the cure of the tumor and the preservation of function 
and cosmesis.  
The primary treatment for cSCC is usually surgical excision with predetermined margins; 
however, other locally destructive techniques (e.g., cryotherapy or electrodessication and 
curettage, non-surgical treatments including topical imiquimod, and photodynamic therapy) can 
be employed as indicated, especially for smaller lesions (Stratigos et al., 2015; NCCN 2020).  
A small percentage of cSCC cases is recalcitrant to surgical therapies and may display aggressive 
biology with local recurrences and/or lymphatic spread (Hanlon, 2013). In clinics, of the total of 
patients requiring systemic therapy, approximately 50% have locally advanced and 50% 
metastasized cSCC (Hillen et al., 2018).  


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In the presence of clinically detectable nodal disease, regional lymph node dissection is 
recommended (Stratigos et al., 2015). Guidelines also recommend that adjuvant or post-operative 
radiotherapy can be considered where there is substantial perineural involvement, when tissue 
margins are not tumor-free after surgical excision, and in the presence of regional disease (NCCN 
2020; SIGN, 2014; Stratigos et al., 2015). The NCCN guideline suggests that adding radiotherapy 
to lymph node dissection improves disease-free survival (NCCN 2020). Evidence on the use of 
systemic chemotherapy, either alone or in combination with radiotherapy, in the management of 
cSCC comes mainly from small case series (SIGN, 2014). Agents that have been used include 
cisplatin, or carboplatin, 5-fluorouracil, bleomycin, methotrexate, adriamycin, taxanes, 
gemcitabine, ifosfomide, vindesine, mitomycin C, interferon, or doxorubicin (SIGN, 2014; 
Stratigos et al., 2015). However, responses are mostly short lived and do not lead to a curative 
effect (Stratigos et al., 2015). The NCCN guideline mentions cisplatin (either alone or in 
combination with 5-fluorouracil) or carboplatin as chemotherapeutic options for some patients 
with inoperable or incompletely resected regional disease, although data supporting their efficacy 
for this indication are limited (NCCN 2020). 
In 2018, the antiprogrammed cell death 1 protein (PD-1) antibody cemiplimab was the first drug 
that has been approved for the treatment of locally advanced and metastatic cSCC in the United 
States. Approval was granted based on single arm, Phase II studies showing an unprecedented 50% 
overall best response in both disease stages (Migden et al., 2018). In the European Union, 
cemiplimab was authorized in June 2019 for the treatment of adult patients with metastatic or 
locally advanced cSCC who are not candidates for curative surgery or curative radiation. However, 
patients who do not respond to cemiplimab have no effective treatment options and a dismal 
prognosis with a median overall survival (OS) of <1 year.  
The importance of anti-PD-1 antibodies has been further supported by data on treatment with the 
PD-1 inhibitor pembrolizumab. A Phase II study with pembrolizumab on 39 patients with 
unresectable cSCC, with no prior systemic treatment and a median age of 80 years, showed a 
response rate of 42% and a median progression-free survival (PFS) of around 7 months (reviewed 
in Ascierto and Schadendorf, 2019).  
On June 24, 2020, the Food and Drug Administration of the USA approved pembrolizumab 
(KEYTRUDA, Merck & Co., Inc.) for patients with recurrent or metastatic cutaneous squamous 
cell carcinoma (cSCC) that is not curable by surgery or radiation.  
For patients who have progressed on PD-1 therapies no satisfactory, efficacious treatment is 
available. 


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3.2. 
Study Rationale 
3.2.1. 
Drug Profiles 
3.2.1.1. 
IFX-1 
IFX-1 is a novel immunoglobulin G4 (IgG4) monoclonal antihuman C5a -antibody, which 
specifically binds to the soluble human complement split product C5a. IFX-1 has been 
demonstrated to block C5a-mediated biological effects with high efficacy in vitro. C5a is one of 
the most potent inflammatory factors, triggering innate immune responses and bridging to adaptive 
immune responses (Dunkelberger and Song, 2010). In blood, C5 is cleaved to C5a by components 
of the classical and alternative complement pathway, and the coagulation pathway, whereas in 
tissue, factors of the alternative complement and the coagulation pathway factors play a major role 
in C5a generation (Hess and Kemper, 2016). 
3.2.1.2. 
Pembrolizumab 
Pembrolizumab is a potent humanized IgG4 monoclonal antibody (mAb) with high specificity of 
binding to the PD-1 receptor, thus inhibiting its interaction with programmed cell death ligand 1 
(PD-L1) and programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD-1. Pembrolizumab 
has an acceptable preclinical safety profile and is in clinical development as an intravenous 
immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) is indicated for the 
treatment of patients across a number of indications. For more details on specific indications and 
detailed background information refer to the Investigator’s Brochure (IB). 
3.2.2. 
Non-clinical and Therapeutic Studies 
3.2.2.1. 
IFX-1 
Non-clinical studies were conducted to assess pharmacological and toxicological aspects of IFX-1 
and showed that IFX-1 was able to rapidly bind to its target, the human C5a, and achieve an almost 
complete blockade of C5a-induced biological effects. At the same time, cleavage of C5 and 
formation of the complement membrane attack complex was not disrupted in vitro. 
IFX-1 did not demonstrate any cross-reactivity or bioactivity in species other than humans and 
non-human primates (Section 4.2 of the IB). Therefore, toxicology studies were only conducted in 
cynomolgus monkeys. None of the Good Laboratory Practice-compliant studies in cynomolgus 
monkeys revealed relevant toxicological or safety concerns for IFX-1. During single-dose and 
repeat-dose administration of IFX-1 at doses of up to
mg/kg body weight in cynomolgus 
monkeys no direct IFX-1-related toxicological or adverse findings within an extended core battery 
of safety pharmacology assessments were observed. Results showed dose-related increases in 
systemic and maximum exposure in the investigated dose range of
mg/kg body weight. 
Antidrug antibodies (ADAs) were detected in
animal in the 26-week repeat-dose study. 
 
died, most likely because of an ADA-mediated immune complex formation. 


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An overview of the non-clinical toxicology studies that were conducted with IFX-1 is available in 
Table 8 of the IB. 
For further details refer to Section 4 of the IB. 
3.2.2.2. 
Pembrolizumab 
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of -tumor-specific CD8+ T cells and ultimately 
leads to tumor rejection, either as a monotherapy or in combination with other treatment 
modalities (Hirano et al., 2005; Blank et al., 2004; Weber, 2010; Strome et al., 2003; Spranger 
et al., 2014; Curran et al., 2010; Pilon-Thomas et al., 2010). Anti-mouse PD-1 or antimouse 
PD-L1 antibodies have demonstrated anti-tumor responses in models of SCC, pancreatic 
carcinoma, melanoma, acute myeloid leukemia, and colorectal carcinoma (Strome et al., 2003; 
Curran et al., 2010; Pilon-Thomas et al., 2010; Nomi et al., 2007; Zhang et al., 2004). In such 
studies, tumor infiltration by CD8+ T cells and increased interferon gamma, 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 et al., 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. 
For further details refer to the IB. 
3.2.3. 
Experience in Humans 
3.2.3.1. 
IFX-1 
IFX-1 is being developed for the treatment of inflammatory diseases. Five clinical studies in 
humans have been completed so far. One Phase I study in healthy volunteers (Study IFX-1-P1.1) 
and four Phase II studies; one study in patients with early septic organ dysfunction (Study IFX-1-
P2.1), one study in patients undergoing complex cardiac surgery (Study IFX-1-P2.2), and two 
studies in patients with hidradenitis suppurativa (HS; Study IFX-1-P2.3 and Study IFX-1-P2.4).  
As of 01 November 2019, IFX-1 safety had been assessed in approximately
subjects. IFX-1 
was safe and well tolerated, with no dose relationship in the safety findings. No specific adverse 
reactions emerged in clinical studies of single or multiple doses IFX-1 in healthy volunteers or 
patients with cardiac disease, sepsis, or HS. 
Currently, four further Phase II studies are ongoing; two studies in patients with granulomatosis 
with polyangiitis and microscopic polyangiitis (also referred to as antineutrophil cytoplasmic 
antibody-associated vasculitis; Study IFX-1-P2.5 and IFX-1-P2.6), one study in patients with 
pyoderma gangrenous (Study IFX-1-P2.7) and one study in severe COVID-19 pneumonia (Study 
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Treatment with IFX-1 was safe and well tolerated with rare occurrence of adverse events (AEs) of 
special interest (AESIs) that were defined as 
 
. As of December 11, 2019,
patients 
experienced AEs suggestive of 
. The reactions were 
moderate, and treatment continued with adequate prophylactic medication. ADAs during treatment 
were observed in a range of
% with a trend towards increasing frequency with low 
dose and larger administration intervals. 
3.2.3.2. 
Pembrolizumab 
Extensive clinical experience is available for pembrolizumab, either as single agent therapy or in 
combination with mAbs, chemotherapies, and radiotherapy. This has been reported by several 
authors and is regularly updated by the US Food and Drug Administration and the EU Medicines 
Agency in the respective prescribing information. 
The major on-target side effects of single agent pembrolizumab are infusion-related reactions and 
immune-related AEs (irAEs; including but not limited to pneumonitis, colitis, hepatitis, and 
endocrinopathies). 
Other common pembrolizumab-related AEs are fatigue, musculoskeletal pain, decreased appetite, 
pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain.  
A comparison of several immune checkpoint inhibitor therapies across solid tumors alone or in 
combination with conventional anticancer therapy showed that PD-1 or PD-L1 checkpoint 
inhibitors have a favorable safety profile and can be safely combined with other antibodies and 
small molecules without leading to unforeseen AEs (Xu et al., 2018). An overlap of toxicities was 
most often seen with immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated 
antigen 4. When combining immune checkpoint inhibitor therapy with chemotherapy or with small 
therapeutic molecules, drug-specific toxicities are combined rather than potentiated. 
3.2.4. 
Scientific Rationale for the Study  
In the context of cancer, C5 can be produced by a plethora of tissue-resident cells, such as immune, 
stromal, and tumor cells. Tissue-present plasmin, trypsin, thrombin, and coagulation factors can 
then cleave C5a from C5 (Amara et al., 2010; Corrales et al., 2012). Recent scientific data imply 
the C5a/C5a receptor (C5aR) axis as a potential driver for tumorigenesis and metastases 
particularly in the context of SCC (Medler et al., 2018).  
C5a has been shown to increase metastatic potential by increasing epithelial-to-mesenchymal 
transition, tumor cell motility, and vascular permeability and to foster an immunosuppressive 
tumor microenvironment (TME) (Markiewski et al., 2008; Nitta et al., 2016; Hu et al., 2016). 
Medler et al., 2018 showed in the TME of SCC in mice that C5a is being split from C5 by plasmin, 
whereas plasmin is produced by urokinase plasminogen activator (uPA)-positive mast cells. The 
latter stem from myeloid derived cells, which express C5aR and are attracted by C5a to the TME. 


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In addition, C5a drives macrophages from a M1- to an immunosuppressive M2-like type and limits 
CD8 T cell activity (Markiewski et al., 2008). Consequently, tumor development was decreased 
in a similar extent in either C5a receptor (C5aR)-deficient or in uPA-deficient mice (Medler et al., 
2018). Of note, C5aR, uPA, and uPA receptor overexpression is described for human SCC, 
including cSCC, and has been linked to decreased survival (Imamura et al., 2016; Nitta et al., 2016; 
Chen et al., 2018; Wada et al., 2016; Rømer et al., 2001; Christensen et al., 2017).  
Moreover, C5a can induce PD-L1 on human monocytes (An et al., 2016). PD-L1 is overexpressed 
by human cSCC and other forms of SCC including non-small cell lung cancer (NSCLC). In 
addition, PD-L1 expressing tumor-associated macrophages have been linked to PD-1 checkpoint 
inhibitor failure in the treatment of patients with NSCLC (Liu et al., 2019).  
Along that line, in a PD-1 inhibitor resistant melanoma mouse model, the combination of a 
C5a/C5aR pathway inhibitor with inhibition of the PD-1/PD-L1 axis showed a strong antitumoral 
effect, which was weaker when one of the axes was inhibited alone (Ajona et al., 2017; Zha et al., 
2017).  
Based on these findings, it is planned to investigate the antitumoral activity of the clinical stage 
C5a-inhibitor IFX-1 alone or in combination with a PD-1 inhibitory antibody in 
PD-1/PD-L1-resistant or refractory cSCC. 
3.2.5. 
Justification for Dose 
3.2.5.1. 
IFX-1 
The aim when determining the dose and administration frequency for IFX-1 is to achieve complete 
or nearly complete inhibition of C5a signaling at the C5a receptors at the tumor site. In addition, 
it was regarded as important to establish a convenient administration schedule for the elderly 
patient population being treated for locally advanced and metastatic cSCC. IFX-1 dose and 
administration schedule were chosen based on pharmacokinetic (PK) and pharmacodynamic 
observations and modeling based on human data obtained in the studies conducted to date.  
The observed half-life of IFX-1 with a single dose of 800 mg was 3 to 4 days in Study IFX-1-P2.2 
in patients undergoing complex cardiac surgery. Thus, an additional dose of 800 mg at Day 4, 
followed by weekly (QW) administration of 800 mg IFX-1 has been chosen for Study IFX-1-P2.3 
in patients with HS. This fractionated loading dose, 800 mg administered on days 1, 4, and 8 was 
well tolerated.  
In Study IFX-1-P2.3 in patients with HS, 800 mg QW IFX-1 was administered for up to 9 times 
including the additional dose of 800 mg at Day 4. This administration schedule resulted in IFX-1 
trough concentrations of around
µg/mL and a decrease of elevated baseline C5a levels to 
approximately detection limit throughout the treatment duration in the majority of patients. This 
dosing regimen, providing the same overall drug exposure for the duration of the study 
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800 mg) as planned in this study, was well tolerated, with no new safety signals, and clinical 
improvement of HS was observed in some patients. 
In another clinical study in HS (Study IFX-1-P2.4), four different dosing schedules have been 
explored, of which the highest dose of 1200 mg Q2W achieved sufficient IFX-1 levels to decrease 
elevated baseline plasma C5a levels to approximately normal throughout the administration period 
of 16 weeks in the majority of patients. Safety findings were similar in all dose groups, and similar 
to safety findings in previous studies, with no new specific AESIs. 
As of July 06, 2020, in the clinical study IFX-1-P2.7 nine doses of 1600 mg Q2W were 
administered and well tolerated. By the time this study, IFX-1-P2.8, is initiated, dose escalation in 
study IFX-1-P2.7 will have progressed to higher doses of 2400 mg unless a DLT will have been 
experienced.  
Based on the available data of studies IFX-1-P2.3 and IFX-1-P2.4, a PK model has been developed 
in order to understand the PK of IFX-1. (“Abbreviated Population Pharmacokinetic/ 
Pharmacodynamic Modeling Report for IFX-1”, 06 April 2020). The population PK model described 
the PK as 
 clearance with elimination 
at clinical concentrations being 
. This means 
that this PK model is transferable between indications even when concentrations of C5a are 
different. The target-dependent Michaelis-Menten component of the clearance is 
at 
most clinical concentrations, as the Km is estimated to be
ng/ml. This translates into a 
target Cmin of
ng/ml in order to fully saturate the target C5a and therefore to minimize its 
signaling to its receptors. This PK result is also supported by the fact that a Ctrough threshold of 
ng/ml for IFX-1 
µg/ml) was found to be correlated with clinical response. The 1600 mg 
Q2W dose was the lowest dose that on average could keep the IFX-1 concentrations for greater than 
of the dosing period above the threshold of
ng/ml. Simulations of the dosing regimens 
indicates that when dosing patients with 1200 mg Q2W,
% of the patients will achieve a trough 
concentration 
ng/ml, while when dosing patients with 1600 mg Q2W,
of the patients 
will remain above the threshold of 
ng/ml throughout the entire dosing interval. Moreover, at 
the dose of 1600 mg Q2W
 of 1000 simulated patients crossed the NOAELs of 
mcg/ml 
and
mcg/ml defined by the toxicology studies. 
A sophisticated physiology-based PK modelling report was created based on existing data 
specifically for the indication cSCC (“IFX-1 PBPK Modelling For Cutaneous Squamous Cell 
Carcinoma (non-melanoma skin cancer)”, September 2019). This analysis similarly indicates that 
at doses
mg/kg the linear clearance
over the target-mediated catabolism. 
Regarding blockage of C5a binding to C5aR, this was found to be incomplete for the HS patients 
in study IFX-1-P2.3 receiving
, indicating that increasing the dose may be beneficial. 
The modelling report states that for cSCC patients receiving the dose of 
, the 
blockage of the C5a-C5aR interaction in tumor is considered sufficient with
% inhibition 
throughout the whole therapeutic treatment. However, this is contingent on a number of 
assumptions, which cannot be confirmed by experimental means. Taking into account this 


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uncertainty and the high variability of the pharmacokinetic data, a higher dose than
 
is considered to increase the likelihood that treated cSCC patient will receive a dose that is 
sufficient to provide optimal therapeutic effects. 
Based on these results, the dose of 1600 mg Q2W is considered to be the target dose for this 
Phase II study and, if supported by the results, for future confirmatory studies.  
3.2.5.2. 
Pembrolizumab 
The planned dose of pembrolizumab for this study is 400 mg every 6 weeks (Q6W). A 400 mg 
Q6W dosing regimen of pembrolizumab is expected to have a similar benefit-risk profile as 
200 mg every 3 weeks (Q3W), in all treatment settings in which 200 mg Q3W pembrolizumab is 
currently approved (see pembrolizumab IB for details). Specifically, the dosing regimen of 400 mg 
Q6W for pembrolizumab is considered adequate based on modeling and simulation analyses, given 
the following rationale: 
• 
PK simulations demonstrating that in terms of pembrolizumab exposures: 
− 
Average concentration over the dosing interval (Cavg) (or area under the curve [AUC]) at 
400 mg Q6W is similar to that at the approved 200 mg Q3W dose, thus bridging efficacy 
between dosing regimens. 
− 
Trough concentrations (Ctrough) at 400 mg Q6W are generally within the range of those 
achieved with 2 mg/kg or 200 mg Q3W in the majority (>99%) of patients. 
− 
Peak concentrations (Cmax) at 400 mg Q6W are well below the Cmax for the highest 
clinically tested dose of 10 mg/kg Q2W, supporting that the safety profile for 400 mg 
Q6W should be comparable to the established safety profile of pembrolizumab. 
• 
Exposure-response for pembrolizumab has been demonstrated to be flat across indications, 
and OS predictions in melanoma and NSCLC demonstrate that efficacy at 400 mg Q6W is 
expected to be similar to that at 200 mg or 2 mg/kg Q3W, given the similar exposures, thus 
400 mg Q6W is expected to be efficacious across indications. 
On June 24, 2020, the Food and Drug Administration of the USA approved pembrolizumab 
(KEYTRUDA, Merck & Co., Inc.) for patients with recurrent or metastatic cutaneous squamous 
cell carcinoma (cSCC) that is not curable by surgery or radiation. The recommended 
pembrolizumab doses for cSCC are 200 mg every 3 weeks or 400 mg every 6 weeks. 
3.3. 
Benefit/Risk Assessment 
IFX-1 is a drug that has been safely administered to more than 300 subjects. In non-clinical safety 
studies, a NOAEL of
mg/kg has been established resulting in pharmacokinetic NOAEL PK 
values, which will not be reached in this study based on the simulations stated in section 3.2.5.1 
of this protocol. 
unexplained death occurred in
cynomolgus monkey during the non-clinical 
safety studies, which retrospectively showed development of anti-IFX-1 antibodies, and resulting 
circulating immune complexes, which has been described in monkeys before. In humans, this 
chimeric IgG4 antibody has the potential to elicit infusion-related reactions, including 




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cSCC, who have not responded or have progressed on cemiplimab, pembrolizumab, or another 
PD-1/PD-L1-directed therapy, no other efficacious therapy exists currently.  
Because no efficacious therapy is currently available in the setting of PD-1 or PD-L1-refractory or 
resistant locally advanced or metastatic cSCC and a good AE profile was observed for IFX-1 so 
far, the hypothesized benefit outweighs the potential risks for the patients participating in this 
study. 
More detailed information about IFX-1, the known and expected benefits and risks, including 
safety experience gained in clinical studies investigating inflammatory diseases, may be found in 
the IB. 
4. 
OBJECTIVES AND ENDPOINTS 
4.1. 
Study Objectives 
4.1.1. 
Monotherapy Arm A 
Primary objective: 
• 
To assess the antitumor activity of IFX-1 
Secondary objectives: 
• 
To further assess efficacy of IFX-1 
• 
To assess the safety profile of IFX-1 
• 
To assess the PK of IFX-1 
• 
To monitor the immunogenicity of IFX-1 
• 
To assess the impact of IFX-1 on quality of life (QoL) 
Other objectives:  
• 
To describe the TME in primary tumor samples and metastases 
• 
To assess pharmacodynamic effects of IFX-1 in skin tumors and peripheral blood 
• 
To describe oncogenic alterations of the tumor at baseline 
4.1.2. 
Combination Therapy Arm B 
Primary objectives: 
Safety run-in part 
• 
To determine the maximum tolerated dose (MTD) or recommended Phase II dose (RP2D) 
 


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Phase II portion 
• 
To assess the antitumor activity of IFX-1 + pembrolizumab 
• 
To assess the safety profile of IFX-1 + pembrolizumab 
Secondary objectives: 
• 
To further assess efficacy of IFX-1 
• 
To assess the PK of IFX-1 
• 
To monitor the immunogenicity of IFX-1 
• 
To assess the impact of IFX-1 + pembrolizumab on QoL 
Other objectives: 
• 
To describe the TME in primary tumor samples and metastases 
• 
To assess the pharmacodynamic effects of IFX-1 + pembrolizumab in skin tumors and 
peripheral blood 
• 
To describe oncogenic alterations of the tumor at baseline 
4.2. 
Study Endpoints 
4.2.1. 
Primary Endpoints 
4.2.1.1. 
Monotherapy Arm A 
The primary endpoint of monotherapy Arm A is investigator assessed best overall response rate 
(ORR) for IFX-1, with response being defined as best response of complete response 
(CR)/confirmed CR (iCR) or partial response (PR)/confirmed PR (iPR) per modified response 
evaluation criteria in solid tumors (RECIST) version 1.1/RECIST for immune-related therapeutics 
(iRECIST). 
4.2.1.2. 
Combination Therapy Arm B 
Safety run-in part 
The primary endpoint of the safety run-in part of combination therapy Arm B is the frequency of 
dose-limiting toxicities (DLTs) by dose cohort. 
Phase II portion 
The co-primary endpoints of the Phase II portion of Arm B are investigator assessed best ORR for 
IFX-1 + pembrolizumab, with response being defined as best response of CR/confirmed CR (iCR) 
or PR/confirmed PR (iPR) per modified RECIST v1.1/iRECIST  and frequency, severity, and 
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to the Medical Dictionary for Regulatory Activities (MedDRA) coding (version valid at time of 
reporting) and the NCI CTCAE grading system v5.0. 
4.2.2. 
Secondary Endpoints 
4.2.2.1. 
Monotherapy Arm A 
Secondary endpoints comprise the following: 
• 
Response (CR/iCR/PR/iPR) and stable disease (SD) duration 
• 
Disease control rate (CR/iCR+PR/iPR+SD) 
• 
PFS 
• 
OS 
• 
Frequency, severity, and IND attribution of treatment-emergent AEs (TEAEs) and SAEs 
according to MedDRA coding (version valid at time of reporting) and the National Cancer 
Institute common terminology criteria for AEs (NCI CTCAE) grading system (version 5.0, 
27 November 2017) 
• 
Post infusion (Cmax) and trough concentration (Ctrough) of IFX-1 
• 
Development of human ADAs against IFX-1 
• 
Changes in QoL as per the European Organisation for Research and Treatment of Cancer 
(EORTC)-QoL questionnaire (QLQ)-C30 total score 
4.2.2.2. 
Combination Therapy Arm B 
Secondary endpoints comprise the following: 
• 
Response (CR/iCR/PR/iPR) and SD duration 
• 
Disease control rate (CR/iCR+PR/iPR+SD) 
• 
PFS 
• 
OS 
• 
Cmax, and Ctrough of IFX-1 
• 
Development of human ADAs against IFX-1 
• 
Changes in QoL as per the EORTC-QLQ-C30 total score 
4.2.3. 
Explorative Endpoints 
Other endpoints across both arms are: 
• 
Tissue-based biomarkers in skin-based tumor lesions, before and during IFX-1 administration 
• 
C5a concentration in plasma before treatment start, during treatment, and at treatment 
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5. 
STUDY DESIGN 
5.1. 
Overall Design 
The study is an open-label, non-randomized, 2-stage, 2-arm, Phase II study, investigating 
antitumor activity of IFX-1 alone or IFX-1 in combination with pembrolizumab for the treatment 
of locally advanced or metastatic PD-1- or PD-L1-resistant/refractory cSCC.  
It is planned to include up to approximately 70 patients in the 2 arms: IFX-1 monotherapy Arm A 
and IFX-1 + pembrolizumab combination therapy Arm B.  
Arm A consists of 2 stages where patients will receive IFX-1 monotherapy (see Section 5.2.1).  
Arm B will start after ≥3 patients have been treated in Arm A and no toxicity concerns have 
emerged. Arm B consists of a safety run-in part in Stage 1 with 3 dose cohorts, and a Phase II 
portion in Stage 1 and Stage 2 (see Section 5.2.2 and Figure 1). In the 3 dose cohorts of the safety 
run-in, escalating doses of IFX-1 will be investigated in combination with 400 mg pembrolizumab 
every 6 weeks [Q6W], in order to identify the MTD. 6 patients will need to be treated at the MTD 
or at the highest IFX-1 dose level (Regimen 3, if MTD was not reached) to decide if this dose can 
be selected as RP2D which will then be explored in the Phase II portion of Arm B. In case only 3 
patients will have been previously treated at the MTD or highest IFX-1 dose level, 3 more patients 
will be added to this cohort. If 6 patients were already treated at the proposed dose level, then 
additional patients will not be required and the decision on the RP2D will be made based on the 
available data.  
Patients will be treated until disease progression, occurrence of unacceptable toxicity, or treatment 
discontinuation for any other reason. 
Patient enrollment into each of the treatment arms follows an optimal Simon’s 2-stage design 
(Simon, 1989) with an interim analysis of treatment response after Stage 1 prior to patient 
enrollment into Stage 2 (see Section 10.3.4). 
Patients will be assigned to treatment Arm A or B as enrollment rules allow and stratified by locally 
advanced or metastatic cSCC.  


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A schematic overview of the overall study design and patient enrollment is given in 
Figure 1Figure 1 Study Design 
 
 
CR: complete response; DLT: dose-limiting toxicity; LA: locally advanced; mcSCC: metastatic cutaneous squamous 
cell carcinoma; N: number of patients; PD1: programmed cell death 1 protein; PD-L1: programmed cell death 
ligand 1; PR: partial response. 
The IFX-1 dosing in Stage 2 of Arm B will be IFX-1 dose in regimens 1, 2, or 3 depending on the maximum tolerated 
dose (MTD) or recommended Phase II dose (RP2D) from Stage 1. In case only 3 patients have been previously 
treated at the MTD or highest IFX-1 dose level, then 3 more patients will be enrolled into the respective dose level 
cohort before the dose can be finally selected for Stage 2. 
. 
 


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A steering committee will be established to support the patient enrollment in both treatment arms 
and monitor patient safety throughout the study. For further details see Section 5.3. 
5.1.1. 
Method of Treatment Assignment 
Patients will be centrally assigned to a treatment arm by the Sponsor according to proceeding of 
enrollment and safety evaluation by the steering committee (see Section 5.3). Treatment 
assignment will be stratified by locally advanced or metastatic cSCC; ≥3 out of 10 in Stage 1 and 
≥9 out of 29 patients in Stage 2 in each treatment arm must have either locally advanced or 
metastatic disease at time of (interim) analyses. The investigational medicinal product (IMP) will 
be centrally assigned using an Interactive Web Response System (IWRS). Before the study is 
initiated, user access codes (log in information), user instructions, and training will be provided to 
responsible personnel at each site. 
IMP will be dispensed at the study visits as summarized in the schedule of assessments (SoA, 
Table 1). 
Returned IMP must not be re-dispensed to the patients. 
5.1.2. 
Blinding 
This is an open-label study; however, the IMP kit numbers will be assigned to each patient using 
an IWRS. The site will contact the IWRS prior to the start of IMP for each patient. The site will 
record the IMP assignment on the applicable case report form if required.   
5.2. 
Patient Enrollment 
A Simon’s 2-stage design will be applied in each independent cohort/treatment arm. 
After informed consent, screening procedures are to be performed within 4 weeks before first study 
treatment administration. For details on the role of the steering committee, see Section 5.3. 
5.2.1. 
Monotherapy Arm A  
Three patients will be enrolled in treatment Arm A to receive IFX-1 monotherapy. After these 
three patients have been treated and their safety closely monitored by the steering committee, as 
described in Section 5.3, enrollment into Arm A will continue with additional 7 patients. If one or 
more of the 10 patients enrolled in Stage 1 of Arm A have a response evaluation of PR or CR at 
their third tumor assessment (no confirmation of response evaluation necessary), enrollment of 
19 additional patients in Stage 2 of Arm A will continue without specific enrollment rules. If there 
are no responders in Stage 1 of Arm A, enrollment will be stopped and there will be no Stage 2 for 
Arm A. 
For the definitions of CR and PR refer to Appendix 3. 


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5.2.2. 
Combination Therapy Arm B  
5.2.2.1. 
Safety Run-In 
After ≥3 patients have been treated in Arm A under close monitoring by the steering committee, 
the safety run-in of Stage 1 of treatment Arm B will be opened. Patients will be sequentially 
enrolled into 3 escalating dose cohorts and their safety will be monitored by the steering 
committee, as described in Section 5.3.2. 
The safety run-in part will follow a 3+3 design as described in 10.3.4.2 and monitored by the 
steering committee: 3 patients will be enrolled in the lowest dose cohort (IFX-1 regimen 1 + 
pembrolizumab). If 1 of the 3 patients experiences a DLT (see Section 7.2.2.2.3), the cohort will 
be expanded to a total of 6 patients. If ≥1 patient of 3 or >1 patient of 6 develop a DLT, further 
dose escalation is not pursued, and the next lower dose will be chosen as the MTD (see 
Section 7.2.2.2.4). If there is no DLT observed in any of the first 3 patients, or in only 1 of 
6 patients, 3 new patients will be enrolled in the next higher dose cohort (IFX-1 regimen 2 + 
pembrolizumab). For the second and third dose cohort (IFX-1 regimen 3 + pembrolizumab), the 
same rules apply. If the MTD is not reached, the highest dose (IFX-1 regimen 3 + pembrolizumab) 
will be chosen as potential RP2D (see Section 7.2.2.2.4). 6 patients will have to be treated at the 
highest IFX-1 or MTD dose level to confirm the respective dose to be used in Stage 2. In case only 
3 patients will have been previously treated at the MTD or highest IFX-1 dose level, 3 more 
patients will be added to this cohort. If 6 patients were already treated at the proposed dose level, 
then additional patients will not be required and the decision on the RP2D will be made based on 
the available data. When the MTD or RP2D has been established, Stage 1 of Arm B will continue 
with the Phase II portion (see Section 5.2.2.2). 
5.2.2.2. 
Arm B Phase II Portion 
After the MTD or RP2D dose have been identified and confirmed, the safety run-in part is 
completed and, under close monitoring of the steering committee (see Section 5.3), additional 
patients will be enrolled in Stage 1 of Arm B until 10 patients will have received the RP2D. If ≥1 
of the 10 patients has a response evaluation of PR/iPR or CR/iCR after their third tumor assessment 
(confirmation not necessary), enrollment of 19 additional patients in Stage 2 of Arm B will 
continue without specific enrollment rules. If there are no responders in Stage 1 of Arm B, 
enrollment will be stopped and there will be no Stage 2 for Arm B. 
For the definitions of CR/iCR and PR/iPR refer to Appendix 3 and Appendix 4. 
5.3. 
Steering Committee 
A steering committee will be constituted to support the patient enrollment in both treatment arms 
and monitor patient safety throughout the study. The steering committee will include the clinical 
study monitor and ≥3 cSCC experts (principal investigators included). At all safety reviews 
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stage 2 of the protocol in each treatment arm, the committee will review the adverse event data in 
the same way as outlined for the definition of DLTs in Section 7.2.2.2.3. Detailed information will 
be provided in the Steering Committee Charter.  
5.3.1. 
Monotherapy Arm A  
In Arm A, IFX-1 will be dosed as monotherapy utilizing a dosing regimen that is consistent with 
prior exposures in the HS patient population (study IFX-1-P2.3) and the pyoderma gangrenosum 
patient population (study IFX-1-P2.7). In Arm A, the Committee will review the safety after three 
patients have reached day 36 of their treatment. At this point of time, during their treatment they 
will have received the fractionated loading dose of 800 mg IFX-1 on days 1, 4, 8, 15 and the first 
two doses of 1600 mg IFX-1, which means that they will have experienced peak concentrations of 
IFX-1. 
Criteria for the decision to proceed with enrolment in Arm A and to initiate enrollment in Arm B, 
will be based on assessment of general safety of IFX-1 treatment administration and with specific 
focus on occurrence of any of the following conditions: 
• 
 
   
 
 
 
If any of these conditions occur in the first 3 patients treated with IFX-1 monotherapy, the steering 
committee will assess safety data and give recommendation on whether more patients should be 
enrolled into monotherapy Arm A before recruitment in Arm B may commence. 
The steering committee will continue assessing the totality of safety information during the 
meetings scheduled for the review of the safety of the Combination Therapy Arm B. 
5.3.2. 
Combination Therapy Arm B  
In Arm B, during the safety run-in for each combination regimen cohort, the first 2 patients must 
be enrolled sequentially separated by a minimum of one week. 
At the following time points, the Committee will review patient safety: 
• 
For the very first patient receiving the combination therapy: After Cycle 1, Day 36, when this 
patient will have received the four consecutive IFX-1 fractionated loading dose 
administrations, one pembrolizumab administration, and two of the higher IFX-1 Q2W doses 
(to allow inclusion of subsequent patients) 
• 
For each escalating dosing regimen: After 3 patients of each combination regimen cohort will 
have reached Cycle 1, day 36, at which they will have received the four consecutive IFX-1 
fractionated loading dose administrations, one pembrolizumab administration, and two of the 
higher IFX-1 Q2W doses (to determine occurrence of DLT and necessity to include 3 more 
patients in a given dose cohort, to allow treatment in the next higher dose cohort, or to 
determine the MTD or RP2D) 


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To determine the RP2D, 6 patients should be treated at the MTD or highest dose level. If only 3 
patients will have been enrolled into the respective cohort, 3 more patients will be enrolled at the 
same dose level. If no further toxicities are observed, this MTD will be selected as dose for Stage 
2 and recommended combination regimen. Further patient enrollment in Arm B can proceed 
without specific rules.  
The steering committee will continue to meet every three months until the last patient will have 
completed the third month of treatment in Stage 1 of the study and every six months thereafter to 
further confirm safety of the MTD or RP2D, and to further assess general safety of study treatment 
administration. All available safety data will be provided to the steering committee before each 
meeting.  
5.4. 
Patient and Study Completion 
This study plans to enroll a total of up to approximately 70 patients: 
• 
Arm A (Phase II portion), Stage 1: 10 patients 
• 
Arm A (Phase II portion), Stage 2: 19 patients 
• 
Arm B (safety run-in): 12 to 18 patients (3 to 6 patients per regimen, out of which 6 patients 
must be treated at MTD or highest dose level) 
• 
Arm B (Phase II portion), Stage 1: additional 4 patients (to reach the required 10 patients on 
the selected MTD or RP2D) 
• 
Arm B (Phase II portion), Stage 2: 19 patients (to reach the total number of 29 patients on the 
selected combination dose) 
In case none of the patients enrolled in Stage 1 of Arms A or B has a response evaluation of 
CR/iCR or PR/iPR, enrollment in the treatment arm can individually be stopped. All enrolled 
patients will be allowed to continue treatment until the end of treatment (EOT) criteria are met 
(see Sections 5.4.1 and 7.2.4); after the EOT Visit, they will proceed through the planned follow-
up period (see Section 5.4.2) until end of study (EOS) (see Section 5.4.3). 
5.4.1. 
End of Treatment Definition 
EOT is defined as discontinuation of all study treatment administrations, i.e., IFX-1 alone or in 
combination with pembrolizumab treatment. 
Discontinuation of study treatment does not represent withdrawal from the study. 
An EOT Visit will be scheduled 30 days after last study treatment administration or before the 
patient starts on another antineoplastic therapy, whatever occurs earlier.  
A patient, who discontinues study treatment administrations without progressive disease 
(PD)/confirmed PD (iCPD) will have tumor assessments at follow-up visits until PD/iCPD or start 
of subsequent antineoplastic therapy.  


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All patients will be followed for disease progression, survival status, and subsequent antineoplastic 
therapies as described in Section 5.4.2. 
For details on treatment discontinuation criteria, see Section 7.2.4. 
5.4.2. 
Follow-Up 
Patients will be followed for survival and subsequent antineoplastic therapies every 3 months for 
12 months after the EOT Visit. After the EOT Visit, tumor assessments will continue every 
12 weeks until PD/iCPD or initiation of subsequent antineoplastic therapy for patients who 
discontinued study treatment for other reasons than progression. If required, information can be 
obtained by a phone call; a follow-up visit can be replaced by a phone call. 
5.4.3. 
End of Study Definition 
The EOS for the individual patient is defined as the date of the last contact of the 12 months follow-
up period, date of death, date of consent withdrawal from study participation (see Section 5.4.4), 
or the date of last contact when patients are lost to follow-up (see Section 5.4.5). 
The entire study will end when all patients have discontinued IFX-1 and IFX-1 + pembrolizumab 
treatment, AND all patients ended the study as described above.  
The sponsor may prematurely terminate the study at any time earlier than planned for the following 
reasons: 
• 
Unacceptable toxicity 
• 
Administrative reasons 
5.4.4. 
Consent Withdrawal/Discontinuation of Study Participation 
A patient may withdraw from the entire study at any time at his/her own request without the need 
to provide any reason(s). 
If the patient withdraws from study participation, the sponsor may retain and continue to use any 
data collected before such a withdrawal of consent. Patients who wish to withdraw 
consent/discontinue the study while still on treatment should be encouraged by the investigator to 
perform the EOT Visit for their own safety before any further data collection for study purposes 
will be terminated. In such a case the EOS Visit information will be added to the EOT Visit 
information. 
If a patient withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the investigator must document this in the site study records. 


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5.4.5. 
Lost to Follow-Up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and the study site is unable to make contact as described below.  
The following actions must be taken if a patient fails to return to the study site for a required study 
visit: 
• 
The site must attempt to contact the patient and reschedule the missed visit as soon as possible 
and counsel the patient on the importance of maintaining the assigned visit schedule and 
ascertain whether or not the patient wishes to and/or should continue in the study. 
• 
Before a patient is deemed lost to follow-up, the investigator or designee must make every 
effort to regain contact with the patient (where possible, 3 telephone calls and, if necessary, a 
certified letter to the patient’s last known mailing address or local equivalent methods). These 
contact attempts should be documented in the patient’s medical record. 
• 
Should the patient continue to be unreachable, he/she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up. 
6. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
6.1. 
Inclusion Criteria 
Type of Patients and Disease Characteristics 
1. At least 18 years of age on day of signing informed consent 
2. Patients with biopsy-proven, histologically or cytologically confirmed (a.) locally 
advanced cSCC not amenable for curative treatment or (b.) metastatic cSCC. Patients 
must have been treated with all approved therapies for (a.) inoperable locally advanced 
cSCC contraindicated for radiation therapy or (b.) metastatic cSCC. All patients to be 
included must have  progressed on PD-1- or PD-L1-inhibitory antibody therapy.  
a. 
Locally advanced cSCC not amenable for curative treatment: 
Patients must have disease that is considered inoperable or medical contraindication to 
surgery or radiation or have not achieved disease control with these treatments. 
Patients must have ≥1 measurable baseline lesion in which the longest diameter and the 
perpendicular diameter are both ≥10 mm on digital medical photography or that can be 
measured by CT/MRI as outlined in inclusion criterion 2b (metastatic cSCC).  
Note: Non-measurable disease is defined as either uni-dimensionally measurable lesions, 
tumors with margins that are not clearly defined, or lesions with maximum perpendicular 


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diameters <10 mm. Patients without measurable disease at baseline are not eligible for 
the study. 
• Surgery must be deemed contraindicated in the opinion of an expert in micrographics-
controlled surgery (Moh’s surgery, e.g., specifically trained dermatologic surgeon), 
a head and neck surgeon, or a plastic surgeon. A copy of the surgeon’s consultation 
note from a clinical visit within 60 days of enrollment must be submitted. Acceptable 
contraindications in the surgeon’s note include: 
o cSCC that has recurred in the same location after ≥2 surgical procedures and 
curative resection is deemed unlikely 
o cSCC with relevant local invasion that precludes complete resection 
o cSCC in anatomically challenging locations for which surgery may result in 
severe disfigurement or dysfunction (e.g., removal of all or part of a facial 
structure, such as nose, ear, or eye; or requirement for limb amputation) 
o Other conditions deemed to be contraindicating for surgery must be discussed 
with the medical monitor before enrolling the patient 
• Patients must be deemed as not appropriate for radiation therapy. Specifically, 
patients must meet ≥1 of the following criteria: 
o A patient previously received radiation therapy for cSCC, such that further 
radiation therapy would exceed the threshold of acceptable cumulative dose, per 
the radiation oncologist. A copy of the radiation oncologist’s consultation note, 
from a clinical visit within 60 days of enrollment, must be submitted. 
o Judgment of radiation oncologist that such tumor is unlikely to respond to 
therapy. A copy of the radiation oncologist’s consultation note, from a clinical 
visit within 60 days of enrollment, must be submitted. 
o A clinic note from the investigator indicating that an individualized benefit-risk 
assessment was performed by a multidisciplinary team (consisting of, at 
minimum, a radiation oncologist AND EITHER a medical oncologist with 
expertise in cutaneous malignancies OR a dermato-oncologist, OR a head and 
neck surgeon) within 60 days prior to enrollment in the proposed study, and the 
radiation therapy was deemed to be contraindicated 
• Acceptable contraindications to radiation therapy in the investigator’s note for 
patients who have not received any prior radiation include: 
o cSCC in anatomically challenging locations for which radiation therapy would be 
associated with unacceptable toxicity risk in the context of the patient’s overall 
medical condition in the opinion of the multidisciplinary team (e.g., a neck tumor 


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for which radiation therapy would result in potential need for a percutaneous 
gastrostomy tube). A copy of the investigator’s consultation note documenting 
the multidisciplinary assessment must be submitted. 
o Other conditions deemed to be contraindicating for radiation therapy must be 
discussed with the medical monitor before enrolling the patient. 
• The diagnosis of cSCC must be confirmed in all patients with locally advanced cSCC 
by histopathological examination of archived or newly obtained tumor material 
(biopsy at screening) to be performed centrally by a sponsor-appointed cutaneous 
histopathologist. Treatment with the investigational drug must not commence prior 
to confirmation of the diagnosis. If archived tumor material is not available requiring 
a new biopsy for the confirmation of the diagnosis, it should be considered to obtain 
the mandatory biomarker biopsy at baseline (inclusion criterion 5) at the same time 
in order to avoid having to perform a second biopsy prior to the initiation of treatment. 
If the biopsies to confirm the diagnosis and to conduct the biomarker assessments are 
taken at the same time, it is important to obtain sufficient material to allow for the 
biomarker assessments (the equivalent of a 4 mm x 4 mm punch biopsy) in addition 
to the material required for the confirmation of the diagnosis. This can be achieved 
by either by taking a sufficiently large biopsy to be divided prior to fixation or by 
obtaining two biopsies.  
• An investigator note which states that the natural history of the patient’s advanced 
cSCC would likely be life-threatening within 3 years with currently available 
management options outside of a clinical study 
b. Metastatic cSCC treated with all approved therapies for metastatic disease: 
Patients are required to have histologic confirmation of distant cSCC metastases (e.g. 
lung, liver, bone, or lymph node). This confirmation of the diagnosis can be provided by 
a local investigator note based on the pathology review conducted locally. 
Patients must have ≥1 baseline measurable lesion ≥10 mm in maximal diameter (1.5 cm 
in short axis for lymph nodes) according to RECIST v1.1 criteria (Appendix 3; 
Eisenhauer et al., 2009). 
Note: In the case of a patient with metastatic disease that does not meet target lesion 
criteria by RECIST v1.1 criteria (e.g., bone only lesions, perineural disease) and with 
externally visible cSCC target lesions, Appendix 3 may be used, in which bi-dimensional 
measurements are required (at baseline, perpendicular diameters must both be ≥10 mm), 
after communication with and approval from medical monitor. The patient would then be 
enrolled with the plan to follow externally visible disease as target lesion(s), and 
metastatic lesions that are not measurable by RECIST v1.1 criteria may be followed as 
non-target lesions. 
Note: There is no limit to the number of prior treatment regimens. 
3. Patients must have progressed on treatment with an anti-PD1/L1 monoclonal antibody 
(mAb) administered either as monotherapy, or in combination with other checkpoint 


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inhibitors or other therapies. PD-1 treatment progression is defined by meeting all of the 
following criteria: 
a. 
Has received ≥2 doses of an anti-PD-1/L1 mAb that has been approved for treatment of 
cSCC or any solid tumor 
b. Has demonstrated PD/iCPD after PD-1/L1 inhibitor treatment as defined by 
RECIST v1.1/iRECIST. The initial evidence of disease progression is to be confirmed by 
a second assessment ≥4 weeks from the date of the first documented disease progression, 
unless there is rapid clinical progression. 
c. 
Disease progression has been documented within 12 weeks from the last dose of anti-
PD-1/L1 mAb. 
4. The PD-1-/PD-L1 infusion must have been the most recent treatment for locally advanced 
or metastatic cSCC. 
5. In addition to providing the material for ensuring the diagnosis as stated in inclusion 
criterion 2a for patients with locally advanced cSCC, patients must consent to undergo 
the following  biopsies (at each time point a punch biopsy of externally visible cSCC 
lesions or a biopsy of material from accessible metastases) for biomarker assessments:  
a. 
At baseline prior to the first administration of the investigational therapy and if possible, 
within 7 days prior to initiation of study treatment administration (mandatory for all 
patients) 
b. For Stage 2 patients only: on Cycle 2 Day 1 (±3 days) (mandatory) 
c. 
For Stage 2 patients only: at the time of CR/iCR/PR/iPR (optional, to be conducted only 
if the investigator considers this biopsy as clinically possible and potentially informative)  
d. For Stage 2 patients only: At the time of tumor progression (optional, to be conducted 
only if the investigator considers this biopsy as clinically possible and potentially 
informative).  
For all biopsies intended to analyze biomarkers, which needs to be the equivalent of a 4 mm 
x 4 mm punch biopsy. If biopsies for biomarkers are not feasible due to the complete absence 
of any suitable cutaneous or metastatic lesions, then this is not an exclusion criterion. 
However, this needs to be documented and confirmed by the investigator.  
The biopsied lesion is not considered a target lesion.  
6. Patients must have the following minimum washout before first study treatment 
administration from previous treatments: 
a. 
≥4 weeks for mAbs, systemic cytotoxic anticancer therapy, treatment with other 
anticancer investigational agents 
b. ≥3 weeks for local radiation therapy 
Note: Patients must have recovered from all radiation-related toxicities, not require 
corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted 
for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system disease. 
7. Eastern Cooperative Oncology Group performance status (ECOG PS) status of ≤1 


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8. Adequate organ function: 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count 
≥1500/µL 
Platelets 
≥100 000/µL 
Hemoglobin 
≥9.0 g/dL or ≥5.6 mmol/La 
Renal 
 
Creatinine OR 
Measured or calculatedb creatinine clearance 
(GFR can also be used in place of creatinine 
or CrCl) 
≤1.5 × ULN OR 
≥30 mL/min for patient with creatinine 
levels >1.5 × institutional ULN 
Hepatic 
 
Total bilirubin 
≤1.5 × ULN OR direct bilirubin ≤ULN for 
patients with total bilirubin levels 
>1.5 × ULN 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN (≤5 × ULN for patients with 
liver metastases) 
Coagulation 
 
International normalized ratio OR PT 
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 
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); 
aPTT=activated partial thromboplastin time; AST (SGOT)=aspartate aminotransferase 
(serum glutamic oxaloacetic transaminase); CrCL=creatinine clearance; GFR=glomerular 
filtration rate; PT=prothrombin time; ULN=upper limit of normal. 
a Hematology test should be obtained without transfusion or receipt of stimulating factors 
within 2 weeks before obtaining screening blood sample. 
b CrCl should be calculated per institutional standard. 
 
9. Patient (or legally acceptable representative if applicable) provides written informed 
consent for the study. 
6.2. 
Exclusion Criteria 
1. Patients with limited cSCC, who do not require systemic therapy 
2. Has known active central nervous system metastases and/or carcinomatous meningitis. 
Patients with previously treated brain metastases may participate provided they are 
radiologically stable, i.e., without evidence of progression for ≥4 weeks by repeat 
imaging (note that the repeat imaging should be performed during study screening), 


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clinically stable and without requirement of steroid treatment for ≥14 days prior to first 
dose of study treatment. 
3. Has a diagnosis of immunodeficiency or autoimmune disease, or is receiving chronic 
systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or 
any other form of immunosuppressive therapy within 3 weeks prior the first dose of study 
treatment 
4. Patients who have a history of (non-infectious) pneumonitis that required steroids or have 
current pneumonitis 
5. 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., cytotoxic 
T-lymphocyte-associated antigen 4, OX 40, CD137) and was discontinued from that 
treatment due to a ≥Grade 3 irAE 
6. Has severe hypersensitivity (≥Grade 3) to pembrolizumab or IFX-1 and/or any of their 
excipients or had a severe (≥Grade 3) infusion-related reaction to treatments with other 
mAbs 
7. Patients who fulfil inclusion criterion 6 (washout times) but who have not recovered from 
side effects of such therapies 
Note: Patients must have recovered from all AEs due to previous therapies to ≤Grade 1 or 
baseline. Patients with ≤Grade 2 neuropathy may be eligible. If patients received major 
surgery, they must have recovered adequately from the toxicity and/or complications from the 
intervention prior to starting study treatment. 
8. Has received a live vaccine within 30 days prior to the first dose of study treatment (see 
Section 7.4.1) 
9. Patients who have undergone major surgery <4 weeks prior to starting study treatment 
10. 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: Patients 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. 
11. Patients with known ≥Grade 3 (per NCI CTCAE v5.0 criteria) active systemic or 
cutaneous viral, bacterial, or fungal infection 
12. Patients with known history of Hepatitis B or C infections or known to be positive for 
Hepatitis B antigen (HBsAg)/ Hepatitis B virus (HBV) DNA or Hepatitis C Antibody or 
RNA. Active Hepatitis C is defined by a known positive Hep C Ab result and known 
quantitative HCV RNA results greater than the lower limits of detection of the assay. 
13. Patients who have a history of human immunodeficiency virus infection 
14. Patients who have a history of interstitial lung disease 
15. Patients who have had an allogeneic tissue/solid organ transplant 
16. Patients with a history of other malignancies during the past 5 years.  


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Note: The following are exempt from the 5-year limit: curatively resected basal cell 
carcinoma, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy. 
17. Patients who are pregnant or breastfeeding or expecting to conceive or father children 
within the projected duration of the study, starting with the screening visit through 
after the last dose of IFX-1 or 120 days after the last dose of pembrolizumab 
18. Women of childbearing potential (WOCBP) who have a positive serum pregnancy test 
result within 7 days before treatment  
Note: Post-menopausal women must be amenorrheic for ≥12 months to be considered not 
WOCBP (Appendix 7).  
19. Male patients and WOCBP who do not agree to practice an effective method of 
contraception during study and 
after last dose of IFX-1 or 120 days after 
last dose of pembrolizumab (Appendix 7) 
20. Patients with congestive heart failure, Class III or IV, by New York Heart Association 
criteria 
21. Patients with any serious underlying medical condition that would impair their ability to 
receive or tolerate the planned treatment 
22. Patients with dementia or altered mental status that would preclude understanding and 
rendering of informed consent document 
6.3. 
Screening Failures 
Screening failures are defined as patients who are enrolled (i.e., consent to participate) in the 
clinical study but are not subsequently assigned to study treatment. A set of screen failure 
information will be collected and include demography, eligibility criteria, AE, and reason for 
screening failure. 
Individuals who do not meet the criteria for participation in this study (screening failure) may be 
rescreened if failed eligibility criteria can only be corrected outside the first screening period. 
6.4. 
Meals and Dietary Restrictions 
Patients should maintain a normal diet unless modifications are required to manage an AE such as 
diarrhea, nausea, or vomiting. 
7. 
STUDY DRUG(S) AND ADMINISTRATION 
7.1. 
Investigational Medicinal Product 
IMP is defined as any investigational treatment(s), marketed product(s), placebo, or medical 
device(s) intended to be administered to a study patient according to the study protocol. 


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7.1.1. 
IFX-1 
7.1.1.1. 
Packaging and Labelling of Investigational Medicinal Product 
IFX-1 concentrate for solution for infusion will be supplied in 
mL glass vials at a concentration 
of
mg/mL (
mg per vial) for reconstitution and intravenous administration. Apart from 
IFX-1, the solution will contain sodium chloride, sodium phosphate, and polysorbate 80. 
IFX-1 will be packaged in cartons and labeled in accordance with all legal requirements. 
Each carton (or IMP kit) will be labeled with a unique number (IMP kit number). The glass vials 
containing IFX-1 will be labeled with the same medication number as the cartons in which they 
are packed. 
Each carton and each vial will be labeled with a multilingual booklet label or a country specific 
single panel label as applicable. 
7.1.1.2. 
Storage, Handling, and Accountability 
Vials of IFX-1 must be stored 
 
. All supplies of IFX-1 must be stored 
separately or segregated from other study supplies and site stock in a dedicated locked facility with 
access limited to authorized personnel. All storage facilities must be temperature controlled and 
monitored and compliant with applicable regulatory requirements. 
An established and validated local temperature management system with temperature logs should 
be used to record the storage temperature. If this is not possible, the study site will be provided 
with a temperature record form by the Contract Research Organization and the site personnel will 
maintain temperature records for the entire duration of the study. At a minimum, the daily (working 
day) minimum and maximum temperatures must be documented. 
Any deviation from the specified temperature range must be documented and reported   within 
24 hours (or the next working day). Further instruction on the management and reporting of 
temperature deviations is provided in the Pharmacy Manual. 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during shipment for all IMP received and any discrepancies are reported and resolved 
before use of the IMP. 
Only patients enrolled in the study may receive IMP and only authorized site staff may prepare 
and administer IMP. The IMP must be prepared in a controlled area in accordance with local 
regulations/requirements for reconstitution of products for intravenous administration; see 
Pharmacy Manual for more details. 


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The investigator, institution, or the head of the medical institution (where applicable) is responsible 
for the correct storage of IMP, IMP accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused IMP are provided in the 
Pharmacy Manual. 
7.1.1.3. 
Drug Preparation and Administration Instructions 
The IFX-1 for infusion will be reconstituted (prepared) in a controlled area at the study site or at 
the 
study 
site’s 
pharmacy, 
in 
accordance 
(compliance) 
with 
applicable 
local 
regulations/requirements for reconstitution of products for intravenous administration.  
The reconstituted IFX-1 should be used within
hours after dilution when stored at room 
temperature. Otherwise, the reconstituted IFX-1 has to be stored at
 
and used within 24 hours; if the reconstituted IFX-1 solution is stored in a refrigerator, it must be 
left to acclimatize to room temperature prior to administration. Details on reconstituting the IFX-1 
will be provided in the Pharmacy Manual. 
The number of unused, partially used, and empty vials will be documented accurately, and the 
vials will be kept at the site until the drug accountability documentation has been checked by the 
study monitor. 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
7.1.1.4. 
Recall of Investigational Medicinal Product 
Instructions (actions to be taken by site) in the case of IMP recall will be provided in the Pharmacy 
Manual. 
7.1.2. 
Pembrolizumab 
7.1.2.1. 
Packaging and Labelling of Investigational Medicinal Product 
Pembrolizumab, 25 mg/mL concentrate for solution for infusion will be supplied as described in 
the Pharmacy Manual. 
7.1.2.2. 
Storage, Handling, and Accountability 
Storage conditions for pembrolizumab are described in the Pharmacy Manual. 
An established and validated local temperature management system with temperature logs should 
be used to record the storage temperature. If this is not possible, the study site will be provided 
with a temperature record form by the Contract Research Organization and the site personnel will 


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maintain temperature records for the entire duration of the study. At a minimum, the daily (working 
day) minimum and maximum temperatures must be documented. 
Any deviation from the specified temperature range must be documented and reported within 
24 hours (or the next working day). Further instruction on the management and reporting of 
temperature deviations is provided in the Pharmacy Manual. 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during shipment for all IMP received and any discrepancies reported and resolved 
before use of the IMP. 
Only patients enrolled in the study may receive IMP and only authorized site staff may prepare 
and administer IMP. The IMP must be prepared in a controlled area in accordance with local 
regulations/requirements for reconstitution of products for intravenous administration 
The investigator, institution, or the head of the medical institution (where applicable) is responsible 
for the correct storage of IMP, IMP accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused IMP are provided in the 
Pharmacy Manual. 
7.1.2.3. 
Drug Preparation and Administration Instructions 
The pembrolizumab for infusion will be reconstituted (prepared) in a controlled area at the study 
site or at the study site’s pharmacy, in accordance (compliance) with applicable local regulations/ 
requirements for reconstitution of products for intravenous administration. Details on preparation 
and administration of pembrolizumab will be provided in the Pharmacy Manual. 
The number of unused, partially used, and empty vials will be documented accurately, and the 
vials will be kept at the site until the drug accountability documentation has been checked by the 
study monitor. 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
7.1.2.4. 
Recall of Investigational Medicinal Product 
Instructions (actions to be taken by site) in the case of IMP recall will be provided in the Pharmacy 
Manual. 


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7.2. 
Administration and Dosage 
Patients will be openly assigned to either receive IFX-1 as monotherapy in treatment Arm A or 
IFX-1 in combination with pembrolizumab in treatment Arm B. IFX-1 will generally be 
administered 60 minutes (±10 minutes) post administration of pembrolizumab. 
The first dose of IFX-1 is administered at Cycle 1 Day 1. The first dose of pembrolizumab is 
administered at Cycle 1 Day 8. Subsequent doses of IFX-1 and pembrolizumab may be 
administered up to 1 day before or after the scheduled day within the Cycle 1 and up to 3 days 
before or after the scheduled day of all following cycles due to administrative reasons. 
To allow for a close observation of study treatment infusion(s), patients should remain at the study 
site for ≥60 minutes after end of infusion(s). Appropriate treatment for potential infusion-related 
reactions must be available during this time. 
7.2.1. 
Treatment Administered 
7.2.1.1. 
Monotherapy Arm A 
IFX-1 monotherapy will be administered as a 30-minute (-5/+10 minutes) intravenous infusion. 
Because of the variability of infusion pumps from site to site, a window between -5 minutes and 
+10 minutes is allowed. Administrations will be given as follows (Figure 2): 
• 
Cycle 1 Days 1, 4, 8, and 15: 800 mg IFX-1 (4 administrations). 
• 
From Cycle 1 Day 22 on: 1600 mg IFX-1 Q2W until EOT (two administrations during Cycle 
1 on Days 22 and 36 and 3 administrations per cycle on Days 1, 15, and 29 of Cycle 2 and all 
subsequent cycles). 
Cycle 1 will comprise 7 weeks, whereas all following cycles will comprise 6 weeks of treatment. 
Treatment will be continued until either disease progression is diagnosed, unacceptable toxicity 
occurred, or treatment has been administered for approximately 2 years. 


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Figure 2 
Patient Calendar: Arm A (IFX-1 Monotherapy)  
C: cycle; D: day; IC: informed consent; PD: progressive disease; Q2W: bi-weekly; Q6W: every 6 weeks; TA: 
tumor assessment. 
7.2.1.2. 
Combination Therapy Arm B 
As detailed in Section 5.1, Stage 1 of treatment Arm B consists of a safety run-in with patients 
being sequentially assigned to 1 out of 3 different escalating treatment regimens (Figure 3).  
IFX-1 will be administered as a 30-minute (-5/+10 minutes) intravenous infusion as follows: 
• 
Cycle 1: 400 mg (regimen 1), 600 mg (regimen 2), or 800 mg (regimen 3) IFX-1 
(4 administrations on Days 1, 4, 8, and 15) 
• 
From Cycle 1 Day 22 on:800 mg IFX-1 Q2W (regimen 1), 1200 mg IFX-1 Q2W (regimen 2), 
or 1600 mg IFX-1 Q2W (regimen 3) until EOT (2 administrations during Cycle 1 on Days 22 
and 36 and 3 administrations per cycle on Days 1, 15, and 29 of Cycle 2 and all subsequent 
cycles) 
IFX-1 treatment will be combined with pembrolizumab, starting at Cycle 1 Day 8 and then on 
Day 1 of each treatment cycle after all other procedures and assessments have been completed. 
IFX-1 infusion will start 60 minutes (±10 minutes) after the pembrolizumab infusion has been 
finished. 
For those patients receiving less than 1600 mg IFX-1 Q2W (regimen 1 and 2) the dose of IFX-1 
may be increased to 1600 mg Q2W at the discretion of the investigator after consultation of the 
sponsor as soon as the safety of this dose will have been confirmed in at least 3 patients receiving 
1600 mg Q2W (regimen 3). This intrapatient dose escalation will only be allowed provided that 
patient has received at least 2 cycles of IFX-1 and had no Grade ≥ 2 treatment related adverse 
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Pembrolizumab will be administered as a 30-minute (-5/+10 minutes) intravenous infusion at a 
dose of 400 mg Q6W. Sites should make every effort to target infusion timing to be as close to 
30 minutes as possible. 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion and administration of infusion solution. 
Treatment will continue until PD/iCPD or treatment discontinuation for any other reason (see 
Section 7.2.4) or treatment has been administered for approximately 2 years. If treatment will 
discontinue due to toxicity, continuation of either IFX-1 or pembrolizumab is allowed, given that 
the toxicity can be unequivocally attributed to 1 of the drugs (see Section 7.2.4.2). 
Figure 3 
Patient Calendar: Combination Arm B (IFX-1 + Pembrolizumab) 
C: cycle; D: day; IC: informed consent; PD: progressive disease; Q2W: bi-weekly; Q6W: every 6 weeks; TA: 
tumor assessment. 
3 more patients will be enrolled at the identified MTD or highest IFX-1 dose level (Regimen 3) in case only 3 patients 
have been previously treated in this dose cohort before it can be finally selected for Stage 2. 
7.2.2. 
Treatment Modification 
This protocol allows some alteration from the currently outlined dosing schedule, but a dose 
reduction of study treatment is generally not allowed. Patients treated in the safety run-in part of 
Arm B will be allowed to increase the assigned IFX-1 dose when the next higher dosing regimen 
was found to be safe by the steering committee (see Section 5.3.2). Increase to a higher than the 
planned highest dose, i.e., 800 mg QW as part of the fractionated loading dose on Cycle 1 Days 1, 
4, 8, and 15 or 1600 mg Q2W from Cycle 1 Day 22 on, is not allowed and would require a protocol 
amendment. 
All AEs leading to treatment modifications will be graded using NCI CTCAE v5.0 based on the 
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7.2.2.1. 
Monotherapy Arm A 
In case of toxicity, IFX-1 dosing can be held by a maximum of 4 weeks. If therapy is continued 
during this time span, dosing will resume within the initial schedule and allowed administration 
window for a specific visit. 
IFX-1 has the potential to elicit infusion-related reactions, including hypersensitivity or 
anaphylaxis. Treatment modification criteria due to infusion-related reactions are listed in 
Appendix 8, Table 5. 
For treatment discontinuation criteria, see Section 7.2.4. 
There are no DLTs defined for Arm A. 
7.2.2.2. 
Combination Therapy Arm B 
In case of toxicity, IFX-1 dosing can be held by a maximum of 4 weeks and pembrolizumab dosing 
by a maximum of 12 weeks. If therapy is continued during this time span, dosing will resume 
within the initial schedule and allowed administration window for a specific visit. 
For treatment modifications due to irAEs, see Section 7.2.2.2.1 and due to infusion-related 
reactions, see Section 7.2.2.2.2. 
IFX-1 and pembrolizumab may be interrupted for situations other than treatment-related AEs such 
as medical/surgical events or logistical reasons not related to study therapy. However, 
pembrolizumab is to be restarted within 6 weeks or 42 days of the originally scheduled dose and 
within 12 weeks or 84 days of the previously administered dose, unless otherwise discussed with 
the Sponsor. IFX-1 is to be restarted within 2 weeks or 14 days of the originally scheduled dose 
and within 4 weeks or 28 days of the previously administered dose.  The interruption shall not lead 
to a longer dosing interval than 4 weeks for IFX-1 and 12 weeks for pembrolizumab. The reason 
for interruption should be documented in the patient’s study record. 
For treatment discontinuation criteria, see Section 7.2.4. 
7.2.2.2.1. 
Immune-Related Adverse Events 
AEs associated with pembrolizumab exposure may represent an immune-related response. 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 treatment is critical to reduce complications. Based on existing clinical study data, 
most irAEs were reversible and could be managed with interruptions of pembrolizumab, 
administration of corticosteroids, and/or other supportive care. For suspected irAEs, ensure 
adequate evaluation to confirm etiology or exclude other causes. Additional procedures or tests 
such as bronchoscopy, endoscopy, and skin biopsy may be included as part of the evaluation. Dose 
modification criteria for pembrolizumab in response to Grade 2 or higher irAEs are listed in 


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Appendix 8, Table 4. If treatment should be withheld due to toxicity, both pembrolizumab and 
IFX-1 should be withheld (see Appendix 8, Table 4).  
 
7.2.2.2.2. 
Infusion-Related Reactions 
IFX-1 as well as pembrolizumab may cause severe or life-threatening infusion-related 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 criteria for infusion-related reactions are listed in Appendix 8, 
Table 5. 
 
7.2.2.2.3. 
Dose-Limiting Toxicities 
DLTs are only defined for combination Arm B. All DLTs will be graded using NCI-CTCAE 
Version 5.0 based on the investigator assessment.   
A DLT is a toxicity that occurs during the DLT assessment period up to and including Cycle 1 
treatment day 36 and is assessed by the investigator as being possibly, probably, or definitely 
related to study treatment administration. DLTs are defined by the following: 
1. Nonhematologic toxicity (not laboratory): 
• Drug related Grade 3 or 4 infections and infestations 
• Any treatment-related toxicity that causes the patient to discontinue treatment; see 
Appendix 8, Table 4 for dose modification criteria in case of irAEs, and Table 5 in case 
of infusion-related reactions 
2. Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia: 
• Grade 4 thrombocytopenia of any duration 
• Grade 3 thrombocytopenia associated with clinically significant bleeding that may 
require transfusion, invasive intervention, or hospitalization 
3. Any nonhematologic AE ≥Grade 3 in severity should be considered a DLT, with the 
following exceptions: Grade 3 fatigue lasting ≤ 3 days; Grade 3 diarrhea, nausea, or 
vomiting without use of anti-emetics or anti-diarrheals per standard of care; Grade 3 rash 
without use of corticosteroids or anti-inflammatory agents per standard of care. 
4. Any Grade 3 or Grade 4 non-hematologic laboratory value if: 
• Clinically significant medical intervention is required to treat the participant or 
• The abnormality leads to hospitalization, or 


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• The abnormality persists for >1 week. 
• The abnormality results in a Drug-induced Liver Injury (DILI)  
5. Febrile neutropenia Grade 3 or Grade 4: 
• Grade 3 is defined as ANC <1000/mm3 with a single temperature of >38.3 degrees C 
(101 degrees F) or a sustained temperature of ≥38 degrees C (100.4 degrees F) for more 
than 1 hour 
• Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3 degrees C 
(101 degrees F) or a sustained temperature of ≥38 degrees C (100.4 degrees F) for more 
than 1 hour, with life-threatening consequences and urgent intervention indicated. 
6. Prolonged delay (>2 weeks) in initiating Cycle 2 due to treatment-related toxicity. 
7. Any treatment-related toxicity that causes the participant to discontinue treatment during 
Cycle 1. 
8. Missing >25% of 1 or both IND doses (IFX-1 and/or pembrolizumab) doses as a result of 
drug-related AE(s) during the first cycle. 
9. Grade 5 toxicity. 
The frequency, time to onset, and severity of toxicities, as well as the success of standard medical 
management and dosing interruptions/delays, will be analyzed to determine if a given toxicity 
should be considered a DLT for dose escalation purposes.  
TEAEs that appear to meet the DLT definition will be discussed between the investigator, the 
sponsor and the steering committee (see Section 5.3.2). The final decision of whether or not the 
AE meets the DLT definition will be based on a careful review of all relevant data and consensus 
between the investigator, sponsor, and steering committee. 
7.2.2.2.4. 
Maximum Tolerated Dose 
The MTD is defined as the highest dose at which ≤1 of 3 patients or ≤1 of 6 patients (in an 
expanded cohort) experience a DLT with IFX-1 in combination with 400 mg pembrolizumab. 
Thus, the MTD is defined as the dose level immediately below the level at which dosing is stopped 
due to the occurrence of >1 DLT in a cohort with 3 patients or of >1 DLT in an expanded cohort 
of 6 patients. If dose escalation is not stopped due to the occurrence of DLTs, it will be considered 
that the MTD has not been determined and the highest IFX-1 dose level will be considered as dose 
for Stage 2. 6 patients will need to be treated at the MTD or at the highest IFX-1 dose level 
(Regimen 3, if MTD was not reached) to decide if this dose can be selected as RP2D which will 
then be explored in the Phase II portion of Arm B. In case only 3 patients will have been previously 
treated at the MTD or highest IFX-1 dose level, 3 more patients will be added to this cohort. If 6 
patients were already treated at the proposed dose level, then additional patients will not be 
required and the decision on the RP2D will be made based on the available data. 


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7.2.3. 
Re-Dosing Criteria 
The following criteria must be fulfilled to allow for re-dosing of study treatment: 
• 
Absence of treatment discontinuation criteria (see Section 7.2.4) 
• 
AEs fulfilling DLT criteria (see Section 7.2.2.2.3) must have been reviewed by the steering 
committee (see Section 5.3.2) and found not to be limiting.  
• 
Any other Grade 3 or higher AEs have to improve to Grade 1 or baseline OR a Grade 3 AE 
can be managed and stabilized by supportive/medical therapy, e.g., Grade 3 hypertension can 
be controlled by addition of a second antihypertensive medication and should improve to 
Grade 1 or baseline.  
7.2.4. 
Treatment Discontinuation Criteria 
Discontinuation of study treatment does not represent withdrawal from the study. See Section 5.4.1 
for the EOT definition and procedures at EOT Visit. 
Patients should be treated with IFX-1 or the IFX-1+pembrolizumab combination until disease 
progression or unacceptable toxicity occurs or treatment has been administered for approximately 
2 years. With Sponsor agreement, drug administration can continue for patients with initial 
evidence of PD according to RECIST v1.1 (Eisenhower et al., 2009) but are clinical stable in line 
with the concept of unconfirmed PD (iUPD) according to iRECIST criteria (Seymore et al., 2017). 
For the purpose of this decision process, lack of clinical stability is defined as: 
• Unacceptable toxicity 
• Clinical signs or symptoms indicating clinically significant disease progression 
• Decline in performance status 
Rapid disease progression or threat to vital organs or critical anatomical sites (eg, CNS metastasis, 
respiratory failure due to tumor compression, spinal cord compression) requiring urgent alternative 
medical intervention. 
7.2.4.1. 
Monotherapy Arm A 
Possible reasons for treatment discontinuation for individual patients are: 
• 
PD/iCPD 
• 
Clinical deterioration 
• 
Non-compliance with protocol procedures 
• 
Study participation consent withdrawal (see Section 5.4.4) 
• 
Pregnancy 
• 
Safety: 


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− 
Grade 2 infusion-related reactions despite adequate premedication (see Appendix 8, 
Table 5) 
− 
Grade 3 or 4 infusion-related reactions (see Appendix 8, Table 5) 
 
7.2.4.2. 
Combination Therapy Arm B 
Possible reasons for treatment discontinuation for individual patients are: 
• 
PD/iCPD 
• 
Clinical deterioration 
• 
Non-compliance with protocol procedures 
• 
Study participation consent withdrawal (see Section 5.4.4) 
• 
Pregnancy 
• 
Safety: 
− 
Any study intervention-related toxicity (immune-related adverse events or infusion-
related reactions) specified as a reason for permanent discontinuation as defined in the 
guidelines for dose modification due to AEs (see Appendix 8, Table 4, Table 5)  
• 
Discontinuation of pembrolizumab treatment may be considered for patients who have 
attained a confirmed CR and have received ≥2 doses of pembrolizumab beyond the date when 
the initial CR was declared 
• 
Discontinuation of pembrolizumab treatment may be considered after completion of 18 cycles 
(approximately 2 years) with pembrolizumab 
Upon occurrence of any TEAE that, in the opinion of the investigator, is solely related to either 
IFX-1 or pembrolizumab, continuation of treatment with the other combination partner alone is 
possible but requires sponsor agreement. In case of specific IFX-1 toxicities pembrolizumab may 
be continued as a monotherapy for approximately 2 years. 
7.3. 
Premedication and Postmedication 
Routine premedication is not required prior to the first dose of IFX-1 or pembrolizumab. 
Patients with mild or moderate infusion reaction following IFX-1 or pembrolizumab 
administration may continue to receive IFX-1 or pembrolizumab with close monitoring; 
premedication with antipyretic and antihistamine may be considered.  
Patients should be observed in the treatment facility for 60 minutes, or longer per clinical 
judgment, after study treatment administrations. 
Treatment guidelines are detailed in Appendix 8, Table 5. 


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7.4. 
Concomitant Medication/Treatments 
Any medication or treatment that the patient is receiving within 28 days prior to the first dose of 
study treatment and up to 30 days after the last dose should be recorded. 
For details, please see Section 8.1.4. 
7.4.1. 
Prohibited Concomitant Medication/Treatment 
Medications or vaccinations specifically prohibited in the exclusion criteria (see Section 6.2) are 
not allowed during the ongoing study. If there is a clinical indication for any medication or 
vaccination specifically prohibited during the study, discontinuation from study therapy or 
vaccination may be required. The investigator should discuss any questions regarding this with the 
medical monitor. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the patient’s primary physician. However, the decision to continue the patient 
on study treatment requires the mutual agreement of the investigator, the sponsor, and the patient. 
The following concomitant therapies or vaccinations are prohibited during the course of the study: 
• 
Antineoplastic systemic chemotherapy or biological therapy 
• 
Immunotherapy not specified in this protocol 
• 
Chemotherapy not specified in this protocol 
• 
Investigational agents other than pembrolizumab and IFX-1 
• 
Radiation therapy 
• 
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed at the 
investigator’s discretion. 
• 
Live vaccines within 30 days prior to the first dose of study treatment and while participating 
in the study. Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster, yellow fever, rabies, Bacillus Calmette-Guérin, 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. See exclusion criterion #8. 
• 
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 of the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study.  
All treatments that the investigator considers necessary for a patient’s welfare may be administered 
at the discretion of the investigator in keeping with the community standards of medical care. 


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7.5. 
Rescue Medications and Supportive Care 
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
investigator. Suggested supportive care measures for the management of AEs with potential 
immunologic etiology are outlined along with the dose modification guidelines in Section 7.2.2 
and Appendix 8, Table 4. Where appropriate, these guidelines include the use of oral or 
intravenous treatment with corticosteroids, as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids. Note that several courses of 
steroid tapering may be necessary as symptoms may worsen when the steroid dose is decreased. 
For each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be related to 
pembrolizumab.  
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, the 
investigator does not need to follow the treatment guidance. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. 
7.6. 
Treatment of Overdose 
No specific information is available on the treatment of overdose of pembrolizumab or IFX-1. For 
this study, an overdose of pembrolizumab will be defined as any dose of ≥1000 mg. In the event 
of overdose, the participant should be observed closely for signs of toxicity. Appropriate 
supportive treatment should be provided if clinically indicated. 
In the event of an overdose, the investigator should: 
1. Contact the medical monitor immediately 
2. Closely monitor the patient for any AE/SAE and laboratory abnormalities 
3. Report the overdose (IFX-1 only symptomatic, pembrolizumab symptomatic and 
asymptomatic overdoses) in accordance with the Section 9.2 through the SAE page in the 
eCRF. Document the actually delivered dose of the IMP as well as the duration of infusion 
in the eCRF SAE page (narrative section) within 24 hours of event occurrence.  
4. In addition, document the actual dose added to the infusion bag, the duration of the infusion, 
and the actually delivered dose on the respective IMP administration pages in the eCRF. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the patient. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Patient consent will be obtained prior to performance of any study related procedures; standard of 
care procedures applicable to screening obtained within 28 days of first drug administration (or 


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clearly medically relevant for this period, as agreed by the sponsor,) can be used for qualification 
unless otherwise specified.  
Study procedures and their timing are summarized in the SoA (Table 1) and further detailed per 
study period and visit in Appendix 1. 
Details on the assessments and procedures are given in the following subsections.  
Safety concerns should be discussed with the sponsor immediately upon occurrence or awareness 
to determine if the patient should continue or discontinue any study treatment. 
Adherence to the study design requirements, including those specified in the SoA (Table 1), is 
essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential patients meet 
all eligibility criteria (Sections 6.1 and 6.2). An eligibility form will be used to enable the sponsor 
to agree on inclusion and assignment to a treatment arm. The investigator will maintain a screening 
log to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
For details on the amount of blood collected from each patient over the duration of the study, see 
Laboratory Manual.  
8.1. 
Baseline Assessments 
The following procedures will be performed to assess baseline characteristics during screening 
evaluations and before study treatment administration: 
• 
Documentation of demographic details (age, gender, race, and ethnicity), medical and disease 
history (see Sections 8.1.1 and 8.1.2) 
• 
Disease assessments (see Section 8.2 and Appendix 3) 
• 
QoL/EORTC (see Section 8.8) 
• 
Documentation of concomitant disease and prior and concomitant medications (see 
Sections 8.1.3 and 8.1.4) 
• 
Baseline safety assessment (height, weight, physical exam, vital signs, electrocardiogram 
(ECG), AEs, and safety laboratory; see Section 8.3) 
• 
Skin or metastasis biopsy (if skin biopsy is not possible) for biomarker assessments (see 
Section 8.6) 
• 
Baseline assessment of pharmacodynamic parameters (C3a, C5a, ADA) and PK 


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8.1.1. 
Medical History (Except cSCC History) 
The documentation of the patient’s medical history includes any details on the patient’s medical 
history before enrollment into the study. The information must be documented as such in the source 
documentation and eCRF. 
8.1.2. 
cSCC (Disease) History 
Any details on the patient’s cSCC disease history including any cSCC therapy (surgery, systemic 
therapy, radiation therapy by verbatim name with start and end dates, dosages) that the patient 
received will be documented in the source documentation and in the eCRF. 
8.1.3. 
Concomitant Disease  
All ongoing diseases diagnosed prior to enrollment into the study are regarded as concomitant 
diseases. All concomitant diseases must be documented in the patient file and in the eCRF. 
8.1.4. 
Prior and Concomitant Medication/Treatments 
All prior anticancer medication irrespective of the time of treatment and  any medication or vaccine 
(including over the counter or prescription medicines, vitamins, and/or herbal supplements) that 
the patient is receiving within 28 days prior to the first dose of study treatment and up to 30 days 
after the last dose should be recorded in the patient file and in the eCRF along with: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose, route and frequency 
The medical monitor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
In case of SAEs occurring later than 30 days after the last dose of study treatment, respective 
concomitant medications administered should be recorded. 
 
8.2. 
Efficacy Assessments 
Tumor assessments and response evaluation will be done per modified RECIST v1.1 (Eisenhauer 
et al., 2009) followed by iRECIST. iRECIST introduces additional tumor assessment and response 
evaluation criteria at time of a first response evaluation of PD according to RECIST v1.1, to 
accommodate for situations where a pseudo-progression is suspected (Seymore et al., 2017). 
Tumor assessments, using adequate imaging techniques including standardized medical 
photography, and response evaluation will be performed and documented after every cycle 
throughout the study. In case patients experience a PR/iPR or CR/iCR that lasts ≥1 year, imaging 
frequency can be decreased to every other cycle. For further details see Appendix 3. Independent 


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response evaluation could be initiated by the sponsor any time during the study. In preparation of 
a conditional, result-driven independent response evaluation, copies of all tumor assessment 
images will be collected. 
8.2.1. 
Imaging Requirements 
Medical photography and computed tomography (CT) or magnetic resonance imaging (MRI) for 
tumor assessment will be performed locally at each scheduled tumor assessment time point (after 
every cycle), and at any time when disease progression is suspected. 
Note: after a response evaluation of PD/iCPD while on study treatment, additional scans are not 
required at scheduled follow-up visit procedures.  
The choice of whether the imaging is by CT or MRI is an investigator decision (see Appendix 3). 
Once the choice has been made to use CT scan or MRI, subsequent assessments should be made 
using the same modality whenever possible. 
8.2.2. 
Evaluation of Overall Response 
The best overall response is the best response recorded from the start of the study treatment until 
EOT or documentation of disease progression according to RECIST v1.1/iRECIST (PD/iCPD). 
The patient’s best overall response assignment will depend on the findings of both target and 
non-target disease, appearance and size of new lesions, and clinical stability (see Appendix 4). For 
patients discontinuing treatment for other reasons than PD/iCPD, the tumor assessments will 
continue during the follow-up period (also see the SoA, Table 1). 
8.3. 
Safety Assessments 
Safety will be assessed based on the following variables: 
• 
AEs (see Section 9 and Section 8.3.1) 
• 
Laboratory safety parameters and pregnancy test (see Section 8.3.2) 
• 
Vital signs (see Section 8.3.3) 
• 
ECG (see Section 8.3.4) 
• 
Physical examination, ECOG PS (see Section 8.3.5) 
• 
Immunogenicity/IFX-1 ADA status (see Section 8.3.6) 
Planned time points for all safety assessments are provided in the SoA (Table 1). 
8.3.1. 
Adverse Events Assessments 
AEs will be assessed throughout the study from informed consent to EOS at each study visit. For 
details on AE collection and reporting, see Section 9. The investigator should take appropriate 
measures to follow all AEs until clinical recovery is complete and laboratory results have returned 


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to normal, or until progression has been stabilized, or until death, in order to ensure the safety of 
the patients. This may imply that observations will continue beyond the last planned visit per 
protocol, and that additional investigations may be requested by the sponsor. When study treatment 
is prematurely discontinued, the patient’s observation will continue until the EOS for that patient. 
8.3.2. 
Clinical Safety Laboratory Assessments 
Blood samples for safety laboratory analysis should be obtained after the patients have provided 
responses to QoL questionnaire and after vital signs assessments have been performed, but before 
administration of study treatment.  
See Appendix 2 for the list of clinical laboratory tests to be performed and the SoA (Table 1) for 
timing and frequency.  
The investigator must review the laboratory report, document this review, and record any clinically 
relevant changes (clinically relevant abnormal findings) occurring during the study in the AE 
section of the eCRF. The laboratory reports must be filed in the patient file. Clinically relevant 
abnormal laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the patient’s condition. 
All laboratory tests with values considered clinically relevantly abnormal occurring until 30 days 
after EOT should be reported in the AE section of the eCRF and repeated until the values return 
to normal or baseline, are no longer considered clinically relevant by the investigator or medical 
monitor, or until the EOS (also see Section 9 and Appendix 6). 
If such values do not return to normal/baseline within a period of time judged reasonable by the 
investigator, the etiology should be identified, and the sponsor notified. 
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted in 
accordance with the SoA (Table 1).  
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in patient management or are considered clinically 
relevant by the investigator (e.g., SAE or AE or dose modification), then the results must be 
recorded in the eCRF. 
For details on pregnancy testing, refer to Appendix 7. 
8.3.3. 
Vital Signs 
Core body temperature, heart rate, respiratory rate, and blood pressure (diastolic and systolic) will 
be assessed at each visit at pre-dose, and H0+1h (±5 minutes), where H0 is the beginning of IFX-1 
administration, on the days of study treatment administration and at further time points whenever 
medically indicated. 


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Blood pressure and pulse measurements will be assessed with a completely automated device. 
Manual techniques will be used only if an automated device is not available. 
Vital signs will be measured in a semi-supine position after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure, and pulse and respiratory rate.  
8.3.4. 
Electrocardiograms 
Triplicate 12-lead ECG will be obtained as outlined in the SoA (Table 1) using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT (QTc) 
intervals. 
At each ECG time point triplicate ECG are required, 3 individual ECG tracings should be obtained 
as closely as possible in succession, but ≤2 minutes apart. The full set of triplicates should be 
completed in <4 minutes. 
The ECG should be performed at screening, on Cycle 1 Day 1 pre-dose and at H0+1 (±5 minutes), 
on Cycle 2 Day 1 at H0+1 (±5 minutes), and at the EOT Visit. 
8.3.5. 
Physical Examination 
A physical examination will be conducted at screening and each study visit. 
The physical examination includes, at a minimum, assessments of the skin, cardiovascular, 
respiratory, gastrointestinal, and neurological systems. Height (at screening) and weight will also 
be measured and recorded, and ECOG PS must be assessed and documented (Appendix 9). 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.3.6. 
Immunogenicity 
Serum immunogenicity samples will be collected from all patients at time points specified in the 
SoA (Table 1). The ADA assays for IFX-1 will be performed by a bioanalytical laboratory under 
the responsibility of the sponsor. These assays and analysis methods will be defined in a 
Bioanalytical Protocol and the results will be included in a Bioanalytical Report. 
8.3.7. 
Survival Status 
The patient survival status will be assessed during follow-up and will be documented in the eCRF. 
In case the patient has died, and the date of death is unknown, the date of the last personal contact 
should be documented at a minimum. 
8.3.8. 
Antineoplastic Therapies 
Any antineoplastic therapy or medication administered to the patients after completion or 
discontinuation of study treatment administration until EOS must be documented in the patient file 


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and eCRF with details on the date(s) of administration (with start and end dates), and dosing 
information, including dose, route, and frequency of administration. 
8.4. 
Pharmacokinetics 
Samples will be used to evaluate the PK of IFX-1. 
Plasma samples will be collected for measurement of plasma concentrations of IFX-1 as specified 
in the SoA (Table 1).  
Additional samples may be collected at additional time points during the study if warranted and 
agreed upon between the investigator and the sponsor. Instructions for the collection and handling 
of biological samples will be provided in the Laboratory Manual. The actual date and time (24-
hour clock time) of each sample will be recorded. 
8.5. 
Pharmacodynamics 
Venous blood samples will be collected for measurement of C3a and C5a at the time points 
specified in the SoA (Table 1) pre-dose.  
8.6. 
Explorative Biomarkers 
Tumor samples will be taken in order to characterize the tumor and its tumor microenvironment 
(TME) and to evaluate association of TME characteristics with the observed clinical responses to 
IFX-1. These biopsies (punch biopsies of externally visible cSCC lesions or biopsies of material 
from accessible metastases) are to be obtained at the following time points: 
a. 
At baseline, prior to the first administration of the investigational therapy and if possible, 
within 7 days prior to initiation of study treatment administration (mandatory for all 
patients) 
b. For Stage 2 patients only: on Cycle 2 Day 1 (±3 days) (mandatory) 
c. 
For Stage 2 patients only: at the time of CR/iCR/PR/iPR (optional, to be conducted only 
if the investigator considers this biopsy as clinically possible and potentially 
informative)  
d. For Stage 2 patients only: At the time of tumor progression (optional, to be conducted 
only if the investigator considers this biopsy as clinically possible and potentially 
informative).  
For all biopsies intended to analyze biomarkers, it is important to obtain sufficient material to 
conduct the biomarker program, which needs to be the equivalent of a 4 mm x 4 mm punch biopsy. 
If biopsies for biomarkers are not feasible due to the complete absence of any suitable cutaneous 
or metastatic lesions, then this is not an exclusion criterion for enrollment into the study. However, 
the fact that a mandatory biopsy was not possible needs to be clearly documented and justified by 
the investigator.  


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Sampling must be obtained at minimal clinical risk from a skin lesion that has not been previously 
irradiated and that does not represent target lesions for response assessment. Detailed sampling 
instructions will be provided in the Laboratory Manual. 
Explorative biomarker analyses will include tissue-based biomarkers in skin-based tumor lesions, 
before and during IFX-1 administration 
In addition, samples will be stored and analysis may be performed on biomarker variants thought 
to play a role in development of cSCC or mode of action of the studied drug(s) including, but not 
limited to specific candidate genes, genome-wide analysis for RNA, plasma/serum analytes, or 
tissue biomarkers. 
Other samples (e.g., unused samples collected for ADA assessments) may be used for research to 
develop treatments, methods, assays, prognostics, and/or companion diagnostics related to 
potential complement driven diseases. 
Further instructions regarding the collection, processing, and shipping of samples for central 
analysis will be available in the Laboratory Manual. 
8.7. 
Genetics 
Germline genetic samples will not be obtained during this study. 
8.8. 
Quality of Life (EORTC-QLQ-C30) 
The EORTC-QLQ-C30 was designed to measure cancer patients’ physical, psychological and 
social functions. The questionnaire is composed of 5 multi-item scales (physical, role, social, 
emotional, and cognitive functioning) and 9 single items (pain, fatigue, financial impact, appetite 
loss, nausea/vomiting, diarrhea, constipation, sleep disturbance, and QoL) (available at 
https://qol.eortc.org/questionnaire/eortc-qlq-c30/). The EORTC-QLQ-C30 will be provided to the 
sites. 
8.9. 
Health Economics 
Health Economics are not evaluated in this study. 
9. 
ADVERSE EVENT COLLECTION AND REPORTING 
AEs will be documented in the patient files, and reported via the eCRF, including a seriousness 
assessment (see Appendix 6 I). SAE reports (on paper only if the eCRF is unavailable, see 
Appendix 6 II) will be processed by the safety vendor (see Section 9.2.1). The safety vendor for 
this study is IQVIA Pharmacovigilance (see Appendix 10 for details on external responsibilities). 
Instructions for AE reporting are provided by the eCRF completion guidelines.  


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The investigator is responsible for detecting, documenting, recording, and following up on events 
that meet the definition of an AE and remains responsible for following up on AEs considered 
related to the study treatment or to study procedures (see Section 9.3 and Appendix 6 II), or that 
caused the patient to discontinue study treatment (see Section 7.2.4) or study participation.  
AE records describe  the diagnosis (alternatively signs and symptoms), seriousness, severity (NCI 
CTCAE v5.0 grading), start date and time, stop date and time, actions taken with respect to the 
study treatment, corrective treatment/therapy given, additional investigations performed, outcome, 
and the relationship to study treatment (see Section 9.3). 
Terms like “disease progression” or “progressive disease”, do not sufficiently describe the nature 
of an AE. For example, if a patient is hospitalized for disease progression with hemoptysis, the 
investigator needs to report an AE and SAE for the hemoptysis. Data related to disease progression 
should be captured in the tumor assessment and response evaluation section of the eCRF. 
9.1. 
Duration of Adverse Event Collection and Reporting 
The following timeframes for reporting apply: 
9.1.1. 
Non-serious Adverse Events 
• 
All non-serious AEs must be reported from patient's informed consent until 30 days following 
discontinuation of study treatment  
• 
All AEs must be followed until the outcome of the event is “recovering” (for stabilization of 
chronic conditions), or recovered (/with sequelae), and until all queries related to these AEs 
have been resolved. 
• 
Ongoing AEs should be reviewed at each visit until EOT Visit or study discontinuation. If 
resolved, the details should be recorded in the eCRF.  
• 
All ongoing AEs at the EOT Visit will have to be followed up until the outcome of the event 
is “recovering” (for chronic conditions), or recovered, until the EOS visit and until all 
queries related to these AEs have been resolved. 
• 
If during an AE period, changes for the worse, in frequency of episodes/symptoms or in 
severity are observed, the final AE entry/report must include the maximum severity and 
frequency observed for this AE.  
• 
If the patient dies from an event, ongoing AEs can be closed with an outcome “not known” if 
the outcome was not re-assessed at the day of death. 
9.1.2. 
Adverse Events of Special Interest (AESI) 
• 
All AESIs must be reported from first study drug administration until 30 days following 
discontinuation of study treatment. Please see Section 9.7 for the definition of AESIs. 


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9.1.3. 
Serious Adverse Events 
• 
All SAEs from patient's informed consent on until 90 days following discontinuation of study 
treatment must be reported 
• 
All related SAEs must be followed until resolution, death, loss to FU or EOS 
• 
SAEs related to study treatment with onset during the follow-up period (from the EOT Visit 
until the EOS) will have to be collected and followed until resolution. 
• 
After the EOS, only new SAEs related to study treatment must be reported to the sponsor. 
9.1.4. 
Pregnancies 
• 
All pregnancies from the time of treatment allocation until
after the last dose of 
IFX-1 or 120 days after the last dose of pembrolizumab, whichever is later, must be reported 
by the investigator as described in Section 9.6.2. 
• 
If the patient initiates new anticancer therapy after discontinuation of the study treatment, 
pregnancy must be reported until 30 days following discontinuation of the study treatment, as 
described in Section 9.6.2. 
9.1.5. 
Breastfeeding 
• 
All exposures during breastfeeding from the time of treatment allocation until
after 
the last dose of IFX-1 or 120 days after the last dose of pembrolizumab, whichever is later, 
must be reported by the investigator as described in Section 9.6.2. 
• 
If the patient initiates new anticancer therapy after discontinuation of the study treatment, 
exposure during breastfeeding must be reported until 30 days following discontinuation of the 
study treatment, as described in Section 9.6.2. 
9.2. 
Serious Adverse Event Reporting and Timelines 
9.2.1. 
Initial Reporting of Serious Adverse Events 
All SAEs should be reported within 24 hours in the SAE section of the eCRF and approved by the 
investigator (see Appendix 6 II). Subsequent to an immediate automatic alert, triggered by the 
eCRF system, the SAE report will be processed by the safety vendor. In addition, SAEs need to 
be reported in the (non-serious) AE section of the eCRF. The investigator is obligated to provide 
all information of the event that is available at the time of the initial contact. 
In case of disturbed or interrupted access to eCRF, please use the following FAX line or 
e-mail account for submission of SAEs (related/unrelated): 
Fax: +353 1 809 9501 
QLS_IFX1@iqvia.com 


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In addition, care should be taken to ensure that the patient’s identity is protected and the patient 
identifier in the clinical study are properly mentioned on any copy of a source document provided 
to the sponsor. If laboratory results are provided, they must be supplemented by laboratory normal 
ranges. 
9.2.2. 
Follow-Up Reporting of Serious Adverse Events 
Follow-up information on SAEs must be reported by the investigator within the same time frames 
as the initial reporting.  
A follow-up report to an SAE should be prepared if any relevant change in the patient’s medical 
condition occurs, or any new relevant information becomes available.  
Further information on follow-up procedures is given in Appendix 6. 
9.3. 
Determination of Relationship 
The investigator will use medical consideration to determine the relationship of an AE to study 
treatment based on the following definitions (see also Appendix 6 II):  
Unrelated 
This category applies to AEs that are due to extraneous causes (disease, concomitant medication, 
environment, etc.) and are not related to study treatment.  
Unlikely Related 
This category applies to AEs that are unlikely related to study treatment. The relationship of an 
AE to study treatment can be considered unlikely related if (must have at least 2 criteria listed 
below):  
• 
The AE does not follow a reasonable temporal sequence from administration of the drug 
• 
The AE could readily have been a result of the patient’s clinical state or other underlying 
medical condition, environmental or toxic factors, or other modes of therapy administered to 
the patient 
• 
The AE does not follow a known response pattern to the suspected drug 
• 
The AE does not reappear or worsen when study treatment is re-administered 
Possibly Related 
This category applies to AEs that are unlikely to be related to the administration of study treatment, 
but the possibility cannot be ruled-out with certainty. The relationship of an AE to study treatment 
can be considered possibly related if (must have at least 2 criteria listed below):  
• 
The AE follows a reasonable temporal sequence from administration of study treatment 


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• 
The AE could readily have been a result of the patient’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the patient 
• 
The AE follows a known response pattern to the suspected study treatment 
Probably Related 
This category applies to AEs that are considered with a high degree of certainty to be related to 
study treatment. The relationship of an AE to study treatment can be considered probably related 
if (must have at least 3 criteria listed below): 
• 
The AE follows a reasonable temporal sequence from administration of study treatment 
• 
The AE could not be reasonably explained by the known characteristics of the patient’s 
clinical state, environmental or toxic factors, or other modes of therapy administered to the 
patient 
• 
The AE disappears or decreases upon discontinuation of study treatment or reduction in dose 
• 
The AE follows a known response pattern to the suspected study treatment 
Definitely Related 
This category applies to AEs that are determined with certainty to be related to study treatment. 
The relationship of an AE to study treatment can be considered definitely related if (must have at 
least 3 criteria listed below): 
• 
The AE follows a reasonable temporal sequence from administration of study treatment or 
study treatment levels have been established in body fluids or tissues 
• 
The AE could not be reasonably explained by the known characteristics of the patient’s 
clinical state, environmental or toxic factors, or other modes of therapy administered to the 
patient 
• 
The AE disappears or decreases upon discontinuation of study treatment or reduction in dose 
and, if applicable, appears upon re-challenge 
• 
The AE follows a known response pattern to the suspected study treatment 
• 
There are exceptions when an AE does not disappear upon discontinuation of study treatment, 
yet study treatment relatedness clearly exists; e.g., 1) tardive dyskinesia, 2) fixed drug 
eruptions 
9.4. 
Death Reporting 
The site should follow all patients for survival and collect information around the death on the 
appropriate eCRF form until the end of the study. 
Primary cause of death should be reported in AE section and SAE form, as well as appropriate 
eCRF section(s). If symptoms of disease progression occurred and constitute the primary cause of 
death, these symptoms could be reported as fatal (S)AE (see Section 9.3). 


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9.5. 
Abnormal Laboratory Values/Vital Signs/Electrocardiogram/Physical 
Examination 
Abnormalities of Laboratory results/vital signs/ECG/physical examination should be reported as 
AEs (using the NCI CTCAE v5.0 terminology) particularly if ≥1 of the following is met: 
• 
Any criterion for an SAE is fulfilled 
• 
The abnormality causes the patient to discontinue from the study treatment. 
• 
The abnormality causes the patient to interrupt the study treatment or a modification of dosing. 
• 
The abnormality requires intervention as corrective treatment or consultation. 
• 
The investigator judges that the abnormality is clinically relevant and should be reported as 
an (S)AE in the eCRF. 
All laboratory tests for which abnormal results are collected after the initiation of study treatment 
should be repeated until the values return to normal or to a stable status. All abnormal results are 
assessed as clinically relevant by the investigator must be reported as an AE. The frequency of 
such checks is at the investigator’s discretion depending on the degree of abnormality. The 
reporting of laboratory/vital signs/ECG/physical examination abnormalities (e.g., anemia) as both 
AEs and a specific finding of laboratory values/vital signs/ECG (e.g., decrease in red blood cells) 
should be avoided.  
9.6. 
Events to be Handled as Serious Adverse Events 
9.6.1. 
Overdose Reporting 
An overdose is defined as the accidental or intentional ingestion or infusion of any dose of a 
product that is considered both excessive and medically relevant.  
Generally, overdoses should be handled as SAEs and should be reported via the eCRF SAE page. 
In case of an asymptomatic overdose for IFX-1, please do not report it as serious AE. 
 
These steps must be followed: 
 
1. 
Report the overdose (IFX-1: only symptomatic; pembrolizumab: symptomatic and 
asymptomatic overdoses) in accordance with the Section 9.2 through the SAE page in 
eCRF. Document the actually delivered dose of the IMP as well as the duration of infusion 
in the eCRF SAE page (narrative section) within 24 hours of event occurrence. 
2. 
In addition, document the actual dose added to the infusion bag, the duration of the 
infusion, and the actually delivered dose on the respective IMP administration page in the 
eCRF. 
Refer to Section 7.6 for details on the treatment of overdose. 


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9.6.2. 
Pregnancy and Breastfeeding Reporting 
If the patient or partner of a patient participating in the study becomes pregnant or in case of 
breastfeeding, during treatment or within
after the last dose of IFX-1 or 120 days after 
the last dose of pembrolizumab treatment, or until
ollowing discontinuation of study 
treatment if the patient initiates new anticancer therapy, the investigator should report the 
pregnancy and breastfeeding exposure to QLS_IFX1@iqvia.com via e-mail within 24 hours of 
being notified using the paper based pregnancy/breastfeeding reporting form. In case e-mail 
contact is not possible, the site can provide the form via FAX line: +353 1 809 9501. 
In case of any accompanying Serious Adverse Events the standard reporting procedure via eCRF 
must be followed (see Section 9.2). 
A patient becoming pregnant while on study treatment will immediately be discontinued from 
treatment and the EOT Visit will be performed. 
The patient or partner should be followed by the investigator until completion of the pregnancy. If 
the pregnancy ends for any reason before the anticipated date, the investigator should notify the 
sponsor. At the completion of the pregnancy, the investigator will document the outcome of the 
pregnancy.  
9.6.3. 
Drug-Induced Liver Injury 
Potential drug induced liver injury is considered an important medical event. Although it is not 
always serious by regulatory definition, such event must be handled as SAE. 
Wherever possible, timely confirmation within 48 to 72 hours of initial liver-related laboratory 
abnormalities should occur prior to the reporting of a potential drug induced liver injury event. All 
occurrences of potential drug induced liver injuries, meeting the defined criteria, must be reported 
as SAEs. 
Potential drug induced liver injury is defined as: 
• 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation ≥3 × upper 
limit of normal (ULN) 
AND 
• 
Total bilirubin ≥2 × ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase) 
AND  
• 
No cholestatic or other immediately apparent possible causes of AST or ALT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic 


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9.6.4. 
Suspected Transmission of an Infectious Agent via Study Drug 
For the purposes of reporting, any suspected transmission of an infectious agent (pathogenic or 
non-pathogenic) via the investigational drug should be considered as an SAE. 
A transmission of an infectious agent may be suspected from clinical signs or symptoms, or 
laboratory findings indicating an infection in a patient exposed to a medicinal product.  
In the context of evaluating a suspected transmission of an infectious agent via a medicinal product, 
care should be taken to discriminate, whenever possible, between the cause (e.g., 
injection/administration) and the source (e.g., contamination) of the infection and the clinical 
conditions of the patient at the time of the infection (immuno-suppressed/vaccine). 
9.7. 
Adverse Events of Special Interest 
AESIs are events that are considered to have a special meaning or importance for a particular drug 
or class of drugs. They may be non-serious or serious. Therefore, they should be closely monitored. 
The site must report all AESIs that occur with start of study treatment, whether considered to be 
related to study treatment or not, according to Appendix 6. Moreover, AESIs should be 
documented in the general AE section of the eCRF as well as in the patient file. 
9.7.1. 
IFX-1 
This is the first study investigating IFX-1 in a malignant disease. Clinical experience with IFX-1 
has been generated in >300 patients with inflammatory diseases, including sepsis and HS.  
For this study, the following AEs are defined as AESIs: 
• 
  
 
 
 
 
 
 
 
  
 
 
 
  


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• 
  
 
 
 
 
 
  
• 
 
 
 
 
 
 
 
  
9.7.2. 
Pembrolizumab 
For pembrolizumab, AESIs for this study include:  
• An overdose of pembrolizumab, as defined in Section 7.6, that is not associated with 
clinical symptoms or abnormal laboratory results 
• An elevated AST or ALT lab value ≥3 × ULN and an elevated total bilirubin lab value 
≥2 × ULN and, at the same time, an alkaline phosphatase lab value <2 × ULN, 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 study site guidance for assessment 
and follow-up of these criteria can be made available. It may also be appropriate to conduct 
additional evaluation for an underlying etiology in the setting of abnormalities of liver 
blood tests including AST, ALT, bilirubin, and alkaline phosphatase that do not meet the 
criteria noted above. In these cases, the decision to proceed with additional evaluation will 
be made through consultation between the study investigators and the sponsor clinical 
director. However, abnormalities of liver blood tests that do not meet the criteria noted 
above are not AESIs for this study. 


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9.8. 
Reporting to Competent Authorities and Ethics Committees 
The IBs will be the reference document for safety information. 
The safety vendor is responsible for submission of suspected unexpected serious adverse reactions 
(see Appendix 6 I for a definition) to health authorities and Independent Ethic Committees (IEC) 
in accordance with local regulations. 
The investigator is responsible for informing the Independent Review Board (IRB)/IEC in a timely 
manner and in accordance with local procedures 
10. 
STATISTICAL CONSIDERATIONS 
10.1. Sample Size Determination 
This study plans to enroll a total of up to approximately 70 patients, including up to 29 patients in 
Arm A to receive IFX-1 monotherapy and up to 41 patients in Arm B (safety run-in: 9 to 
18 patients; Phase II portion: 23 patients) to receive combination therapy with IFX-1 and 
pembrolizumab. 
The 2 treatment arms are evaluated separately. No adjustment for multiplicity will be performed 
for the application of Simon’s 2-stage design in each arm. The sample size of 29 for analyses of 
the Phase II portion in each treatment arm is based on an optimal Simon’s 2-stage design, with 
10 patients planned for the first stage and 19 patients planned for the second stage. This sample 
size is based on a proportion of responders for a drug which is not worth to pursue further of 
p0=5%. The proportion of responders of a good drug was set to p1=20% for this sample size. The 
null hypothesis that the best ORR p≤0.05 will be tested versus the alternative hypothesis that 
p>0.05. This design leads to an expected sample size of about 18 patients per arm and a probability 
of early termination of 59.9%. If the drug is actually not effective, there is a 4.7% probability of 
concluding that it is effective (Type I error). If the drug is actually effective, there is a 19.9% 
probability of concluding that it is not effective (Type II error). After testing the drug on 10 patients 
in the first stages of both arms, the study will be terminated if no patient responds. If a treatment 
arm proceeds to the second stage, a total of 29 patients (10 in Stage 1 plus 19 in Stage 2) will be 
studied for this dose in this treatment arm. If the total number responding is ≤3, the hypothesis of 
a potentially effective drug is rejected. 
10.2. Analysis Sets 
For purposes of analysis, the following analysis sets are defined: 
 
 


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Analysis Set 
Description 
Enrolled Set 
All patients who sign the informed consent form 
Safety Analysis Set (SAS) 
All patients assigned to study treatment and who received 
≥1 dose of study treatment (IFX-1 for monotherapy arm, 
IFX-1 or pembrolizumab for combination arm) 
Full Analysis Set (FAS) 
All patients assigned to study treatment 
Per Protocol Set (PPS) 
All patients who received ≥1 dose of study treatment and 
who have ≥1 post-baseline tumor assessment 
Protocol violations will be reviewed in the data review meeting. The decisions will be documented 
in the meeting minutes and finalized before database lock. 
In general, safety analyses will be based on the SAS. The primary efficacy analyses will follow an 
intention-to-treat concept and will be performed on the FAS. 
10.3. Statistical Analyses 
The statistical analysis plan (SAP) will be developed and finalized before the first patient is 
enrolled. The SAP will include the exact definition of endpoints and variables to be analyzed, 
extensive details on the statistical analysis methods to be used together with the structure of tables 
and figures to be included as end-of-text tables and figures as well as appended listings for the 
clinical study report. It will also describe procedures for accounting for missing, unused, and 
spurious data. This section is a summary of the planned statistical analyses of the primary and 
secondary endpoints. 
Individual data will be listed. Data will be summarized using suitable descriptive statistics; 
depending on the structure of the data, summary statistics (e.g., number of observations, mean, 
standard deviation, minimum, median, maximum, lower quartile, upper quartile) or frequency 
tables may be used.  
All data will be displayed by treatment arm if not specified otherwise. 
10.3.1. 
Efficacy Analyses 
All efficacy analyses will be performed on the FAS. All analyses will be conducted separately by 
treatment arm. The 2 treatment arms will be compared descriptively. Patients will be analyzed 
descriptively and stratified by locally advanced or metastatic cSCC.  
The primary efficacy variable is the best ORR (investigator assessed) based on modified RECIST 
v1.1 criteria (Eisenhauer et al., 2009) and iRECIST criteria (Seymore et al., 2017). The number 
and percentage of responders will be displayed per treatment arm along with its 95% confidence 
interval according to Clopper-Pearson. 


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Patients who discontinue the study after assignment to treatment due to 1 of the following reasons 
will be counted as non-responder if they have not shown response before discontinuation: 
• 
Lack of efficacy 
• 
AE at least possibly related to study treatment 
• 
PD/iCPD 
• 
Clinical deterioration 
Statistical inference will be based on the thresholds defined by the Simon’s 2-stage design. For 
decision criteria at the interim analysis, please refer to Section 10.3.4. At the final analysis, the 
null hypothesis of an ORR of ≤5% will be rejected if >3 patients out of a total of 29 patients 
respond (CR/iCR/PR/iPR). Due to dropouts, the number of patients evaluable for the primary 
endpoint might not be exactly 29. In this case, appropriate statistical methods will be applied to 
correct for the deviation from the planned sample size of 29 evaluable patients (Koyama and Chen, 
2008). In this case, appropriate statistical methods will be applied to correct for the deviation from 
the planned sample size of 29 evaluable patients (Koyama and Chen, 2008). Further details will 
be specified in the SAP.  
Additionally, the number and percentage of patients per RECIST tumor response category will be 
displayed for each scheduled tumor assessment time point.  
Secondary Endpoint 
Statistical Analysis Methods 
Response (CR/iCR/PR/iPR) 
duration 
Duration of response will be analyzed for patients who 
reach at least PR/iPR at any time during the study using 
Kaplan-Meier methods. A responding patient who 
experiences any form of progression will be evaluated as 
a patient with event. The starting point is the first 
diagnosis of CR/iCR or PR/iPR. The time point of the 
event will be the diagnosis of progression according to 
RECIST. Responding patients without progression will 
be censored at their last tumor assessment showing 
response. Patients who never responded will be excluded 
from this analysis. 
SD duration 
Duration of SD will be analyzed using Kaplan-Meier 
methods. The starting point is the first study treatment 
administration. A patient who experiences any form of 
progression will be evaluated as a patient with event. The 
time point of the event will be the diagnosis of 
progression according to RECIST (PD) or iRECIST 
(iCPD). Patients without progression will be censored at 
their last tumor assessment showing response or any 
other best overall response except PD/iCPD. 
PFS 
PFS will be analyzed using Kaplan-Meier methods. A 
patient who experiences any form of progression or who 


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dies of any cause will be evaluated as a patient with event. 
The time point of the event will be the diagnosis of the 
first progression according to RECIST/iRECIST or the 
date of death. Patients without progression and still alive 
will be censored at their last tumor assessment. 
OS 
OS will be analyzed using Kaplan-Meier methods. Death 
by any cause will be evaluated as event. Patients who are 
still alive when they discontinue the study will be 
censored at their last recorded date of being alive. 
Disease control rate 
The 
number 
and 
percentage 
of 
patients 
with 
SD/confirmed SD (iSD) per modified RECIST 
v1.1/iRECIST or PR/iPR or CR/iCR will be displayed 
per tumor assessment timepoint. 
Exploratory endpoints will be analyzed descriptively. Further details will be provided in the SAP. 
10.3.2. 
Safety Analyses 
All safety analyses will be performed on the SAS. 
An AE is considered as treatment emergent if it starts during or after first administration of study 
treatment (IFX-1 or pembrolizumab). The number and percentage of patients with TEAEs, SAEs, 
and AESIs for IFX-1 and/or pembrolizumab will be analyzed, as well as the number of TEAEs, 
SAEs, and AESIs with the respective MedDRA System Organ Class and Preferred Term. Where 
AEs are grouped by NCI CTCAE grade or relationship, the maximum grade/relationship per 
patient and class of AE will be considered. The described analyses will be performed for the 
treatment period and the follow-up period separately. AEs reported during screening or before first 
study treatment administration will be categorized as pre-treatment AEs. 
Safety laboratory, vital signs, and 12-lead ECG parameters will be analyzed by summary statistics 
(e.g., number of observations, mean, standard deviation, minimum, median, maximum, lower 
quartile, upper quartile) for absolute values and changes from baseline by visit. Shift tables 
comparing baseline and the worst post-baseline assessment will be prepared if applicable. 
Categorical safety parameters, like findings from physical examination, will be summarized by 
absolute and relative frequencies by time point. 
10.3.3. 
Exploratory Analyses 
PK, pharmacodynamics, and biomarker exploratory analyses will be described in the SAP 
finalized before database lock.  
10.3.3.1. 
Pharmacokinetic Analyses 
Actual PK sampling date and times will be documented and the plasma concentration of IFX-1 
will be assessed by time point. Summary statistics will be provided for the PK concentrations of 


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IFX-1 at all measured time points including also the geometric mean and its coefficient of 
variation. PK parameters including but not limited to Cmax and Ctrough, will be analyzed using 
descriptive statistics including also the geometric mean and its coefficient of variation. 
10.3.3.2. 
Immunogenicity Analyses 
The number and percentage of patients with detectable ADAs against IFX-1 will be displayed per 
time point and overall post-baseline. 
10.3.3.3. 
Quality of Life Analyses  
QoL will be assessed by the EORTC-QLQ-C30. The change from baseline of the total score will 
be analyzed descriptively at each measured time point as a secondary endpoint. 
10.3.3.4. 
Pharmacodynamic Analyses 
Pharmacodynamics endpoints will be analyzed using descriptive statistics. 
10.3.4. 
Interim Analyses 
10.3.4.1. 
Formal Interim Analysis Based on Simon’s 2-Stage Design 
An interim analysis based on Simon’s 2-stage design (Simon, 1989) of treatment response will be 
performed after Stage 1 in both treatment arms (monotherapy Arm A and combination therapy 
Arm B) before enrollment into Stage 2. 
The interim analysis will be performed on the first 10 patients evaluable for the Phase II portion 
per arm when these 10 patients have performed their third post-baseline tumor assessment OR 
discontinued treatment. At the time of the interim analysis, a treatment arm will be discontinued if 
0 responders are observed in the respective treatment arm. A responder is defined as in 
Section 10.3.1. Each treatment arm will be evaluated separately such that it may occur that 
enrollment into both arms is stopped, enrollment into 1 arm is stopped and the other is continued 
to the second stage, or enrollment into both arms is continued. If both arms are discontinued after 
Stage 1, the final analysis will be performed after all patients enrolled in Stage 1 will have 
completed or discontinued the study and described in a clinical study report. If enrollment is 
stopped, patients will still receive treatment until disease progression (EOT), or are discontinued 
due to other reasons, and will then be followed up for 12 months. 
10.3.4.2. 
Safety Run-In Based on 3+3 Design (Combination Therapy Arm B) 
The safety run-in phase in the combination Arm B will follow a 3+3 design for escalation of the 
IFX-1 treatment regimen based on the following escalation rules: 
• 
If 0 of 3 patients experience a DLT during the DLT observation period (see Section 7.2.2.2.3) 
at a certain IFX-1 treatment regimen, the subsequent 3 patients will be enrolled in the next 
higher IFX-1 treatment regimen. 


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• 
If 1 of 3 patients experience a DLT, another 3 patients will be enrolled at the same IFX-1 
treatment regimen. 
− 
If 1 of 6 patients (i.e., none of the subsequent 3 patients) experiences a DLT, the 
combination arm will escalate to the next IFX-1 treatment regimen. 
− 
If >1 of 6 patients at the same IFX-1 treatment regimen experience a DLT, this treatment 
regimen will be stopped. 
• 
If >1 of 3 patients at the same IFX-1 treatment regimen experience a DLT, this treatment 
regimen will be stopped. 
• 
If a treatment regimen is stopped, the next lower treatment regimen is considered as MTD.  
• 
In the highest IFX-1 treatment regimen (regimen 3): if ≤1 of 6 patients experience a DLT, this 
will be determined as RP2D.  
• 
6 patients will need to be treated at the MTD or at the highest IFX-1 dose level (Regimen 3, 
if MTD was not reached) to decide if this dose can be selected as RP2D which will then be 
explored in the Phase II portion of Arm B. In case only 3 patients will have been previously 
treated at the MTD or highest IFX-1 dose level, 3 more patients will be added to this cohort. 
If 6 patients were already treated at the proposed dose level, then additional patients will not 
be required and the decision on the RP2D will be made based on the available data.   
• 
The subsequent patients will be enrolled at the RP2D to fill up the first stage of the Simon’s 
2-stage design for the combination arm (4 additional patients to reach the required sample size 
of 10). 
 
 


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12. 
APPENDICES 


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Appendix 1 
Visit Procedures 
Screening Visit 
• 
Informed consent procedures 
• 
Check of all inclusion and exclusion criteria 
• 
Biopsy for confirmation of diagnosis of cSCC for locally advanced cSCC patients if no 
archival tumor tissue is available 
• 
Document demography, medical and disease history (including hepatitis), prior medication 
• 
Disease/response assessment 
• 
QoL assessment 
• 
Documentation of concomitant disease and concomitant medication 
• 
Safety assessments: 
− 
Height, weight 
− 
Physical examination, ECOG PS 
− 
Vital signs 
− 
AEs 
− 
ECG 
• 
Blood and urine samples for complete safety laboratory 
• 
Pregnancy testing (WOCBP only): serum beta-HCG test within 72 hours before first drug 
administration 
• 
Tissue sampling for biomarker assessments (skin, metastasis) 
Treatment Visits 
The Treatment Period will comprise mainly weekly visits until Cycle 1 Days 22 followed by bi-
weekly visits until the EOT. Visits will have an accepted time window of between 1 and ±3 days 
as specified in the SoA (Table 1).  
The following assessments and procedures will be performed during the treatment period:  
• 
Re-check of all inclusion and exclusion criteria (Cycle 1 Day 1 pre-dose) 
• 
Disease/response assessment (Day 1 of each cycle from Cycle 2 on until EOT Visit) 
• 
QoL assessment (Cycle 1 Day 1 pre-dose-; Day 1 of each cycle from Cycle 2 on until EOT 
Visit)  
• 
Documentation of concomitant disease and concomitant medication (Cycle 1 Days 1 
[pre-dose], 4, 8, 15, 22, and 36; Days 1, 15, and 29 of each cycle from Cycle 2 on until EOT 
Visit) 


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• 
Check of re-dosing criteria pre-dose at Cycle 1 Days 4, 8, 15, 22, and 36, and Days 1, 15, and 
29 of each cycle from Cycle 2 on until EOT Visit 
• 
Study treatment administration by intravenous route as 30-minute (-5/+10 minutes) infusion: 
− 
Arm A (IFX-1 monotherapy):  
o Cycle 1 Days 1, 4, 8, and 15: 800 mg IFX-1 
o Cycle 1 Day 22 and Day 36, and from Cycle 2 onwards until EOT (Days 1, 15, 29 of 
each cycle): 1600 mg IFX-1 Q2W 
− 
Arm B – combination regimen 1:  
o Cycle 1 Days 1, 4, 8, and 15: 400 mg IFX-1 + 400 mg pembrolizumab on Day 8 
o Cycle 1 Day 22 and Day 36, and from Cycle 2 onwards until EOT (Days 1, 15, 29 of 
each cycle): 800 mg IFX-1 Q2W + 400 mg pembrolizumab Q6W (on Day 1 of each 
cycle) 
− 
Arm B – combination Regimen 2:  
o Cycle 1 Days 1, 4, 8, and 15: 600 mg IFX-1 + 400 mg pembrolizumab on Day 8 
o Cycle 1 Day 22 and Day 36, and from Cycle 2 onwards until EOT (Days 1, 15, 29 of 
each cycle): 1200 mg IFX-1 Q2W + 400 mg pembrolizumab Q6W (on Day 1 of each 
cycle) 
− 
Arm B – combination regimen 3:  
o Cycle 1 Days 1, 4, 8, and 15: 800 mg IFX-1 + 400 mg pembrolizumab on Day 8 
o Cycle 1 Day 22 and Day 36, and from Cycle 2 onwards until EOT (Days 1, 15, 29 of 
each cycle): 1600 mg IFX-1 Q2W + 400 mg pembrolizumab Q6W (on Day 1 of each 
cycle) 
• 
Safety assessments:  
− 
Weight (Cycle 1 Days 1 [pre-dose], 4, 8, 15, 22, and 36; Days 1, 15, and 29 of each cycle 
from Cycle 2 on until EOT Visit) 
− 
Physical examination (Cycle 1 Days 1 [pre-dose], 4, 8, 15, 22 and36; Days 1, 15, and 29 
of each cycle from Cycle 2 on until EOT Visit) 
− 
Vital signs (Cycle 1 Days 1 [pre- and post-dose], 4, 8, 15, 22 and 36; Days 1, 15, and 29 
of each cycle from Cycle 2 on until EOT Visit) 
− 
AEs (Cycle 1 Days 1 [pre- and post-dose], 4, 8, 15, 22 and 36; Days 1, 15, and 29 of each 
cycle from Cycle 2 on until EOT Visit) 
− 
ECG (Cycle 1 Day 1 [pre- and post-dose], Cycle 2 Day 1 [post-dose]) 
• 
Blood and urine samples for safety laboratory: 
− 
Hematology (Cycle 1 Days 1 [pre-dose], 8, 15, 22, and 36; Cycle 2 Days 1, 15, and 29; 
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− 
Biochemistry (Cycle 1 Days 1 [pre-dose], 8, 15, 22, and 36; Cycle 2 Days 1, 15, and 29; 
and Day 1 of each subsequent cycle onwards until EOT Visit) 
− 
Coagulation parameters (Cycle 1 Day 1 [pre-dose], Cycle 2 Day 1) 
− 
Urinalysis (Cycle 1 Days 1 [pre-dose], 8, 15, 22, and 36; Cycle 2 Days 1, 15, and 29; and 
Day 1 of each subsequent cycle onwards until EOT Visit) 
− 
Thyroid stimulating hormone, preferably total T3, free T4 (or other T3/T4 fractions 
depending on local standards) (Cycle 1 Day 8, and Day 1 of each subsequent cycle until 
EOT Visit) 
− 
Urine pregnancy test (WOCBP) (Cycle 1 Days 8, 22, and 36; Days 1, 15, and 29 in 
Cycle 2 and each subsequent cycle until EOT Visit)  
• 
Plasma and serum sampling pre-dose: 
− 
C3a at Cycle 1 Day 1 [pre-dose]  
− 
C5a in plasma (Cycle 1 Days 1 [pre-dose], 8, 15, 36 and 22; Day 1 of Cycles 2, 3, 5, and 
then of every other cycle until EOT Visit) 
− 
ADAs against IFX-1 in serum (Cycle 1 Days 1 [pre-dose] 15, 22 and 36; Day 1 of 
Cycles 2, 3, 5, and then of every other cycle until EOT Visit) 
• 
PK parameter assessment: 
− 
At pre-dose on Cycle 1 Days 1, 8, 15, 22, and 36; Day 1 of Cycles 2, 3, 5, and then of 
every other cycle until EOT Visit 
− 
Additionally, post dose H0+0.5h (-5/+10 minutes, but not before the end of IFX-1 
administration), or just after the end of administration in case of decrease in infusion rate 
on Cycle 1 Days 1 and 22 
• 
Tumor biomarkers 
− 
Skin biopsy (Screening, and for Stage 2 patients only: Cycle 2 Day 1 (mandatory), once 
at time of CR/iCR/PR/iPR (optional), and/or at PD (optional) 
− 
If skin biopsy is not possible: Metastasis biopsy (Screening, and for Stage 2 patients only: 
Cycle 2 Day 1, once at time of CR/iCR/PR/iPR, and/or at PD (optional) 
End of Treatment Visit 
• 
Disease/response assessments 
• 
QoL 
• 
Documentation of concomitant disease and concomitant medication 
• 
Safety assessments: 
− 
Weight 
− 
Physical examination, ECOG PS 
− 
Vital signs 


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− 
AEs 
− 
ECG 
• 
Safety laboratory (hematology, biochemistry, coagulation parameters, urinalysis, thyroid 
stimulating hormone, preferably total T3, free T4 (or other T3/T4 fractions depending on local 
standards), urine pregnancy test [WOCBP]) 
• 
Sampling for PK, C5a, immunogenicity of IFX-1(ADA) 
• 
Only Stage 2 patients: Skin and metastasis biopsy (optional) 
Follow-Up Visits (every 12 weeks [±7d]) and End of Study Visit (=last follow-up) 
• 
Disease/response assessment (only if discontinuation of IFX-1 treatment for other reasons 
than PD/iCPD) 
• 
QoL 
• 
Documentation of: 
− 
AEs 
− 
Survival status 
− 
Further antineoplastic therapies 
• 
Urine pregnancy test (WOCBP): on the first FU Visit for Arm A, on the first FU visit and 120 
days after the last dose of pembrolizumab for Arm B. 
• 
Only at first FU Visit: Sampling for PK, C5a 
• 
ADAs against IFX1 (only at first FU Visit)


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Appendix 2 
Clinical Laboratory Tests 
Protocol-required laboratory assessments are detailed in Table 2, specific requirements for in- or 
exclusion in Section 6.1 and Section 6.2. Additional tests may be performed at any time during the 
study as determined necessary by the investigator or required by local regulations. 
Table 2 
Protocol-Required Safety Laboratory Assessments 
Assessment 
Parameters 
Hematology 
Hemoglobin 
Hematocrit 
Platelet count 
Red blood cell count 
Red blood cells (MCV) 
White blood cell count with 
differentials 
(neutrophils, 
lymphocytes, 
monocytes, 
eosinophils, basophils) 
Coagulation parameters 
aPTT 
PT 
Clinical chemistry a 
ALT (SGPT) 
AST (SGOT) 
ALP 
LDH 
Total bilirubin 
Total protein 
Albumin 
Amylase 
Lipase 
Urea 
Uric acid 
Sodium 
Potassium 
Calcium 
Magnesium 
Creatinine 
Glucose 
CRP 
Urinalysis (Dipstick)b 
PH 
Glucose 
Leucocytes 
Protein 
Blood 
Other screening tests 
TSH, Total T3, Free T4 (or other T3/T4 fractions depending on local standard) 
FSH and estradiol (as needed in women of non-childbearing potential only) 
Serum or urine hCG pregnancy test (as needed in women of childbearing 
potential) 
ALP=alkaline phosphatase; ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic 
transaminase); aPTT=activated partial thromboplastin time; AST (SGOT)=aspartate aminotransferase 
(serum glutamic oxaloacetic transaminase); CRP=C reactive protein; FSH=follicle stimulating hormone; 
hCG=human chorionic gonadotropin; LDH=lactate dehydrogenase; MCV=mean corpuscular volume; 
PT=prothrombin time; TSH=thyroid stimulating hormone. 
a Details of liver chemistry stopping criteria, required actions, and follow up assessments are given in 
Section 9.6.3. All events of ALT ≥3 × ULN and bilirubin ≥2 × ULN (35% direct bilirubin) or ALT 
≥3 ULN and INR >1.5 (if measured), may indicate severe liver injury (possible Hy’s Law) and must 
be reported as an SAE. 
b Local urine testing will be standard for the protocol unless serum testing is required by local regulation 
or IRB/IEC. 
Investigators must document their review of each laboratory safety report.


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Appendix 3 
RECIST 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS: RECIST GUIDELINE 
(VERSION 1.1) 
Response and progression will be evaluated in this study using the international criteria proposed 
by the revised RECIST v1.1 guideline (Eisenhauer et al., 2009) and according to iRECIST 
(Seymore et al., 2017; see Appendix 4), which introduces additional tumor assessments and 
evaluation criteria in situations where pseudo-progression is suspected.  
Changes in the largest diameter (uni-dimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. 
Selection of Lesions 
• 
Measurable disease: Measurable lesions are defined as those that can be accurately measured 
in ≥1 dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) by chest x-ray or as 
≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam. All tumor measurements 
must be recorded in millimeters (or decimal fractions of centimeters). 
• 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be ≤5 mm [0.5 cm]). At baseline and in follow-up, only the short 
axis will be measured and followed.  
• 
Non-measurable disease: All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 to 
<1.5 cm] short axis), are considered non-measurable disease. Bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory 
breast disease, and abdominal masses (not followed by CT or MRI), are considered as 
non-measurable. Note: Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. “Cystic lesions” thought to represent cystic 
metastases can be considered as measurable lesions, if they meet the definition of 
measurability described above. However, if non cystic lesions are present in the same patient, 
these are preferred for selection as target lesions. 
• 
Target lesions: All measurable lesions ≤2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes 
are to be included in the sum, then only the short axis is added into the sum. The baseline sum 


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diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
• 
Non-target lesions: All other lesions (or sites of disease) including all measurable lesions not 
selected as one of the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be noted throughout follow-
up. 
Methods for Assessment of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never >4 weeks before the beginning of the treatment. The same method of assessment and the 
same technique should be used to characterize each identified and reported lesion at baseline and 
during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination 
unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
• 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter as assessed using 
calipers (e.g., skin nodules). In the case of skin lesions, documentation by standardized 
medical color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
• 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
• 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less. If CT scans have 
slice thickness >5 mm (0.5 cm), the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situation. 
• 
Positron emission tomography (PET)-CT: At present, the low dose or attenuation correction 
CT portion of a combined PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements. However, if the site can document that the CT performed as part of 
a PET-CT is of identical diagnostic quality to a diagnostic CT (with intravenous and oral 
contrast), then the CT portion of the PET-CT can be used for RECIST measurements and can 
be used interchangeably with conventional CT in accurately measuring cancer lesions over 
time. Note, however, that the PET portion of the CT introduces additional data which may 
bias an investigator if it is not routinely or serially performed. 
• 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from 1 assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by 
CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances.  


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• 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation 
is not advised. However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in studies where recurrence 
following CR or surgical resection is an endpoint. 
• 
Tumor markers. Tumor markers alone cannot be used to assess response. If markers are 
initially above the ULN, they must normalize for a patient to be considered in complete 
clinical response. 
• 
Cytology, histology: These techniques can be used to differentiate between PR and CR in 
rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known 
residual benign tumors can remain).The cytological confirmation of the neoplastic origin of 
any effusion that appears or worsens during treatment when the measurable tumor has met 
criteria for response or SD is mandatory to differentiate between response or SD (an effusion 
may be a side effect of the treatment) and PD. 
• 
Fluorodeoxyglucose (FDG)-PET. While FDG-PET response assessments need additional 
study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to complement 
CT scanning in assessment of progression (particularly possible “new” disease). New lesions 
on the basis of FDG-PET imaging can be identified according to the following algorithm: 
− 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
− 
No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly progression occurring at that 
site (if so, the date of PD will be the date of the initial abnormal FDGPET scan). If the 
positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that 
is not progressing on the basis of the anatomic images, this is not PD. 
− 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.  
Note: A “positive” FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
Response Criteria 
Evaluation of Target Lesions 
• 
CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to <10 mm (<1 cm). 
• 
PR: ≥30% decrease in the sum of the diameters of target lesions, taking as reference the 
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• 
PD: ≥20% increase in the sum of the diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase 
of ≥5 mm (0.5 cm). 
Note: The appearance of ≥1 new lesion is also considered progression. 
• 
SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum diameters while on study 
Evaluation of Non-Target Lesions 
• 
CR: Disappearance of all non-target lesions and normalization of tumor marker level. All 
lymph nodes must be non-pathological in size (<10 mm [<1 cm] short axis). 
Note: If tumor markers are initially above the ULN, they must normalize for a patient to be 
considered in complete clinical response. 
• 
Non-CR/Non-PD: Persistence of ≥1 non-target lesion(s) and/or maintenance of tumor marker 
level above the normal limits 
• 
PD: Appearance of ≥1 new lesions and/or unequivocal progression of existing non-target 
lesions. Unequivocal progression should not normally trump target lesion status. It must be 
representative of overall disease status change, not a single lesion increase. Although a clear 
progression of “non-target” lesions only is exceptional, the opinion of the treating physician 
should prevail in such circumstances, and the progression status should be confirmed at a later 
time by the review panel (or principal investigator). 
Evaluation of Response 
The best overall response is the best response recorded from the start of the treatment until 
PD/recurrence (taking as reference for PD the smallest measurements recorded since the treatment 
started). The patient’s best overall response assignment will depend on the achievement of both 
measurement and confirmation criteria over the several tumor response assessment time points. 
Revised RECIST v1.1 (Eisenhauer et al., 2009) criteria for response evaluation at a specific tumor 
assessment are summarized in the table: 


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Response Assignment According to Revised Response Evaluation Criteria in Solid Tumors 
(Version 1.1) 
Target Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
When Confirmation is 
Requireda 
CR 
CR 
No 
CR 
>4 weeks confirmation 
CR 
Non-CR/Non-PD 
No 
PR 
>4 weeks confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated 
No 
SD 
Documented at least once 
>4 weeks from baseline 
PD 
Any 
Yes or No 
PD 
No prior SD, PR, or CR 
Any  
PD 
Yes or No 
PD 
Any 
Any 
Yes  
PD 
CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease. 
a In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as PD. 
 
COMPOSITE RESPONSE CRITERIA FOR PATIENTS 
WITH LOCALLY ADVANCED cSCC 
This appendix describes clinical response criteria for externally visible lesions that can be 
measured bi-dimensionally using digital medical photography. This appendix also provides 
composite response criteria for disease that is measurable by both clinical response criteria and 
RECIST v1.1.  
Radiologic imaging (preferably, MRI with gadolinium) will be essential in the evaluation of 
tumors that have subdermal components that cannot be adequately assessed by digital medical 
photography. 
Response assessments occur after every cycle. Standardized digital photographs of the externally 
visible component of all target lesions must be obtained at baseline and at the time of each 
subsequent tumor assessment. Guidelines for digital medical photography will be provided to the 
sites. Investigators will also provide a clinical description of the externally visible target lesion(s) 
at baseline and at each tumor assessment, as well as comments on any changes in the lesion(s) 
since the previous assessment. 


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SPECIAL ISSUES FOR EXTERNALLY VISIBLE TUMORS: 
1) Anatomic Defects 
Regarding tumor around a surgical cavity/anatomic defect (e.g., rhinectomy), such lesions should 
be considered non-measurable unless there is a nodular lesion measuring ≥10 mm in maximal 
bi-dimensional perpendicular diameters. The surgical cavity or anatomic defect should not be 
considered in measuring the lesion. 
2) Indeterminate-Appearing Tissue 
If there is uncertainty about whether a given lesion or area of a lesion represents malignancy versus 
benign process (e.g., scarring, fibrosis), biopsies should be obtained at any tumor assessment time 
point. Indeterminate-appearing areas (e.g., scarring, fibrosis) are included in the tumor 
measurements unless biopsies are obtained to establish benign status. To reduce risk of sample 
error, biopsy of only a single area on the tumor is not allowed. Biopsy of ≥2 separate areas of the 
lesion are required when biopsy is indicated. Each biopsy will be performed in a pairwise manner 
(approximately adjacent) so that there will be 1 sample for local review and 1 for optional central 
review for each biopsy. As such, when the decision is made to perform biopsy, ≥4 biopsy samples 
are obtained (biopsy of 2 separate areas, with 2 biopsies in each area: 1 for central, 1 for local from 
each area). Biopsy samples will not be bisected or split in half for local and central review; rather, 
separate adjacent samples will be obtained. Further details will be given in the Biopsy Handling 
Manual. 
Note on Timeline for Finalization of Measurement/Response Assessment: Generally, baseline 
disease measurements and response evaluation should be completed on the day of the visit at which 
digital medical photography was performed. However, for visits in which tumor biopsies are 
performed, it is understood that the local pathology report may not be available for up to 5 business 
days after the biopsy.  
When biopsies are performed to distinguish between benign versus malignant tissue, the annotated 
photograph for that visit should clearly indicate the region of the tumor that was biopsied to 
distinguish benign versus malignant tissue. Within 1 week of the date of biopsies, the investigator 
should finalize the tumor measurements for that visit with the benefit of the local pathology report. 
For circumstances in which the intent of the biopsy is to distinguish between disease stability and 
response, it is not necessary to hold study treatment while the local pathology report is pending.  
For circumstances in which the biopsy, if positive, would result in discontinuation of study 
treatment due to progression, treatment should be held until biopsy results are finalized and 
progression has been ruled out. 


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3) Local Versus Central Review 
An independent photographic review committee, with access to de-identified digital medical 
photography results and biopsy results, may be installed by the sponsor upon emerging results. As 
such, independent photographic reviews will not be “real-time”. Clinical management decisions 
generally will be as per investigator response assessments and local pathology review. In case an 
independent photographic review committee will be installed during ongoing treatment of patients 
in the study, and in the unlikely event that independent review yields major differences with the 
local response assessment that could have implications for the ongoing management of an active 
patient on study, the situation will be discussed between the sponsor and the investigator in order 
to determine patient management. 
4) Confirmation of Responses 
After any observation of an objective response (i.e., CR/iCR, PR/iPR), confirmatory digital 
standardized medical photography (and radiologic imaging, if performed as part of the initial 
response assessment) will be obtained ≥4 weeks following initial documentation of objective 
response. For any complete responses observed in digital medical photography of externally 
visible target lesions, confirmatory biopsies are required to establish status of CR/iCR. 
5) Metastatic cSCC Patients with Externally Visible Tumors 
Externally visible tumors will generally be followed by RECIST v1.1 and iRECIST criteria. It is 
possible that some patients with metastatic cSCC may also have externally visible lesions that are 
measurable by digital medical photography. In such circumstances, the externally visible lesions 
generally will be followed as nontarget lesions. The exception to this rule would be a patient with 
externally visible lesions in whom the only M1 lesions are not measurable by RECIST (e.g., a 
patient with bone-only metastases), in which case the externally visible lesions (lesion size 
≥10 mm in baseline dimensional perpendicular axes) would be target lesions and followed as per 
clinical response criteria in this appendix, and the -non-measurable metastatic lesions (e.g., bone 
metastases) would be followed as non-target lesions. For any target lesions that are measured by 
digital medical photography, measurements will be bi-dimensional. 
6) Patients with Deeply Invasive Tumors 
Tumor measurements for these patients will generally be performed with digital medical 
photography (bi-dimensional measurements). However, some patients may have deeply invasive 
target lesions in which tumor measurements can better be obtained with cross-sectional imaging 
(e.g., MRI with gadolinium or CT with contrast). For any target lesions that are measured by cross-
sectional imaging (MRI gadolinium or CT with contrast), measurements will uni-dimensional 
according to RECIST v1.1. 


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Clinical Response Criteria for Externally Visible Tumors (for patients with locally advanced 
cSCC, and patients with metastatic cSCC in which target lesions are followed by digital medical 
photography) 
A. Externally Visible Tumor Dimension 
The externally visible component of target lesion(s) will be measured using bi-dimensional World 
Health Organization (WHO) criteria as the sum of the products (of individual target lesions) in the 
longest dimension and perpendicular second longest dimension at each tumor assessment and will 
be documented as described in a separate manual. In the absence of substantial change in lesion 
geometry, subsequent visit measurements should be performed in the same axes and the 
investigator should refer to the previous visit’s annotated photographs as a starting point to identify 
axis for measurement when making subsequent assessments. 
Clinical response criteria for externally visible tumor(s) require bi-dimensional measurements 
according to WHO criteria, and are as follows: 
• 
CR of externally visible disease: All target lesion(s) and non-target lesion(s) no longer 
visible, maintained for ≥4 weeks. Documentation of CR requires confirmation by biopsies of 
site(s) of externally visible target lesion(s) with histologic confirmation of no residual 
malignancy, per central pathology review, as described in a separate manual. In the absence 
of such histologic confirmation, a patient cannot be deemed to have experienced CR and the 
best response would be PR. 
• 
PR of externally visible disease: Decrease of 50% (WHO criteria) or greater in the sum the 
products of perpendicular longest dimensions of target lesion(s), maintained for ≥4 weeks 
• 
Progression of visible disease: Increase of ≥25% (WHO criteria) in the sum of the products 
of perpendicular longest dimensions of target lesion(s). In rare cases, unequivocal progression 
of a non-target lesion may be accepted as PD. 
• 
Stable externally visible disease: Not meeting criteria described above for CR or PR or SD 
of externally visible disease 
B. New Lesions 
A new cutaneous lesion consistent with cSCC will be considered as clinical PD if the lesion is 
≥10 mm in both maximal perpendicular diameters and can be clearly documented as not being 
previously present, unless it is confirmed on biopsy not to be consistent with cSCC. If a new 
cutaneous lesion is not biopsied or if the histology is inconclusive, it should be considered cSCC 
and deemed clinical PD.  


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Overall Clinical Responses for Locally Advanced cSCC Lesions That are Measured by 
Digital Medical Photography 
Externally Visible 
Tumor Dimensiona 
New Lesionsa 
Clinical Response 
CR of externally visible disease 
No 
Clinical CRb 
PR of externally visible disease 
No 
Clinical PR 
SD of externally visible disease 
No 
Clinical SD 
PD of externally visible disease 
Yes or No 
Clinical PD 
Any  
Yes 
Clinical PD 
CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease 
a See above for definitions. 
b Negative biopsy showing no residual malignant cells is required for any lesion be deemed clinical CR. 
Composite Response Criteria 
These criteria are for patients who have locally advanced or metastatic cSCC that is measurable 
by BOTH clinical response criteria by digital medical photography and RECIST v1.1 using 
radiologic imaging.  


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The “Clinical Response” column in this table will be based on the results of the “Clinical 
Response” (far-right) column of the table above. 
Clinical Response (Digital 
Medical Photography) 
RECIST 
v1.1 
Response 
(Radiology) 
Composite 
(Overall): 
Clinical 
+ 
RECIST 
Response 
clinical CR 
CR or NA 
CR 
NA 
CR 
CR 
clinical CR 
PR or SD 
PR 
clinical PR 
CR, PR, or SD, or NA 
PR 
NA 
PR 
PR 
clinical SD 
CR or PR 
PR 
clinical SD 
SD or NA 
SD 
NA 
SD 
SD 
clinical PD 
Any  
PD 
Any 
PD 
PD 
CR=complete response; NA=”not applicable” (e.g., assessment not done); PD=progressive disease; 
PR=partial response; SD=stable disease. 
In addition, if all previously inoperable target lesions are rendered operable with clear margins 
obtained at the time of surgery, this will be considered a PR. If the investigator deems a previously 
unresectable lesion to be potentially resectable, due to response to study treatment, the medical 
monitor should be consulted prior to any surgical procedure being performed. A decision will be 
rendered by the sponsor as to whether the planned surgical intervention is compatible with study 
requirements. (This statement does not apply to patients in emergency life-threatening situations 
that require immediate surgery). 
Note: If composite (overall) response evaluation of PD emerges for the first time, iRECIST 
assessment criteria for new lesion documentation apply (see Appendix 4) and the investigator will 
assess the clinical status of the patient in case pseudo-progression is suspected.  
C. Ulcerated Lesions 
This section only pertains to target lesions that have extensive ulceration at baseline that prevents 
measurement by the above methods in this appendix. Response criteria are as follows:  
• 
CR: Re-epithelialization of the entire baseline area of ulceration of target lesion(s), 
maintained over ≥4 weeks  
• 
PR: There are no criteria for partial response. 


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• 
SD: Not meeting criteria for CR or PD 
• 
PD: New ulceration of target lesion(s) not related to (i.e., in a location separate from) tissue 
biopsy or other known trauma, persistent without evidence of healing for ≥2 weeks 
Response and progression will be evaluated in this study using the international criteria proposed 
by the revised RECIST v1.1 guideline (Eisenhauer et al., 2009) and according to iRECIST 
(Seymore et al., 2017; see Appendix 4), which introduces additional tumor assessments and 
evaluation criteria in situations where pseudo-progression is suspected.  


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Appendix 4 
iRECIST 
Response and progression will be evaluated in this study using the international criteria proposed 
by the revised RECIST v1.1 guideline (Eisenhauer et al., 2009) and according to iRECIST 
(Seymore et al., 2017), which introduces additional tumor assessments and evaluation criteria in 
situations where pseudo-progression is suspected. 
This appendix describes the iRECIST process for assessment and evaluation of disease 
progression. 
Tumor Assessment at Screening and Prior to iRECIST Progression 
At every tumor assessment, target and non-target lesions identified at baseline by RECIST v1.1 
will be assessed according RECIST v1.1. Until first radiographically assessed disease progression 
based on RECIST v1.1, there is no distinct iRECIST assessment. Accordingly, possible response 
evaluation outcomes are CR, PR, SD, PD, and not evaluable. 
Response Evaluation and Decision at RECIST v1.1 Progression 
At first radiographic assessment of disease progression according to RECIST v1.1, new lesions 
will be classified as measurable or non-measurable, using the same size thresholds and rules as for 
baseline lesion assessment in RECIST v1.1. From measurable new lesions, ≤5 lesions total (≤2 per 
organ), may be selected as New Lesions – Target. The sum of diameters of these lesions will be 
calculated and kept distinct from the sum of diameters for target lesions at baseline. All other new 
lesions will be followed qualitatively as New Lesions – Non-target. 
For patients whose radiological tumor assessment show evidence of disease progression by 
RECIST v1.1 criteria, the investigator will decide whether to continue a patient on study treatment 
and repeat imaging according to iRECIST or discontinue the patient according to disease 
progression according to RECIST v1.1. This decision by the investigator should be based on the 
patient’s overall clinical condition, in particular in the assessment of clinical stability. 
Clinical stability is defined as the following:  
• 
No decline in ECOG PS 
• 
Absence of increases of clinically relevant disease-related symptoms and signs assessed to be 
associated with disease progression 
• 
No requirements for intensified management of disease-related symptoms, including 
increased analgesia, radiation, or other palliative care 
Any patient deemed clinically unstable should be discontinued from study treatment at site-
assessed first radiologic evidence of disease progression and assigned a response evaluation of PD 
(according to RECIST v1.1), and it is not required to have repeat tumor imaging for confirmation 
of PD by iRECIST (iCPD). 


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If the patient is deemed to be clinically stable, and the investigator decides to continue treatment, 
new response categories defined by iRECIST, including iUPD and iCPD, will be used from there 
on (using iRECIST for patient management as shown in the figure below). 
RECIST v1.1 and iRECIST: An Example of Assessment 
 
iCR=complete response; iCPD=confirmed progression; iPR=partial response; iSD=stable disease; 
iUPD=unconfirmed progression; RECIST=Response Evaluation Criteria in Solid Tumors; 
TP=timepoint. 
Note: Prefix “i” indicates immune responses assigned using iRECIST; others without “i” are 
confirmed by RECIST v1.1. 
Source: Seymore et al., 2017 
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on which 
iUPD is seen. This may correspond to the next visit in the original visit schedule. Images should 
continue to be sent to the central imaging vendor for potential retrospective independent response 
evaluation 
Response Evaluation After the First iUPD 
The response evaluation of the subsequent confirmation imaging proceeds at scheduled visits, as 
before, with possible outcomes of iCPD, iUPD, and iSD/iPR/iCR, see table below. 
 


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Example Scenarios of Assignments of Best Overall Response using iRECIST After First 
Diagnosis of iUPD 
 
Timepoint 
response  
n 
Timepoint 
response  
n+1 
Timepoint 
response 
n+2 
Timepoint 
response 
n+3 
Timepoint 
response  
n+4 
iBOR  
Example 1  iUPD  
iPR, iSD, or NE  
iCR  
iCR 
Any 
iCR  
Example 2  iUPD  
iPR 
iPR 
Any except iCR 
Any except iCR 
iPR  
Example 3  iUPD  
iUPD, iSD or NE  
iPR  
iPR 
Any except iCR 
iPR  
Example 4  iUPD  
iSD  
Any, except iPR, 
iCR 
Any, except iPR, 
iCR 
Any, except iPR, 
iCR 
iSD  
Example 5  iUPD  
Any (no iCPD) 
iUPD  
iCPD  
NA 
iCPD  
Example 6  iUPD  
iUPD (no iCPD)  
iCPD  
NA 
NA 
iCPD  
Example 7  iUPD  
iCPD  
NA 
NA 
NA 
iCPD  
iBOR=best overall response; iCR=complete response; iCPD=confirmed progression; iPR=partial 
response; iSD=stable disease; iUPD=unconfirmed progression; NA=not applicable; NE=not 
evaluable; RECIST=Response Evaluation Criteria in Solid Tumors. 
Note: Prefix “i” indicates immune responses assigned using iRECIST; others without “i” are 
confirmed by RECIST v1.1. 
Adapted from Seymore et al., 2017 
 
If progression is confirmed, the overall response will be iCPD. iCPD is present if any of the factors 
that were the basis for the initial iUPD show worsening, e.g., ANY of the following occurs: 
• 
For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, compared 
to any prior iUPD time point. 
• 
For non-target lesions, worsening is any relevant growth in lesions overall, compared to a 
prior iUPD time point; this does not have to meet the “unequivocal” standard of RECIST v1.1. 
• 
For new lesions, worsening is any of these: 
− 
An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD time point 
− 
Visible growth of new non-target lesions 
− 
The appearance of additional new lesions 
− 
Any new factor appears that would have triggered PD by RECIST v1.1 
NOTE: If a patient has iCPD as defined above, but is achieving a clinically meaningful benefit, an 
exception to continue study treatment may be considered following consultation with the sponsor. 
In this case, if study treatment is continued, tumor imaging should continue following the intervals 
as outlined in the SoA (Table 1) and submitted to the central imaging vendor. 
Persistent iUPD 
If progression is not confirmed, the overall response remains iUPD. iUPD is present if: 
• 
None of the progression-confirming factors identified above occurs AND 


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• 
The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST v1.1). 
Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 
• 
None of the progression-confirming factors identified above occurs, AND 
• 
The target lesion sum of diameters (initial target lesions) is not above the initial PD threshold.  
The response is classified as iSD or iPR (depending on the sum of diameters of the target lesions), 
or iCR if all lesions resolve. 
In this case (iSD, iPR, or iCR could be assigned), the initial iUPD is considered to be pseudo 
progression, and the level of suspicion for progression is ‘reset’. This means that the next visit that 
shows radiographic progression, whenever it occurs, is again classified as iUPD by iRECIST, and 
the confirmation process is repeated before a response of iCPD- can be assigned. 
Detection of Progression at Visits After Pseudo-progression Resolves 
After resolution of pseudo-progression (i.e., achievement of iSD/iPR/iCR), iUPD is indicated by 
any of the following events: 
• 
Target lesions 
− 
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from nadir) either 
for the first time, or after resolution of previous pseudo-progression. The nadir is always 
the smallest sum of diameters seen during the entire study, either before or after an 
instance of pseudo-progression. 
• 
Non-target lesions 
− 
If non-target lesions have never shown unequivocal progression, their doing so for the 
first-time results in iUPD. 
− 
If non-target lesions have shown previous unequivocal progression, and this progression 
has not resolved, iUPD results from any relevant further growth of non-target lesions, 
taken as a whole. 
• 
New lesions 
− 
New lesions appear for the first time 
− 
Additional new lesions appear 
− 
Previously identified new target lesions show an increase of ≥5 mm in the new lesion sum 
of diameters, from the nadir value of that sum. 
− 
Previously identified non-target lesions show any relevant growth. 


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If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Response Evaluation After the First iUPD, described above) is repeated. 
Progression must be confirmed before iCPD can occur. 
The decision process is identical to the iUPD confirmation process for the initial PD, with 
1 exception: If new lesions occurred at a prior instance of iUPD, and at the confirmatory imaging 
the burden of new lesions has increased from its smallest value (for new target lesions, the sum of 
diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve to iSD or iPR. It will 
remain iUPD until either a decrease in the new lesion burden allows resolution to iSD or iPR, or 
until a confirmatory factor causes iCPD. 
Additional details about iRECIST are provided in the iRECIST publication (Seymore et al., 2017). 


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Appendix 5 
Regulatory and Ethical Considerations 
I. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences International 
Ethical Guidelines 
• 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines 
• 
Applicable laws and regulations 
The protocol, protocol amendments, informed consent form (ICF), IB, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.  
Any amendments to the protocol will require IRB/IEC approval before implementation of changes 
made to the study design, except for changes necessary to eliminate an immediate hazard to study 
patients.  
The investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC 
• 
Notifying the IRB/IEC of SAEs or other relevant safety findings as required by IRB/IEC 
procedures 
• 
Providing oversight of the conduct of the study at the site and adherence to requirements of 
21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local regulations 
II. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
III. 
Informed Consent Process 
The investigator or his/her representative will explain the nature of the study to the patient or 
his/her legally authorized representative and answer all questions regarding the study.  


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Patients must be informed that their participation is voluntary. Patients or their legally authorized 
representative will be required to sign a statement of informed consent that meets the requirements 
of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and Accountability 
Act requirements, where applicable, and the IRB/IEC or study site.  
The medical record must include a statement that written informed consent was obtained before 
the patient was enrolled in the study and the date the written consent was obtained. The authorized 
person obtaining the informed consent must also sign the ICF. 
Patients must re-consent to the most current version of the ICF(s) during their participation in the 
study.  
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorized 
representative.  
A patient who is rescreened is not required to sign another ICF if the rescreening occurs within the 
originally planned screening window before drug administration. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples for 
optional exploratory research. The investigator or authorized designee will explain to each patient 
the objectives of the exploratory research. Patients will be told that they are free to refuse to 
participate and may withdraw their consent at any time and for any reason during the storage 
period. A separate signature will be required to document a patient’s agreement to allow any 
remaining specimens to be used for exploratory research. Patients who decline to participate in 
this optional research will not provide this separate signature. 
IV. 
Data Protection 
Patients will be assigned a unique identifier by the sponsor. Any patient records or datasets that 
are transferred to the sponsor will contain the identifier only; patient names or any information 
which would make the patient identifiable will not be transferred.  
The patient must be informed that his/her personal study-related data will be used by the sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to the 
patient.  
The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
The sponsor will ensure that all safeguards are in place to minimize any eventual risk of breaches 
and complies otherwise with the requirements of European Union General Data Protection 
Regulation (GDPR Regulation (EU) 2016/679). The sponsor will regularly check all procedures 


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relevant to the processing of personal data, as to ensure privacy by design and compliance with 
this regulation. 
V. 
Administrative and Committees Structure 
Detailed information will be provided in the Steering Committee Charter. 
VI. 
Publication Policy 
The results of this study may be published or presented at scientific meetings. Individual 
publications are allowed only after publication of the entire study. If this is foreseen, the 
investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. This 
allows the sponsor to protect proprietary information and to provide comments.  
The sponsor will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the sponsor will generally support publication of multicenter 
studies only in their entirety and not as individual site data. In this case, a coordinating investigator 
will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
In accordance with consistent editorial practice, the sponsor supports publication of multicenter 
studies in their entirety and not as individual center data unless as ancillary study/data.  
All publications in peer-reviewed medical journals resulting from this study will be listed in the 
original study protocol registration record (e.g., on ClinicalTrials.gov). 
VII. 
Dissemination of Clinical Study Information 
The sponsor will provide the relevant study protocol information in a public database (e.g., 
ClinicalTrials.gov, https://clinicaltrials.gov/) before or at commencement of the study. The 
sponsor may also provide study information for inclusion in national registries according to local 
regulatory requirements.  
If a potential patient contacts the sponsor regarding participation in the study, the investigator 
agrees that the sponsor may forward the study site and contact details to the patient. Based on the 
inclusion and exclusion criteria for the study, the investigator will assess the suitability of the 
patient for enrollment into the study. 
Results of this study will be disclosed according to the relevant regulatory requirements. All 
publications in peer-reviewed medical journals resulting from this study will be listed in the 
original study protocol registration record (e.g., on ClinicalTrials.gov). 


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VIII. 
Data Quality Assurance 
All patient data relating to the study will be recorded on the eCRF unless transmitted to the sponsor 
or designee electronically (e.g., laboratory data). The investigator is responsible for verifying that 
data entries are accurate and correct by physically or electronically signing the eCRF.  
The investigator must maintain accurate documentation (source data) that supports the information 
entered in the eCRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.  
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data.  
Study monitors will perform ongoing source data verification to confirm that data entered into the 
eCRF by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of patients are being protected; and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, ICH GCP, and 
all applicable regulatory requirements.  
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for 10 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor.  
IX. 
Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the investigator’s site. 
Data entered in the eCRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. The investigator may need to request 
previous medical records or transfer records, depending on the study. Also, current medical records 
must be available. 
X. 
Study and Site Closure 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies have 
been collected and a study-site closure visit has been performed. 


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The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are not 
limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor’s procedures, or GCP guidelines 
• 
Inadequate recruitment of patients by the investigator 
• 
Discontinuation of further study treatment development 












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Appendix 7 
Contraceptive Guidance and Collections of Pregnancy 
Information 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
23. 
Premenopausal female with 1 of the following: 
− 
Documented hysterectomy 
− 
Documented bilateral salpingectomy 
− 
Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s review of the patient’s medical records, 
medical examination, or medical history interview. 
24. 
Post-menopausal female: 
− 
A post-menopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone level in the post-menopausal range 
may be used to confirm a post-menopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single follicle stimulating hormone measurement is 
insufficient.  
− 
Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-hormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of 
post-menopausal status before study enrollment. 
Contraception Guidance 
Male Patients 
Male patients with female partners of childbearing potential are eligible to participate if they agree 
to ONE of the following during the study and
after last dose of IFX-1 or 120 days 
after last dose of pembrolizumab:  
• 
Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent 


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• 
Agree to use a male condom plus partner use of a contraceptive method with a failure rate of 
<1% per year as described in Table 3 when having penile-vaginal intercourse with a woman 
of childbearing potential who is not currently pregnant 
Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile vaginal 
intercourse or use a male condom during each episode of penile penetration [during the 
protocol-defined time frame]. 
Men must refrain from donating sperm for the duration of the study and for 3 months after the last 
dose of IFX-1 or 120 days after last dose of pembrolizumab. 
Female Patients 
Female patients of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception (from the day of study medication initiation [or 14 days prior to 
the initiation of study medication for oral contraception] throughout the study period and
 
for IFX-1 or 120 days for pembrolizumab after the last dose of study medication) 
consistently and correctly as described in Table 3. 
Table 3 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a  
(failure rate of <1% per year when used consistently and correctly) 
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: b 
• 
Oral 
• 
Intravaginal 
• 
Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral 
• 
Injectable 
Highly Effective Methods That Are User Independent a 
Implantable progestogen only hormonal contraception associated with inhibition of ovulation: b 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system 
• 
Bilateral tubal occlusion 


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Vasectomized partner: 
A vasectomized partner is a highly effective contraception method provided that the partner is the 
sole male sexual partner of the WOCBP, and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used. 
Sexual abstinence: 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the patient. 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for patients participating in 
clinical studies.  
b Hormonal contraception may be susceptible to interaction with study treatment, which may reduce the 
efficacy of the contraceptive method. In this case, 2 highly effective methods of contraception should 
be utilized during the treatment period and
 
after the last dose of IFX-1 or 120 days after 
last dose of pembrolizumab. 
Pregnancy Testing 
WOCBP who have a positive serum pregnancy test result within 7 days before treatment should 
be excluded. 
Additional urine pregnancy testing will be performed Q2W during the treatment period and at the 
first follow-up visit for Arm A and the first follow-up visit and 120 days after the last dose of 
pembrolizumab for Arm B. 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when pregnancy is 
otherwise suspected. 
Collection of Pregnancy Information  
Male Patients With Partners who Become Pregnant  
The investigator will attempt to collect pregnancy information on any male patient’s female partner 
who becomes pregnant while the male patient is in this study. This applies only to male patients 
who receive IFX-1 or pembrolizumab. 
After obtaining the necessary signed informed consent from the pregnant female partner directly, 
the investigator will record pregnancy information on the appropriate form and submit it to the 
sponsor within 24 hours of learning of the partner’s pregnancy. The female partner will also be 
followed to determine the outcome of the pregnancy. Information on the status of the mother and 


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child will be forwarded to the sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks 
following the estimated delivery date. Any termination of the pregnancy will be reported 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure. 
Female Patients who Become Pregnant  
The investigator will collect pregnancy information on any female patient who becomes pregnant 
while participating in this study. Information will be recorded on the appropriate form and 
submitted to the sponsor within 24 hours of learning of a patient’s pregnancy. The patient will be 
followed at least monthly to determine the outcome of the pregnancy. The investigator will collect 
follow-up information on the patient and the neonate and the information will be forwarded to the 
sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the 
estimated delivery date. Any termination of pregnancy will be reported, regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous abortion is 
always considered to be an SAE and will be reported as such. Any post-study pregnancy related 
SAE considered reasonably related to study treatment by the investigator will be reported to the 
safety vendor as described in Appendix 6. While the investigator is not obligated to actively seek 
this information in former study patients, he or she may learn of an SAE through spontaneous 
reporting.  
Any female patient who becomes pregnant while participating in the study will discontinue study 
treatment. 


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Appendix 8 
Treatment Modification Guidelines 
 
Table 4 
Dose Modification and Toxicity Management Guidelines for Immune-Related 
Adverse Events Associated with Pembrolizumab or IFX-1 
General instructions: 
1. Severe and life-threatening irAEs should be treated with intravenous 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 ≥4 weeks. 
4. If pembrolizumab and IFX-1 have been withheld, pembrolizumab and/or IFX-1 may resume after the irAE 
decreased to ≤Grade 1 after corticosteroid taper. 
irAEs 
Toxicity Grade 
(CTCAE v5.0) 
Action with 
pembrolizumab 
and IFX-1 
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 patients for 
signs and symptoms of 
pneumonitis 
• 
Evaluate patients 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 patients for 
signs and symptoms of 
enterocolitis (i.e., diarrhea, 
abdominal pain, blood or 
mucus in stool with or 
without fever) and of bowel 
perforation (i.e., peritoneal 
signs and ileus) 
• 
Patients with ≥Grade 2 
diarrhea suspecting colitis 
should consider GI 
consultation and performing 
endoscopy to rule out colitis 
• 
Patients 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 intravenous 
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) 


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Grade 3 b or 4 c 
Permanently 
discontinue 
Administer 
corticosteroids (initial 
dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
hyperglycemia 
New 
onset 
T1DM 
or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence 
of 
-cell failure 
Withhold d 
• 
Initiate insulin 
replacement therapy for 
patients with T1DM 
• 
Administer 
antihyperglycemic in 
patients with 
hyperglycemia 
Monitor patients 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 
Hyperthyroidis
m  
Grade 2 
Continue 
Treat with nonselective 
beta-blockers (e.g., 
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 
(e.g., 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 - 5.0 × ULN if baseline normal; >3.0 - 5.0 × baseline, if baseline abnormal;  
bilirubin:>1.5 - 3.0 × ULN if baseline normal; >1.5 - 3.0 × baseline if baseline abnormal 
b AST/ALT: >5.0 - 20.0 × ULN, if baseline normal; >5.0 - 20.0 × baseline, if baseline abnormal; 
bilirubin: >3.0 - 10.0 × ULN if baseline normal; >3.0 - 10.0 × baseline if baseline abnormal 
c AST/ALT: >20.0 × ULN, if baseline normal; >20.0 × baseline, if baseline abnormal;  
bilirubin: >10.0 × ULN if baseline normal; >10.0 × baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab and/or IFX-1 is at the discretion of the 
investigator or treating physician. If control achieved or ≤Grade 2, pembrolizumab and/or IFX-1 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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Table 5 
Dose Modification and Toxicity Management Guidelines for Infusion-Related 
Reactions Associated with Pembrolizumab or IFX-1 
 
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 patient 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, 
intravenous fluids); 
prophylactic medications 
indicated for ≤24 hrs. 
• 
Stop Infusion. 
• 
Additional appropriate medical therapy may include 
but is not limited to: 
• 
Intravenous fluids 
• 
Antihistamines 
• 
Non-steroidal anti-inflammatory drugs 
• 
Acetaminophen 
• 
Narcotics 
• 
Increase monitoring of vital signs as medically 
indicated until the patient 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/hour). Otherwise dosing will be held until 
symptoms resolve and the patient should be premedicated 
for the next scheduled dose. 
Patients who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued 
from further study treatment 
Patient may be 
premedicated 1.5 hour 
(±30 minutes) prior to 
infusion of study 
treatment with: 
diphenhydramine 
50 mg orally (or 
equivalent dose of 
antihistamine)., 
acetaminophen 
500-1000 mg orally 
(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** 
• 
Intravenous fluids 
• 
Antihistamines 
• 
Non-steroidal anti-inflammatory drugs 
• 
Acetaminophen 
• 
Narcotics 
• 
Oxygen 
• 
Pressors 
• 
Corticosteroids 
• 
Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically stable in the 
opinion of the investigator. 
• 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used 
immediately. Patient is permanently discontinued from 
further study 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 v4.0 
(CTCAE) at http://ctep.cancer.gov 


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Appendix 9 
Eastern Cooperative Oncology Group 
 
Grade 
Description 
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 housework, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities; up and about >50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair ≥50% of waking 
hours 
4 
Completed disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair. 
5 
Dead 
Source: Oken et al., 1982 


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Appendix 10 
List of Vendors 
Legal name of 
3rd Party 
Business address 
Study activity 
performed 
Street 
City 
Zip Code 
Country 
 
 
 
 
 
 
IFX-1 measurement, 
C3a measurement 
 
 
 
 
 
 
 
 
 
ADA measurement 
InflaRx GmbH 
Winzerlaer Str. 
2 
Jena 
07745 
Germany 
C5a measurement 
 
 
 
 
 
 
 
 
IMP packaging, QP 
release and distribution 
 
 
 
 
 
 
 
 
IXRS 
PSI CRO AG 
Baarerstr. 113a Zug 
6300 
Switzerland 
Feasibility & Site 
Identification, Project 
management, Site 
Management, Clinical 
Monitoring, Vendor 
Management, Medical 
Monitoring, 
Development of Study 
Documents, 
Regulatory, Trial 
Master File 
Metronomia 
Clinical Research 
GmbH 
Paul-Gerhardt-
Allee 42 
Munich 
81245 
Germany 
EDC system, Data 
Management, 
Statistical Analysis 
IQVIA Ltd. 
Green Park, 
500 Brook 
Drive 
Reading 
Berkshire 
RG2 v6UU 
United 
Kingdom 
Safety Management 
 
 
 
 
 
 
Image collection, QC, 
and storage until 
decision for or against 
central imaging read 
 
 
 
 
 
 
 
Kitting and Shipment 
of lab samples, 
Biomarker Analysis