A Phase 2, Open-label, Single-arm, Multicenter Study of SOT101 in Combination With Pembrolizumab to Evaluate the Efficacy and Safety in Patients With Selected Advanced/Refractory Solid Tumors
Phase: PHASE2
Conditions: Non-Small Cell Lung Cancer, Colorectal Cancer, Cutaneous Squamous Cell Carcinoma, Hepatocellular Carcinoma, Castration-resistant Prostate Cancer, Ovarian Cancer
Sponsor: SOTIO Biotech AG

 
 
 
SC104 Protocol Amendment 1, Final, 20Apr2023 
Page 1 of 108 
 
 
 
A phase 2, open-label, single-arm, multicenter study of SOT101  
in combination with pembrolizumab to evaluate the efficacy and safety  
in patients with selected advanced/refractory solid tumors 
 
 
 
Study interventions 
Product code: SOT101 (previously SO-C101, 
RLI-15); International Nonproprietary Name: 
Nanrilkefusp alfa 
Pembrolizumab 
Regulatory agency identifier numbers 
EudraCT number: 2021-005774-25 
IND number: 140011 
Protocol number 
SC104 
Phase 
2 
Version 
Protocol Amendment 1 
Date 
20Apr2023 
Sponsor 
SOTIO Biotech AG 
Legal registered address 
Lichtstrasse 35 - WSJ-210 
4056 Basel 
Switzerland 
 
 
 
 
 
This document contains proprietary information and trade secrets of SOTIO Biotech 
AG. This information may not be used, divulged, published, copied, or otherwise 
disclosed to any third party without the prior written consent of SOTIO Biotech AG. 

 
 
 
SC104 Protocol Amendment 1, Final, 20Apr2023 
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SIGNATURES/PROTOCOL APPROVAL AND RELEASE: SOTIO 
We, the undersigned, have read this Protocol and agree that it contains all the necessary 
information required for the conduct of this clinical trial. 
 
 
 
For SOTIO Biotech AG: 
 
Signature: ...………………………………… 
 
Date:         ...………………………………… 
 
Signature: ...………………………………… 
 
Date:        ...………………………………… 

 
 
 
SC104 Protocol Amendment 1, Final, 20Apr2023 
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SIGNATURES/PROTOCOL APPROVAL AND RELEASE: 
COORDINATING INVESTIGATOR 
I, the undersigned, have read this Protocol and agree that it contains all the necessary 
information required for the conduct of this clinical trial. 
 
 
 
Coordinating investigator: 
 
 
Stéphane Champiat, M.D., Ph.D. 
Assistant Professor  
Institut Gustave Roussy 
Villejuif, France 
Signature: …………………………………… 
 
Date:         …………………………………… 

 
 
 
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INVESTIGATOR’S DECLARATION 
I have read this Protocol and I agree that it contains all the necessary details for carrying out 
this clinical trial. I agree to personally conduct or supervise the clinical trial as described in 
accordance with the relevant current Protocol and within the time designated. I will only make 
changes after receiving the sponsor’s approval, except when necessary to protect the safety, 
rights, or welfare of patients. 
I verify that I am suitably qualified by education, scientific medical training, and experience to 
conduct the clinical trial. Documentation of my qualifications and professional affiliations are 
contained in my up-to-date curriculum vitae. 
I will provide the Protocol and all information relating to pre-clinical and previous clinical 
experience (e.g., Investigator’s Brochure) to all associates, colleagues, and staff assisting in the 
conduct of this clinical trial. I will discuss the material with them to ensure that they are fully 
conversant with the Protocol, the medical treatment, and the conduct of the clinical trial, and 
that they will handle the data and information generated in the clinical trial confidentially. I 
agree to ensure that they are informed about their obligations in meeting the investigator’s 
commitments listed in this Investigator’s Declaration, as delegated and applicable to them. 
I agree to personally conduct or supervise the clinical trial in accordance with: i) the current 
version of the Declaration of Helsinki; ii) the current version of International Council for 
Harmonisation (ICH) guidelines on Good Clinical Practice (ICH E6); iii) the moral, ethical, 
and scientific principles that justify medical research; and iv) all relevant national and regional 
laws and regulations relating to clinical trials and the protection of patients of the country in 
which the clinical trial will be performed. 
I will ensure that an institutional review board (IRB) or independent ethics committee (IEC; in 
the US)/ethics committee (EC; in the EU)/equivalent committee (outside the US and EU) that 
complies with the requirements of national and regional legislation and the Declaration of 
Helsinki, and that follows the recommendations in ICH E6, will be responsible for the initial 
and continuing review and approval of the clinical investigation. I also agree to promptly report 
to the IRB/IEC (in the US)/EC (in the EU)/equivalent committee (outside the US and EU) all 
changes in research activity and all unanticipated problems involving risks to patients or others. 
Additionally, I will not make any changes in the research without IRB/IEC (in the US)/EC (in 
the EU)/equivalent committee (outside the US and EU) approval, except where necessary to 
eliminate apparent immediate hazards to patients. 
I agree to inform all patients and associates, colleagues, and staff assisting in the conduct of 
this clinical trial that the drugs are being used for investigational purposes, and I will ensure 
that the requirements relating to obtaining informed consent and IRB/IEC (in the US)/EC (in 
the EU)/equivalent committee (outside the US and EU) review and approval are met in 
accordance with national and regional legislation and the Declaration of Helsinki, and 
consistent with the recommendations in ICH E6. 
All patients will be informed that they may withdraw from the clinical trial at their discretion 
at any time. I will use only the information sheet and consent form approved by the sponsor 
and the IRB/IEC (in the US)/EC (in the EU)/equivalent committee (outside the US and EU) 
which has reviewed this clinical trial. 
I will provide the sponsor with any material written by myself (e.g., clinical trial summary) 
which is given to the IRB/IEC (in the US)/EC (in the EU)/equivalent committee (outside the 

 
 
 
SC104 Protocol Amendment 1, Final, 20Apr2023 
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US and EU) in support of the application. I agree to maintain adequate and accurate records 
and to make those records available for inspection in accordance with national and regional 
legislation and the Declaration of Helsinki, and consistent with the recommendations in ICH 
E6. I agree to the audit and monitoring procedures that involve verification of clinical trial 
records against the original records by direct access. In case the source documentation and 
clinical trial data are kept electronically, I agree to ensure that these comply with the 
requirements on computerized systems and their validation in line with national and regional 
legislation and recommendations in ICH E6. 
I will retain the trial-related essential documents until the sponsor informs me that these 
documents are no longer needed but no sooner than the requirements in national and regional 
legislation. 
I certify that any laboratory, excluding the central laboratory (laboratories) appointed for the 
clinical trial, in which laboratory parameters will be determined, is subject to regular external 
quality control. 
I agree to report to the sponsor adverse events that occur in the course of the clinical trial in 
accordance with national and regional legislation and the Declaration of Helsinki, and 
consistent with the recommendations in ICH E6. I have read and understand the information in 
the Investigator’s Brochure, including the potential risks and side effects of the study 
intervention. 
I agree to the collection, processing, transfer, use, and storing of my personal data and details 
relating to my professional activities for the purposes of the clinical trial by the sponsor and/or 
by a delegated party (e.g., a contract research organization). 
I understand that the (e)CRFs and other data pertinent to this clinical trial are the property of 
the sponsor and are confidential. I will supply the sponsor with the clinical trial data in such a 
way that the patient’s personal information and identity are protected. 
I agree to comply with all other requirements regarding obligations of clinical investigators and 
with all other pertinent requirements in accordance with national and regional legislation and 
the Declaration of Helsinki. I also agree to follow the recommendations in ICH E6. 
Investigator’s signature: 
__________________________________________________ 
Date:  
 
 
__________________________________________________ 
Printed name:  
 
__________________________________________________ 
Street address: 
 
__________________________________________________ 
Telephone number: 
 
__________________________________________________ 
Other contact information 
Full contact details for each investigational site, the sponsor, and key coordinating and 
operational personnel involved in this clinical trial will be maintained in the Trial Master File 
and in the Investigator Site File. 
 
 

 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Change 
number 
Description of change 
Rationale for change 
Section(s) in Protocol 
Amendment 1 
1 
Clarification that during 
futility analyses, 
recruitment may be 
paused 
Clarification  
9.4 Interim analysis 
 
2 
Benefit/risk assessment 
update 
Update 
2.3 Benefit/risk 
assessment 
3 
Reduction of 
pharmacokinetics 
sampling time points 
To reduce the volume of blood 
drawn and number of samples 
to be withdrawn from patients 
1.3.5 Nanrilkefusp alfa 
PK sampling 
 
4 
Addition of a time 
window for blood 
sampling 
To allow the sites to collect 
blood within a defined time 
interval 
1.3.3 Collection of 
blood samples, 
nanrilkefusp alfa 
combined with 
pembrolizumab 
5 
Guidance for prevention 
of fever before dosing 
Some patients who were 
hospitalized to monitor 
whether there is a further 
increase which in some cases 
resulted in a serious adverse 
event and/or next dose was not 
given. 
6.5.1 Dose modification 
and toxicity 
management for 
nanrilkefusp alfa 
6 
Clarification that tumor 
imaging is to be 
continued irrespective of 
clinical progression 
Clarification 
8.1.1.3 End of treatment 
and follow-up tumor 
imaging 
7 
Reduction of 
nanrilkefusp alfa anti-
drug antibody sampling 
time points 
To reduce the volume of blood 
drawn from patients 
1.3.3 Collection of 
blood samples, 
nanrilkefusp alfa 
combined with 
pembrolizumab 
8 
Re-screening to be 
allowed 
To allow more patients to be 
enrolled 
5.4 Screen failures 
9 
Reduction of prostate 
cancer-specific 
biomarker sampling time 
points 
To reduce the volume of blood 
drawn from patients 
1.3.3 Collection of 
blood samples, 
nanrilkefusp alfa 
combined with 
pembrolizumab 

 
 
 
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Change 
number 
Description of change 
Rationale for change 
Section(s) in Protocol 
Amendment 1 
10 
Clarification that legally 
speaking, all contractors 
of SOTIO Biotech AG 
are third parties 
Clarification 
10.1.12 Future research 
11 
Change of the sponsor’s 
address 
Sponsor moved 
Title page 
12 
Clarification that not all 
benchmark treatments 
consist of 
pembrolizumab alone 
Clarification/ 
Simplification 
1.1 Synopsis, 9.4 
Interim analysis 
13 
Correction of a typo in 
the definition of 
circulating tumor cell 
count conversion: from 
“>5” to “≥5” 
Typo 
1.1 Synopsis, 3 
OBJECTIVES AND 
ENDPOINTS, 5.1 
Inclusion criteria, 
9.3.3.2 Efficacy 
endpoints 
14 
Replacement of the 
product code “SOT101” 
with the International 
Nonproprietary Name 
“nanrilkefusp alfa” in 
the body of the protocol 
for better clarity; the 
product code remains the 
same, i.e., “SOT101” 
Clarification 
Throughout the 
protocol 
15 
Clarification that day 6 
blood sampling should 
be performed 
irrespective of any 
cytokine trends 
RNA analysis is needed for all 
patients on day 6 to have 
relevant results 
1.3 Schedule of 
activities  
16 
Clarification that for 
ovarian cancer, the last 
progression on platinum-
based therapy should be 
considered in the 
calculation of the 6 
months within when the 
study treatment should 
start 
Clarification 
1.1 Synopsis, 1.2 
Schema, 4.2 Scientific 
rationale for study 
design, 5.1 Inclusion 
criteria 

 
 
 
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Change 
number 
Description of change 
Rationale for change 
Section(s) in Protocol 
Amendment 1 
17 
Clarification that left 
ventricular ejection 
fraction should be 
determined by 
echocardiography or 
multigated acquisition 
scanning 
Clarification 
1.3 Schedule of 
activities, 8.2.4 
Electrocardiography 
and left ventricular 
ejection fraction 
18 
Change of the 
progression-free survival 
and time to response 
censoring rule when no 
tumor assessments were 
performed from 
“eligibility” to “the first 
day of study treatment” 
The censoring rules were not 
aligned with the study 
population. As only treated 
patients are considered, the 
first day of study treatment 
should be the censoring 
timepoint (in case of no tumor 
assessments) in order to avoid 
negative values. 
9.3.3.2 Efficacy 
endpoints 
 
19 
Clarification that 
nanrilkefusp alfa and 
pembrolizumab 
concentrations over time 
are analyzed in serum 
not plasma 
Clarification 
1.1 Synopsis, 3 
OBJECTIVES AND 
ENDPOINTS 
20 
Correction that serum 
clearance is not 
evaluated after oral 
administration 
Typo  
8.4 Pharmacokinetics 
21 
Reduction of the number 
of ECG assessments 
No significant cardiac toxicity 
has been observed in a 13-
week repeated dose toxicology 
study in cynomolgus monkeys 
and in clinical studies with 
nanrilkefusp alfa 
1.3.1 Schedule of 
activities, nanrilkefusp 
alfa combined with 
pembrolizumab 
22 
Clarification that a fresh 
biopsy must be taken 
during screening unless 
the biopsy cannot be 
obtained due to safety 
reasons or non-
accessibility of the 
tumor site. If it is not 
possible to obtain a fresh 
biopsy, every effort 
To allow inclusion of patients 
without accessible tumor tissue 
1.3.1 Schedule of 
activities, nanrilkefusp 
alfa combined with 
pembrolizumab, 5.1 
Inclusion criteria 

 
 
 
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Change 
number 
Description of change 
Rationale for change 
Section(s) in Protocol 
Amendment 1 
should be taken to 
retrieve an archival 
biopsy. Archived, fixed 
tumor tissue may only be 
collected if taken 
preferentially after 
completion of the most 
recent systemic tumor 
therapy and within 12 
months prior to the first 
dose of study treatment. 
Investigators are highly 
encouraged to obtain an 
optional biopsy at cycle 
2 day 13 and at disease 
progression or at any 
other clinically relevant 
event if it does not 
expose the patient to an 
increased risk.  
23 
Change to exclusion 
criterion 3: from “before 
study entry (ICF 
signature)” to “before 
study treatment (cycle 1 
day 1)” 
Four weeks plus up to another 
4 weeks of screening is too 
long for patients to be off 
systemic therapy 
5.2 Exclusion criteria 
24 
Clarification of 
exclusion criterion 8.3 
(added text underlined, 
deleted text crossed out): 
“and any clinically 
significant history of 
coronary heart disease 
and clinically significant 
peripheral and/or carotid 
artery disease within the 
past 5 years” 
Clarification 
5.2 Exclusion criteria 
25 
Standardization of 
adverse event (AE) 
terminology according to 
NCI CTCAE version 5.0 
To standardize AE reporting 
8.3.8.1 Adverse events, 
8.3.8.2 Documenting on 
eCRFs 
26 
Deletion of the row 
“Whole blood biomarker 
Redundant 
1.3.3 Collection of 
blood samples, 

 
 
 
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Change 
number 
Description of change 
Rationale for change 
Section(s) in Protocol 
Amendment 1 
analysis” in the table 
“Collection of blood 
samples, nanrilkefusp 
alfa combined with 
pembrolizumab” 
nanrilkefusp alfa 
combined with 
pembrolizumab 
27 
Clarification that a 
maximum of 3 lines of 
previous treatment are 
allowed for patients with 
advanced hepatocellular 
carcinoma and a 
maximum of 4 lines are 
allowed for patients with 
metastatic castration-
resistant prostate cancer 
and ovarian cancer  
To clarify the number of 
previous lines of therapy 
1.2 Schema, 4.2 
Scientific rationale for 
study design, 5.1 
Inclusion criteria, 
28 
Update of the 
information on the 
combination 
recommended phase 2 
dose 
To update the information on 
the combination recommended 
phase 2 dose 
2.1 Study rationale, 4.3 
Justification for dose 
29 
Clarification of the end 
of the study 
Clarification 
1.1 Synopsis, 1.3 
Schedule of activities, 
4.1.3 Follow-up, 4.4 
End of study definition 
30 
Addition that 
live/attenuated vaccines 
are prohibited 90 days 
after the last dose of 
nanrilkefusp alfa and/or 
pembrolizumab, 
whichever is later 
Revised according to the 
Czech State Institute for Drug 
Control (SUKL)’s 
recommendation (SUKL RFI 
25Mar2022): 
We request to add to the 
protocol that live/attenuated 
vaccines are prohibited even 
90 days after the last dose of 
study treatment. This is 
standard procedure in 
immunotherapy studies. 
6.8.2 Prohibited 
medications 
31 
Addition that serology 
testing is mandatory 
Revised according to SUKL’s 
recommendation (SUKL RFI 
25Mar2022): 
We request to state in the 
protocol that HIV, HBV and 
5.1 Inclusion criteria, 
5.2 Exclusion criteria, 
8.2.5.5 Serology testing 
for infections 

 
 
 
SC104 Protocol Amendment 1, Final, 20Apr2023 
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Change 
number 
Description of change 
Rationale for change 
Section(s) in Protocol 
Amendment 1 
HCV tests are a mandatory 
part of screening in the Czech 
Republic. These infections are 
in exclusion criteria and 
therefore pose a risk to clinical 
trial subjects. This is a 
standard requirement for 
immunotherapy studies. 
32 
Addition of cytokine 
release syndrome 
management 
recommendations 
Revised according to SUKL’s 
recommendation (SUKL RFI 
25Mar2022): 
We require that the exact 
cytokine release syndrome 
(CRS) management procedure 
be added to the protocol. It is 
not enough to just refer to 
standard workplace 
procedures, the protocol 
should include the 
management of all major 
toxicities, especially those for 
the tested product. 
6.5.1 Dose modification 
and toxicity 
management for 
nanrilkefusp alfa, 6.5.3 
Clinical management of 
cytokine release 
syndrome 
33 
Addition of more 
detailed information 
about nanrilkefusp alfa 
application 
Revised according to SUKL’s 
recommendation (SUKL RFI 
25Mar2022): 
The protocol is missing more 
detailed information about the 
SOT101 application. Where 
will it be administered 
subcutaneously (abdomen, 
buttocks,...), will application 
site change, what exactly will 
be the procedure? We require 
proper adjustment of the 
protocol. 
6.5.1 Dose modification 
and toxicity 
management for 
nanrilkefusp alfa 
34 
Addition of information 
about SUSAR reporting  
Revised according to SUKL’s 
recommendation (SUKL RFI 
25Mar2022): 
The protocol does not mention 
SUSAR reporting. We request 
that the protocol be 
8.3.5 Regulatory 
reporting requirements 
for SAEs 

 
 
 
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Change 
number 
Description of change 
Rationale for change 
Section(s) in Protocol 
Amendment 1 
supplemented in accordance 
with KLH-21. 
35 
Removal of the 
possibility of 
nanrilkefusp alfa 
monotherapy treatment 
after pembrolizumab 
discontinuation 
(applicable in the Czech 
Republic only) 
Revised according to SUKL’s 
recommendation (SUKL RFI 
14Apr2022): 
We acknowledge that SOT101 
monotherapy is only 
considered when 
pembrolizumab is discontinued 
due to unacceptable toxicity. 
However, we do not agree with 
the sponsor’s opinion, 
monotherapy with SOT101 is 
unacceptable. Following 
discontinuation of 
pembrolizumab, there are 
other proven lines of treatment 
to which patients are entitled. 
To keep the patients on the 
experimental medicinal 
product with uncertainty of its 
effect would be unethical. 
Especially in patients who will 
be on the first / second line of 
treatment. Therefore, we 
request to remove information 
from the protocol about the 
possibility of continuing 
SOT101 monotherapy in case 
of discontinuation of 
pembrolizumab. 
1.3.1 Schedule of 
activities, nanrilkefusp 
alfa combined with 
pembrolizumab, 7.1 
Discontinuation of 
study intervention 
 
36 
Addition of cytokine 
release syndrome 
management 
recommendations 
Revised in response to the 
Spanish Agency of Medicines 
and Health Products 
(AEMPS)’s request for 
information (AEMPS RFI 
21Apr2022): 
In protocol section 6.5.1 on 
toxicity management and 
SOT101 dose modification, it is 
specified that the procedures 
and changes will be discussed 
on a case-by-case basis with 
6.5.1 Dose modification 
and toxicity 
management for 
nanrilkefusp alfa, 6.5.3 
Clinical management of 
cytokine release 
syndrome 

 
 
 
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Change 
number 
Description of change 
Rationale for change 
Section(s) in Protocol 
Amendment 1 
the sponsor’s medical monitor 
primarily to avoid symptoms 
related to cytokine release 
syndrome. Justify or clarify the 
reason for not standardizing 
the procedures for managing 
these symptoms per protocol. 
37 
Addition of specific risk 
minimization measures 
for nanrilkefusp alfa-
related hepatic toxicities 
Revised in response to the 
Belgian Federal Agency for 
Medicines and Health Products 
(AFMPS)’s requirement dated 
16May2022: 
The sponsor is required to add 
specific RMM for Liver Events 
in the study protocol... 
6.5.1 Dose modification 
and toxicity 
management for 
nanrilkefusp alfa 
38 
Addition of instructions 
for reporting of certain 
liver adverse events 
Revised in response to 
AFMPS’s requirement dated 
16May2022: 
In addition the sponsor is 
required to add in the protocol 
instructions for Reporting of 
Liver Adverse Event (AE) 
including, for immediate and 
expedited reporting, 
requirements from Investigator 
to Sponsor and from Sponsor 
to Health Authority, 
Investigators, and EC/IRB of 
‘Suspected Unexpected Serious 
Adverse Reaction’… 
8.3.1.3 Adverse events 
of special interest 
39 
Clarification that the 
study investigator will 
make every effort to 
obtain consent from the 
pregnant patient to 
follow the outcome of 
the pregnancy and report 
the condition of the fetus 
or newborn to the 
sponsor or designee  
Revised in response to the 
Belgian central ethics 
committee’s request dated 
27Apr2022 concerning the 
Informed Consent Form for 
pregnant patients / pregnant 
partners 
8.3.6 Pregnancy 
40 
Clarification that egg 
and sperm donation is 
Revised in response to the 
Belgian central ethics 
8.3.6 Pregnancy 

 
 
 
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Change 
number 
Description of change 
Rationale for change 
Section(s) in Protocol 
Amendment 1 
not allowed during the 
treatment period and for 
at least 120 days after 
the last dose of 
pembrolizumab or at 
least 30 days after the 
last dose of nanrilkefusp 
alfa, whichever is later 
committee’s request dated 
27Apr2022 
41 
Addition that serology 
testing is mandatory 
Revised in response to the 
Italian Medicines Agency 
(AIFA)’s request (AIFA RFI 
17Jun2022): 
Section 5.1-Inclusion Criteria-
Hepatitis: Baseline HCV and 
HBV testing should be 
required in order to assure 
appropriate patient 
management and monitoring, 
according to medical 
judgement. 
5.1 Inclusion criteria, 
5.2 Exclusion criteria, 
8.2.5.5 Serology testing 
for infections 
42 
Addition of toxicity 
management 
recommendations for 
nanrilkefusp alfa 
Revised in response to AIFA’s 
request (AIFA RFI 
17Jun2022): 
Section 6.5.1 Dose 
modification and toxicity 
management for SOT101: for 
the sake of safety and in order 
to assure homogeneity in 
toxicity management, the dose 
modification should not be 
only discussed on a case-by-
case basis. General 
recommendation should be 
reported in the study protocol. 
6.5.1 Dose modification 
and toxicity 
management for 
nanrilkefusp alfa, 6.5.3 
Clinical management of 
cytokine release 
syndrome 
43 
Specification of study 
population in response to 
the French National 
Agency for the Safety of 
Medicines and Health 
Products (ANSM)’s 
request 
Revised in response to 
ANSM’s request (ANSM 
22Apr2022): 
To amend inclusion criterion 4 
for disease characteristics as 
following : 
- NSCLC: add to the 
description of the advanced 
1.1 Synopsis, 1.2 
Schema, 4.2 Scientific 
rationale for study 
design, 5.1 Inclusion 
criteria 
 

 
 
 
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number 
Description of change 
Rationale for change 
Section(s) in Protocol 
Amendment 1 
setting “not amenable to 
curative treatment” and 
change “and/or” by “and” for 
immune checkpoint inhibitor 
and platinum containing 
regimen  
- cSCC : mention that inclusion 
of patients is possible only in 
cSCC when association with 
RT is not feasible  
In addition the sponsor is 
requested to further 
substantiate the rationale for a 
direct rechallenge with 
immunotherapy instead of 
using cytotoxic chemotherapy 
- mCRPC : make clear that 
patients should have received 
abiraterone and enzalutamide  
44 
Addition of management 
recommendations for 
cytokine release 
syndrome, shortening of 
the QT interval, and 
injection site reaction  
Revised in response to 
ANSM’s request (ANSM 
22Apr2022): 
To amend study protocol 
section 6.5 so as to include 
description of toxicity 
management for identified and 
potential risks of SOT101, 
especially CRS, shortening of 
QT and injection site reaction. 
Indeed, the sole reference of 
“discussion on a case-by-case 
basis between the site and the 
sponsor’s medical monitor” is 
not considered sufficient. 
Protocol should include or 
refers to guidelines for the 
management of the identified 
and potential risks for the 
experimental treatment. 
Management of increased ALT 
and AST is adequately 
described in table 6.2. 
Considering the risk of CRS, 
the protocol should include 
6.5.1 Dose modification 
and toxicity 
management for 
nanrilkefusp alfa, 6.5.3 
Clinical management of 
cytokine release 
syndrome 

 
 
 
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Change 
number 
Description of change 
Rationale for change 
Section(s) in Protocol 
Amendment 1 
stopping rules for the 
experimental product in 
addition to the reference to 
guidelines for the management 
of CRS. 
45 
Addition of a 
biochemistry test on day 
8 of cycle 3 
Revised in response to 
ANSM’s request (ANSM 
22Apr2022): 
To amend protocol section 
“1.3.3 Collection of blood 
samples, SOT101 combined 
with pembrolizumab” so as to 
add a Biochemistry test on day 
8 of cycle 3. 
1.3 Schedule of 
activities 
46 
Addition of pregnancy 
testing until the end of 
mandatory contraception 
defined in the protocol 
Revised in response to 
ANSM’s request (ANSM 
22Apr2022): 
To amend schedule of activities 
so as to extend pregnancy 
testing, for WOCBP until the 
end of mandatory 
contraception defined in the 
protocol, per CTFG guideline. 
1.3.1 Schedule of 
activities, nanrilkefusp 
alfa combined with 
pembrolizumab 
47 
Specification of study 
population in response to 
ANSM’s request 
Revised in response to 
ANSM’s request (ANSM 
19Aug2022): 
Regarding NSCLC, our request 
for amending “and/or” by 
“and” for immune checkpoint 
inhibitor and platinum 
containing regimen is 
maintained… 
1.1 Synopsis, 1.2 
Schema, 4.2 Scientific 
rationale for study 
design, 5.1 Inclusion 
criteria, 9.4 Interim 
analysis, 9.5 Sample 
size determination 
48 
Specification of the 
study population in 
response to the request 
of the Hungarian central 
ethics committee (CEC) 
Revised in response to the 
Hungarian CEC’s request 
dated 09Sep2022: 
The inclusion criteria should 
be supplemented; mCRPC: for 
the second-line or later-line 
treatment of patients with 
mCRPC after recurrence or 
failure of docetaxel therapy. In 
the above indication, the 
1.1 Synopsis, 
1.2 Schema, 
4.2 Scientific rationale 
for study design, 
5.1 Inclusion criteria 

 
 
 
SC104 Protocol Amendment 1, Final, 20Apr2023 
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Change 
number 
Description of change 
Rationale for change 
Section(s) in Protocol 
Amendment 1 
criterion recommended by the 
Committee for the efficacy of 
the androgen receptor 
inhibitor therapy is as follows: 
“For the second-line or later-
line treatment of patients with 
mCRPC after recurrence or 
failure of docetaxel and 
androgen receptor target 
therapy” 
49 
Update of dose 
modification and 
toxicity management 
guidelines for 
hypothyroidism and 
myocarditis associated 
with pembrolizumab 
To provide investigators with 
up-to-date information on the 
management of irAEs 
associated with 
pembrolizumab 
6.5.2.1.3 Restarting 
study interventions 
50 
Clarification that any 
licensed COVID-19 
vaccine (including for 
emergency use) in a 
particular country is 
allowed in the study as 
long as they are mRNA 
vaccines, adenoviral 
vaccines, or inactivated 
vaccines 
Clarification 
6.8.2 Prohibited 
medications 
51 
Correction of 
typographical errors, 
minor editing 
To improve clarity 
Throughout the 
document 
 
 
 

 
 
 
SC104 Protocol Amendment 1, Final, 20Apr2023 
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DOCUMENT HISTORY 
Version 
Date 
Protocol 
18Nov2021 
Protocol Amendment CZ-1 
04Apr2022 
Protocol Amendment CZ-2 
28Apr2022 
Protocol Amendment ES-1 
29Apr2022 
Protocol Amendment BE-1 
30Jun2022 
Protocol Amendment FR-1 
12Jul2022 
Protocol Amendment IT-1 
12Jul2022 
Protocol Amendment FR-2 
23Aug2022 
Protocol Amendment HU-1 
16Sep2022 
Protocol Amendment UK-1 
11Oct2022 
Protocol Amendment 1 
20Apr2023 
 
 
 

 
 
 
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TABLE OF CONTENTS 
SIGNATURES/PROTOCOL APPROVAL AND RELEASE: SOTIO .................................... 2 
SIGNATURES/PROTOCOL 
APPROVAL 
AND 
RELEASE: 
COORDINATING 
INVESTIGATOR ...................................................................................................................... 3 
INVESTIGATOR’S DECLARATION ..................................................................................... 4 
PROTOCOL AMENDMENT SUMMARY OF CHANGES .................................................... 6 
TABLE OF CONTENTS ......................................................................................................... 19 
1 
PROTOCOL SUMMARY ............................................................................................... 24 
1.1 
Synopsis ...................................................................................................................... 24 
1.2 
Schema ....................................................................................................................... 30 
1.3 
Schedule of activities .................................................................................................. 31 
1.3.1 
Schedule of activities, nanrilkefusp alfa combined with pembrolizumab .......... 31 
1.3.2 
Schedule of activities, for patients who continue pembrolizumab after 
discontinuation of nanrilkefusp alfa .................................................................... 33 
1.3.3 
Collection of blood samples, nanrilkefusp alfa combined with pembrolizumab 34 
1.3.4 
Collection of blood samples, for patients who continue pembrolizumab after 
discontinuation of nanrilkefusp alfa .................................................................... 35 
1.3.5 
Nanrilkefusp alfa pharmacokinetic sampling ..................................................... 36 
2 
INTRODUCTION ............................................................................................................ 37 
2.1 
Study rationale ............................................................................................................ 37 
2.2 
Background ................................................................................................................ 37 
2.3 
Benefit/risk assessment .............................................................................................. 39 
3 
OBJECTIVES AND ENDPOINTS .................................................................................. 40 
4 
STUDY DESIGN ............................................................................................................. 42 
4.1 
Overall design ............................................................................................................. 42 
4.1.1 
Screening............................................................................................................. 42 
4.1.2 
Treatment ............................................................................................................ 42 
4.1.3 
Follow-up ............................................................................................................ 42 
4.2 
Scientific rationale for study design ........................................................................... 42 
4.3 
Justification for dose .................................................................................................. 45 
4.3.1 
Nanrilkefusp alfa ................................................................................................. 45 
4.3.2 
Pembrolizumab ................................................................................................... 45 
4.4 
End of study definition ............................................................................................... 46 
5 
STUDY POPULATION ................................................................................................... 47 

 
 
 
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5.1 
Inclusion criteria ......................................................................................................... 47 
5.2 
Exclusion criteria ........................................................................................................ 50 
5.3 
Lifestyle considerations .............................................................................................. 52 
5.3.1 
Meals and dietary restrictions ............................................................................. 52 
5.3.2 
Contraception ...................................................................................................... 52 
5.3.3 
Use in nursing women ........................................................................................ 52 
5.4 
Screen failures ............................................................................................................ 52 
5.5 
Criteria for temporarily delaying enrollment/administration of study intervention ... 52 
6 
STUDY INTERVENTIONS AND CONCOMITANT THERAPY ................................ 53 
6.1 
Study interventions administered ............................................................................... 53 
6.2 
Preparation, handling, storage, accountability ........................................................... 53 
6.3 
Measures to minimize bias: randomization and blinding ........................................... 54 
6.4 
Study intervention compliance ................................................................................... 54 
6.5 
Dose modification and toxicity management ............................................................. 54 
6.5.1 
Dose modification and toxicity management for nanrilkefusp alfa .................... 54 
6.5.2 
Dose modification and toxicity management for pembrolizumab ...................... 55 
6.5.2.1 
Dose modification and toxicity management for immune-related AEs 
associated with pembrolizumab .................................................................... 55 
6.5.2.1.1 
Attribution of toxicity ......................................................................... 55 
6.5.2.1.2 
Holding study interventions ............................................................... 56 
6.5.2.1.3 
Restarting study interventions ............................................................ 56 
6.5.2.2 
Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab ............................................................................................. 60 
6.5.2.3 
Other allowed dose interruption for pembrolizumab .................................... 62 
6.5.3 
Clinical management of cytokine release syndrome .......................................... 62 
6.6 
Continued access to study intervention after the end of the study ............................. 63 
6.7 
Treatment of overdose ................................................................................................ 63 
6.8 
Concomitant therapy .................................................................................................. 64 
6.8.1 
Rescue medication and supportive care .............................................................. 64 
6.8.2 
Prohibited medications........................................................................................ 64 
7 
DISCONTINUATION 
OF 
STUDY 
INTERVENTION 
AND 
PATIENT 
DISCONTINUATION/WITHDRAWAL................................................................................ 66 
7.1 
Discontinuation of study intervention ........................................................................ 66 
7.2 
Patient discontinuation/withdrawal from the study .................................................... 67 
7.3 
Lost to follow-up ........................................................................................................ 67 

 
 
 
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8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................... 68 
8.1 
Efficacy assessments .................................................................................................. 68 
8.1.1 
Tumor imaging and assessment of disease ......................................................... 68 
8.1.1.1 
Initial tumor scans ......................................................................................... 69 
8.1.1.2 
Tumor scans during the study ....................................................................... 69 
8.1.1.3 
End of treatment and follow-up tumor imaging ........................................... 69 
8.1.1.4 
RECIST 1.1 assessment of disease ............................................................... 70 
8.1.1.5 
iRECIST assessment of disease .................................................................... 70 
8.1.1.6 
PD-1 treatment progression .......................................................................... 71 
8.2 
Safety assessments ..................................................................................................... 71 
8.2.1 
Physical examinations, ECOG performance status, body height, and body weight
............................................................................................................................. 71 
8.2.2 
Vital signs ........................................................................................................... 71 
8.2.3 
Special assessments on treatment days ............................................................... 71 
8.2.3.1 
Cycle 1 day 1 ................................................................................................ 71 
8.2.3.2 
Cycle 1 day 2, day 8, and day 9; and treatment days of cycle 2 ................... 72 
8.2.3.3 
Treatment days of cycle 3 and onwards ........................................................ 72 
8.2.4 
Electrocardiography and left ventricular ejection fraction ................................. 72 
8.2.5 
Clinical safety laboratory assessments ................................................................ 72 
8.2.5.1 
Coagulation ................................................................................................... 73 
8.2.5.2 
Hematology ................................................................................................... 73 
8.2.5.3 
Biochemistry ................................................................................................. 73 
8.2.5.4 
Urinalysis ...................................................................................................... 73 
8.2.5.5 
Serology testing for infections ...................................................................... 73 
8.2.6 
Monitoring of thyroid function ........................................................................... 73 
8.2.7 
Pregnancy testing ................................................................................................ 73 
8.3 
Adverse events, serious adverse events, and other safety reporting........................... 73 
8.3.1 
Definitions........................................................................................................... 73 
8.3.1.1 
Adverse events .............................................................................................. 73 
8.3.1.2 
Serious adverse events .................................................................................. 74 
8.3.1.3 
Adverse events of special interest ................................................................. 74 
8.3.1.4 
Excluded events ............................................................................................ 75 
8.3.1.5 
Severity/intensity vs. seriousness.................................................................. 75 
8.3.2 
Time period and frequency for collecting AE, SAE, and other reportable safety 
event information ................................................................................................ 75 

 
 
 
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8.3.3 
Method of detecting AEs and SAEs ................................................................... 76 
8.3.4 
Follow-up of AEs and SAEs ............................................................................... 76 
8.3.5 
Regulatory reporting requirements for SAEs ..................................................... 76 
8.3.6 
Pregnancy ............................................................................................................ 77 
8.3.7 
Assessing AEs ..................................................................................................... 77 
8.3.7.1 
Causality ....................................................................................................... 77 
8.3.7.2 
Severity/intensity .......................................................................................... 78 
8.3.8 
Reporting by the investigational site................................................................... 78 
8.3.8.1 
Adverse events .............................................................................................. 78 
8.3.8.2 
Documenting on eCRFs ................................................................................ 79 
8.3.8.3 
Immediately reportable events ...................................................................... 79 
8.3.8.4 
Report forms ................................................................................................. 80 
8.4 
Pharmacokinetics ........................................................................................................ 80 
8.5 
Genetics ...................................................................................................................... 81 
8.6 
Biomarkers ................................................................................................................. 81 
8.6.1 
Tumor tissue........................................................................................................ 81 
8.6.2 
Blood sample for RNA and DNA analyses and biomarker studies .................... 82 
8.7 
Immunogenicity assessments ..................................................................................... 82 
8.8 
Health economics ....................................................................................................... 82 
8.9 
Pharmacodynamics ..................................................................................................... 82 
9 
STATISTICAL CONSIDERATIONS ............................................................................. 83 
9.1 
Statistical hypotheses ................................................................................................. 83 
9.2 
Analysis sets ............................................................................................................... 83 
9.2.1 
All-subjects-as-treated population ...................................................................... 83 
9.2.2 
PK population ..................................................................................................... 83 
9.2.3 
Efficacy population ............................................................................................. 83 
9.2.4 
Per Protocol population....................................................................................... 83 
9.3 
Statistical analyses ...................................................................................................... 83 
9.3.1 
General considerations ........................................................................................ 83 
9.3.2 
Primary endpoint analysis ................................................................................... 84 
9.3.3 
Secondary endpoints analysis ............................................................................. 84 
9.3.3.1 
Safety endpoints ............................................................................................ 84 
9.3.3.2 
Efficacy endpoints ........................................................................................ 85 
9.3.4 
Exploratory endpoint analysis ............................................................................. 87 

 
 
 
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9.3.5 
Other analyses ..................................................................................................... 87 
9.4 
Interim analysis .......................................................................................................... 87 
9.5 
Sample size determination .......................................................................................... 88 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ... 90 
10.1 Appendix 1: Regulatory, ethical, and study oversight considerations ....................... 90 
10.1.1 Regulatory and ethical considerations ................................................................ 90 
10.1.2 Financial disclosure ............................................................................................ 91 
10.1.3 Informed consent process ................................................................................... 91 
10.1.3.1 Clinical trial participation ............................................................................. 91 
10.1.3.2 Pharmacogenomic research .......................................................................... 91 
10.1.4 Data protection .................................................................................................... 92 
10.1.5 Organizational structure of the study .................................................................. 94 
10.1.6 Dissemination of clinical study data ................................................................... 94 
10.1.7 Data quality assurance ........................................................................................ 94 
10.1.8 Trial monitoring, access to source documentation, and data retention ............... 94 
10.1.9 Study and site start and closure ........................................................................... 95 
10.1.10 Publication policy ............................................................................................... 95 
10.1.11 Independent Data Monitoring Committee .......................................................... 96 
10.1.12 Future research .................................................................................................... 96 
10.2 Appendix 2: Description of the iRECIST process for assessment of disease progression
 .................................................................................................................................... 96 
10.2.1 Assessment at screening and prior to RECIST 1.1 progression ......................... 96 
10.2.2 Assessment and decision at RECIST 1.1 progression ........................................ 96 
10.2.3 Assessment at the confirmatory scans ................................................................ 97 
10.2.4 Confirmation of progression ............................................................................... 97 
10.2.5 Persistent iUPD ................................................................................................... 97 
10.2.6 Resolution of iUPD ............................................................................................. 98 
10.2.7 Management following the confirmatory scan ................................................... 98 
10.2.8 Detection of progression at visits after pseudoprogression resolves .................. 98 
10.3 Appendix 3: Abbreviations ...................................................................................... 100 
10.4 Appendix 4: Protocol Amendment history ............................................................... 103 
10.5 Appendix 5: Country-specific requirements/differences ......................................... 104 
11 REFERENCES ............................................................................................................... 105 

 
 
 
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1 PROTOCOL SUMMARY 
1.1 Synopsis 
Study title 
A phase 2, open-label, single-arm, multicenter study of SOT101  
in combination with pembrolizumab to evaluate the efficacy and 
safety in patients with selected advanced/refractory solid tumors 
Rationale 
Nanrilkefusp alfa is a fusion protein which consists of the N-terminal 
domain of human interleukin 15 (IL-15) receptor  covalently 
coupled to human IL-15. Pembrolizumab is a potent humanized IgG4 
monoclonal antibody with high specificity of binding to the 
programmed cell death protein 1 receptor, thus inhibiting its 
interaction with programmed cell death ligand 1 and programmed cell 
death ligand 2. The combination of nanrilkefusp alfa and 
pembrolizumab is expected to lead to synergistic outcomes in the 
induction and/or maintenance of antitumor responses. 
Overall design 
This is a phase 2, open-label, single-arm, multicenter study of 
nanrilkefusp alfa in combination with pembrolizumab to evaluate the 
efficacy and safety in patients with selected advanced/refractory solid 
tumors. 
Objectives  
and endpoints 
 
 
 
Objective 
Endpoint(s) 
Primary 
• To estimate the antitumor 
efficacy of nanrilkefusp alfa 
in combination with 
pembrolizumab 
• Objective response rate 
(ORR) according to 
Response Evaluation Criteria 
In Solid Tumors version 1.1 
(RECIST 1.1) in patients 
with measurable disease 
Secondary 
• To assess the safety and 
tolerability of nanrilkefusp 
alfa in combination with 
pembrolizumab according to 
Common Terminology 
Criteria for Adverse Events 
(CTCAE) version 5.0 
• Type, frequency, and 
severity of treatment-
emergent adverse events 
(TEAEs); adverse events of 
special interest (AESIs); 
safety laboratory findings; 
vital signs; 
electrocardiography (ECG) 
findings 

 
 
 
SC104 Protocol Amendment 1, Final, 20Apr2023 
Page 25 of 108 
• To further evaluate the 
antitumor efficacy of 
nanrilkefusp alfa in 
combination with 
pembrolizumab 
• ORR according to RECIST 
for immune-based 
therapeutics (iRECIST) 
(iORR) in patients with 
measurable disease 
• 
Best overall response 
according to RECIST 1.1 
(BOR) and iRECIST (iBOR) 
in patients with measurable 
disease 
• Duration of response 
according to RECIST 1.1 
(DoR), iRECIST (iDoR), 
and Prostate Cancer Clinical 
Trials Working Group 3 
(PCWG3)-modified RECIST 
1.1 (metastatic castration-
resistant prostate cancer 
[mCRPC] only) 
• Clinical benefit rate 
according to RECIST 1.1 
(CBR), iRECIST (iCBR), 
and PCWG3-modified 
RECIST 1.1 (mCRPC only) 
• Progression-free survival 
according to RECIST 1.1 
(PFS), iRECIST (iPFS), and 
PCWG3-modified RECIST 
1.1 (mCRPC only) 
• Time to response according 
to RECIST 1.1 (TtR) and 
iRECIST (iTtR) in patients 
with measurable disease 
• mCRPC only: 
o Circulating tumor cell 
(CTC) count conversion 
from ≥5 to <5 cells per 
7.5 mL of blood 
o Confirmed prostate-
specific antigen (PSA) 
decline of ≥50% 
o Time to confirmed PSA 
progression 

 
 
 
SC104 Protocol Amendment 1, Final, 20Apr2023 
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• (Population) 
pharmacokinetics (PK) of 
nanrilkefusp alfa in 
combination with 
pembrolizumab 
• Concentrations of 
nanrilkefusp alfa over time 
• To determine the 
immunogenicity of 
nanrilkefusp alfa in 
combination with 
pembrolizumab 
• Incidence, titer, and time 
course of anti-drug 
antibodies (ADAs) against 
nanrilkefusp alfa 
Exploratory 
• To identify immune and 
molecular (including 
genomic, metabolic, and/or 
proteomic) biomarker(s) in 
archival and/or fresh tumor 
tissue and blood that may be 
indicative of clinical 
response/resistance, safety, 
pharmacodynamic (PD) 
activity, and/or the 
mechanism of action of 
nanrilkefusp alfa and 
pembrolizumab 
• Changes in the expression of 
immune biomarkers as 
compared to baseline in 
tumor tissue 
• Circulating 
tumor 
DNA 
fraction (mCRPC only) 
• Status of immune, 
molecular, disease-related, 
and other exploratory 
biomarkers in blood and 
archival and/or freshly 
obtained tumor tissue 
• To determine the 
immunogenicity of 
pembrolizumab in 
combination with 
nanrilkefusp alfa 
• Incidence, titer, and time 
course of ADAs against 
pembrolizumab 
• (Population) PK of 
pembrolizumab in 
combination with 
nanrilkefusp alfa 
• Concentrations of 
pembrolizumab over time 
• To further evaluate the 
antitumor efficacy of 
nanrilkefusp alfa in 
combination with 
pembrolizumab 
• Overall survival (OS) 
 
 
 

 
 
 
SC104 Protocol Amendment 1, Final, 20Apr2023 
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Study 
interventions 
Patients will be treated with nanrilkefusp alfa 12 µg/kg 
subcutaneously on day 1 (±1 day for the cycle start), day 2, day 8, and 
day 9 in combination with pembrolizumab 200 mg intravenously (IV) 
on day 1 in 3-week cycles after all procedures and assessments have 
been completed. 
Pembrolizumab will be administered as an IV infusion via peripheral 
or central venous line within 30 minutes after the first dose (day 1) of 
nanrilkefusp alfa in each 3-week cycle. 
Study population 
Based on encouraging data on the combination therapy with efficacy 
signals as well as on pembrolizumab single-agent treatment, the 
following indications have been selected for this study: 
• Advanced and/or metastatic non-small cell lung cancer (NSCLC) 
with disease progression on or after an immune checkpoint 
inhibitor-containing regimen and a platinum-containing regimen, 
with no epidermal growth factor receptor (EGFR) or anaplastic 
lymphoma kinase (ALK) genomic tumor aberrations, and who are 
not amenable to curative treatment 
• Microsatellite instability-high (MSI-H) or mismatch repair 
deficient (dMMR) colorectal cancer that is unresectable or 
metastatic 
• Recurrent or metastatic cutaneous squamous cell carcinoma 
(cSCC) that is not curable by surgery or radiation and in second 
line if refractory or relapsed after a checkpoint inhibitor-
containing regimen and radiotherapy is not feasible 
• Advanced hepatocellular carcinoma after recurrence or failure of 
an immune checkpoint inhibitor (not applicable in France) 
• Treatment-refractory mCRPC after recurrence or failure of 
docetaxel and prior treatment with abiraterone, enzalutamide, or 
any other androgen receptor-targeted agent 
• Advanced recurrent ovarian cancer after recurrence or failure on 
the last platinum-based therapy within 6 months 
Study duration 
The study will end one year after the last patient’s last dose of study 
interventions or 3 years after the last patient’s first dose of study 
interventions (whichever occurs earlier). 
Estimated sample 
size 
• NSCLC: 50 patients 
• MSI-H/dMMR colorectal cancer: 57 patients 
• cSCC: 57 patients 
• Advanced hepatocellular carcinoma: 55 patients (not applicable 
in France) 
• mCRPC: 51 patients 
• Recurrent ovarian cancer: 50 patients 

 
 
 
SC104 Protocol Amendment 1, Final, 20Apr2023 
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Statistical 
considerations 
Interim analysis, stopping/discontinuation criteria 
An analysis for futility will be performed when the sample size is 
considered enough for such analysis and for each indication, as 
described below in this section. Efficacy data and outputs will also be 
a part of the Independent Data Monitoring Committee (IDMC) 
review. 
Assuming a desired ORR, the futility analysis will be based on a 
comparison against a minimal ORR considered as both statistically 
and clinically relevant improvement as compared to the benchmark 
ORR. An 80% confidence interval (CI) using the exact method for 
the ORR (alpha = 0.2, alpha = 0.1 one-sided) will be used. 
If, for a certain indication, the ORR is: 
• lower than the minimal ORR, and 
• the 80% CI for the ORR does not include the minimal ORR, 
it will be concluded that the combination treatment is futile as 
compared to benchmark treatment and thus the indication will be 
discontinued. However, patients still on treatment in the indication 
can continue combination therapy if recommended by the IDMC. 
The criteria for conclusion of futility, for each indication, are defined 
as follows: 
• Indication 1 (NSCLC): Benchmark ORR = 15%; minimal  
ORR = 23%; desired ORR = 30.6% 
o N = 21 patients if the number of responses is less than 2  
(r < 2) 
• Indication 2 (MSI-H/dMMR colorectal cancer): Benchmark  
ORR = 44%; minimal ORR = 54.1%; desired ORR = 62.5% 
o N = 12 patients if the number of responses is less than 4  
(r < 4) 
• Indication 3 (cSCC): Benchmark ORR = 44%; minimal  
ORR = 54.1%; desired ORR = 62.5% 
o N = 12 patients if the number of responses is less than 4  
(r < 4) 
• Indication 4 (advanced hepatocellular carcinoma): Benchmark 
ORR = 17%; minimal ORR = 25.3%; desired ORR = 33% (not 
applicable in France) 
o N = 19 patients if the number of responses is less than 2  
(r < 2) 
• Indication 5 (mCRPC): Benchmark ORR = 5%; minimal  
ORR = 10.4%; desired ORR = 16.4% 

 
 
 
SC104 Protocol Amendment 1, Final, 20Apr2023 
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o N = 35 patients if the number of responses is less than 1  
(r < 1) 
• Indication 6 (recurrent ovarian cancer): Benchmark ORR = 15%; 
minimal ORR = 23%; desired ORR = 30.6% 
o N = 21 patients if the number of responses is less than 2  
(r < 2) 
Additionally, the ORR will be evaluated on an ongoing basis (without 
stopping of recruitment). Other efficacy endpoints will be used as 
supportive information. 
Statistical analyses 
Analyses will be descriptive. The ORR will be presented with 
95% CIs. 
Kaplan-Meier estimations of time-to-event data will be performed, 
together with an estimation of the median (if reached). 
If appropriate regarding the number of patients, descriptive statistics 
for other endpoints will be presented with 95% CIs. 
Independent Data 
Monitoring 
Committee 
An IDMC will be established for this study to safeguard the interest 
and safety of the patients participating in the study and provide 
independent review and assessment of the efficacy and safety data in 
a systematic manner. In addition, the IDMC will review safety data 
from the first 10-12 patients across all indications. 
 
 
 

 
 
 
SC104 Protocol Amendment 1, Final, 20Apr2023 
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1.2 Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Advanced hepatocellular carcinoma after recurrence or failure  
of an immune checkpoint inhibitor (not applicable in France) 
Second- to fourth-line 
55 patients 
Advanced recurrent ovarian cancer after recurrence or failure  
on the last platinum-based therapy within 6 months 
Second- to fifth-line 
50 patients 
Treatment-refractory mCRPC after recurrence or failure of docetaxel and 
prior treatment with abiraterone, enzalutamide, or any other androgen 
receptor-targeted agent 
Second- to fifth-line 
51 patients 
Phase 2, single-arm,  
open-label, 
multicenter study 
Nanrilkefusp alfa 
combined with 
pembrolizumab 
Primary endpoint ORR 
ALK, anaplastic lymphoma kinase; cSCC, cutaneous squamous cell carcinoma; dMMR, mismatch repair deficient; EGFR, epidermal growth factor 
receptor; mCRPC, metastatic castration-resistant prostate cancer; MSI-H, microsatellite instability-high; NSCLC, non-small cell lung cancer; ORR, 
objective response rate 
Advanced and/or metastatic NSCLC with disease progression  
on or after an immune checkpoint inhibitor-containing regimen  
and a platinum-containing regimen, with no EGFR or ALK  
genomic tumor aberrations, and who are not amenable to curative 
treatment 
Second-line or third-line 
50 patients 
Recurrent or metastatic cSCC that is not curable by surgery or radiation 
and in second line if refractory or relapsed after a checkpoint inhibitor-
containing regimen and radiotherapy is not feasible 
First-line or second-line 
57 patients 
MSI-H/dMMR colorectal cancer that is unresectable or metastatic 
First-line 
57 patients 

 
 
 
 
SC104 Protocol Amendment 1, Final, 20Apr2023 
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1.3 Schedule of activities 
1.3.1 
Schedule of activities, nanrilkefusp alfa combined with pembrolizumab 
Cycle 
Screening 
Up to 28 
days  
before day 1 
of cycle 1 
Cycle 1 and cycle 2 
From cycle 3 onwards 
End  
of treatment1 
Within 7 (+7) days after 
the last dose of 
nanrilkefusp alfa and/or 
pembrolizumab 
(whichever occurs later) 
Follow-up 
Visit 
Day 1 
Day 2 
Day 6 Day 8 Day 9 Day 13 
Day 1 
Day 2 
Day 8 
Day 9 
Informed consent2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Cancer4 and medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X  
(blood) 
X  
(urine or blood)5 
 
 
 
 
 
X  
(urine or blood)5 
 
 
 
 
X  
(urine  
or blood)6 
Physical examination 
X 
X7 
X7 
X 
X7 
X7 
X 
X7 
X7 
X7 
X7 
X 
X8 
Body weight 
X 
X5 
 
 
 
 
 
X5 
 
 
 
X 
 
Vital signs 
X 
X9 
X9 
X 
X9 
X9 
X 
X9 
X9 
X9 
X9 
X 
X8 
Urinalysis10 
X 
X5 
 
 
X5 
 
 
X5 
 
X5 
 
X 
 
Electrocardiography 
X 
X5 
 
 
 
 
 
X5 
 
 
 
X 
 
Left ventricular ejection fraction11 
X 
End of each second cycle (i.e., cycle 2, 4, 6…; allowed interval from day 9 of the current cycle to day 2 of the next 
cycle) 
X 
 
Eastern Cooperative Oncology Group 
performance score 
X 
X5 
 
 
 
 
 
X5 
 
 
 
X 
X8 
Tumor assessment  
(CT/MRI/bone scan) 
X12 
Every 6 weeks (±2 weeks) starting from day 1 of cycle 1 until disease progression identified by the investigator, start of a new anti-cancer treatment, 
pregnancy of the patient, withdrawal of consent by the patient, or end of the study 
Nanrilkefusp alfa administration13 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
 
Pembrolizumab administration14 
 
Every 3 weeks (day 1) according to the prescribing information 
 
 
Tumor biopsy15 
X 
X 
 
 
 
 
 
 
Adverse events 
X 
X 
X8 
Concomitant medication/ non-drug 
therapies 
X 
X 
X8 
Survival information 
 
 
 
 
 
 
 
 
 
 
 
 
X16 
 

 
 
 
SC104 Protocol Amendment 1, Final, 20Apr2023 
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1. 
Criteria for discontinuation of study interventions are listed in section 7.1. In case nanrilkefusp alfa needs to be discontinued for reasons other than disease progression, pembrolizumab treatment can continue for 
up to a total of 35 administrations (approximately 2 years) in patients without disease progression or unacceptable toxicity. A schedule of activities for patients who continue pembrolizumab after discontinuation 
of nanrilkefusp alfa is shown in section 1.3.2. In case pembrolizumab needs to be discontinued, nanrilkefusp alfa treatment can continue until disease progression or unacceptable toxicity and the schedule of 
activities for patients receiving nanrilkefusp alfa combined with pembrolizumab will apply (not applicable in the Czech Republic). In the Czech Republic: In case pembrolizumab needs to be discontinued, 
nanrilkefusp alfa treatment will be discontinued as well. 
2. 
No study-specific procedures are to be performed before ICF signature. 
3. 
Age at screening and gender 
4. 
Primary tumor location, histology/cytology, initial diagnosis date, lines of previous treatment, start and stop dates of the treatments before this study, any prior mutations/genetic analysis (e.g., EGFR, ALK 
mutations), and the date of the latest disease progression if not coinciding with the stop date 
5. 
Before nanrilkefusp alfa administration 
6. 
Every 30 (±2) days until 120 (±2) days after the last dose of pembrolizumab or 30 (±2) days after the last dose of nanrilkefusp alfa, whichever is later 
7. 
Before nanrilkefusp alfa administration and afterwards as clinically required 
8. 
Follow-up visits 30 (±2) days and 90 (+2) days after the last dose of nanrilkefusp alfa and/or pembrolizumab (whichever occurs later) 
9. 
Before and after nanrilkefusp alfa administration as described in section 8.2.3 
10. In case of proteinuria ≥100 mg/dL at screening, a 24-hour urine analysis will have to be performed (before the start of nanrilkefusp alfa treatment) to document 24-hour proteinuria levels and a urine test will continue 
during the treatment period. In case of increase of proteinuria with ≥300 mg/dL (at any time), a 24-hour urine analysis will be performed. 
11. Using either echocardiography or MUGA; the method chosen needs to stay the same throughout the trial 
12. Tumor scans performed as part of routine clinical management are acceptable for screening if they are of acceptable diagnostic quality and performed within 28 days of day 1 of cycle 1. 
13. Time to be recorded 
14. Time to be recorded; pembrolizumab will be administered within 30 minutes following nanrilkefusp alfa administration 
15. A fresh biopsy must be taken during screening unless the biopsy cannot be obtained due to safety reasons or non-accessibility of the tumor site. If it is not possible to obtain a fresh biopsy, every effort should be 
taken to retrieve an archival biopsy. Archived, fixed tumor tissue may only be collected if taken preferentially after completion of the most recent systemic tumor therapy and within 12 months prior to the first dose 
of study treatment. Investigators are highly encouraged to obtain an optional biopsy at cycle 2 day 13 and at disease progression or at any other clinically relevant event if it does not expose the patient to an increased 
risk. 
16. Contacts every 3 months (±2 weeks) during year 1 and then every 6 months (±2 weeks) until the end of the study 
ALK, anaplastic lymphoma kinase; CT, computed tomography; EGFR, epidermal growth factor receptor; ICF, Informed Consent Form; MRI, magnetic resonance imaging; MUGA, multigated acquisition scanning 
 
 

 
 
 
SC104 Protocol Amendment 1, Final, 20Apr2023 
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1.3.2 
Schedule of activities, for patients who continue pembrolizumab after discontinuation of nanrilkefusp alfa 
1. 
Before pembrolizumab administration 
2. 
Every 30 (±2) days until 120 (±2) days after the last dose of pembrolizumab 
3. 
Follow-up visits 30 (±2) days and 90 (+2) days after the last dose of pembrolizumab 
4. 
In case of proteinuria ≥100 mg/dL at screening, a 24-hour urine analysis will have to be performed (before the start of nanrilkefusp alfa treatment) to document 24-hour proteinuria levels and a urine test will continue 
during the treatment period. In case of increase of proteinuria with ≥300 mg/dL (at any time), a 24-hour urine analysis will be performed. 
5. 
Using either echocardiography or MUGA; the method chosen needs to stay the same throughout the trial 
6. 
Contacts every 3 months (±2 weeks) during year 1 and then every 6 months (±2 weeks) until the end of the study 
CT, computed tomography; MRI, magnetic resonance imaging; MUGA, multigated acquisition scanning 
 
 
Visit 
Day 1 of each cycle 
End of treatment 
Within 7 (+7) days after the last dose of pembrolizumab 
Follow-up 
Pregnancy test 
X (urine or blood)1 
 
X (urine or blood)2 
Physical examination 
X1 
X 
X3 
Body weight 
X1 
X 
 
Vital signs 
X1 
X 
X3 
Urinalysis4 
X1 
X 
 
Electrocardiography 
X1 
X 
 
Left ventricular ejection fraction5 
 
X 
 
Eastern Cooperative Oncology Group  
performance score 
X1 
X 
X3 
Tumor assessment (CT/MRI/bone scan) 
Every 6 weeks (±2 weeks) starting from day 1 of cycle 1 until disease progression identified by the investigator, start of a new anti-cancer treatment, pregnancy of the 
patient, withdrawal of consent by the patient, or end of the study 
Pembrolizumab administration 
Every 3 weeks (day 1) according to the prescribing information 
 
 
Adverse events 
X 
X3 
Concomitant medication/non-drug therapies 
X 
X3 
Survival information 
 
 
X6 

 
 
 
 
SC104 Protocol Amendment 1, Final, 20Apr2023 
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1.3.3 
Collection of blood samples, nanrilkefusp alfa combined with pembrolizumab 
All attempts should be made to collect the samples on time. 
 Cycle 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
From cycle 4 
End of 
treatment 
Day 
1 
2 
6 
8 
9 
13 
1 
2 
6 
8 
9 
1 
2 
8 
9 
1 
2 
8 
9 
Nanrilkefusp alfa administration1 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pembrolizumab administration2 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Serum for nanrilkefusp alfa PK 
See section 1.3.5 
Serum for cytokines3 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
Serum for nanrilkefusp alfa 
immunogenicity4 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Cycle 4  
only 
 
 
 
X 
Serum for pembrolizumab PK5 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Cycles 4  
and 8 only 
 
 
 
X 
Serum for pembrolizumab 
immunogenicity6 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Cycle 4 only 
 
 
 
X 
Whole blood for RNA and DNA analysis7 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
HIV, HBV, and HCV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology (full complete blood count 
including absolute lymphocyte count) 
X 
X4 
X8 
X 
X4 
X8 
X 
X4 
 
X 
X4 
 
X4 
 
X4 
 
X4 
 
X4 
 
X 
Biochemistry 
(including C-reactive protein) 
X 
X4 
X8 
X 
 
X8 
X 
X4 
 
X 
 
X8 
X4 
 
X4 
 
X4 
 
X4 
 
X 
Creatinine clearance 
X 
X4 
 
X 
 
X8 
 
X4 
 
X 
 
X8 
X4 
 
X4 
 
X4 
 
X4 
 
 
C-reactive protein 
 
 
 
 
X4 
 
 
 
X8 
 
X4 
 
 
 
 
 
 
 
 
 
 
Coagulation 
X 
X4 
 
 
X4 
 
 
X4 
 
 
X4 
 
X4 
 
X4 
 
X4 
 
X4 
 
X 
TSH, T3 or free T3, free T4 
X 
X4 
 
 
 
 
 
 
 
 
 
 
X4 
 
 
 
X4,9 
 
 
 
X 
Patients with mCRPC: PSA, alkaline 
phosphatase, lactate dehydrogenase, 
CTCs, circulating tumor DNA fraction 
X 
X4 
 
 
 
 
 
 
 
 
 
 
X4 
 
 
 
X4,9 
 
 
 
 
Serum pregnancy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. 
Time to be recorded 
2. 
Time to be recorded; pembrolizumab will be administered within 30 minutes following nanrilkefusp alfa administration. 
3. 
Before nanrilkefusp alfa administration and 4 hours (±30 min) after nanrilkefusp alfa administration 
4. 
Within 1 day before nanrilkefusp alfa administration 
5. 
Up to 24 hours before pembrolizumab infusion at cycles 1, 2, 4, and 8; within 30 minutes of the end of pembrolizumab infusion at cycles 1, 2, and 8; and at the End of treatment visit; sampling times to be recorded 
6. 
Up to 24 hours before pembrolizumab infusion at cycles 1, 2, and 4; and at the End of treatment visit; sampling times to be recorded 
7. 
Samples for RNA analysis: day 1 (before nanrilkefusp alfa administration) and day 6 of cycles 1 and 2; samples for DNA analysis: day 1 (before nanrilkefusp alfa administration) of cycle 1 only 
8. 
On the day of dosing before nanrilkefusp alfa administration 
9. 
Every other cycle 
CTC, circulating tumor cell; HBV, hepatitis B; HCV, hepatitis C; mCRPC, metastatic castration-resistant prostate cancer; PK, pharmacokinetics; PSA, prostate-specific antigen; T3, triiodothyronine; T4, thyroxine; 
TSH, thyroid stimulating hormone  

 
 
 
SC104 Protocol Amendment 1, Final, 20Apr2023 
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1.3.4 
Collection of blood samples, for patients who continue pembrolizumab after 
discontinuation of nanrilkefusp alfa 
All attempts should be made to collect the samples on time. 
Cycle 
From cycle 1 
End of treatment 
Day 
1 
Pembrolizumab administration1 
X 
 
Hematology 
X2 
X 
Biochemistry 
X2 
X 
Coagulation 
X2 
X 
TSH, T3 or free T3, free T4 
X2,3 
X 
1. 
Time to be recorded 
2. 
Before pembrolizumab administration 
3. 
Every other cycle 
T3, triiodothyronine; T4, thyroxine; TSH, thyroid stimulating hormone 
 
 

 
 
 
 
SC104 Protocol Amendment 1, Final, 20Apr2023 
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1.3.5 
Nanrilkefusp alfa pharmacokinetic sampling 
All attempts should be made to collect the samples on time. 
Cycle, day 
Time point 
(pre-dose or time after nanrilkefusp alfa 
administration) 
12 patients per indication Rest of the patients 
Cycle 1 day 1 
Pre-dose to nanrilkefusp alfa  
X 
 
30 min (±5 min) 
X 
 
1 h (±5 min) 
X 
 
2 h (±15 min) 
X 
 
4 h (±30 min) 
X 
X 
 
12 h (±2 h) (optional) 
X 
 
Cycle 1 day 2 
Pre-dose to nanrilkefusp alfa (-2 h [-15 min] to 0 h) 
X 
X 
Cycle 1 day 8 
Pre-dose to nanrilkefusp alfa (-2 h [-15 min] to 0 h) 
X 
 
Cycle 1 day 9 
Pre-dose to nanrilkefusp alfa (-2 h [-15 min] to 0 h) 
X 
 
2 h (±15 min) 
X 
 
4 h (±30 min) 
X 
X 
Cycle 2 day 1 
Pre-dose to nanrilkefusp alfa (-2 h [-15 min] to 0 h) 
X 
 
2 h (±15 min) 
X 
 
4 h (±30 min) 
X 
X 
Cycle 2 day 9 
Pre-dose to nanrilkefusp alfa (-2 h [-15 min] to 0 h) 
X 
 
2 h (±15 min) 
X 
 
4 h (±30 min) 
X 
X 
Cycle 3 day 1 
Pre-dose to nanrilkefusp alfa (-2 h [-15 min] to 0 h) 
X 
 
2 h (±15 min) 
X 
X 
 

 
 
 
SC104 Protocol Amendment 1, Final, 20Apr2023 
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2 INTRODUCTION 
2.1 Study rationale 
The involvement of the immune system in the control of tumor growth is well accepted and 
immunotherapy is taking a major place in the treatment of cancers.1 Current cancer 
immunotherapies that have been investigated for their efficacy include, among others, cytokine 
therapy and immune checkpoint inhibition. Emerging clinical data showed that cytokine 
therapy is safe and feasible in the outpatient setting and can be safely combined with immune 
checkpoint inhibitors.2,3 We hypothesize that this combination leads to synergistic outcomes in 
the induction and/or maintenance of the antitumor responses by activation of both innate and 
adaptive cellular immune responses against tumor cells. 
This basket study is planned based on results from pre-clinical studies of nanrilkefusp alfa 
(SOT101) and preliminary results from an ongoing clinical study of nanrilkefusp alfa (study 
SC103 [AURELIO-03, NCT04234113], a multicenter, open-label, phase 1/1b study to evaluate 
the safety and preliminary efficacy of SO-C101 [nanrilkefusp alfa] as monotherapy and in 
combination with pembrolizumab in patients with selected advanced/metastatic solid tumors). 
Study SC103 (AURELIO-03) shows that the combination of nanrilkefusp alfa and 
pembrolizumab can be safely administered. The safe recommended dose of nanrilkefusp alfa 
in combination with pembrolizumab is 12 µg/kg body weight on days 1, 2, 8, and 9 every 
3 weeks, the same as for nanrilkefusp alfa monotherapy. Preliminary efficacy signals were seen 
both in monotherapy and even stronger in combination therapy. 
2.2 Background 
Therapy with recombinant interleukin (IL)-2, a T-cell and natural killer (NK)-cell growth 
factor, was one of the earliest successes in immunotherapy. IL-2 (International Nonproprietary 
Name: aldesleukin) was approved in some countries in the EU to treat metastatic renal cell 
carcinoma and by the US Food and Drug Administration (FDA) to treat metastatic renal cell 
carcinoma and malignant melanoma.4,5 
IL-15 is a cytokine that has many overlapping functions like IL-2, including the ability to 
promote antitumor responses, but with distinct advantages over IL-2. While both IL-2 and  
IL-15 signal through the common IL-2 receptor (IL-2R) chains β and γ (IL-2Rβγ or IL-15 
receptor [IL-15R] βγ) complex, which is responsible for intracellular signaling through the 
JAK/STAT, MAPK, and PI3K pathways in T cells and NK cells, only IL-2 engages the high-
affinity IL-2R chain α (IL-2Rα). As IL-2Rα is expressed on regulatory T cells (Tregs), IL-15 
does not induce the expansion of these immunosuppressive cells.6-8 Because IL-15 can engage 
IL-2Rβγ without engaging IL-2Rα on Tregs, it is thought to have an improved therapeutic 
index compared with IL-2.9-11 
Despite the promising preclinical responses of recombinant IL-15,12 success in the clinical 
setting was limited by its short in vivo half-life. To date, 3 main modifications of IL-15 have 
been made to generate more potent soluble IL-15 agonists: 1) combining IL-15 with a soluble 
IL-15R chain α (IL-15Rα) or the sushi domain of IL-15Rα; 2) fusing IL-15Rα to the Fc portion 
of human IgG1; 3) mutating IL-15 to increase its affinity to IL-2Rβγ. All formulations of  
IL-15 agonists have demonstrated increased strength and duration of IL-15R signaling and 
subsequent enhanced antitumor immunity in nonclinical studies. 

 
 
 
SC104 Protocol Amendment 1, Final, 20Apr2023 
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In order to make use of the enhanced biological activity of the IL-15/IL-15Rα complex for the 
treatment of cancer and to overcome the need for endogenous IL-15Rα or co-administration of 
IL-15 with IL-15Rα, we engineered nanrilkefusp alfa, a fusion protein which consists of the 
N-terminal sushi domain of human IL-15Rα covalently coupled via a linker of 20 amino acids 
to human IL-15. The biological activity of nanrilkefusp alfa stems from the function of the  
IL-15 component, which acts as a pleiotropic cytokine and plays a critical role in stimulating 
both innate and adaptive immune responses. Experimental data have indicated that the 
biological activity of IL-15 was enhanced when co-administered with recombinant soluble  
IL-15Rα. Thus, nanrilkefusp alfa, which fuses the IL-15 component to the IL-15Rα component, 
may be more potent than IL-15 alone and may benefit from an extended half-life. 
Nanrilkefusp alfa promoted mobilization, expansion, and activation of human NK and CD8+ 
T cells in humanized mice and murine NK and CD8+ T cells in syngeneic mice. This NK- and 
CD8+ T-cell activation correlated with the potent anti-cancer therapeutic effects of 
nanrilkefusp alfa.13,14 
For detailed background information on nanrilkefusp alfa refer to the Investigator’s Brochure 
(IB). 
Pembrolizumab is a potent humanized IgG4 monoclonal antibody (mAb) with high specificity 
of binding to the programmed cell death protein 1 (PD-1) receptor, thus inhibiting its 
interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 
(PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity and potent 
receptor blocking activity for PD-1. Pembrolizumab has an acceptable preclinical safety profile 
and is in clinical development as an intravenous (IV) immunotherapy for advanced 
malignancies. Keytruda® (pembrolizumab) is indicated for the treatment of patients across a 
number of indications. For more details on specific indications refer to the IB. 
For detailed background information on pembrolizumab refer to the IB. 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades.15 Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various 
malignancies. In particular, the presence of CD8+ T cells and the ratio of CD8+ effector 
T cells/FoxP3+ Tregs correlates with improved prognosis and long-term survival in solid 
malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular carcinoma; 
malignant melanoma; and renal cell carcinoma. Tumor-infiltrating lymphocytes can be 
expanded ex vivo and reinfused, inducing durable objective tumor responses in cancers such as 
melanoma.16,17 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T cells 
under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) that has 
been shown to negatively regulate antigen receptor signaling upon engagement of its ligands 
(PD-L1 and/or PD-L2).18,19 
The structure of murine PD-1 has been resolved.20 PD-1 and its family members are type I 
transmembrane glycoproteins containing an Ig-variable type domain responsible for ligand 
binding and a cytoplasmic tail responsible for the binding of signaling molecules. The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 

 
 
 
SC104 Protocol Amendment 1, Final, 20Apr2023 
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tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch motif. 
Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to 
the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3 zeta, protein kinase C-theta, and zeta-
chain-associated protein kinase ZAP70, which are involved in the CD3 T-cell signaling 
cascade.19,21-23 The mechanism by which PD-1 down-modulates T-cell responses is similar to, 
but distinct from, that of CTLA-4, because both molecules regulate an overlapping set of 
signaling proteins.24,25 As a consequence, the PD-1/PD-L1 pathway is an attractive target for 
therapeutic intervention in various cancers. 
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.26-32 Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated 
antitumor responses in models of squamous cell carcinoma, pancreatic carcinoma, melanoma, 
acute myeloid leukemia, and colorectal carcinoma.20,29,31-33 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.31 
Experiments have confirmed the in vivo efficacy of anti-mouse PD-1 antibody as a 
monotherapy, as well as in combination with chemotherapy, in syngeneic mouse tumor models 
(see the IB). 
2.3 Benefit/risk assessment 
The risk assessment of nanrilkefusp alfa is based on nonclinical studies in addition to clinical 
experience from completed and ongoing trials with nanrilkefusp alfa as monotherapy and in 
combination with pembrolizumab. Clinical safety data from study SC103 (AURELIO-03) in 
patients with advanced/metastatic solid tumors for nanrilkefusp alfa in combination with 
pembrolizumab showed a similar profile as for nanrilkefusp alfa monotherapy; no relevant 
overlapping toxicities were reported (cut-off date 11Apr2022). The majority of treatment-
emergent adverse events (TEAEs) were of grade 1 or 2. The most common TEAEs for 
nanrilkefusp alfa monotherapy / nanrilkefusp alfa in combination with pembrolizumab were 
pyrexia (70.0/81.0%), decreased lymphocyte count (66.7/47.6%), anemia (60.0/52.4%), 
injection site reaction (56.7/57.1%), and chills (50.0/61.9%). The most common TEAEs of 
grade >2 were decreased lymphocyte, anemia, and pyrexia. These TEAEs could be well 
managed and were self-limiting upon discontinuation of nanrilkefusp alfa.  
Preliminary efficacy results in study SC103 (AURELIO-03) in advanced/metastatic solid 
tumors were encouraging, showing clinical benefit for most patients in the combination part of 
study, including patients pretreated with immune checkpoint inhibitors. Maximum activation 
of NK cells was observed already at low dose levels of nanrilkefusp alfa, and maximum 
activation of CD8+ T cells was reached at 9 to 12 µg/kg nanrilkefusp alfa. 
More recent information about the known and expected benefits and risks and adverse events 
(AEs) that could be associated with the administration of nanrilkefusp alfa and pembrolizumab 
may be found in the nanrilkefusp alfa and pembrolizumab IBs. 
In conclusion, the current nonclinical and clinical data on nanrilkefusp alfa in patients with 
advanced/metastatic solid tumors suggest a favorable benefit/risk ratio and justify further 
clinical development of nanrilkefusp alfa. 

 
 
 
SC104 Protocol Amendment 1, Final, 20Apr2023 
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3 OBJECTIVES AND ENDPOINTS 
Objective 
Endpoint(s) 
Primary 
• To estimate the antitumor efficacy of 
nanrilkefusp alfa in combination with 
pembrolizumab 
• Objective response rate (ORR) according 
to Response Evaluation Criteria In Solid 
Tumors version 1.1 (RECIST 1.1)34 in 
patients with measurable disease 
Secondary 
• To assess the safety and tolerability of 
nanrilkefusp alfa in combination with 
pembrolizumab according to Common 
Terminology Criteria for Adverse Events 
(CTCAE) version 5.035 
• Type, frequency, and severity of TEAEs; 
AEs of special interest (AESIs); safety 
laboratory findings; vital signs; 
electrocardiography (ECG) findings 
• To further evaluate the antitumor efficacy 
of nanrilkefusp alfa in combination with 
pembrolizumab 
• ORR according to RECIST for immune-
based therapeutics (iRECIST)36 (iORR) 
in patients with measurable disease 
• 
Best overall response according to 
RECIST 1.1 (BOR) and iRECIST 
(iBOR) in patients with measurable 
disease 
• Duration of response according to 
RECIST 1.1 (DoR), iRECIST (iDoR), 
and Prostate Cancer Clinical Trials 
Working Group 3 (PCWG3)-modified 
RECIST 1.1 (metastatic castration-
resistant prostate cancer [mCRPC] 
only)37 
• Clinical benefit rate according to 
RECIST 1.1 (CBR), iRECIST (iCBR), 
and PCWG3-modified RECIST 1.1 
(mCRPC only) 
• Progression-free survival according to 
RECIST 1.1 (PFS), iRECIST (iPFS), and 
PCWG3-modified RECIST 1.1 (mCRPC 
only) 

 
 
 
SC104 Protocol Amendment 1, Final, 20Apr2023 
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Objective 
Endpoint(s) 
• Time to response according to RECIST 
1.1 (TtR) and iRECIST (iTtR) in patients 
with measurable disease 
• mCRPC only: 
o Circulating tumor cell (CTC) count 
conversion from ≥5 to <5 cells per 
7.5 mL of blood 
o Confirmed prostate-specific antigen 
(PSA) decline of ≥50% 
o Time to confirmed PSA progression 
• (Population) pharmacokinetics (PK) of 
nanrilkefusp alfa in combination with 
pembrolizumab 
• Concentrations of nanrilkefusp alfa over 
time 
• To determine the immunogenicity of 
nanrilkefusp alfa in combination with 
pembrolizumab 
• Incidence, titer, and time course of anti-
drug antibodies (ADAs) against 
nanrilkefusp alfa 
Exploratory 
• To identify immune and molecular 
(including genomic, metabolic, and/or 
proteomic) biomarker(s) in archival 
and/or fresh tumor tissue and blood that 
may be indicative of clinical 
response/resistance, safety, 
pharmacodynamic (PD) activity, and/or 
the mechanism of action of nanrilkefusp 
alfa and pembrolizumab 
• Changes in the expression of immune 
biomarkers as compared to baseline in 
tumor tissue 
• Circulating tumor DNA fraction (mCRPC 
only)38 
• Status of immune, molecular, disease-
related, and other exploratory biomarkers 
in blood and archival and/or freshly 
obtained tumor tissue 
• To determine the immunogenicity of 
pembrolizumab in combination with 
nanrilkefusp alfa 
• Incidence, titer, and time course of ADAs 
against pembrolizumab 
• (Population) PK of pembrolizumab in 
combination with nanrilkefusp alfa 
• Concentrations of pembrolizumab over 
time 
• To further evaluate the antitumor efficacy 
of nanrilkefusp alfa in combination with 
pembrolizumab 
• Overall survival (OS) 

 
 
 
 
SC104 Protocol Amendment 1, Final, 20Apr2023 
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4 STUDY DESIGN 
4.1 Overall design 
This is a phase 2, open-label, single-arm, multicenter study of nanrilkefusp alfa in combination 
with pembrolizumab to evaluate the efficacy and safety in patients with selected 
advanced/refractory solid tumors. 
Participation of each patient will consist of the following study periods: 
4.1.1 
Screening 
Patients will be screened within a period of not more than 28 days, which will start when the 
Informed Consent Form (ICF) has been signed and end before day 1 of cycle 1. A medical 
monitor will verify and confirm patients’ eligibility. 
4.1.2 
Treatment 
During the treatment period, the trial assessments will be performed as outlined in the Schedule 
of activities. Study interventions will be administered as described in section 6. 
Patients will be treated with nanrilkefusp alfa together with pembrolizumab until any of the 
criteria for treatment discontinuation is met. 
After termination of study interventions, patients will be evaluated at an End of treatment visit. 
This visit will be scheduled within 7 days (+7 days) after the patients’ last dose of nanrilkefusp 
alfa and/or pembrolizumab (whichever occurs later). 
Reasons for study intervention discontinuation are listed in section 7. 
4.1.3 
Follow-up 
All patients will come to the clinic 30 (±2) days and 90 (+2) days after their last dose of 
nanrilkefusp alfa and/or pembrolizumab (whichever occurs later). 
Patients will be followed up for survival every 3 months (±2 weeks) during year 1 and then 
every 6 months (±2 weeks) until the end of the study. 
4.2 Scientific rationale for study design 
Based on previous encouraging data on the combination therapy of nanrilkefusp alfa with 
pembrolizumab from study SC103 (AURELIO-03) with efficacy signals as well as on 
pembrolizumab single-agent treatment, the following indications have been selected for this 
study SC104 entitled “A phase 2, open-label, single-arm, multicenter study of SOT101 in 
combination with pembrolizumab to evaluate the efficacy and safety in patients with selected 
advanced/refractory solid tumors”: 
• Advanced and/or metastatic non-small cell lung cancer (NSCLC) with disease progression 
on or after an immune checkpoint inhibitor-containing regimen and a platinum-containing 
regimen, with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase 
(ALK) genomic tumor aberrations, and who are not amenable to curative treatment 
o Pembrolizumab was investigated in the following clinical trials: 
▪ KEYNOTE-010 (NCT01905657), a randomized, multicenter, open-label, active-
controlled trial conducted in 1033 patients with metastatic NSCLC who had 

 
 
 
SC104 Protocol Amendment 1, Final, 20Apr2023 
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progressed following platinum-containing chemotherapy, and if appropriate, 
targeted therapy for EGFR or ALK genomic tumor aberrations. In this trial, 
pembrolizumab showed superiority over second-line docetaxel.39 
▪ KEYNOTE-024 (NCT02142738), a randomized, multicenter, open-label, active-
controlled trial conducted in 305 patients with previously untreated NSCLC with a 
PD-L1 tumor proportion score of at least 50% and no sensitizing EGFR or ALK 
alterations. In this trial, pembrolizumab provided a durable, clinically meaningful 
long-term OS benefit versus chemotherapy as first-line therapy for metastatic 
NSCLC with PD-L1 tumor proportion score of at least 50%.40 
▪ KEYNOTE-189 (NCT02578680), a randomized, multicenter, double-blind, active-
controlled trial conducted in 616 patients with metastatic non-squamous NSCLC, 
regardless of PD-L1 tumor expression status, who had not previously received 
systemic therapy for metastatic disease and in whom there were no EGFR or ALK 
genomic tumor aberrations. In this trial, the addition of pembrolizumab to standard 
chemotherapy of pemetrexed and a platinum-based drug showed significantly 
longer OS and PFS than chemotherapy alone.41 
▪ PROLUNG (NCT02574598), a randomized, open-label, crossover trial conducted 
in 78 patients with advanced NSCLC. In this trial, the combination of 
pembrolizumab plus docetaxel was well tolerated and substantially improved ORR 
and PFS in patients with advanced NSCLC who had previous progression after 
platinum-based chemotherapy, including NSCLC with EGFR variations.42 
o Atezolizumab was investigated in IMpower110 (NCT02409342), a randomized, 
multicenter, open-label trial conducted in 572 patients with metastatic non-squamous 
or squamous NSCLC who had not previously received chemotherapy and who had PD-
L1 expression on at least 1% of tumor cells or at least 1% of tumor-infiltrating immune 
cells. In this trial, atezolizumab showed superiority over first-line chemotherapy.43  
o This indication is therefore chosen to test the combination of nanrilkefusp alfa and 
pembrolizumab as second-line or third-line treatment after an immune checkpoint 
inhibitor-containing regimen and a platinum-containing regimen. 
• Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal 
cancer that is unresectable or metastatic 
o Pembrolizumab was investigated in KEYNOTE-177 (NCT02563002), a randomized, 
multicenter, open-label trial conducted in 307 patients with advanced MSI-H/dMMR 
colorectal carcinoma. In this trial, first-line pembrolizumab showed superiority over 
first-line chemotherapy.44 
o This indication is therefore chosen to test the ability of the combination of nanrilkefusp 
alfa and first-line pembrolizumab to improve pembrolizumab efficacy while 
maintaining safety (based on data from KEYNOTE-177). 
• Recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by 
surgery or radiation and in second line if refractory or relapsed after a checkpoint inhibitor-
containing regimen and radiotherapy is not feasible  
o Pembrolizumab was investigated in KEYNOTE-629 (NCT03284424), a single-arm 
trial conducted in 105 patients with recurrent or metastatic cSCC. In this trial, 

 
 
 
 
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pembrolizumab demonstrated effective antitumor activity; clinically meaningful, 
durable responses; and acceptable safety in primarily elderly patients with recurrent or 
metastatic cSCC.45 
o Cemiplimab was investigated in a single-arm, multicenter trial (NCT02760498) in  
78 patients with locally advanced cSCC for whom there was no widely accepted 
standard of care. In this trial, cemiplimab showed antitumor activity and an acceptable 
safety profile.46 
o Patients treated with nanrilkefusp alfa showed responses in study SC103 (AURELIO-
03) after resistance to or failure on immune checkpoint inhibitors. 
o This indication is therefore chosen to test the ability of the combination of nanrilkefusp 
alfa and pembrolizumab to improve pembrolizumab efficacy while maintaining safety 
as first-line treatment (based on data from KEYNOTE-629) and as second-line 
treatment if refractory or relapsed after an immune checkpoint inhibitor-containing 
regimen (based on data from study SC103 [AURELIO-03]). 
• Advanced hepatocellular carcinoma after recurrence or failure of an immune checkpoint 
inhibitor (not applicable in France) 
o Pembrolizumab was investigated in KEYNOTE-224 (NCT02702414), a single-arm, 
multicenter trial in 156 patients with hepatocellular carcinoma who had disease 
progression on or after sorafenib or who had not received prior systemic therapy. In this 
trial, pembrolizumab was effective and tolerable in patients who had previously been 
treated with sorafenib. First-line pembrolizumab monotherapy provided durable 
antitumor activity and promising OS.47,48 
o The combination of atezolizumab and bevacizumab was investigated in IMbrave150 
(NCT03434379), a randomized, multicenter, open-label trial in 558 patients with 
unresectable hepatocellular carcinoma who had not previously received systemic 
treatment. Atezolizumab plus bevacizumab resulted in better outcomes than 
sorafenib.49 
o This indication is therefore chosen to investigate the combination of nanrilkefusp alfa 
and pembrolizumab as second- to fourth-line treatment in patients who have received 
immune checkpoint inhibitor therapy. 
• Treatment-refractory mCRPC after recurrence or failure of docetaxel and prior treatment 
with abiraterone, enzalutamide, or any other androgen receptor-targeted agent 
o Pembrolizumab was investigated in KEYNOTE-199 (NCT02787005), a multicohort, 
open-label trial in 370 patients with mCRPC. In this trial, pembrolizumab monotherapy 
showed antitumor activity in a subset of patients with RECIST-measurable and bone-
predominant mCRPC previously treated with docetaxel and targeted endocrine therapy. 
Observed responses seemed to be durable, and OS estimates were encouraging.50 
o This indication is therefore chosen to test the ability of the combination of nanrilkefusp 
alfa and pembrolizumab as second- to fifth-line treatment to improve pembrolizumab 
efficacy (based on data from KEYNOTE-199). 

 
 
 
 
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• Advanced recurrent ovarian cancer after recurrence or failure on the last platinum-based 
therapy within 6 months 
o Pembrolizumab was investigated in KEYNOTE-100 (NCT02674061), a single-arm, 
multicenter study conducted in 376 patients with advanced recurrent ovarian cancer. In 
this trial, single-agent pembrolizumab showed modest activity. Higher PD-L1 
expression was correlated with higher response.51 
o This indication is therefore chosen to investigate the combination of nanrilkefusp alfa 
and pembrolizumab as second- to fifth-line treatment for advanced recurrent ovarian 
cancer (based on data from KEYNOTE-100). 
4.3 Justification for dose 
4.3.1 
Nanrilkefusp alfa  
The planned dose of nanrilkefusp alfa for this study is 12 µg/kg body weight on days 1, 2, 8, 
and 9 every 3 weeks, which is the recommended phase 2 dose defined based on the totality of 
data generated in study SC103 (AURELIO-03) entitled “A multicenter open-label phase 1/1b 
study to evaluate the safety and preliminary efficacy of SO-C101 as monotherapy and in 
combination with pembrolizumab in patients with selected advanced/metastatic solid tumors”. 
4.3.2 
Pembrolizumab 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based on 
the totality of data generated in the Keytruda development program, 200 mg Q3W is an 
appropriate dose of pembrolizumab for adults across all indications. As outlined below, this 
dose is justified by: 
• Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 
10 mg/kg every 2 weeks (Q2W) representing an approximate 5- to 7.5-fold exposure range 
(refer to the IB) 
• Population PK analysis showing that both fixed dosing and weight-based dosing provides 
similar control of PK variability with considerable overlap in the distributions of exposures, 
supporting suitability of 200 mg Q3W 
• Clinical data showing meaningful improvement in benefit-risk including OS at 200 mg 
Q3W across multiple indications 
• Pharmacology data showing full target saturation in both systemic circulation (inferred 
from PK data) and tumor (inferred from physiologically-based PK analysis) at 200 mg 
Q3W 
Among the 8 randomized dose-comparison studies, a total of 2262 patients were enrolled with 
melanoma and NSCLC, covering different disease settings (treatment naïve, previously treated, 
PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and in 
combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 10 mg/kg Q2W 
(KN001 cohort B2, KN001 cohort D, KN002, KN010, and KN021), and 3 studies compared 
10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 cohort B3, KN001 cohort F2 and KN006). All 
of these studies demonstrated flat dose- and exposure-response relationships across the doses 
studied representing an approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg (or 

 
 
 
 
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200 mg fixed-dose) Q3W provided similar responses to the highest doses studied. 
Subsequently, flat dose-exposure-response relationships were also observed in other tumor 
types including head and neck cancer, bladder cancer, gastric cancer, and classical Hodgkin 
lymphoma, confirming 200 mg Q3W as the appropriate dose independent of the tumor type. 
These findings are consistent with the mechanism of action of pembrolizumab, which acts by 
interaction with immune cells, and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data 
in KN001 evaluating target-mediated drug disposition conclusively demonstrated saturation of 
PD-1 in systemic circulation at doses much lower than 200 mg Q3W. Second, a 
physiologically-based PK analysis was conducted to predict tumor PD-1 saturation over a wide 
range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other patient covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight-based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. Supported 
by these PK characteristics and given that fixed-dose has advantages of reduced dosing 
complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected 
for evaluation across all pembrolizumab protocols. 
4.4 End of study definition 
A patient is considered to have completed the study if s/he has completed all phases of the 
study including the last follow-up contact. 
The study will end one year after the last patient’s last dose of study interventions or 3 years 
after the last patient’s first dose of study interventions (whichever occurs earlier). 
The sponsor reserves the right to discontinue the study for medical reasons or any other reason 
at any time. If the study is prematurely terminated or suspended, the sponsor will promptly 
inform the investigators/institutions, regulatory agencies, and institutional review boards 
(IRBs)/independent ethics committees (IECs; in the US), ethics committees (ECs; in the EU), 
or equivalent committees (outside the US and EU) of the termination or suspension and the 
reason(s) for the termination or suspension. 
The investigator reserves the right to discontinue the study should his/her judgment so dictate. 
If the investigator terminates or suspends the study without prior agreement of the sponsor, the 
investigator should inform the institution where applicable, and the investigator/institution 
should promptly inform the sponsor and the IRB/IEC (in the US)/EC (in the EU)/equivalent 
committee (outside the US and EU) and provide the sponsor and the IRB/IEC (in the US)/EC 
(in the EU)/equivalent committee (outside the US and EU) with a detailed written explanation 
of the termination or suspension. 
 
 

 
 
 
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5 STUDY POPULATION 
5.1 Inclusion criteria 
Patients will be eligible to be included in the study only if all of the following criteria apply: 
Type of patients 
1. Be 18 years of age on the day of signing informed consent 
2. Ability to understand and sign written informed consent to participate in the study 
3. Provides written informed consent for the study 
Disease characteristics 
4. Patients with the following histologically or cytologically confirmed solid tumor 
indications and line of treatment: 
• NSCLC 
o For the second-line or third-line treatment of patients with advanced and/or 
metastatic NSCLC with disease progression on or after an immune checkpoint 
inhibitor-containing regimen and a platinum-containing regimen, with no EGFR or 
ALK genomic tumor aberrations, and who are not amenable to curative treatment 
• Colorectal cancer 
o For the first-line treatment of patients with unresectable or metastatic MSI-
H/dMMR colorectal cancer 
• cSCC 
o For the first-line treatment of patients with recurrent or metastatic cSCC or second 
line if refractory or relapsed after an immune checkpoint inhibitor-containing 
regimen, and in whom radiotherapy is not feasible (based on data from study SC103 
[AURELIO-03]) 
• Advanced hepatocellular carcinoma (not applicable in France) 
o For the second- to fourth-line treatment of patients with advanced hepatocellular 
carcinoma having progressed on or after a checkpoint inhibitor-containing regimen 
• mCRPC 
o For the second- to fifth-line treatment of patients with mCRPC after recurrence or 
failure of docetaxel and prior treatment with abiraterone, enzalutamide, or any other 
androgen receptor-targeted agent 
• Ovarian cancer 
o For the second- to fifth-line treatment of patients with advanced ovarian cancer after 
recurrence or failure on the last platinum-based therapy within 6 months 
5. Have measurable disease per RECIST 1.1 as assessed by the local site 
investigator/radiology; lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions 

 
 
 
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mCRPC: Patients with both measurable and non-measurable disease will be enrolled. At 
least 35 patients with measurable disease will be enrolled. Patients with no measurable 
disease and only widespread bone disease must have a CTC count of ≥5 cells per 7.5 mL 
of blood. 
6. Availability of tumor tissue from a fresh biopsy at screening unless the biopsy cannot be 
obtained due to safety reasons or non-accessibility of the tumor site. If it is not possible to 
obtain a fresh biopsy, every effort should be taken to retrieve an archival biopsy. Archived, 
fixed tumor tissue may only be collected if taken preferentially after completion of the most 
recent systemic tumor therapy and within 12 months prior to the first dose of study 
treatment. 
7. Performance status: Eastern Cooperative Oncology Group (ECOG) performance score 0-1 
8. Must have recovered from all AEs (except alopecia) due to previous therapies to grade ≤1 
toxicity (excluding alopecia) or have stable grade 2 neuropathy 
Organ function 
Have adequate organ function as defined below. Specimens must be collected within 10 days 
prior to the start of study interventions. 
9. Hematology: 
9.1. Absolute neutrophil count ≥1500/µL 
9.2. Platelets ≥100 000/µL 
9.3. Hemoglobin ≥9.0 g/dL (criteria must be met without packed red blood cell transfusion 
within the prior 2 weeks; patients can be on a stable dose of erythropoietin  
[≥ 3 months]) 
10. Renal function: Creatinine clearance as measured by glomerular filtration rate ≥30 mL/min 
using Cockcroft-Gault equation 
11. Hepatic function: ALT/AST ≤2.5× upper limit of normal (ULN) and total bilirubin 
≤1.5×ULN or direct bilirubin ≤ ULN in patients without liver metastasis (benign hereditary 
hyperbilirubinemias, e.g., Gilbert’s syndrome, are permitted if total bilirubin is ≤3 mg/dL). 
In patients with liver metastasis, ALT/AST ≤5×ULN is allowed but total bilirubin must be 
≤2×ULN. 
12. Prothrombin time and activated partial thromboplastin time ≤1.5×ULN 
Hepatitis 
13. A locally performed hepatitis B (HBV) test is required during screening. Patients who are 
HBV surface antigen positive are eligible if they have received HBV anti-viral therapy for 
at least 4 weeks and have undetectable HBV viral load before study entry (ICF signature). 
Patients should remain on anti-viral therapy throughout study treatment and follow local 
guidelines for HBV anti-viral therapy post completion of study interventions.  
14. A locally performed hepatitis C (HCV) test is required during screening. Patients with 
history of HCV infection are eligible if HCV viral load is undetectable at screening. Patients 
must have completed anti-viral therapy at least 4 weeks before study entry (ICF signature). 

 
 
 
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Special requirements for female patients and contraception 
15. A female patient is eligible to participate if she is not pregnant, not breastfeeding, and one 
of the following conditions applies: 
15.1. Not a woman of childbearing potential (WOCBP). A WOCBP is defined as fertile, 
following menarche and until becoming post-menopausal unless permanently sterile. 
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and 
bilateral oophorectomy. A postmenopausal state is defined as no menses for  
12 months without an alternative medical cause. A high follicle stimulating hormone 
level in the postmenopausal range may be used to confirm a post-menopausal state 
in women not using hormonal contraception or hormonal replacement therapy. 
However, in the absence of 12 months of amenorrhea, a single follicle stimulating 
hormone measurement is insufficient. 
15.2. A WOCBP who agrees to use a highly effective contraceptive method during the 
treatment period and for at least 120 days after the last dose of pembrolizumab or at 
least 30 days after the last dose of nanrilkefusp alfa, whichever is later 
• WOCBP can only be included after a negative serum pregnancy test at screening. 
• Highly effective contraception includes: 
o Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation: 
▪ Oral 
▪ Intravaginal 
▪ Transdermal 
o Progestogen-only hormonal contraception associated with inhibition of 
ovulation: 
▪ Oral 
▪ Injectable 
▪ Implantable 
o Intrauterine device 
o Intrauterine hormone-releasing system 
o Bilateral tubal occlusion 
o Vasectomized partner provided the partner is the sole sexual partner of the 
WOCBP trial participant and that the vasectomized partner has received 
medical assessment of the surgical success 
o Sexual abstinence defined as refraining from heterosexual intercourse during 
the entire treatment period and for at least 120 days after the last dose of 
pembrolizumab or at least 30 days after the last dose of nanrilkefusp alfa, 
whichever is later. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the patient. 
16. Male patients must agree to use a condom during the treatment period and for at least 
120 days after the last dose of pembrolizumab or at least 30 days after the last dose of 
nanrilkefusp alfa, whichever is later. 
 

 
 
 
 
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5.2 Exclusion criteria 
Patients will be excluded from the study if any of the following criteria apply: 
Prior/concomitant therapy 
1. 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 antigen 4, CD134 [OX40], CD137), and was discontinued from that 
treatment due to a grade ≥3 AE 
2. Prior exposure to drugs that are agonists of IL-2 or IL-15 
3. Prior systemic anti-cancer therapies, including investigational agents, before the first dose 
of study medication (day 1 of cycle 1): 
3.1. Less than 4 weeks for systemic chemotherapy and immuno-oncology therapies; and 
for tyrosine kinase inhibitors 4 weeks or 5 half-lives (whichever is shorter) 
3.2. Less than 4 weeks from major surgeries and not recovered adequately from the 
procedure and/or any complications from the surgery 
4. Has received prior radiotherapy within 2 weeks of the start of study interventions or have 
had a history of radiation pneumonitis.  
Note: Patients must have recovered from all radiation-related toxicities and not require 
corticosteroids. A 1-week washout is permitted for palliative radiation (≤2 weeks of 
radiotherapy) to non-central nervous system disease. 
5. NSCLC indication only: Has received radiation therapy to the lung that is >30 Gy within  
6 months of the first dose of study interventions 
6. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study 
interventions 
Prior/concurrent clinical study experience 
7. Is currently participating in or has participated in a study of an investigational agent or has 
used an investigational device within 4 weeks or 5 half-lives (whichever shorter) before 
study entry (ICF signature). Patients who have entered the follow-up phase of an 
investigational study may participate as long as it has been 4 weeks or 
5 half-lives (whichever shorter) after the last dose of the previous investigational agent. 
Medical conditions 
8. Clinically significant cardiac abnormalities including prior history of any of the following: 
8.1. Cardiomyopathy, with left ventricular ejection fraction ≤50% at screening 
8.2. Congestive heart failure of New York Heart Association grade ≥2 
8.3. History of clinically significant (i.e., active) atherosclerotic cardiovascular disease, 
specifically myocardial infarction, unstable angina, cerebrovascular accident within  
6 months prior to the first dose of study interventions, and any clinically significant 
history of coronary heart disease and clinically significant artery disease within the 
past 5 years 
8.4. Prolongation of QTcF >450 msec 

 
 
 
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8.5. Clinically significant cardiac arrythmia that cannot be controlled with adequate 
medication 
9. Uncontrolled hypertension defined as systolic blood pressure >160 mmHg, diastolic blood 
pressure >110 mmHg. Patients with uncontrolled hypertension should be medically 
managed on a stable regimen to control hypertension prior to study entry (ICF signature). 
10. Has undergone prior allogeneic hematopoietic stem cell transplantation within the last  
5 years. Patients who have had a transplant more than 5 years ago are eligible as long as 
there are no symptoms of graft versus host disease. 
11. Has had an allogeneic tissue/solid organ transplant 
12. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study interventions 
13. History of or serology positive for HIV. A locally performed HIV test is required during 
screening. 
14. Has a known additional malignancy that is progressing or has required active treatment 
within the past 5 years. Patients with basal cell carcinoma of the skin or carcinoma in situ 
excluding carcinoma in situ of bladder that have undergone potentially curative therapy are 
not excluded. 
15. 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 at least 4 weeks by repeat 
imaging (note that the repeat imaging should be performed during study screening), 
clinically stable and without requirement of steroid treatment for at least 14 days prior to 
the first dose of study interventions. 
16. Has severe hypersensitivity (grade ≥3) to pembrolizumab and/or any of its excipients 
17. Has an active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). 
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment 
and is allowed. 
18. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids 
or has current pneumonitis/interstitial lung disease 
19. Has an active infection requiring systemic therapy 
20. Has a history or current evidence of any condition, therapy, or laboratory abnormality, or 
other circumstance that might confound the results of the study or interfere with the 
patient’s participation for the full duration of the study, such that it is not in the best interest 
of the patient to participate, in the opinion of the treating investigator 
21. Has a known psychiatric or substance abuse disorder that would interfere with the patient’s 
ability to cooperate with the requirements of the study 

 
 
 
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5.3 Lifestyle considerations 
5.3.1 
Meals and dietary restrictions 
Patients should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea, or vomiting. 
5.3.2 
Contraception 
Nanrilkefusp alfa and pembrolizumab may have adverse effects on a fetus in utero. 
Furthermore, it is not known if nanrilkefusp alfa and pembrolizumab have transient adverse 
effects on the composition of sperm. 
Patients should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study. If there is any question that a 
patient of childbearing potential will not reliably comply with the requirements for 
contraception, that patient should not be entered into the study. 
Please also see section 5.1. 
5.3.3 
Use in nursing women 
It is unknown whether nanrilkefusp alfa and pembrolizumab are excreted in human milk. Since 
many drugs are excreted in human milk, and because of the potential for serious adverse 
reactions in the nursing infant, patients who are breastfeeding are not eligible for enrollment. 
Please also see section 5.1. 
5.4 Screen failures 
Screen failures are defined as patients who consent to participate in the clinical study but are 
not subsequently entered into the study. A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure patients to meet the Consolidated Standards of 
Reporting Trials publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, reason for screen failure, and AE/serious AE 
(SAE) as listed in section 8.3.2. 
Patients may be rescreened once. 
5.5 Criteria for temporarily delaying enrollment/administration of study 
intervention 
See section 6.5. 
 

 
 
 
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6 STUDY INTERVENTIONS AND CONCOMITANT THERAPY 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study patient according to the 
study Protocol. 
6.1 Study interventions administered 
The interventions to be administered in this study are listed in Table 6.1. 
Patients will be treated with nanrilkefusp alfa 12 µg/kg subcutaneously on day 1 (±1 day for 
the cycle start), day 2, day 8, and day 9 in combination with pembrolizumab 200 mg IV on day 
1 in 3-week cycles after all procedures and assessments have been completed. 
Pembrolizumab will be administered as an IV infusion via peripheral or central venous line 
within 30 minutes after the first dose (day 1) of nanrilkefusp alfa in each 3-week cycle. 
Sites should make every effort to target pembrolizumab infusion timing to be as close to  
30 minutes as possible. However, given the variability of infusion pumps from site to site, a 
window between -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes  
[-5 min/+10 min]). 
The Pharmacy Manual contains specific instructions for the preparation of the nanrilkefusp alfa 
dose and pembrolizumab infusion and administration of nanrilkefusp alfa and pembrolizumab. 
Table 6.1: Study interventions 
Intervention 
name 
Dosage 
formulation 
Unit dose 
strength(s) 
Dosage 
level(s) 
Route of 
administration 
Regimen/ 
treatment period 
Sourcing 
Product code: 
SOT101 
International 
Nonproprietary 
Name: 
Nanrilkefusp 
alfa 
Solution for 
injection 
1.3 mg/vial 12 µg/kg Subcutaneous 
Administration on 
day 1 (±1 day for 
the cycle start), 
day 2, day 8, and 
day 9 of each 3-
week cycle 
Provided 
centrally 
by the 
sponsor 
Pembrolizumab Solution for 
infusion 
100 mg/vial 200 mg IV infusion via 
peripheral or 
central venous 
line 
Administration 
within 30 minutes 
after the first dose 
of nanrilkefusp 
alfa (day 1) of 
each 3-week cycle 
Provided 
centrally 
by the 
sponsor 
6.2 Preparation, handling, storage, accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study interventions received and any discrepancies are reported 
and resolved before use of the study interventions. 

 
 
 
 
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Only patients enrolled in the study may receive study interventions and only authorized site 
staff may supply or administer study interventions. All study interventions must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual. 
6.3 Measures to minimize bias: randomization and blinding 
This single-arm clinical trial will not be blinded. 
6.4 Study intervention compliance 
Treatment for each patient will be recorded during the study. 
6.5 Dose modification and toxicity management 
6.5.1 
Dose modification and toxicity management for nanrilkefusp alfa 
Dose modification and toxicity management for nanrilkefusp alfa for safety reasons will be 
discussed on a case-by-case basis between the site and the sponsor’s medical monitor.  
Transient pyrexia is a frequent AE after nanrilkefusp alfa injection. The use of, e.g., ibuprofen, 
and other non-steroid premedication can be considered according to local standard practice for 
prevention and treatment of fever. 
Recommendations for clinical management of cytokine release syndrome are provided in 
section 6.5.3. 
To minimize the risk for injection site reaction, subcutaneous injection sites should be rotated 
to different areas of the body (upper and lower extremities, each of the 4 quadrants of the 
abdomen). 
To minimize the risks associated with shortening of the QT interval, vital signs and ECG must 
be closely monitored as per Protocol and institutional guidelines. 
Liver function tests for nanrilkefusp alfa toxicity evaluation in this study will include AST, 
ALT, total bilirubin, and alkaline phosphatase. 
Nanrilkefusp alfa-related hepatic toxicities should be managed as shown in Table 6.2. 
 
 

 
 
 
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Table 6.2: Management of nanrilkefusp alfa-related hepatic toxicities 
Nanrilkefusp alfa-related 
hepatic toxicity 
Severity 
Nanrilkefusp alfa dose 
modification 
AST increased or ALT 
increased, or blood 
bilirubin increased 
Grade 2 with AST or ALT 
>3 to ≤5×ULN or total 
bilirubin >1.5 to ≤3×ULN 
Withhold nanrilkefusp alfa 
Resume nanrilkefusp alfa if 
increased values return to 
grade ≤1 
Grade ≥3 with AST or 
ALT >5×ULN or total 
bilirubin >3×ULN 
Withhold nanrilkefusp alfa 
Resume nanrilkefusp alfa at 
9 µg/kg if increased values 
return to grade ≤1 
Permanently discontinue 
nanrilkefusp alfa on second 
occurrence of grade ≥3 hepatic 
event 
Please also refer to the IB, section 6.6 (Management guidelines for identified and potential 
risks). 
6.5.2 
 Dose modification and toxicity management for pembrolizumab 
6.5.2.1 Dose modification and toxicity management for immune-related AEs associated 
with pembrolizumab 
AEs associated with pembrolizumab combination exposure, including coadministration with 
additional compounds, may represent an immune-related response. These immune-related AEs 
(irAEs) may occur shortly after the first dose or several months after the last dose of 
pembrolizumab combination treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical study data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab combination treatment, administration of 
corticosteroids, and/or other supportive care. For suspected irAEs, ensure adequate evaluation 
to confirm etiology or exclude other causes. Additional procedures or tests such as 
bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Dose 
modification and toxicity management guidelines for irAEs associated with pembrolizumab 
are provided in Table 6.3. 
6.5.2.1.1 Attribution of toxicity 
When study interventions are administered in combination, attribution of an AE to a single 
component is likely to be difficult. Therefore, while the investigator may attribute a toxicity 
event to the combination, to nanrilkefusp alfa alone, or to pembrolizumab alone, for AEs listed 
in Table 6.3, both interventions must be held according to the criteria in Table 6.3 and these 
cases should be discussed with the sponsor’s medical monitor. 

 
 
 
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6.5.2.1.2 Holding study interventions 
When study interventions are administered in combination, if the AE is considered immune-
related, both interventions should be held according to recommended dose modifications. 
6.5.2.1.3 Restarting study interventions 
Patients may not have any dose modifications (no change in dose or schedule) of 
pembrolizumab in this study, as described in Table 6.3. 
If the toxicity does not resolve or the criteria for resuming treatment are not met, the patient 
must be discontinued from all study interventions. 
If the toxicities do resolve and conditions are aligned with what is defined in Table 6.3, the 
combination of nanrilkefusp alfa and pembrolizumab may be restarted at the discretion of the 
investigator. In these cases where the toxicity is attributed to the combination or to nanrilkefusp 
alfa alone, re-initiation of pembrolizumab as a monotherapy may be considered after 
communication with and agreement by the sponsor. 
Table 6.3: Dose modification and toxicity management guidelines for irAEs associated 
with pembrolizumab 
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by 
oral steroids. Other immunosuppressive treatment should begin if the irAEs are not 
controlled by corticosteroids. 
2. Pembrolizumab must be permanently discontinued if the irAE does not resolve or the 
corticosteroid dose is not ≤10 mg/day within 12 weeks of the last pembrolizumab 
treatment. 
3. Corticosteroid taper should begin when the irAE is grade ≤1 and continue at least 
4 weeks. 
4. If pembrolizumab has been withheld, pembrolizumab may resume after the irAE 
decreased to grade ≤1 after corticosteroid taper. 
 
irAEs 
Toxicity grade 
(CTCAE 
version 5.0) 
Action with 
pembrolizumab 
Corticosteroid 
and/or other 
therapies 
Monitoring and 
follow-up 
Pneumonitis 
Grade 2 
Withhold 
Administer 
corticosteroids (initial 
dose of 1 to 2 mg/kg 
prednisone or 
equivalent) followed 
by taper 
Add prophylactic 
antibiotics for 
opportunistic 
infections 
Monitor 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 
grade 4 
Permanently 
discontinue 

 
 
 
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irAEs 
Toxicity grade 
(CTCAE 
version 5.0) 
Action with 
pembrolizumab 
Corticosteroid 
and/or other 
therapies 
Monitoring and 
follow-up 
Diarrhea/colitis 
Grade 2 or 
grade 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 
gastrointestinal 
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 IV infusion 
Recurrent 
grade 3 or 
grade 4 
Permanently 
discontinue 
AST or ALT 
elevation or 
increased bilirubin 
Grade 2 a 
Withhold 
Administer 
corticosteroids (initial 
dose of 
0.5 to 1 mg/kg 
prednisone or 
equivalent) followed 
by taper 
Monitor with liver 
function tests 
(consider weekly or 
more frequently until 
liver enzyme value 
returned to baseline 
or is stable) 
Grade 3 b or 
grade 4 c 
Permanently 
discontinue 
Administer 
corticosteroids (initial 
dose of 1 to 2 mg/kg 
prednisone or 
equivalent) followed 
by taper 

 
 
 
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irAEs 
Toxicity grade 
(CTCAE 
version 5.0) 
Action with 
pembrolizumab 
Corticosteroid 
and/or other 
therapies 
Monitoring and 
follow-up 
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 
antihyperglycemics 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 
grade 4 
Withhold or 
permanently 
discontinue d 
Hyperthyroidism 
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 
grade 4 
Withhold or 
permanently 
discontinue d 
Hypothyroidism 
Grade 2 
Continue 
Initiate thyroid 
replacement 
hormones (e.g., 
levothyroxine or 
liothyronine) per 
standard of care 
Monitor for signs 
and symptoms of 
thyroid disorders 
 Grade 3 or 
grade 4 
Withhold or 
permanently 
discontinue 
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 
grade 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 
grade 4 
Permanently 
discontinue 

 
 
 
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irAEs 
Toxicity grade 
(CTCAE 
version 5.0) 
Action with 
pembrolizumab 
Corticosteroid 
and/or other 
therapies 
Monitoring and 
follow-up 
Myocarditis 
Asymptomatic 
cardiac 
enzyme 
elevation with 
clinical 
suspicion of 
myocarditis 
(previously 
CTCAE 
version 4.0 
grade 1) 
Withhold 
Based on severity of 
AE administer 
corticosteroids 
Ensure adequate 
evaluation to confirm 
etiology and/or 
exclude other causes 
Grade 2, grade 
3, or grade 4 
Permanently 
discontinue 
Exfoliative 
dermatologic 
conditions 
Suspected SJS, 
TEN, or 
DRESS 
Withhold 
Based on severity of 
AE administer 
corticosteroids 
Ensure adequate 
evaluation to confirm 
etiology or exclude 
other causes 
Confirmed 
SJS, TEN, or 
DRESS 
Permanently 
discontinue 
All other irAEs 
Persistent 
grade 2 
Withhold 
Based on severity of 
AE administer 
corticosteroids 
Ensure adequate 
evaluation to confirm 
etiology or exclude 
other causes 
Grade 3 
Withhold or 
discontinue 
based on the 
event e 
Recurrent 
grade 3 or 
grade 4 
Permanently 
discontinue 

 
 
 
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irAEs 
Toxicity grade 
(CTCAE 
version 5.0) 
Action with 
pembrolizumab 
Corticosteroid 
and/or other 
therapies 
Monitoring and 
follow-up 
AE(s), adverse event(s); ALT, alanine transaminase; AST, aspartate transaminase; CTCAE, 
Common Terminology Criteria for Adverse Events; DRESS, drug rash with eosinophilia and 
systemic symptom; irAE(s), immune-related AE(s); IV, intravenous; SJS, Stevens-Johnson 
syndrome; T1DM, type 1 diabetes mellitus; TEN, toxic epidermal necrolysis; ULN, upper limit of 
normal 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to 5.0×ULN if baseline normal; >3.0 to 5.0×baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0×ULN if baseline normal; >1.5 to 3.0×baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0×ULN, if baseline normal; >5.0 to 20.0×baseline, if baseline abnormal; 
bilirubin:>3.0 to 10.0×ULN if baseline normal; >3.0 to 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 is at the discretion of the 
investigator or treating physician. If control achieved or grade ≤2, pembrolizumab may be resumed. 
e Events that require discontinuation include but are not limited to: encephalitis and other clinically 
important irAEs (e.g., vasculitis and sclerosing cholangitis) 
 
 
6.5.2.2 Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab 
Pembrolizumab may cause severe or life-threatening infusion reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab associated infusion 
reaction are provided in Table 6.4. 
Table 6.4: Pembrolizumab infusion reaction dose modification and treatment guidelines 
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 
• Stop infusion 
• Additional appropriate 
medical therapy may 
Patient may be premedicated 
1.5 hour (±30 minutes) prior 
to infusion of study 
 

 
 
 
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CTCAE grade 
Treatment 
Premedication at 
subsequent dosing 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤24 hours 
include but is not limited 
to: 
o IV fluids 
o Antihistamines 
o NSAIDs 
o Acetaminophen 
o 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/hour 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 drug treatment. 
intervention with: 
• Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine) 
• Acetaminophen  
500-1000 mg po (or 
equivalent dose of 
analgesic) 
Grade 3 or 4 
 
Grade 3: 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
• Stop infusion 
• Additional appropriate 
medical therapy may 
include but is not limited 
to: 
o Epinephrine** 
o IV fluids 
No subsequent dosing 

 
 
 
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CTCAE grade 
Treatment 
Premedication at 
subsequent dosing 
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 
 
o Antihistamines 
o NSAIDs 
o Acetaminophen 
o Narcotics 
o Oxygen 
o Pressors 
o 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 drug treatment. 
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 CTCAE version 5.0 at http://ctep.cancer.gov. 
6.5.2.3 Other allowed dose interruption for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical or surgical events and/or unforeseen circumstances not related to study interventions. 
However, study interventions are to be restarted within 21 days of the originally scheduled 
dose and within 42 days of the previously administered dose, unless otherwise discussed with 
the sponsor. The reason for interruption is to be documented in the patient’s study record. 
6.5.3 
Clinical management of cytokine release syndrome 
The cytokine release syndrome management recommendations described in Table 6.5 can be 
modified by investigational sites as medically necessary or as appropriate without requiring a 
Protocol Amendment or being considered a Protocol deviation. 
 
 

 
 
 
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Table 6.5: Clinical management of cytokine release syndrome52 
Grading assessment 
Treatment and measures 
Grade 1 
• Fever, constitutional symptoms 
• Vigilant supportive care 
• Assess for infections 
(Treat fever and neutropenia if present, 
monitor fluid balance, antipyretics, 
analgesics as needed) 
Grade 2 
• Hypotension: responds to fluids or one 
low dose pressor 
• Hypoxia: responds to <40% O2 
• Organ toxicity: grade 2 
Extensive comorbidities or older age? 
→ No: Vigilant supportive care 
(Monitor cardiac and other organ function 
closely) 
→ Yes: Vigilant supportive care 
Tocilizumab* ± corticosteroids 
Grade 3 
• Hypotension: requires multiple pressors 
or high dose pressors 
• Hypoxia: requires ≥40% O2 
• Organ toxicity: grade 3, grade 4 
transaminitis 
• Vigilant supportive care 
• Tocilizumab* ± corticosteroids 
Grade 4 
• Mechanical ventilation 
• Organ toxicity: grade 4, excluding 
transaminitis 
• Vigilant supportive care 
• Tocilizumab* ± corticosteroids 
*Should be used if no other treatment option, only 
6.6 Continued access to study intervention after the end of the study 
Patients who are still on study interventions at the time of study completion/termination may 
continue to receive study interventions if they are experiencing clinical benefit. The continued 
access to study interventions will end when a criterion for discontinuation is met or 35 doses 
of pembrolizumab have been administered (also see section 7.1). 
6.7 Treatment of overdose 
For this study, an overdose of nanrilkefusp alfa will be defined as any dose above 13 µg/kg. 
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater. 

 
 
 
 
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No specific information is available on the treatment of overdose of nanrilkefusp alfa and/or 
pembrolizumab. In the event of overdose, the patient should be observed closely for signs of 
toxicity. Appropriate supportive treatment should be provided if clinically indicated. 
6.8 Concomitant therapy 
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. 
All concomitant medications will be recorded on the electronic Case Report Form (eCRF) 
including all prescription, over-the-counter products, herbal supplements, and IV medications 
and fluids. If changes occur during the study period, documentation of drug dosage, frequency, 
route, and date should also be included on the eCRF. 
All concomitant medications received within 28 days before the first dose of study 
interventions and up to 90 days after the last dose of study interventions should be recorded. 
All concomitant medications administered during SAEs or AESIs are to be recorded. SAEs 
and AESIs are defined in section 8.3. 
6.8.1 
Rescue medication 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 6.5. 
Note: If after the evaluation of the event it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. Refer to section 6.5 for 
guidelines regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
6.8.2 
Prohibited medications 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from study interventions or vaccination 
may be required (also see section 7.1). The investigator is to discuss prohibited 
medication/vaccination with the sponsor’s 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 interventions requires the 
mutual agreement of the investigator, the sponsor, and the patient. 
The following medications and vaccinations are prohibited during the study: 
• Concomitant use of drugs known to prolong the QT/QTc interval is prohibited during the 
study. Some of the medications known to prolong the QT interval are53: amiodarone, 
azithromycin, ciprofloxacin, chlorpromazine, citalopram, domperidone, donepezil, 
escitalopram, fluconazole, haloperidol, levofloxacin, levomepromazine, methadone, 
ondansetron, and sulpiride. A complete list of medications known to prolong the QT 
interval can be found at www.crediblemeds.org. 

 
 
 
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• Antineoplastic systemic chemotherapy or biological therapy 
• Immunotherapy not specified in this Protocol 
• Chemotherapy not specified in this Protocol 
• Investigational agents other than nanrilkefusp alfa and pembrolizumab 
• Radiation therapy 
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed at 
the investigator’s discretion. Palliative radiotherapy of, e.g., painful bone metastases not 
defined as indicator lesions is allowed. 
• Live or live attenuated vaccines within 30 days prior to the first dose of study interventions, 
during treatment with nanrilkefusp alfa and/or pembrolizumab, and within 90 days after the 
last dose of nanrilkefusp alfa and/or pembrolizumab, whichever is later. Note: Killed 
vaccines are allowed. 
Note: Any licensed COVID-19 vaccine (including for emergency use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, adenoviral vaccines, 
or inactivated vaccines. These vaccines will be treated just as any other concomitant 
therapy. 
Investigational vaccines (i.e., those not licensed or approved for emergency use) are not 
allowed. 
• Systemic glucocorticoids except when used for the following purposes: 
o 
To modulate symptoms of an AE that is suspected to have an immunologic etiology 
o 
For the prevention of emesis 
o 
To premedicate for IV contrast allergies 
o 
To treat chronic obstructive pulmonary disease exacerbations (only short-term oral or 
IV use in doses >10 mg/day prednisone equivalent) 
o 
For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent 
o 
Other glucocorticoid use except when used for the following purposes: 
▪ For topical use or ocular use 
▪ Intraarticular joint use 
▪ For inhalation in the management of asthma or chronic obstructive pulmonary 
disease 
Note: Inhaled steroids are allowed for management of asthma. 
If the investigator determines that a patient requires any of the aforementioned treatments for 
any reason, study interventions must be discontinued. 
 

 
 
 
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7 DISCONTINUATION OF STUDY INTERVENTION AND PATIENT 
DISCONTINUATION/WITHDRAWAL 
7.1 Discontinuation of study intervention 
Discontinuation of study interventions does not represent withdrawal from the study. 
A patient must be discontinued from study interventions but continue to be monitored in the 
study (if possible) for any of the following reasons: 
• Confirmed radiographic disease progression (please refer to section 10.2) 
• Clinical disease progression (investigator’s assessment) 
• AE (intercurrent illness or study intervention-related toxicity that would, in the judgment 
of the investigator, affect assessments of the patient’s clinical status to a significant degree 
or require discontinuation of study interventions) 
• Patient may withdraw from the study at any time for any reason; the investigator must make 
every effort to determine the reason for this decision and record it in source documentation 
of the patient 
• Discontinuation of treatment may be considered for patients who have attained a confirmed 
complete response (CR) and have been treated for at least 8 cycles (at least 24 weeks), 
receiving 2 cycles of the combination including 2 doses of pembrolizumab and at least 80% 
of the planned doses of nanrilkefusp alfa beyond the date when the initial CR was declared 
• Any study intervention-related toxicity specified as a reason for permanent discontinuation 
as defined in the guidelines for dose modification due to AEs in section 6.5 
• Death of the patient 
• Pregnancy of the patient 
• Concomitant treatment with a prohibited medication, including further lines of systemic 
anti-cancer therapy (also see section 6.8.2) 
• Patient’s non-compliance 
• Lost to follow-up 
• Study terminated by the sponsor 
Pembrolizumab will be discontinued after the completion of 35 administrations (approximately 
2 years; also see section 6.6). 
In case nanrilkefusp alfa needs to be discontinued for reasons other than disease progression, 
pembrolizumab treatment can continue for up to a total of 35 administrations (approximately 
2 years) in patients without disease progression or unacceptable toxicity. In case 
pembrolizumab needs to be discontinued, nanrilkefusp alfa treatment can continue until disease 
progression or unacceptable toxicity (not applicable in the Czech Republic). In the Czech 
Republic: In case pembrolizumab needs to be discontinued, nanrilkefusp alfa treatment will be 
discontinued as well. 
See the Schedule of activities for data to be collected at the time of intervention discontinuation 
and follow-up and for any further evaluations that need to be completed. 

 
 
 
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7.2 Patient discontinuation/withdrawal from the study 
A patient may withdraw from the study at any time at his/her own request, or may be withdrawn 
at any time at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons, or when the study is discontinued by the sponsor. This is expected to 
be uncommon. 
The patient will be permanently discontinued both from the study interventions and from the 
study at that time. 
If the patient withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a patient withdraws from the study, s/he may request destruction of any samples taken and 
not tested, and the investigator must document this in the site study records. 
7.3 Lost to follow-up 
A patient will be considered lost to follow-up if s/he repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible 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, s/he will be considered to have withdrawn 
from the study.  
 

 
 
 
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8 STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the Schedule of activities. Protocol 
waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the patient should continue or discontinue study interventions. 
Adherence to the study design requirements, including those specified in the Schedule of 
activities, is essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. 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. 
Procedures conducted as part of the patient’s routine clinical management (e.g., blood count) 
and obtained before signing of the ICF may be utilized for screening or baseline purposes 
provided the procedures met the Protocol-specified criteria and were performed within the time 
frame defined in the Schedule of activities. 
8.1 Efficacy assessments 
8.1.1 
Tumor imaging and assessment of disease 
Throughout this section, the term “scan” refers to any medical imaging data used to assess 
tumor burden and may include cross-sectional imaging (such as computed tomography [CT] 
or magnetic resonance imaging [MRI]), medical photography, or other methods as specified in 
this Protocol. 
Scan evaluation by a local radiologist or by the investigator will be used for the main analyses. 
However, all scheduled scans for patients will be collected. In case of a deemed need for health 
authority interactions, a sensitivity analysis will be considered based on evaluation of imaging 
documentation by an independent blinded radiologist. A scan that is obtained at an unscheduled 
time point, for any reason (including suspicion of progression or other clinical reason), will 
also be collected if it shows disease progression, or if it is used to support a response 
assessment. In addition, historical scans that were obtained at disease progression on previous 
systemic anti-cancer treatment will be collected. 
The process for scan collection can be found in the Site Imaging Manual. CT scans are 
preferred over other tumor imaging methods. For the abdomen and pelvis, contrast-enhanced 
MRI may be used when CT with iodinated contrast is contraindicated, or when mandated by 
local practice. The same type of scan should be used in a patient throughout the study to 
optimize the reproducibility of the assessment of existing and new tumor burden and improve 
the accuracy of the assessment of response or progression based on imaging. Note: for the 
purposes of assessing tumor scans, the term “investigator” refers to the local investigator at the 
site and/or the radiological reviewer located at the site or at an offsite facility. 
If brain scans are performed, magnetic resonance scans are preferred; however, CT scans are 
acceptable if MRI is medically contraindicated. 

 
 
 
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Bone scans may be performed to evaluate bone metastases. Any supplemental scans done to 
support a positive or negative bone scan, such as plain X-rays acquired for correlation, should 
also be collected. 
At screening, patient eligibility will require radiographic documentation of at least one lesion 
that meets the requirements for selection as a target lesion (as defined by RECIST 1.1) before 
the start of study interventions. 
8.1.1.1 Initial tumor scans 
Initial tumor scans at screening must be performed within 28 days prior to day 1 of cycle 1. 
The site study team must review screening scans to confirm the patient has measurable disease 
per RECIST 1.1. 
Tumor scans performed as part of routine clinical management are acceptable for screening if 
they are of acceptable diagnostic quality and performed within 28 days of day 1 of cycle 1. 
If brain scans are performed to document the stability of existing metastases, the brain MRI 
should be acquired during screening. If MRI is medically contraindicated, CT with contrast is 
an acceptable alternative. 
8.1.1.2 Tumor scans during the study 
The first on-study scan assessment should be performed at 6 weeks (±2 weeks; starting from 
cycle 1 day 1). Subsequent tumor scans should be performed every 6 weeks (±2 weeks) or more 
frequently if clinically indicated. Scan timing should follow calendar days and should not be 
adjusted for delays in cycle starts. 
All supplemental imaging must be collected. 
Objective response should be confirmed by repeat scan performed at least 4 weeks after the 
first indication of a response is observed. Patients will then return to the regular scan scheduled, 
starting with the next scheduled time point. Patients who receive additional scans for 
confirmation do not need to undergo the next scheduled scan if it is fewer than 4 weeks later; 
scans may resume at the subsequent scheduled time point. 
When radiological disease progression is identified by the investigator in clinically stable 
patients, disease progression is to be confirmed by another set of scans performed 4 to 8 weeks 
later, per iRECIST guidelines in section 8.1.1.5. 
If disease progression is not confirmed, clinically stable patients are to continue study 
interventions until progression is confirmed. Patients are to return to their regular scan 
schedule. If the next scheduled scan will occur in less than 4 weeks, this scheduled scan may 
be skipped. 
If disease progression is confirmed, study interventions will be discontinued. Exceptions are 
detailed in section 8.1.1.5. 
8.1.1.3 End of treatment and follow-up tumor imaging 
If patients discontinue study interventions, tumor scans should be performed at the time of 
discontinuation (±4-week window) unless previous scans were obtained within 4 weeks of 
discontinuation. If patients discontinue study interventions due to documented disease 
progression, this is the final required tumor scan if the investigator elects not to implement 
iRECIST. 

 
 
 
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If patients discontinue study interventions without documented disease progression, every 
effort should be made to monitor disease status by acquiring tumor scans using the same 
schedule used while on treatment (every 6 weeks [±2 weeks]). 
Scans are to be continued until one of the following conditions are met: 
• Disease progression identified by the investigator (radiological progression per [i]RECIST 
[1.1] or mCRPC-specific progression) 
• Start of a new anti-cancer treatment 
• Pregnancy of the patient 
• Withdrawal of consent by the patient 
• End of the study 
For clinically unstable patients, a scan obtained within 2 weeks after clinical progression is 
recommended. Scans are to be continued as per regular schedule (section 1.3). 
8.1.1.4 RECIST 1.1 assessment of disease 
RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of 
disease progression, and as a basis for all Protocol guidelines related to disease status (e.g., 
discontinuation of study interventions). 
8.1.1.5 iRECIST assessment of disease 
iRECIST is based on RECIST 1.1 but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor 
response and progression and make treatment decisions. When clinically stable, patients may 
continue study interventions beyond RECIST 1.1 progression with continued assessment of 
response according to the rules outlined in section 10.2. iRECIST reflects that some patients 
can have a transient tumor flare after the start of immunotherapy, then experience subsequent 
disease response. This data will be captured in the clinical database. 
• If the patient is clinically stable, continue study interventions per Protocol 
o Continue scans per Protocol schedule (the next scheduled scan should be ≥4 weeks from 
most recent scan acquired) 
o Continue investigator assessment per iRECIST 
o Collect scans 
• If the patient is not clinically stable, best medical practice is to be applied 
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 (e.g., central 
nervous system metastasis, respiratory failure due to tumor compression, spinal cord 
compression) requiring urgent alternative medical intervention 

 
 
 
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8.1.1.6 PD-1 treatment progression 
PD-1 treatment progression is defined by meeting all of the following criteria: 
1. Has received at least 2 doses of an approved anti-PD-1/L1 mAb 
2. Has demonstrated disease progression after PD-1/L1 
3. Progressive disease has been documented within 12 weeks from the last dose of  
anti-PD-1/L1 mAb 
3.1. Progressive disease is determined according to iRECIST 
3.2. This determination is made by the investigator. Once progressive disease is confirmed, 
the initial date of disease progression documentation will be considered the date of 
disease progression. 
8.2 Safety assessments 
If patients feel unwell at any point in time during the study after being discharged from the 
hospital, they should contact their study investigator as indicated in the ICF. 
8.2.1 
Physical examinations, ECOG performance status, body height, and body 
weight 
General physical examination with organ/system-specific physical examination will be carried 
out by a licensed physician (or the physician’s assistant or a nurse practitioner). 
For screening, a complete physical examination will be performed including head (eyes, ear, 
nose, and throat), neck, cardiovascular, chest/lungs, abdomen (including liver and spleen size), 
extremities, neurological, skin, and lymph nodes. For subsequent visits, a physical examination 
is to be done with the focus on abdomen (including liver and spleen size), lymph nodes, and 
any other system that may contribute to clinical disease assessments. 
An ECOG performance status will be assigned as indicated in the Schedule of activities. 
Body height and body weight will be measured. Body height will be measured only at 
screening. Body weight will be measured before the start of each treatment cycle and as 
indicated in the Schedule of activities. 
8.2.2 
Vital signs 
Vital signs will include blood pressure (systolic and diastolic, after ≥5 minutes of rest), body 
temperature, heart rate, and respiratory rate. 
8.2.3 
Special assessments on treatment days 
8.2.3.1 Cycle 1 day 1 
Patients will be observed in the hospital up to 12 hours following nanrilkefusp alfa 
administration. Vital signs (systolic and diastolic blood pressure after ≥5 minutes of rest, body 
temperature, heart rate, and respiratory rate) will be documented at the following frequency at 
minimum unless clinically required otherwise: 
• Before nanrilkefusp alfa administration 
• 15 minutes (±5 minutes) after nanrilkefusp alfa administration 

 
 
 
 
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• 30 minutes (±5 minutes) after nanrilkefusp alfa administration 
• 2 hours (±15 minutes) after nanrilkefusp alfa administration 
• 4 hours (±30 minutes) after nanrilkefusp alfa administration 
• 12 hours (±2 hours) after nanrilkefusp alfa administration 
8.2.3.2 Cycle 1 day 2, day 8, and day 9; and treatment days of cycle 2 
Patients will be observed in the hospital up to 4 hours following nanrilkefusp alfa 
administration. Vital signs (systolic and diastolic blood pressure after ≥5 minutes of rest, body 
temperature, heart rate, and respiratory rate) will be documented at the following frequency 
until discharge: 
• Before nanrilkefusp alfa administration 
• 15 minutes (±5 minutes) after nanrilkefusp alfa administration 
• 30 minutes (±5 minutes) after nanrilkefusp alfa administration 
• 2 hours (±15 minutes) after nanrilkefusp alfa administration 
• 4 hours (±30 minutes) after nanrilkefusp alfa administration 
8.2.3.3 Treatment days of cycle 3 and onwards 
Patients will be observed in the hospital up to 2 hours following nanrilkefusp alfa 
administration. Vital signs (systolic and diastolic blood pressure after ≥5 minutes of rest, body 
temperature, heart rate, and respiratory rate) will be documented at the following frequency 
until discharge: 
• Before nanrilkefusp alfa administration 
• 15 minutes (±5 minutes) after nanrilkefusp alfa administration 
• 30 minutes (±5 minutes) after nanrilkefusp alfa administration 
• 2 hours (±15 minutes) after nanrilkefusp alfa administration 
8.2.4 
Electrocardiography and left ventricular ejection fraction 
During the study, patients with signs or symptoms of chest pain, murmurs, gallops, irregular 
rhythm, or palpitations must be further assessed if clinically indicated, including the need for 
hospitalization. Standard 12-lead ECG will be done locally at the site for assessment of any 
change in QTcF interval and other parameters. 
Left ventricular ejection fraction will be assessed using either echocardiography or multigated 
acquisition scanning (MUGA). However, the method chosen needs to stay the same throughout 
the trial. 
8.2.5 
Clinical safety laboratory assessments 
Instructions on sample collection, handling, storage, and shipment of samples are detailed in 
the study-specific Laboratory Manual provided to the study site. 

 
 
 
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8.2.5.1 Coagulation 
Coagulation tests will include prothrombin time, activated partial thromboplastin time, 
international normalized ratio, D-dimer, and fibrinogen. 
8.2.5.2 Hematology 
Hematology tests will include hemoglobin, glycated hemoglobin at screening, hematocrit, red 
blood cell count, reticulocytes, white blood cell count (with full differentiation), absolute 
lymphocyte count, and platelet count. 
8.2.5.3 Biochemistry 
Blood biochemistry tests will include Na, K, Cl, phosphate, Mg, Ca, albumin, total protein, 
ALT, AST, bilirubin (direct, total), alkaline phosphatase, lactate dehydrogenase, creatinine 
clearance calculated by the Cockcroft-Gault formula, creatinine, glucose (preferably fasting), 
urea or blood urea nitrogen, cholesterol, triglyceride, C-reactive protein, uric acid, amylase, 
and lipase. 
8.2.5.4 Urinalysis 
The following parameters are to be analyzed: pH, glucose, protein, bilirubin, urobilinogen. 
Microscopic examination (mandated only if clinically indicated): red blood cell count, white 
blood cell count, epithelial cells, bacteria. 
In case of proteinuria ≥100 mg/dL at screening, a 24-hour urine analysis will have to be 
performed (before the start of nanrilkefusp alfa treatment) to document 24-hour proteinuria 
levels and a urine test will continue during the treatment period. In case of increase of 
proteinuria with ≥300 mg/dL (at any time), a 24-hour urine analysis will be performed. 
8.2.5.5 Serology testing for infections 
Mandatory serology testing for infections will include testing for HIV, HBV, and HCV. Should 
the patient refuse testing, his/her participation will be terminated. 
8.2.6 
Monitoring of thyroid function 
Thyroid function will be monitored by means of thyroid stimulating hormone (TSH), 
triiodothyronine (T3) or free T3, and free thyroxine (T4) testing. 
8.2.7 
Pregnancy testing 
WOCBP will be tested for pregnancy. 
8.3 Adverse events, serious adverse events, and other safety reporting 
8.3.1 
Definitions 
8.3.1.1 Adverse events 
International Council for Harmonisation (ICH) guideline E2A defines an AE as any untoward 
medical occurrence in a patient or clinical investigation subject administered a pharmaceutical 
product and which does not necessarily have to have a causal relationship with this treatment. 

 
 
 
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An AE can therefore be any unfavorable and unintended sign (e.g., tachycardia, enlarged 
liver), symptom (e.g., nausea, chest pain), abnormal result of an investigation (e.g., laboratory 
finding), or disease temporarily associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
According to the FDA (21CFR312.32), an AE means any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered drug related. 
8.3.1.2 Serious adverse events 
A SAE is any untoward medical occurrence that at any dose fulfills one or more of the 
following criteria: 
• Results in death 
• Is immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at immediate risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe. 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
A hospitalization is defined as an inpatient overnight stay, but this can be shorter than  
24 hours. 
• Is another medically significant event defined as an event that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may 
require intervention to prevent any of the above listed outcomes 
8.3.1.3 Adverse events of special interest 
The following AEs are defined for this Protocol as AESIs and must be reported to the sponsor 
or designee within 24 hours of awareness: 
1. For patients without liver metastases or liver cancer or patients who do not receive 
hepatotoxic concomitant medications, the following AESIs must be reported: 
a. On-treatment (i.e., from the first dose of study treatment to 90 days after the last dose 
of study treatment) ALT or AST increase that is greater than 3×ULN in combination 
with clinical jaundice 
b. On-treatment ALT increase that is greater than or equal to 3×ULN and international 
normalized ratio increase that is greater than 1.5 
c. Recurrence of CTCAE grade 3 ALT and/or AST increase in combination with total 
bilirubin increase greater than 2×ULN or greater than 2×baseline level 
2. For patients with liver metastases or liver cancer or patients who receive hepatotoxic 
concomitant medications, the following AESIs must be reported: 
a. On-treatment ALT or AST increase that is greater than 5×ULN in combination with 
total bilirubin increase greater than 2×ULN (of which more than or equal to 35% is 
direct bilirubin) 

 
 
 
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b. On-treatment ALT or AST increase that is greater than 5×ULN in combination with 
clinical jaundice 
3. An overdose of pembrolizumab, as defined in section 6.7 
4. An elevated AST or ALT laboratory value that is greater than or equal to 3×ULN and an 
elevated total bilirubin laboratory value that is greater than or equal to 2×ULN and, at the 
same time, an alkaline phosphatase laboratory value that is less than 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 trial site guidance for assessment 
and follow-up of these criteria can be made available. It may also be appropriate to conduct 
additional evaluation for an underlying etiology in the setting of abnormalities of liver 
blood tests including AST, ALT, bilirubin, and alkaline phosphatase that do not meet the 
criteria noted above. In these cases, the decision to proceed with additional evaluation will 
be made through consultation between the study investigators and the sponsor’s medical 
monitor for the trial.  
However, abnormalities of liver blood tests that do not meet the criteria noted above are 
not AESIs for this trial. 
8.3.1.4 Excluded events 
Hospitalization for the following reasons will not be regarded as serious (not immediately 
reportable): 
• Routine treatment or monitoring of the disease under study, including hospitalization due 
to study-related procedures, not associated with any deterioration of the patient’s status 
• Elective or pre-planned treatment (before signing the ICF) for a pre-existing condition that 
is unrelated to the disease under study and has not worsened since signing the ICF 
• Social reasons, respite care, and in the absence of a medical condition (e.g., for 
observational purposes without any intervention) 
8.3.1.5 Severity/intensity vs. seriousness 
ICH E2A: The term “severe” is often used to describe the intensity (severity) of a specific event 
(as mild, moderate, or severe myocardial infarction); the event itself, however, may be of a 
relatively minor medical significance (such as a severe headache). This is not the same as 
“serious”, which is based on patient/event outcome or action criteria usually associated with 
events that pose a threat to a patient’s life or functioning. Seriousness (not severity) serves as 
a guide for defining regulatory reporting obligations. 
8.3.2 
Time period and frequency for collecting AE, SAE, and other reportable safety 
event information 
Every effort should be taken to collect all AEs, AESIs, and SAEs from the date of the patient’s 
signing the ICF until 90 days after the final administration of nanrilkefusp alfa and/or 
pembrolizumab (whichever is later) or until the start of a new anti-cancer therapy, whichever 
is earlier. 

 
 
 
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Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified above must be reported immediately to the sponsor or designee if the 
event is considered as having a suspected causal relationship to nanrilkefusp alfa and/or 
pembrolizumab per the investigator’s judgment. 
Pregnancies of the patient or patient’s female partner must be reported from the date of the 
patient’s signing the ICF up to 120 days following the last dose of pembrolizumab or 30 days 
after the last dose of nanrilkefusp alfa, whichever is later. 
8.3.3 
Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences. A standardized question such as “Have you had any health problems since 
your last visit or since you were last questioned?” will be given by the investigator or the 
investigational site personnel at each contact with the patient. 
The investigator assesses at each visit (or more frequently, if necessary) if there are any changes 
in AE diagnosis, severity, suspected causal relationship to clinical trial medication/procedure, 
interventions required to treat the event, and AE outcome. 
8.3.4 
Follow-up of AEs and SAEs 
After the initial (S)AE report, the investigator is required to proactively follow each patient at 
subsequent visits/contacts (or more frequently, if necessary). 
AEs are monitored (followed up) until resolution or until 90 days after the last dose of 
nanrilkefusp alfa and/or pembrolizumab, whichever is later. 
All SAEs and AESIs will be followed until resolution, stabilization (becoming a permanent 
condition), or the patient is lost to follow-up as defined in section 7.3. 
8.3.5 
Regulatory reporting requirements for SAEs 
Prompt notification by the investigator to the sponsor or designee of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of patients and the safety of a 
study intervention under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of an investigational product under clinical investigation. 
The sponsor or designee will comply with country-specific regulatory requirements relating to 
safety reporting to the regulatory authority, IRB/IEC (in the US)/EC (in the EU)/equivalent 
committee (outside the US and EU), and investigators. 
An investigator who receives a periodic or expedited safety report (e.g., suspected unexpected 
serious adverse reaction report, summary or line listing of suspected unexpected serious 
adverse reactions) or other specific safety information from the sponsor or designee will review 
and then file it along with the IB and will notify the IRB/IEC (in the US)/EC (in the 
EU)/equivalent committee (outside the US and EU), if appropriate according to local 
requirements. 

 
 
 
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8.3.6 
Pregnancy 
Pregnancy is not considered an AE unless it meets any criteria for becoming serious (see the 
definitions in section 8.3.1.2). Patients must inform the investigator of any newly identified 
pregnancy or pregnancy of their partners without delay. 
If a patient inadvertently becomes pregnant while on treatment with nanrilkefusp alfa and/or 
pembrolizumab, the patient will be immediately discontinued from study interventions (see 
section 7.1). The site will contact the patient at least monthly and document the patient’s or 
patient’s female partner status until the pregnancy has been completed or terminated. The 
outcome of the pregnancy will be reported to the sponsor or designee within 24 hours of 
awareness. In addition, if the outcome is a SAE in line with section 8.3.1.2, e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn, the SAE report form needs to be completed. The study investigator will make every 
effort to obtain permission (consent) from the pregnant patient to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the sponsor or designee. Every 
infant must be followed up for 2 months after delivery. 
Consent to report information on the outcome of the pregnancy of male patients’ partners needs 
to be obtained from the pregnant partners. 
Egg and sperm donation is not allowed during the treatment period and for at least 120 days 
after the last dose of pembrolizumab or at least 30 days after the last dose of nanrilkefusp alfa, 
whichever is later. 
8.3.7 
Assessing AEs 
Information about adverse reactions (causally related events) already known for the 
investigational medicinal products can be found in the nanrilkefusp alfa and pembrolizumab 
IBs and Keytruda’s current package insert/US prescribing information (for the US) and current 
Summary of Product Characteristics (for the EU)54,55 or will be communicated between IB 
updates in the form of “Dear Investigator Letter”. 
8.3.7.1 Causality 
The investigator needs to assess the causal relationship of any AE to: 
• Nanrilkefusp alfa and/or pembrolizumab 
• Other suspected cause(s) of the event (e.g., concurrent disease, concomitant medication) 
This assessment is based on the investigator’s clinical judgment, taking into account all 
relevant information available at the time of AE reporting including (but not limited to): 
• Temporal association of the event onset with administration of the medication/procedure 
• Known type of reaction for any of the administered drugs 
• Disappearance or abating of symptoms when the drug is discontinued or the dose is reduced 
• Reappearance of symptoms when the drug is re-administered 
• Event may or may not be caused by the patient’s health condition 
• Presence of risks or factors not related to nanrilkefusp alfa and/or pembrolizumab or 
procedure that are known to be associated with the occurrence of the event 

 
 
 
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Causal relationship of all AEs will be classified as follows: 
• Not suspected: It is not plausible that the AE is caused by medication/procedure and a 
likely alternative explanation exists. 
No reasonable possibility of a causal or temporal relationship. 
• Suspected: It is plausible that the AE is caused by medication/procedure. 
Reasonable possibility of a causal relationship. 
For the purposes of safety reporting, “reasonable possibility” means there is evidence to 
suggest a causal relationship between one of the drugs/procedure and the AE. 
8.3.7.2 Severity/intensity 
Severity or intensity of an AE has to be assessed according to the CTCAE, version 5.0. A 
grading scale is provided for AE terms displaying grades 1 through 5 with unique clinical 
descriptions of severity for each AE. 
Grading refers to the severity of the AE. 
8.3.8 
Reporting by the investigational site 
8.3.8.1 Adverse events 
Any AE, whether or not considered to be causally related to the trial medication and regardless 
of its seriousness, must be reported (described and recorded) in the AE section of the patient’s 
eCRF on an ongoing basis. Each AE will be evaluated by the investigator to determine its term 
and grade according to the CTCAE, version 5.0. In case a suitable CTCAE term is not available, 
an appropriate medical verbatim term may be used instead. 
Only clinically relevant abnormal laboratory values, vital signs, or examination abnormalities 
need to be documented as AEs. Whenever possible, a diagnosis rather than symptoms should 
be provided on the AE eCRF page (e.g., anemia instead of low hemoglobin). 
Clinically relevant here means: induce clinical signs or symptoms, require therapy (e.g., 
hematologic abnormality requiring treatment), require a change in trial medication(s), or 
require a change in the clinical trial schedule or per investigator’s discretion. 
Physical examination findings will be compared with the baseline status and any significant 
change, as assessed by the investigator, must be documented as an AE. 
A surgical procedure is not an AE but a therapeutic measure for a condition that necessitates 
surgery. Therefore, the condition for which the surgery is required has to be reported as an AE. 
Any pre-planned surgery (i.e., planned before signature of the ICF) or other intervention 
permitted by this study Protocol and the condition leading to that measure are not AEs. In such 
cases, the underlying condition needs to be documented in the patient’s medical history on the 
eCRF. 
Death itself is not an AE term but the outcome of an event, which needs to be described using 
medical terminology. Information about death will be captured on the respective eCRF page 
along with relevant details (date of death, immediate and underlying causes of death). 

 
 
 
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8.3.8.2 Documenting on eCRFs 
The reported term should be a medical diagnosis or sign/symptom of the event according to 
the CTCAE, version 5.0 (whenever possible), not a procedure. Each symptom in a constellation 
of symptoms should be listed separately if the investigator has not set a diagnosis. 
Fluctuations or re-occurrences of a condition, which are considered normal for the patient and 
are recorded on the patient’s eCRF medical history, do not need to be reported as an AE. 
However, if the condition deteriorates during the trial, it needs to be captured as an AE. 
If the same AE occurs repeatedly, it must be assessed and documented separately each time. 
If possible, each AE should be evaluated to determine: 
• Event term (according to the CTCAE, version 5.0, not as reported by the patient) or a 
description of the AE in medical terms  
• Severity grade or intensity of the event as assessed by the investigator (1-5 according to the 
CTCAE, version 5.0) 
• Its causal relationship to nanrilkefusp alfa and/or pembrolizumab, as assessed by the 
investigator (suspected; not suspected) 
• Other suspected cause(s) of the event (e.g., concurrent disease, concomitant medication) 
• Event duration, including onset date and end date 
• Action taken with nanrilkefusp alfa and/or pembrolizumab due to the reported event 
• Other action taken 
• Event seriousness (non-serious or serious AE) 
• Event outcome 
8.3.8.3 Immediately reportable events 
The investigator or any investigational site staff must immediately (within 24 hours of 
awareness at the latest) notify/report to the sponsor or designee any initial or medically 
relevant follow-up information about these events: 
• SAE 
• AESI 
• Pregnancy of the patient or patient’s female partner 
The initial notification can be made by phone on +420 725 385 443. This notification must be 
followed within an additional 24 hours by a written report (i.e., a completed SAE Report Form 
or Pregnancy Data Collection Form), providing all available information and a detailed 
narrative description. A formless notification (without a report form) is not required if the 
initial/follow-up information is reported on the appropriate form within 24 hours of knowledge. 
The investigator must not wait to receive additional information to fully document the event 
before notifying the sponsor or designee primarily via the eCRF system; or via: 
Email: safety@sotio.com 
Fax: +420 224 175 498 
Phone: +420 725 385 443 

 
 
 
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Follow-up information must be sent within the same timelines using the same contact details 
as outlined above. 
Additionally, refer to the safety reporting instructions for sites for information on how to report 
these events. 
Minimum notification/reporting requirements 
The following information must be provided for a valid notification/report: 
1. Identification of the notifying/reporting person (e.g., name of the reporter) 
2. Identification of the patient (e.g., patient number) 
3. Concerned study treatment(s) (nanrilkefusp alfa and/or pembrolizumab) or clinical trial 
(e.g., SC104) 
4. Reason for notification/reporting (i.e., SAE, AESI, pregnancy of the patient or patient’s 
female partner) 
5. Event term 
In addition, providing the assessment of the causal relationship is necessary for 
comprehensive evaluation by the sponsor and potential regulatory submission. 
8.3.8.4 Report forms 
The SAE Report Form, primarily completed within the eCRF system for the study, will be 
used for reporting of SAEs and AESIs and submitted to the sponsor or designee. In case the 
eCRF system is not available/accessible, a paper SAE Report Form is filled out and sent to the 
sponsor or designee (see details above). 
For reporting of pregnancies, the paper Pregnancy Data Collection Form is to be used. 
Completion guidelines provide information on format and details of the information required. 
The originals of the paper report forms must be kept in the site study file. 
The report forms need to be completed in English. 
All immediately reportable events from the investigational site to the sponsor or designee (i.e., 
SAEs, AESIs, and patients’ or partners’ pregnancies) must also be recorded in the site’s source 
documentation and on the eCRF as appropriate. 
8.4 Pharmacokinetics 
The following PK parameters will be analyzed (nanrilkefusp alfa and pembrolizumab; 
pembrolizumab samples will be collected to be analyzed later during the course of the study if 
needed): 
• Area under the curve 
• Measured maximal concentration 
• Time corresponding to occurrence of maximal concentration 
• Apparent terminal elimination half-life 
• Apparent total serum clearance after administration 

 
 
 
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• Apparent volume of distribution during terminal phase 
• Accumulation ratio 
Further details will be specified in the PK Analysis Plan. 
The actual date and time (24-hour clock time) of each sample will be recorded. 
Instructions on sample collection, handling, storage, and shipment of samples are detailed in 
the study-specific Laboratory Manual provided to the study site. 
8.5 Genetics 
Participation in genetic research is optional. Patients who do not wish to participate in genetic 
research may still participate in the study. 
Genetic research will include the following: DNA analysis such as targeted sequencing (tumor 
mutational burden [TMB] in blood and tumor), MSI analysis, and circulating tumor DNA 
analysis. 
Instructions on sample collection, handling, storage, and shipment of samples are detailed in 
the study-specific Laboratory Manual provided to the study site. 
8.6 Biomarkers 
Collection of samples for biomarker research is also part of this study. The following samples 
will be collected from patients in this study: 
• Archival and/or freshly obtained tumor tissue: Newly obtained tissue is preferred to an 
archival sample. Formalin-fixed, paraffin-embedded block specimens are preferred to 
slides. Fine needle aspirate samples are not acceptable. 
• Blood 
DNA and RNA analyses are optional. Patients who do not wish to participate in this research 
may still participate in the study. 
8.6.1 
Tumor tissue 
Tumor PD-L1 expression (tumor proportion score ≥1% or combined positive score ≥1%) will 
be determined by an FDA-approved immunohistochemistry assay performed by a central 
laboratory using previously obtained archival tumor tissue or tissue obtained from a biopsy at 
screening. For patients whose initial tumor tissue sample is PD-L1 negative, a biopsy can be 
performed at screening to submit fresh tissue for testing PD-L1 status. 
PD-(L)1 expression status is not for eligibility. 
Other immune-related features to be measured may include but are not limited to the presence 
of tumor-infiltrating lymphocytes (T cells, NK cells, FoxP3+ cells) and myeloid cells, immune-
related messenger RNA expression signatures, and mutational burden and MSI present in the 
collected biospecimens. Appropriate methods will be used including but not limited to 
immunohistochemistry, targeted sequencing, gene expression profiling using RNA sequencing 
analysis or NanoString analysis, PCR, metabolomics, and/or measurement of other analytes. 

 
 
 
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8.6.2 
Blood sample for RNA and DNA analyses and biomarker studies 
Immune-related features measured in blood samples may include immune-related messenger 
RNA expression signatures, blood TMB, and/or measurement of other analytes. 
Additional translational research might be conducted as appropriate including but not limited 
to the assessment of T-cell clonality, neoantigen expression, metabolomics, proteomics, and 
presence and changes in the circulating tumor markers such as circulating tumor DNA at 
screening and following nanrilkefusp alfa and pembrolizumab treatment. 
The correlation/relationship between biomarkers in tumor tissue and blood and measures of 
clinical efficacy, safety, PD activity, and/or mechanism of action will be evaluated. 
For patients with mCRPC, CTC count and circulating tumor DNA will be analyzed. 
Instructions on sample collection, handling, storage, and shipment of samples are detailed in 
the study-specific Laboratory Manual provided to the study site. 
Samples may be stored for a maximum of 20 years (or according to local regulations) after the 
end of the study at a facility selected by the sponsor to enable further analysis of biomarker 
responses to nanrilkefusp alfa in combination with pembrolizumab. 
8.7 Immunogenicity assessments 
Samples for ADAs will be collected to assess nanrilkefusp alfa tolerability, correlation with 
PK, and potential AEs associated with ADAs against nanrilkefusp alfa and for the prediction 
of nanrilkefusp alfa ADA production. 
Samples for pembrolizumab ADAs will be collected. These samples will be stored and a 
decision about their analysis will be taken at a later date. 
Instructions on sample collection, handling, storage, and shipment of samples is detailed in the 
study-specific Laboratory Manual provided to the study site. 
Samples may be stored for a maximum of 20 years (or according to local regulations) after the 
end of the study at a facility selected by the sponsor to enable further analysis of immune 
responses to nanrilkefusp alfa in combination with pembrolizumab. 
8.8 Health economics 
Health economics parameters will not be evaluated in this study. 
8.9 Pharmacodynamics 
PD markers will be assessed in paired tumor tissue collected before and after treatment with 
nanrilkefusp alfa in combination with pembrolizumab. Activation/expansion of various 
immune cell populations (leukocytes including NK cells, CD8+ and CD4+ T cells, myeloid 
cells) will be detected based on the expression of specific markers by immunohistochemistry 
analysis or genetic analysis (optional). 
 

 
 
 
 
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9 STATISTICAL CONSIDERATIONS 
9.1 Statistical hypotheses 
No formal testing of statistical hypotheses is planned in this open-label, single-arm trial. 
The primary objective is to estimate the antitumor efficacy of nanrilkefusp alfa in combination 
with pembrolizumab according to RECIST 1.1 by means of ORR, for each indication or disease 
cohort separately. Other efficacy endpoints (e.g., iORR, [i]PFS, [i]BOR) will also be explored 
to further evaluate the antitumor efficacy of the combination therapy. 
9.2 Analysis sets 
9.2.1 
All-subjects-as-treated population 
The all-subjects-as-treated (ASaT) population will consist of all patients exposed to 
nanrilkefusp alfa or pembrolizumab. 
All safety analyses will be performed on the ASaT population. 
9.2.2 
PK population 
The PK population will consist of all patients who are PK-evaluable. Please also see sections 
1.3.5 and 8.4. 
9.2.3 
Efficacy population 
The efficacy population will consist of all patients exposed to the combination therapy for at 
least one treatment cycle. 
This will be the main population for the analyses of the primary endpoint and efficacy, 
secondary, and exploratory endpoints. 
9.2.4 
Per Protocol population 
The per Protocol (PP) population is defined as all patients who had at least one full treatment 
cycle of nanrilkefusp alfa and pembrolizumab, did not violate any eligibility criteria, and did 
not have any major Protocol deviations. 
9.3 Statistical analyses 
9.3.1 
General considerations 
Analyses will be descriptive (i.e., without a comparison). Efficacy analyses will be performed 
for each indication separately. Safety will be analyzed as described in section 9.3.3. 
Summary statistics will include: 
• Counts and percentages (categorical data) 
• Number of observations, mean, standard deviation, median, minimum, and maximum 
(continuous data) 
The ORR, iORR, BOR, iBOR, CBR, iCBR, CTC response, and PSA response will use the 
exact method based on the binomial distribution56 to derive 95% confidence intervals (CIs). 

 
 
 
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Kaplan-Meier estimations and estimations of median (if reached) with log-log 95% CI, Q1 
(25th percentile), and Q3 (75th percentile) will be used for time to confirmed PSA progression 
(mCRPC only), DoR, iDoR, PFS, iPFS, TtR, iTtR, and OS. In case of a confirmed response or 
disease progression, the date of the first tumor assessment or PSA evaluated as response or 
progression will be used for the time-to-event variables. 
Depending on the amount of missing data, a sensitivity analysis will be performed for time-to-
event endpoints. If such an analysis is planned, it will be described in the final Statistical 
Analysis Plan (SAP). 
The last value of PSA, CTC count, CT scan, bone scan, or MRI on or up to 28 days before the 
date of the first study treatment will be used as the baseline value for each assessment. Only 
tumor assessments prior to or at the date of initiation of further-line therapy and using CT scan, 
bone scan, or MRI will be used for the evaluation of tumor response. 
9.3.2 
Primary endpoint analysis 
The ORR is defined as the proportion of patients with CR or partial response (PR). ORR will 
be analyzed and presented as a point estimate and a 95% CI for each indication separately. 
Patients with missing data will be considered as non-responders. 
Sensitivity analyses will include the use of: 
• ASaT and PP populations 
• No imputation of missing data 
9.3.3 
Secondary endpoints analysis 
9.3.3.1 Safety endpoints 
• TEAEs 
A TEAE is defined as an AE that started or worsened at or after the start of study treatment. 
TEAEs will be summarized with counts and percentages. These will be provided for the 
incidence of, but not limited to: any TEAE, any serious TEAE, any grade 3-5 TEAE, any  
drug-related TEAE, any serious and drug-related TEAE, any grade 3-5 and drug-related TEAE, 
temporarily discontinued due to a TEAE, permanently discontinued due to a TEAE, death. 
TEAE incidence frequencies by system organ class (SOC) and preferred term (PT) will also be 
provided. 
• 
AESIs 
AESIs will be summarized with counts and percentages by SOC and PT. 
• 
Safety laboratory findings, vital signs, and ECG 
Safety laboratory findings, vital signs measurements, and ECG data will be summarized 
accordingly (if categorical or continuous data). Laboratory results will be summarized using 
SI units as appropriate. 
Further details on analyses to be performed by indication and overall will be specified in the 
final SAP. 

 
 
 
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9.3.3.2 Efficacy endpoints 
• iORR 
The iORR is defined as the proportion of patients with complete response (iCR) or partial 
response (iPR) and will be analyzed and presented as a point estimate and a 95% CI for each 
indication separately. Patients with missing data will be considered as non-responders. 
• BOR and iBOR 
The BOR and iBOR are defined as the best response from the start of study treatment until 
progression of disease or death and will be summarized with counts and percentages together 
with a 95% CI for each indication separately. Stable disease (SD, iSD) needs to last at least  
6 weeks from the baseline scan; if not, at least one follow-up scan is required to declare stable 
disease. 
• DoR and iDoR 
The DoR and iDoR are defined as the time until progression of disease for patients with partial 
response (PR, iPR) or complete response (CR, iCR) and will be summarized using Kaplan-
Meier estimates for each indication separately. Responders will be considered to have an 
ongoing response if they: i) have not progressed, and ii) have not started a new anti-cancer 
therapy, and iii) have not been lost to follow-up, and iv) are alive. 
Patients with missing data will be censored/considered as having an event as specified below: 
Situation 
Date of progression or censoring 
Outcome 
No progression, no death. No 
start of new anti-cancer therapy. 
Date of the last evaluable tumor 
assessment. 
Censored 
No progression, no death. Start of 
new anti-cancer therapy. 
Date of the last tumor assessment with 
non-progression before the start of new 
anti-cancer therapy. 
Censored 
Progression or death after one 
missed adequate tumor 
assessment. 
Date of progression or death, whichever 
is earliest (if both occur). 
Progressed 
Progression or death after more 
than one missed adequate tumor 
assessment. 
Date of the last evaluable tumor 
assessment. 
Censored 
• CBR and iCBR 
The CBR and iCBR are defined as the number of partial responses (PR, iPR), complete 
responses (CR, iCR), and stable diseases (SD, iSD) and will be analyzed and presented as a 
point estimate and a 95% CI for each indication separately. Stable disease (SD, iSD) needs to 
last at least 6 weeks from the baseline scan; if not, at least one follow-up scan is required to 
declare stable disease. Patients with missing data will be considered as non-responders. 

 
 
 
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• PFS and iPFS 
PFS and iPFS are defined as the time from the first day of study treatment until the first date 
of radiological disease progression or death and will be summarized using Kaplan-Meier 
estimates for each indication separately. 
Patients with missing data will be censored/considered as having an event as specified below: 
Situation 
Date of progression or censoring 
Outcome 
Incomplete or no baseline tumor 
assessment 
Date of the first day of study treatment 
Censored 
Start of new anti-cancer therapy 
Date of the last tumor assessment with 
non-progression before the start of new 
anti-cancer therapy 
Censored 
Death before the first disease 
progression assessment 
Date of death 
Progressed 
Death between adequate tumor 
assessment visits 
Date of death 
Progressed 
Progression or death after one 
missed adequate tumor 
assessment 
Date of progression or death, whichever 
is earliest (if both occur) 
Progressed 
Progression or death after more 
than one missed adequate tumor 
assessment 
Date of the last evaluable tumor 
assessment 
Censored 
No progression, no death 
Date of the last evaluable tumor 
assessment 
Censored 
• TtR and iTtR 
TtR and iTtR are defined as the time from the first day of study treatment until the first date of 
partial response (PR, iPR) or complete response (CR, iCR) and will be summarized using 
Kaplan-Meier estimates for each indication separately. Patients with missing data will be 
censored at the last assessment date, date of death, or date of the first day of study treatment (if 
incomplete or no baseline tumor assessments), whichever occurs latest. 
• CTC count conversion from ≥5 to <5 cells per 7.5 mL of blood 
The CTC response is defined as the proportion of patients with CTC count conversion from  
≥5 to <5 cells per 7.5 mL of blood and will be analyzed and presented as a point estimate and 
a 95% CI for the mCRPC indication. Patients with missing data will be considered as  
non-responders. 

 
 
 
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• Confirmed PSA decline of ≥50% 
The PSA response is defined as the proportion of patients with a PSA decline of ≥50% and will 
be analyzed and presented as a point estimate and a 95% CI for the mCRPC indication. 
Responses will need confirmation by a second consecutive value obtained 4 or more weeks 
after the first value indicated a response. Response will be evaluated 6 months post trial entry. 
Evaluable patients with no confirmed response as defined above will be classified as non-
responders. 
• Time to confirmed PSA progression 
Time to confirmed PSA progression is defined as the time from the first day of study treatment 
to the date of PSA progression and will be summarized using Kaplan-Meier estimates for the 
mCRPC indication. 
PSA progression is defined as the date when an increase of 25% or more and an absolute 
increase of 2 ng/mL or more from the nadir are documented. For patients who have a decline 
in PSA during treatment, PSA progression must be confirmed by a second value 3 or more 
weeks later increased with respect to the nadir PSA. 
9.3.4 
Exploratory endpoint analysis 
• OS 
OS is defined as the time from the first day of study treatment until the date of death and will 
be summarized using Kaplan-Meier estimates for each indication separately. Patients with 
missing data will be censored at the last time known to be alive. 
9.3.5 
Other analyses 
Other sensitivity, secondary, and exploratory analyses such as PK, immunogenicity, biomarker 
exploratory analyses, and circulating tumor DNA fraction (mCRPC only) will be described in 
the final SAP. The population PK analysis will be presented separately from the main Clinical 
Study Report. 
9.4 Interim analysis 
An analysis for futility will be performed when the sample size is considered enough for such 
analysis and for each indication, as described below in this section. Efficacy data and outputs 
will also be a part of the Independent Data Monitoring Committee (IDMC) review. 
During this period, patient recruitment may be paused if the sponsor deems it appropriate to 
wait for the results of the futility analysis before enrolling additional patients. 
Assuming a desired ORR, the futility analysis will be based on a comparison against a minimal 
ORR considered as both statistically and clinically relevant improvement as compared to the 
benchmark ORR. An 80% CI using the exact method56 for the ORR (alpha = 0.2, alpha = 0.1 
one-sided) will be used. 
The analysis will be based on the efficacy population. 

 
 
 
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If, for a certain indication, the ORR is: 
1. lower than the minimal ORR, and 
2. the 80% CI for the ORR does not include the minimal ORR, 
it will be concluded that the combination treatment is futile as compared to benchmark 
treatment and thus the indication will be discontinued. However, patients still on treatment in 
the indication can continue combination therapy if recommended by the IDMC. 
The criteria for conclusion of futility, for each indication, are defined as follows: 
• Indication 1 (NSCLC): Benchmark ORR = 15%; minimal ORR = 23%;  
desired ORR = 30.6% 
o N = 21 patients if the number of responses is less than 2 (r < 2) 
• Indication 
2 
(MSI-H/dMMR 
colorectal 
cancer): 
Benchmark 
ORR 
= 
44%;  
minimal ORR = 54.1%; desired ORR = 62.5% 
o N = 12 patients if the number of responses is less than 4 (r < 4) 
• Indication 3 (cSCC): Benchmark ORR = 44%; minimal ORR = 54.1%;  
desired ORR = 62.5% 
o N = 12 patients if the number of responses is less than 4 (r < 4) 
• Indication 4 (advanced hepatocellular carcinoma): Benchmark ORR = 17%;  
minimal ORR = 25.3%; desired ORR = 33% (not applicable in France) 
o N = 19 patients if the number of responses is less than 2 (r < 2) 
• Indication 5 (mCRPC): Benchmark ORR = 5%; minimal ORR = 10.4%;  
desired ORR = 16.4% 
o N = 35 patients if the number of responses is less than 1 (r < 1) 
• Indication 6 (recurrent ovarian cancer): Benchmark ORR = 15%; minimal ORR = 23%; 
desired ORR = 30.6% 
o N = 21 patients if the number of responses is less than 2 (r < 2) 
Additionally, the ORR will be evaluated on an ongoing basis (without stopping of recruitment). 
Other efficacy endpoints will be used as supportive information. 
9.5 Sample size determination 
The number of patients per indication to be treated for at least one cycle is based on a Bayesian 
calculation: for each indication separately, Markov chain Monte Carlo has been used for the 
sample size determination. Assuming a desired ORR for the number of responses, and a 
uniform prior distribution between 0 and 1, there will be at least 80% posterior probability to 
achieve an effect above the minimal ORR: 
• Indication 1 (NSCLC): 50 patients 
• Indication 2 (MSI-H/dMMR colorectal cancer): 57 patients 
• Indication 3 (cSCC): 57 patients 

 
 
 
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• Indication 4 (advanced hepatocellular carcinoma): 55 patients (not applicable in France) 
• Indication 5 (mCRPC): 51 patients 
• Indication 6 (recurrent ovarian cancer): 50 patients 
This results in a total of 320 patients. 
 

 
 
 
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10 SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL 
CONSIDERATIONS 
10.1 Appendix 1: Regulatory, ethical, and study oversight considerations 
10.1.1 
Regulatory and ethical considerations 
The Protocol, ICF, and appropriate related documents must be reviewed and approved by an 
IRB/IEC (in the US)/EC (in the EU)/equivalent committee (outside the US and EU) constituted 
and functioning in accordance with ICH Guideline E6 Good Clinical Practice (GCP)57 and any 
local regulations, and by the competent authority (CA). Any Protocol Amendment or revision 
to the ICF will be resubmitted to the IRB/IEC (in the US)/EC (in the EU)/equivalent committee 
(outside the US and EU) and to the CA for review and approval, except for changes involving 
only logistical or administrative aspects of the study (e.g., change of clinical research associates 
[CRAs], change of telephone numbers). Documentation of IRB/IEC (in the US)/EC (in the 
EU)/equivalent committee (outside the US and EU) compliance with ICH E6 and any local 
regulations regarding constitution and review conduct will be provided to the sponsor. 
A signed letter of study approval from the IRB/IEC (in the US)/EC (in the EU)/equivalent 
committee (outside the US and EU) chairman must be sent to the principal investigator or, if 
regionally required, the head of the medical institution with a copy to the sponsor before study 
start and the release of study interventions to the site by the sponsor or its designee. If the 
IRB/IEC (in the US)/EC (in the EU)/equivalent committee (outside the US and EU) decides to 
suspend or terminate the study, the investigator (or if regionally required, the head of the 
medical institution) will immediately send the notice of study suspension or termination by the 
IRB/IEC (in the US)/EC (in the EU)/equivalent committee (outside the US and EU) to the 
sponsor. 
Study progress is to be reported to IRBs/IECs (in the US)/ECs (in the EU)/equivalent 
committees (outside the US and EU) and to CAs annually (or as required) by the investigator 
or sponsor, depending on local regulatory obligations. If the investigator is required to report 
to the IRB/IEC (in the US)/EC (in the EU)/equivalent committee (outside the US and EU), s/he 
will forward a copy to the sponsor at the time of each periodic report. 
The investigator(s) or the sponsor will submit, depending on local regulations, periodic reports 
and inform the IRB/IEC (in the US)/EC (in the EU)/equivalent committee (outside the US and 
EU) (or if regionally required, the investigator and the relevant IRB/IEC [in the US]/EC [in the 
EU]/equivalent committee [outside the US and EU] via the head of the medical institution) and 
the CA of any reportable AEs per ICH guidelines and local IRB/IEC (in the US)/EC (in the 
EU)/equivalent committee (outside the US and EU) standards of practice. Upon completion of 
the study, the investigator or sponsor will provide the IRBs/IECs (in the US)/ECs (in the 
EU)/equivalent committees (outside the US and EU) and the CAs with a brief report of the 
outcome of the study, if required. 
At the end of the study, the sponsor should notify the IRBs/IECs (in the US)/ECs (in the 
EU)/equivalent committees (outside the US and EU) and CAs as regionally required. 
This study will be conducted in accordance with standard operating procedures of the sponsor 
(or designee), which are designed to ensure adherence to applicable regulatory requirements, 
and in accordance with the current version of the Declaration of Helsinki and ICH guidelines 
on GCP. 

 
 
 
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10.1.2 
Financial disclosure 
Information on potential financial interests will be provided by all participating investigators. 
This information will be collected by the sponsor (or a delegated party) before the initiation of 
the clinical trial, during the course of the clinical trial whenever the financial interests may 
change, and for a period of one year after the completion of the clinical trial, or termination of 
a particular individual’s participation in this trial. 
10.1.3 
Informed consent process 
10.1.3.1 Clinical trial participation 
Written informed consent will be given by each patient before any procedure of this clinical 
trial is performed. The process of obtaining the informed consent must comply with applicable 
ICH GCP E6 guidelines as implemented in EU guidelines and national regulatory 
requirements. 
It is the responsibility of the investigator that patients are clearly and fully informed about the 
purpose of the clinical trial, its potential risks and benefits, and other critical issues regarding 
the clinical trial, in which the patient volunteers to participate, before undergoing any clinical 
trial-specific procedure. 
The IRB/IEC- (in the US)/EC- (in the EU)/equivalent committee- (outside the US and EU) 
approved written ICF, which complies with the above-mentioned regulations, will be provided 
to each patient. The patient should be given ample time to read and to understand the ICF, and 
to get the answers to any enquiry related to the clinical trial s/he may have. The ICF should be 
signed personally by the patient and subsequently by the delegated investigator who obtains 
the consent. The patient will be provided with a fully signed ICF printout, and with any other 
written information, before participation in the clinical trial. 
The process of obtaining informed consent should be documented in the patient’s source 
documents. 
The sponsor will provide the investigator with a master ICF that complies with ICH GCP 
guidelines and regulatory requirements and is considered appropriate for this clinical trial. Any 
changes to this master ICF suggested by the investigator must be agreed to by the sponsor 
before being submitted to the IRB/IEC (in the US)/EC (in the EU)/equivalent committee 
(outside the US and EU). A copy of the approved version, together with all accompanying 
approvals, must be provided to the sponsor. 
The ICF and any other information provided to patients are subject to changes and revisions 
whenever important new information relevant to patients’ willingness to continue participation 
in the clinical trial becomes available. Once the IRB/IEC (in the US)/EC (in the EU)/equivalent 
committee (outside the US and EU) approval/favorable opinion on this new information is 
obtained, the delegated investigator should inform each patient about this newly emerging 
information as soon as possible. All procedures and regulations to be followed and mentioned 
above apply also to this scenario, and this process should also be documented in the patient’s 
source documents. 
10.1.3.2 Pharmacogenomic research 
Patients will be asked to participate in pharmacogenomic research (see sections 8.5, 8.6, and 
8.9). Depending on local laws and regulations, the patients might be required to provide their 

 
 
 
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written consent to this research by signing a separate ICF. In such a case, the consent to 
participate in the pharmacogenomic research will be optional and not a prerequisite for entry 
into the clinical trial. 
10.1.4 
Data protection 
In order to ensure that personal information of each patient is kept confidential and protected, 
names and any other information that allow direct identification of a patient will not be on the 
eCRFs or included in any records or samples provided to the sponsor or sponsor’s authorized 
representatives; such information will be pseudonymized, i.e., all such information will be 
replaced by a specific code (patient number) assigned by a study doctor and all patients will be 
identified on eCRFs or any other records or samples by a patient number only. 
The personal information collected for the purposes of this study will be held by the study sites, 
the sponsor, and sponsor’s authorized representatives, which together are responsible for 
processing of personal information in accordance with the applicable data protection laws, 
including the Swiss Data Protection Act, the Swiss revised Data Protection Act, the General 
Data Protection Regulation (EU) 2016/679, and any corresponding local legislation. 
The sponsor and its authorized representatives will analyze and use the personal information 
they receive for the purposes of this study only. These include: 
• checking patients’ suitability to take part in the study, 
• monitoring patients’ health during treatment with nanrilkefusp alfa in combination with 
pembrolizumab, 
• comparing and pooling study results, 
• establishing whether nanrilkefusp alfa in combination with pembrolizumab meets the 
appropriate standards of safety set by the authorities, 
• establishing whether nanrilkefusp alfa in combination with pembrolizumab is effective, 
• supporting the clinical development of nanrilkefusp alfa in combination with 
pembrolizumab, 
• supporting the licensing application for regulatory approval of nanrilkefusp alfa in 
combination with pembrolizumab anywhere in the world, 
• supporting the marketing, distribution, sale, and use of nanrilkefusp alfa in combination 
with pembrolizumab anywhere in the world, 
• complying with specific regulations governing clinical trials. 
Participation of patients in this study is voluntary and they may withdraw from the study at any 
time by informing the investigator. Their participation in the study will then end and the study 
personnel will stop collecting personal information from the patients, but the sponsor will need 
to retain and use the pseudonymized personal information and associated research results that 
have already been collected from the patient. The sponsor must do this to comply with its legal 
and regulatory obligations, to maintain the scientific integrity of the study, and to complete the 
marketing authorization process for nanrilkefusp alfa in combination with pembrolizumab. It 
may be necessary to retain certain aspects of pseudonymized (coded) personal information for 
at least 25 years following the end of the study to comply with applicable laws and regulatory 
requirements and to ensure the scientific integrity of the study. 

 
 
 
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If necessary for the study purposes mentioned above, the sponsor may communicate such 
pseudonymized personal information to third parties (such as service providers, contractors, 
and research institutions that support the study) and regulatory or other governmental agencies 
that need to check the results of the study. 
These third parties may be located in countries of the European Economic Area (EEA), in 
Switzerland, in the United States, and in other countries that are outside of the EEA. Some non-
EEA countries may not offer the same level of privacy protection. However, the sponsor will 
keep personal information it receives as confidential as possible within the limits of the law. 
The sponsor will implement appropriate contractual measures, including the standard data 
protection contractual clauses, to ensure that the relevant recipients outside the EEA provide 
an adequate level of protection to personal information as set out in this form and as required 
by applicable law. 
The sponsor, either alone or together with other researchers, may publish or present the results 
of the study; however, personal information will not be disclosed in any publication or 
presentation. 
All persons have certain rights to gain access to and correct any inaccuracies in the personal 
information held about them. In certain circumstances, they can also request restriction of 
processing of their personal information, object to certain types of processing of their personal 
information, request their personal information be erased and have their personal information 
provided to them or a third party in a digital format. The sponsor shall comply with the above 
requests to the fullest extent consistent with other legal and regulatory obligations and where 
required by law. 
Personal data cannot be erased, even after patients finish or terminate their participation in the 
study, in order to guarantee the validity of the clinical research and to comply with statutory 
duties and drug authorization requirements. 
Representatives from government agencies, the local EC and sponsor or its authorized 
representatives may also need access to medical records and study records for the purpose of 
checking data collected for the study. 
The sponsor shall process all personal information of the patients in the study in accordance 
with the applicable data protection laws, including the Swiss Data Protection Act, the Swiss 
revised Data Protection Act, the General Data Protection Regulation (EU) 2016/679, any 
applicable local legislation, and the internal data protection policies reflecting organizational 
and technical arrangements to avoid unauthorized access, disclosure, dissemination, alteration, 
or loss of information and personal data processed. The organizational and technical measures 
introduced by the sponsor in relation to a protection of personal information of the patients 
involve the above mentioned pseudonymization of personal information, appropriate controls 
to restrict its employees access to the personal information, a physical access control to any 
premises where the personal information is stored, an electronic access and system control 
logging for any systems containing personal information, data entry and data transfer control, 
availability control (back-up and recovery concept), network protection including firewalls and 
penetration testing procedures for regular testing, industry-standard security policies and 
procedures including assessment and evaluation of processes and regular training procedures. 
In the event of any security breach, the incident management procedures would be 
implemented, and the sponsor would notify such breach as applicable. 

 
 
 
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10.1.5 
Organizational structure of the study 
The sponsor of the clinical trial, SOTIO, may delegate certain tasks to designees, e.g., a contract 
research organization (CRO) or other third-party vendors. A list of such designated 
collaborators, including their contact details, will be documented in the investigator’s 
manuals/Investigator Site File. 
10.1.6 
Dissemination of clinical study data 
By signing the Protocol (INVESTIGATOR’S DECLARATION), every participating 
investigator agrees to keep all information and results concerning the clinical trial and the 
investigational product strictly confidential. The confidentiality obligation also applies to all 
personnel involved at the investigational site. 
10.1.7 
Data quality assurance 
An eCRF is required and must be completed for each patient by qualified and authorized 
personnel. All data on the eCRF must reflect the corresponding source document. Any 
correction to entries made on the eCRF must be documented in a valid audit trail where the 
correction is dated, the individual making the correction is identified, the reason for the change 
is stated, and the original data are not obscured. Only data required by the Protocol for the 
purposes of the study should be collected. The investigator must sign the eCRFs. 
10.1.8 
Trial monitoring, access to source documentation, and data retention 
Before trial initiation, at the investigators’ meeting or during the Site initiation visit, a 
representative of the sponsor or a CRO will review the Protocol and eCRFs with the site staff. 
During the clinical trial, the CRA will oversee the progress of the clinical trial and will visit 
the site regularly to verify the completeness of patient records, reliability and accuracy of 
entries on eCRFs, the site’s adherence to the Protocol and GCP, the progress of enrollment, 
and that study interventions are being stored, dispensed, and accounted for according to 
specifications. The CRA will also ensure that the safety and rights of the patients are not 
compromised. Key clinical trial personnel must be available to assist the CRA during these 
visits. 
For each patient recruited into the clinical trial, the investigator must maintain source 
documents, which should consist of case and visit notes (hospital or outpatient clinic medical 
records) containing demographic and medical information, laboratory data, and results of any 
other tests or assessments. All information on eCRFs must be traceable to these source 
documents in the patient’s file. The investigator must also keep the original of the ICF signed 
by the patient (the second signed original must be given to the patient). 
The investigator must allow the CRAs or other delegated representatives to visit all site 
locations, and to allow direct access to all clinical trial-related documentation and data, as well 
as to the patient’s source documents and other charts and records. 
Monitoring standards of the sponsor require full verification for the presence of a fully signed 
and dated ICF, adherence to the inclusion/exclusion criteria, documentation of SAEs, and 
recording of data that will be used for all primary and safety variables. Additional verification 
of the consistency of the source data with the eCRFs will be performed according to a clinical 
trial-specific Monitoring Plan. 

 
 
 
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Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the Monitoring 
Plan. 
The sponsor assumes accountability for actions delegated to other individuals (e.g., CROs). 
The trial may also be evaluated by any other designee delegated by the sponsor, IRB/IEC (in 
the US)/EC (in the EU)/equivalent committee (outside the US and EU) representatives, or by 
any independent institutional or government inspectors, who must be given direct access to the 
same as mentioned above. Such a possibility must also be clearly mentioned in the patient’s 
ICF. 
The investigator must promptly notify the sponsor or its delegated representatives any time the 
request for inspection is raised by any regulatory agency, and to provide copies of all 
documentation received from such an agency. 
The investigator or institution must retain all trial-related records, materials provided by the 
sponsor or its delegated collaborators, copies of eCRFs, and source documents of patients for 
a specified period of time. This period of time is derived from the locally applicable regulation 
guidelines or requirements, institution procedures, or requirements stipulated by the sponsor or 
its representatives, whichever is longer. 
It is requested that at the completion of the required retention period, or should the investigator 
retire or relocate, the investigator contact the sponsor, allowing the sponsor the option of 
permanently retaining the study records. 
10.1.9 
Study and site start and closure 
The first act of recruitment is the signature of the ICF by the first patient enrolled and will be 
the study start date. 
The end of the study is defined in section 4.4. 
10.1.10 
Publication policy 
The results of this clinical trial will be published and/or presented at scientific meetings in their 
totality in a timely manner. No single institution presentation/publication of data is foreseen if 
not agreed by the sponsor and all relevant investigators of the study. Any formal publication 
of clinical trial results will be a collaborative effort between the sponsor and the investigator(s). 
All manuscripts or abstracts will be reviewed and approved in written by the sponsor before 
submission. The sponsor may request a delay in publication if there are important intellectual 
property concerns but does not have the right to suppress the publication of the clinical trial 
results indefinitely. 
Authorship will be determined by mutual agreement, with the coordinating investigator of this 
clinical trial being given priority for first authorship. Publications will include all clinical trial 
investigators in the order of their relative patient contribution, taking into account also 
contributions during Protocol development and data analyses. 

 
 
 
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10.1.11 
Independent Data Monitoring Committee 
An IDMC will be established for this study to safeguard the interest and safety of the patients 
participating in the study and provide independent review and assessment of the efficacy and 
safety data in a systematic manner. In addition, the IDMC will review safety data from the first 
10-12 patients across all indications. 
The efficacy results will be presented via descriptive statistics during systematic reviews, no 
testing is planned. 
The IDMC will be tasked with making a recommendation to the sponsor to continue, modify, 
or stop recruitment or the trial based on their assessment of efficacy and safety information. 
The membership, key responsibilities of the IDMC, and corresponding procedures will be 
defined in the IDMC charter. 
10.1.12 
Future research 
Biological samples collected during this study may be stored for future research by the sponsor. 
Storage conditions will be in compliance with the standards for repositories of biological 
samples, according to the “Recommendation CM/Rec (2016)6 of the Committee of Ministers 
to member States on research on biological materials of human origin”.58 
The repository will have independent monitoring that will guarantee protection of the data and 
the patients’ interests (also see section 10.1.4). Except for contractors of the sponsor, the 
samples will not be transferred to third parties, and they will not be sold to third parties. The 
exploratory studies that will be conducted with the samples will undergo a rigorous 
independent review evaluating both ethical and scientific aspects. 
10.2 Appendix 2: Description of the iRECIST process for assessment of 
disease progression 
iRECIST is based on RECIST 1.1 but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor 
response and progression, and to guide decisions about changes in management. 
10.2.1 
Assessment at screening and prior to RECIST 1.1 progression 
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment. 
10.2.2 
Assessment and decision at RECIST 1.1 progression 
Patients who show radiological disease progression by RECIST 1.1 will continue treatment 
until repeat scans are obtained, as described in section 8.1.1. 
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including: 
• Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir 
Note: The iRECIST publication uses the terminology “sum of measurements”, but “sum of 
diameters” will be used in this Protocol, consistent with the original RECIST 1.1 
terminology. 

 
 
 
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• Unequivocal progression of non-target lesion(s) identified at baseline 
• Development of new lesion(s) 
iRECIST defines new response categories, including unconfirmed progressive disease (iUPD) 
and confirmed progressive disease (iCPD). For purposes of iRECIST assessment, the first visit 
showing progression according to RECIST 1.1 will be assigned a visit (overall) response of 
iUPD, regardless of which factors caused the progression. 
At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be assessed 
as usual. 
New lesions will be classified as measurable or non-measurable, using the same size thresholds 
and rules as for baseline lesion assessment in RECIST 1.1. From measurable new lesions, up 
to 5 lesions total (up to 2 per organ), may be selected as new lesions – target. The sum of 
diameters of these lesions will be calculated and kept distinct from the sum of diameters for 
target lesions at baseline. All other new lesions will be followed qualitatively as new lesions – 
non-target. 
10.2.3 
Assessment at the confirmatory scans 
On the confirmatory scans, the patient will be classified as progression confirmed (with an 
overall response of iCPD), or as showing persistent unconfirmed progression (with an overall 
response of iUPD), or as showing disease stability or response (iSD/iPR/iCR according to 
iRECIST). 
10.2.4 
Confirmation of progression 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs: 
• Any of the factors that were the basis for the initial iUPD to show worsening 
o For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, 
compared to any prior iUPD time point. 
o For non-target lesions, worsening is any significant growth in lesions overall, compared 
to a prior iUPD time point; this does not have to meet the “unequivocal” standard of 
RECIST 1.1. 
o For new lesions, worsening is any of these: 
▪ 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 disease progression by RECIST 1.1 
10.2.5 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, 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 disease 
progression threshold (by RECIST 1.1). 
Additional scans for confirmation are to be scheduled 4 to 8 weeks from the scans on which 
iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation scan proceeds in an identical manner, with possible 
outcomes of iCPD, iUPD, and iSD/iPR/iCR. 
10.2.6 
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 disease 
progression threshold. 
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve. 
In this case, the initial iUPD is considered to be pseudoprogression, and the level of suspicion 
for progression is “reset”. This means that the next visit that shows radiographic progression, 
whenever it occurs, is again classified as iUPD by iRECIST, and the confirmation process is 
repeated before a response of iCPD can be assigned. 
10.2.7 
Management following the confirmatory scan 
If repeat scans do not confirm disease progression per iRECIST, as assessed by the investigator, 
and the patient continues to be clinically stable, study interventions are to continue and the 
regular scan schedule is to be followed. If disease progression is confirmed, patients may be 
discontinued from study interventions. 
Note: If a patient has iCPD and clinically meaningful, study interventions may be continued 
after consultation with the sponsor. In this case, if study interventions are continued, tumor 
imaging should continue to be performed following the intervals as outlined in section 8.1.1. 
10.2.8 
Detection of progression at visits after pseudoprogression resolves 
After resolution of pseudoprogression (i.e., after iSD/iPR/iCR), another instance of progression 
(another iUPD) is indicated by any of the following events: 
• Target lesions 
o Sum of diameters reaches the disease progression threshold (≥20% and ≥5 mm increase 
from nadir) either for the first time or after resolution of previous pseudoprogression. 
The nadir is always the smallest sum of diameters seen during the entire trial, either 
before or after an instance of pseudoprogression. 
• Non-target lesions 
o If non-target lesions have never shown unequivocal progression, their doing so for the 
first time results in iUPD. 
o If non-target lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of non-
target lesions, taken as a whole. 

 
 
 
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• New lesions 
o New lesions appear for the first time 
o Additional new lesions appear 
o 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 
o Previously identified non-target lesions show any significant growth 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see section 10.2.3) is repeated. Progression must be confirmed before iCPD 
can occur. 
The decision process on the subsequent iUPD is identical to the iUPD confirmation process for 
the initial disease progression, with one exception, which can occur if new lesions had occurred 
at a prior instance of iUPD, had not resolved, then worsened (increase in size or number) 
leading to the second iUPD. If new lesion worsening has not resolved at the confirmatory scan, 
then iUPD cannot resolve to iSD or iPR. It will remain iUPD until either a decrease in the new 
lesion burden allows resolution to iSD or iPR, or until new or worsening causes of progression 
indicates iCPD. 
Additional details about iRECIST are provided in the iRECIST publication.36 
 
 

 
 
 
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10.3 Appendix 3: Abbreviations 
Abbreviation 
Term 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALK 
Anaplastic lymphoma kinase 
ALT 
Alanine transaminase 
ASaT 
All-subjects-as-treated 
AST 
Aspartate transaminase 
BOR 
Best overall response (according to RECIST 1.1) 
CA 
Competent authority 
CBR 
Clinical benefit rate (according to RECIST 1.1) 
CD 
Cluster of differentiation 
CI 
Confidence interval 
CR 
Complete response (according to RECIST 1.1) 
CRA 
Clinical research associate 
CRO 
Contract research organization 
cSCC 
Cutaneous squamous cell carcinoma 
CT 
Computed tomography 
CTC 
Circulating tumor cell 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T lymphocyte-associated protein 4 
dMMR 
Mismatch repair deficient 
DoR 
Duration of response (according to RECIST 1.1) 
DRESS 
Drug rash with eosinophilia and systemic symptom 
EC 
Ethics committee 
ECG 
Electrocardiography 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EEA 
European Economic Area 
EGFR 
Epidermal growth factor receptor 
Fc 
Fragment crystallizable 
FDA 
US Food and Drug Administration 

 
 
 
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Abbreviation 
Term 
FoxP3 
Forkhead box P3 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B 
HCV 
Hepatitis C 
IB 
Investigator’s Brochure 
iBOR 
Best overall response (according to iRECIST) 
iCBR 
Clinical benefit rate (according to iRECIST) 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
iCPD 
Confirmed progressive disease (according to iRECIST) 
iCR 
Complete response (according to iRECIST) 
IDMC 
Independent Data Monitoring Committee 
iDoR 
Duration of response (according to iRECIST) 
IEC 
Independent ethics committee 
Ig 
Immunoglobulin 
IL 
Interleukin 
IL-2R 
IL-2 receptor 
IL-15R 
IL-15 receptor 
iORR 
Objective response rate (according to iRECIST) 
iPFS 
Progression-free survival (according to iRECIST) 
iPR 
Partial response (according to iRECIST) 
irAE 
Immune-related adverse event 
IRB 
Institutional review board 
iRECIST 
Response Evaluation Criteria In Solid Tumors for immune-based 
therapeutics 
iSD 
Stable disease (according to iRECIST) 
iTtR 
Time to response (according to iRECIST) 
iUPD 
Unconfirmed progressive disease (according to iRECIST) 
IV 
Intravenous 
JAK 
Janus kinase 
mAb 
Monoclonal antibody 
MAPK 
Mitogen-activated protein kinase 

 
 
 
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Abbreviation 
Term 
mCRPC 
Metastatic castration-resistant prostate cancer 
MRI 
Magnetic resonance imaging 
MSI(-H) 
Microsatellite instability(-high) 
MUGA 
Multigated acquisition scanning 
NK 
Natural killer 
NSAID 
Non-steroidal anti-inflammatory drug 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective response rate (according to RECIST 1.1) 
OS 
Overall survival 
PCWG3 
Prostate Cancer Clinical Trials Working Group 3 
PD 
Pharmacodynamic(s) 
PD-1 
Programmed cell death protein 1 
PD-L1 
Programmed cell death ligand 1 
PD-L2 
Programmed cell death ligand 2 
PFS 
Progression-free survival (according to RECIST 1.1) 
PI3K 
Phosphatidylinositol-4,5-bisphosphate 3-kinase 
PK 
Pharmacokinetic(s) 
PP 
Per Protocol 
PR 
Partial response (according to RECIST 1.1) 
PSA 
Prostate-specific antigen 
PT 
Preferred term 
Q1 
25th percentile 
Q2W 
Every 2 weeks 
Q3 
75th percentile 
Q3W 
Every 3 weeks 
RECIST 1.1 
Response Evaluation Criteria In Solid Tumors version 1.1 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease (according to RECIST 1.1) 
SHP-1 
Tyrosine phosphatase 
SHP-2 
Tyrosine phosphatase 
SJS 
Stevens-Johnson syndrome 

 
 
 
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Abbreviation 
Term 
SOC 
System organ class 
STAT 
Signal transducer and activator of transcription 
T1DM 
Type 1 diabetes mellitus 
T3 
Triiodothyronine 
T4 
Thyroxine 
TEAE 
Treatment-emergent adverse event 
TEN 
Toxic epidermal necrolysis 
TMB 
Tumor mutational burden 
Treg 
Regulatory T cell 
TSH 
Thyroid stimulating hormone 
TtR 
Time to response (according to RECIST 1.1) 
ULN 
Upper limit of normal 
WOCBP 
Woman of childbearing potential 
ZAP70 
Zeta-chain-associated protein kinase 
Abbreviations of commonly used weight, height, and volume measures are not listed above. 
 
10.4 Appendix 4: Protocol Amendment history 
The PROTOCOL AMENDMENT SUMMARY OF CHANGES for the current Protocol 
Amendment is located directly before the TABLE OF CONTENTS. 
 
 

 
 
 
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10.5 Appendix 5: Country-specific requirements/differences 
Country 
Section(s) in Protocol 
Amendment 1 
Country-specific 
requirements/differences 
Czech Republic (per 
country-specific 
amendment CZ-2 dated 
28Apr2022) 
1.3.1 Schedule of 
activities, nanrilkefusp 
alfa combined with 
pembrolizumab 
“In case pembrolizumab needs to be 
discontinued, nanrilkefusp alfa 
treatment can continue until disease 
progression or unacceptable toxicity 
and the schedule of activities for 
patients receiving nanrilkefusp alfa 
combined with pembrolizumab will 
apply” was replaced with “In case 
pembrolizumab needs to be 
discontinued, nanrilkefusp alfa 
treatment will be discontinued as well.” 
7.1 Discontinuation of 
study intervention 
“In case pembrolizumab needs to be 
discontinued, nanrilkefusp alfa 
treatment can continue until disease 
progression or unacceptable toxicity” 
was replaced with “In case 
pembrolizumab needs to be 
discontinued, nanrilkefusp alfa 
treatment will be discontinued as well.” 
France (per country-
specific amendment 
FR-2 dated 
23Aug2022) 
1.1 Synopsis, Study 
population; 1.2 
Schema; 4.2 Scientific 
rationale for study 
design 
“Advanced hepatocellular carcinoma 
after recurrence or failure of an immune 
checkpoint inhibitor” is not applicable 
1.1 Synopsis, 
Estimated sample size 
“Advanced hepatocellular carcinoma: 
55 patients” is not applicable 
1.1 Synopsis, 
Statistical 
considerations; 9.4 
Interim analysis 
“Indication 4 (advanced hepatocellular 
carcinoma): Benchmark ORR = 17%; 
minimal ORR = 25.3%; desired  
ORR = 33%” is not applicable 
5.1 Inclusion criteria, 
criterion 4 
“Advanced hepatocellular carcinoma” 
is not applicable 
9.5 Sample size 
determination 
“Indication 4 (advanced hepatocellular 
carcinoma): 55 patients” is not 
applicable 
 

 
 
 
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