Clinical trial NCT05619172
Conditions: Colorectal Cancer
Keywords: SOT101 SO-C101 Cetuximab Colorectal cancer AURELIO-05 Nanrilkefusp alfa
Sponsor: SOTIO Biotech AG
Start date: 2022-12-22; Completion date: 2024-06-05
Enrollment: 16 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary objective of the study is to estimate the antitumor efficacy of nanrilkefusp alfa (SOT101) in combination with cetuximab in RAS wild-type colorectal cancer.

Detailed description:

Arms: arm 1: Participants were treated with 9 µg/kg of nanrilkefusp alfa in combination with cetuximab. Nanrilkefusp alfa treatment was administered on day 1 (from cycle 2 onwards, ±1 day), day 2 (±1 day), day 8 (±1 day), and day 9 (±1 day) of each 21-day cycle. Cetuximab treatment was administered on day 1 (from cycle 2 onwards, ±1 day), day 8 (±1 day), and day 15 (±1 day) of each 21-day cycle; on day 1 and day 8, cetuximab infusion started within 30 minutes after nanrilkefusp alfa administration. arm 2: Participants were treated with 12 µg/kg of nanrilkefusp alfa in combination with cetuximab. Nanrilkefusp alfa treatment was administered on day 1 (from cycle 2 onwards, ±1 day), day 2 (±1 day), day 8 (±1 day), and day 9 (±1 day) of each 21-day cycle. Cetuximab treatment was administered on day 1 (from cycle 2 onwards, ±1 day), day 8 (±1 day), and day 15 (±1 day) of each 21-day cycle; on day 1 and day 8, cetuximab infusion started within 30 minutes after nanrilkefusp alfa administration.
Interventions: intervention 1: Nanrilkefusp alfa intervention 2: Cetuximab
Intervention descriptions: intervention 1: Subcutaneous (SC) injection intervention 2: Intravenous (IV) infusion via peripheral or central venous line

Protocol documents:
Prot_000.pdf: 
 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 1 of 83 
 
 
A phase 2, open-label, single-arm, multicenter study to evaluate the efficacy 
and safety of SOT101 in combination with cetuximab  
in patients with RAS wild-type colorectal cancer (AURELIO-05) 
 
 
 
Study interventions 
Product code: SOT101 (previously SO-C101, 
RLI-15); INN: nanrilkefusp alfa 
Cetuximab 
Regulatory agency identifier numbers 
EudraCT number: 2022-001527-32 
IND number: 140011 
Protocol number 
SC105 (AURELIO-05) 
Phase 
2 
Version 
Protocol Amendment 1 
Date 
09Mar2023 
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. 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 2 of 83 
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:         ...………………………………… 
 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 3 of 83 
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: 
 
 
 
 
Signature: …………………………………… 
 
Date:         …………………………………… 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 4 of 83 
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) 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) 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) 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) 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) 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) 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 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 5 of 83 
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. 
 
 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 6 of 83 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Change 
number 
Description of change 
Rationale for change 
Section  
in Protocol 
Amendment 1 
1 
Addition of a urine 
pregnancy test to the End 
of treatment visit and in 
the Follow-up 
Revised according to the Spanish 
Agency of Medicines and Health 
Products (AEMPS)’s (30Aug2022) and 
French Agency of Medicines and 
Health Products (ANSM)’s 
(06Dec2022) request for information 
1.3 Schedule of 
activities 
2 
Timing of body weight 
assessment used for 
calculation of dose 
clarified to be made 
within 3 days prior to day 
1 
To allow use of the most current values 
for dose calculation 
1.3 Schedule of 
activities 
3 
Addition of ECG 
assessment to day 1 of 
each cycle and End of 
treatment visit 
Revised according to ANSM’s request 
for information (06Dec2022): 
1.3 Schedule of 
activities 
4 
Allowed visit window for 
safety laboratory samples 
adjusted 
Revised to provide better guidance 
1.3 Schedule of 
activities 
5 
Collection of samples for 
ADA determination in 
the treatment phase 
limited to cycle 2, 3 and 4 
Sample frequency for determination of 
ADA at multiple intervals throughout 
the trial considered appropriate until 4 
cycles and during follow up as per FDA 
guidance on Immunogenicity Testing of 
Therapeutic Protein Products. 
1.3 Schedule of 
activities 
6 
Initial tumor scans can be 
taken with a visit window 
of 21 days before ICF 
signature 
Revised to provide better guidance 
1.3 Schedule of 
activities; 8.1.1 
Initial tumor scans 
7 
PK sampling schedule 
adjusted  
Adjusted on the basis of developed PK 
model for the optimization of sampling 
times of nanrilkefusp alfa 
1.3 Schedule of 
activities 
8 
Benefit/risk assessment 
updated 
To reflect new available data 
2.3 Benefit/Risk 
assessment 
9 
PK and immunogenicity 
of cetuximab are to be 
determined as an 
exploratory endpoint 
To allow collecting data as supportive 
only 
1.1 Synopsis; 3 
OBJECTIVES AND 
ENDPOINTS 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 7 of 83 
Change 
number 
Description of change 
Rationale for change 
Section  
in Protocol 
Amendment 1 
10 
Inclusion criterion no. 5 
was modified, and 
criterion no. 6 was added 
with specification of tests 
to be used for 
confirmation of RAS 
wild type  
Revised to provide better guidance for 
the screening process 
5.1 Inclusion criteria 
 
11 
Inclusion no. 6 on EGFR 
mutation status 
availability was removed, 
information on status 
determination added into 
another section 
To specify that EGFR status will be 
determined from biomarker samples  
5.1 Inclusion 
criteria; 8-6 
Biomarkers 
12 
Exclusion criterion no. 4 
added to specify allowed 
lines of previous therapy 
to four 
Revised to avoid bias in patient 
population 
5.2 Exclusion 
criteria 
13 
Addition of management 
recommendations for 
cytokine release 
syndrome, shortening of 
the QT interval, increased 
ALT and/or AST, and 
injection site reaction 
Revised according to ANSM’s 
(06Dec2022) and Italian Agency of 
Medicines and Health Products 
(AIFA)’s (19Dec2022) request for 
information 
 
6.5.1 Dose 
modification and 
toxicity management 
for nanrilkefusp alfa; 
6.5.3 Clinical 
management of 
cytokine release 
syndrome 
14 
Guidance added on 
additional diagnostic 
measurements for 
patients with pre-existing 
pulmonary diseases 
and/or presence or 
suspicion of ILD and for 
patients with 
ophthalmological pre-
conditions 
Revised according to response to the 
Belgian Agency of Medicines and 
Health Products (AFMP)’s approval 
letter (23Sep2022) 
6.5.4 Additional 
diagnostic 
measurements 
15 
Clarification added that 
safety assessments are to 
be done by local 
laboratories 
To provide better guidance 
8.2.5 Clinical safety 
laboratory 
assessments 
16 
Hy’s law added and 
referred to in appendix 3 
Revised according to Belgian Agency 
of Medicines and Health Products 
(AFMP)’s request for information 
(06Dec2022): 
4.1.2 DLT 
definition; 10.3 
Appendix 3: Hy’s 
law 


 
 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 8 of 83 
Change 
number 
Description of change 
Rationale for change 
Section  
in Protocol 
Amendment 1 
17 
Cockcroft-Gault formula 
added and referred to in 
appendix 4 
To provide better guidance 
5.1 Inclusion 
criteria; 10.4 
Appendix 4: 
Cockcroft-Gault 
formula 
18 
Sample size of patients 
specified to include 
patients from the safety 
cohorts and the main 
cohort 
To improve clarity 
1.2 Schema; 4.1.1 
Study design; 9.5 
Sample size 
determination 
19 
Change of “SOT101” to 
“nanrilkefusp alfa in 
Protocol body 
Replacement of the product code  
“SOT101” to the International 
Nonproprietary Name “nanrilkefusp 
alfa” in the Protocol body for better 
clarity; product code stays “SOT101” 
Throughout the 
document 
20 
Minor 
formatting/wording 
updates 
To improve clarity 
Throughout the 
document 
 
 
DOCUMENT HISTORY 
Version 
Date 
Original Protocol 
09May2022 
Protocol Amendment ES-1 
31Aug2022 
Protocol Amendment FR-1 
07Dec2022 
Protocol Amendment IT-1 
02Jan2023 
Protocol Amendment 1 
09Mar2023 
 
 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 9 of 83 
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 ........................................................................................................... 9 
1 
PROTOCOL SUMMARY ............................................................................................... 14 
1.1 
Synopsis ...................................................................................................................... 14 
1.2 
Schema ....................................................................................................................... 19 
1.3 
Schedule of activities .................................................................................................. 20 
2 
INTRODUCTION ............................................................................................................ 24 
2.1 
Study rationale ............................................................................................................ 24 
2.2 
Background ................................................................................................................ 24 
2.3 
Benefit/risk assessment .............................................................................................. 25 
3 
OBJECTIVES AND ENDPOINTS .................................................................................. 27 
4 
STUDY DESIGN ............................................................................................................. 29 
4.1 
Overall design ............................................................................................................. 29 
4.1.1 
Study design ........................................................................................................ 29 
4.1.2 
DLT definition .................................................................................................... 30 
4.1.3 
DLT evaluability ................................................................................................. 31 
4.1.4 
Study periods ...................................................................................................... 31 
4.1.4.1 
Screening....................................................................................................... 31 
4.1.4.2 
Treatment ...................................................................................................... 31 
4.1.4.3 
Follow-up ...................................................................................................... 31 
4.2 
Scientific rationale for study design ........................................................................... 31 
4.3 
Justification for dose .................................................................................................. 32 
4.3.1 
Nanrilkefusp alfa (SOT101) ............................................................................... 32 
4.3.2 
Cetuximab ........................................................................................................... 32 
4.4 
End of study definition ............................................................................................... 32 
5 
STUDY POPULATION ................................................................................................... 33 
5.1 
Inclusion criteria ......................................................................................................... 33 
5.2 
Exclusion criteria ........................................................................................................ 35 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 10 of 83 
5.3 
Lifestyle considerations .............................................................................................. 37 
5.3.1 
Meals and dietary restrictions ............................................................................. 37 
5.3.2 
Contraception ...................................................................................................... 37 
5.3.3 
Use in nursing women ........................................................................................ 37 
5.4 
Screen failures ............................................................................................................ 37 
5.5 
Criteria for temporarily delaying enrollment/ administration of study intervention .. 38 
6 
STUDY INTERVENTIONS AND CONCOMITANT THERAPY ................................ 39 
6.1 
Study interventions administered ............................................................................... 39 
6.2 
Preparation, handling, storage, accountability ........................................................... 40 
6.3 
Measures to minimize bias: randomization and blinding ........................................... 40 
6.4 
Study intervention compliance ................................................................................... 40 
6.5 
Dose modification and toxicity management ............................................................. 40 
6.5.1 
Dose modification and toxicity management for nanrilkefusp alfa .................... 40 
6.5.2 
Dose modification and toxicity management for cetuximab .............................. 41 
6.5.3 
Clinical management of cytokine release syndrome .......................................... 42 
6.5.4 
Additional diagnostic measurements .................................................................. 43 
6.6 
Continued access to study intervention after the end of the study ............................. 44 
6.7 
Treatment of overdose ................................................................................................ 44 
6.8 
Concomitant therapy .................................................................................................. 44 
6.8.1 
Rescue medication and supportive care .............................................................. 44 
6.8.2 
Prohibited medications........................................................................................ 44 
7 
DISCONTINUATION 
OF 
STUDY 
INTERVENTION 
AND 
PATIENT 
DISCONTINUATION/WITHDRAWAL................................................................................ 46 
7.1 
Discontinuation of study intervention ........................................................................ 46 
7.2 
Patient discontinuation/withdrawal from the study .................................................... 46 
7.3 
Lost to follow-up ........................................................................................................ 47 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................... 48 
8.1 
Efficacy assessments .................................................................................................. 48 
8.1.1 
Initial tumor scans ............................................................................................... 49 
8.1.2 
Tumor imaging during the study......................................................................... 49 
8.1.3 
End of treatment and follow-up tumor imaging ................................................. 49 
8.1.4 
RECIST 1.1 assessment of disease ..................................................................... 50 
8.1.5 
iRECIST assessment of disease .......................................................................... 50 
8.2 
Safety assessments ..................................................................................................... 50 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 11 of 83 
8.2.1 
Physical examinations, ECOG performance status, body height, and body weight
............................................................................................................................. 51 
8.2.2 
Vital signs ........................................................................................................... 51 
8.2.3 
Special assessments on treatment days ............................................................... 51 
8.2.3.1 
Nanrilkefusp alfa treatment days of cycles 1 to 3 ......................................... 51 
8.2.3.2 
Nanrilkefusp alfa treatment days of cycle 4 and onwards ............................ 51 
8.2.4 
Electrocardiography and left ventricular ejection fraction ................................. 51 
8.2.5 
Clinical safety laboratory assessments ................................................................ 52 
8.2.5.1 
Coagulation ................................................................................................... 52 
8.2.5.2 
Hematology ................................................................................................... 52 
8.2.5.3 
Biochemistry ................................................................................................. 52 
8.2.5.4 
Urinalysis ...................................................................................................... 52 
8.2.5.5 
Serology testing for infections ...................................................................... 52 
8.2.6 
Pregnancy testing ................................................................................................ 52 
8.3 
AEs, SAEs, and other safety reporting ....................................................................... 52 
8.3.1 
Definitions........................................................................................................... 52 
8.3.1.1 
AEs ................................................................................................................ 52 
8.3.1.2 
SAEs ............................................................................................................. 53 
8.3.1.3 
Excluded events ............................................................................................ 53 
8.3.1.4 
Severity/intensity vs. seriousness.................................................................. 53 
8.3.2 
Time period and frequency for collecting AE, SAE, and other reportable safety 
event information ................................................................................................ 54 
8.3.3 
Method of detecting AEs and SAEs ................................................................... 54 
8.3.4 
Follow-up of AEs and SAEs ............................................................................... 54 
8.3.5 
Regulatory reporting requirements for SAEs ..................................................... 54 
8.3.6 
Pregnancy ............................................................................................................ 55 
8.3.7 
Assessing AEs ..................................................................................................... 55 
8.3.7.1 
Causality ....................................................................................................... 55 
8.3.7.2 
Severity/intensity .......................................................................................... 56 
8.3.8 
Reporting by the investigational site................................................................... 56 
8.3.8.1 
AEs ................................................................................................................ 56 
8.3.8.2 
Documenting on eCRFs ................................................................................ 57 
8.3.8.3 
Immediately reportable events ...................................................................... 57 
8.3.8.4 
Report forms ................................................................................................. 58 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 12 of 83 
8.4 
PK ............................................................................................................................... 58 
8.5 
Genetics ...................................................................................................................... 59 
8.6 
Biomarkers ................................................................................................................. 59 
8.7 
Immunogenicity assessments ..................................................................................... 59 
8.8 
Health economics ....................................................................................................... 60 
8.9 
Pharmacodynamics ..................................................................................................... 60 
9 
STATISTICAL CONSIDERATIONS ............................................................................. 61 
9.1 
Statistical hypotheses ................................................................................................. 61 
9.2 
Analysis sets ............................................................................................................... 61 
9.2.1 
All-subjects-as-treated population ...................................................................... 61 
9.2.2 
PK population ..................................................................................................... 61 
9.2.3 
Efficacy population ............................................................................................. 61 
9.2.4 
Per Protocol population....................................................................................... 61 
9.3 
Statistical analyses ...................................................................................................... 61 
9.3.1 
General considerations ........................................................................................ 61 
9.3.2 
Primary endpoint analysis ................................................................................... 62 
9.3.3 
Secondary endpoints analysis ............................................................................. 62 
9.3.3.1 
Efficacy endpoints ........................................................................................ 62 
9.3.3.2 
Safety endpoints ............................................................................................ 65 
9.3.4 
Exploratory endpoint analysis ............................................................................. 65 
9.3.5 
Other analyses ..................................................................................................... 66 
9.4 
Interim analysis .......................................................................................................... 66 
9.5 
Sample size determination .......................................................................................... 66 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ... 67 
10.1 Appendix 1: Regulatory, ethical, and study oversight considerations ....................... 67 
10.1.1 Regulatory and ethical considerations ................................................................ 67 
10.1.2 Financial disclosure ............................................................................................ 67 
10.1.3 Informed consent process ................................................................................... 68 
10.1.3.1 Clinical trial participation ............................................................................. 68 
10.1.3.2 Pharmacogenomic research .......................................................................... 68 
10.1.4 Data protection .................................................................................................... 68 
10.1.5 Organizational structure of the study .................................................................. 70 
10.1.6 Dissemination of clinical study data ................................................................... 70 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 13 of 83 
10.1.7 Data quality assurance ........................................................................................ 71 
10.1.8 Trial monitoring, access to source documentation, and data retention ............... 71 
10.1.9 Study and site start and closure ........................................................................... 72 
10.1.10 Publication policy ............................................................................................... 72 
10.1.11 Internal safety committee .................................................................................... 72 
10.1.12 Independent data monitoring committee ............................................................ 72 
10.1.13 Future research .................................................................................................... 73 
10.2 Appendix 2: Description of the iRECIST process for assessment of disease progression
 .................................................................................................................................... 73 
10.2.1 Assessment at screening and prior to RECIST 1.1 progression ......................... 73 
10.2.2 Assessment and decision at RECIST 1.1 progression ........................................ 73 
10.2.3 Assessment at the confirmatory scans ................................................................ 74 
10.2.4 Confirmation of progression ............................................................................... 74 
10.2.5 Persistent iUPD ................................................................................................... 74 
10.2.6 Resolution of iUPD ............................................................................................. 74 
10.2.7 Management following the confirmatory scan ................................................... 75 
10.2.8 Detection of progression at visits after pseudoprogression resolves .................. 75 
10.3 Appendix 3: Hy’s law ................................................................................................. 77 
10.4 Appendix 4: Cockcroft-Gault formula ....................................................................... 77 
10.5 Appendix 3: Abbreviations ........................................................................................ 78 
10.6 Appendix 4: Protocol Amendment history ................................................................. 81 
11 REFERENCES ................................................................................................................. 82 
 
 
 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 14 of 83 
1 PROTOCOL SUMMARY 
1.1 Synopsis 
Study title 
A phase 2, open-label, single-arm, multicenter study to evaluate the 
efficacy and safety of SOT101 in combination with cetuximab in 
patients with RAS wild-type colorectal cancer (AURELIO-05) 
Rationale 
Cetuximab is a monoclonal IgG1 antibody which binds to the 
extracellular domain of EGFR and inhibits EGFR signaling, an 
important player in the initiation and progression of colorectal cancer. 
Cetuximab also triggers antibody-dependent cellular cytotoxicity 
(ADCC), an immune mechanism by which cells coated with IgG1 are 
destroyed by cells expressing CD16A (FcRIIIA), such as natural 
killer (NK) cells. 
Nanrilkefusp alfa is a fusion protein which consists of the N-terminal 
domain of human interleukin (IL) 15 receptor  covalently coupled 
to human IL-15. In vitro, nanrilkefusp alfa augmented the antitumor 
activity of cetuximab by increasing NK cell-mediated ADCC. In 
clinical study SC103 (AURELIO-03; NCT04234113), nanrilkefusp 
alfa stimulated immune cell infiltration into tumors in clinically 
responsive patients which was accompanied by NK- and CD8+ T-cell 
activation and cytotoxicity. 
It is hypothesized that nanrilkefusp alfa administered in combination 
with cetuximab can potentiate the tumor-directed ADCC and thus 
improve clinical outcomes in patients with EGFR positive, K-
RAS/N-RAS wild-type colorectal cancer. 
Overall design 
Study SC105 (AURELIO-05) is a phase 2, open-label, single-arm, 
multicenter study of nanrilkefusp alfa in combination with cetuximab 
with an initial safety run-in with 3+3 safety cohorts. 
Objectives and 
endpoints 
 
 
 
 
Objective 
Endpoint(s) 
Primary 
• To estimate the antitumor 
efficacy of nanrilkefusp alfa 
in combination with 
cetuximab 
• Objective response rate (ORR) 
according to Response 
Evaluation Criteria In Solid 
Tumors version 1.1 
(RECIST 1.1) 
Secondary 
• To further evaluate the 
antitumor efficacy of 
nanrilkefusp alfa in 
combination with cetuximab 
• ORR according to RECIST for 
immune-based therapeutics 
(iRECIST) (iORR) 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 15 of 83 
• Best overall response according 
to RECIST 1.1 (BOR) and 
iRECIST (iBOR) 
• Duration of response according 
to RECIST 1.1 (DoR) and 
iRECIST (iDoR) 
• Clinical benefit rate according 
to RECIST 1.1 (CBR) and 
iRECIST (iCBR) 
• Progression-free survival (PFS) 
according to RECIST 1.1 and 
iRECIST (iPFS) 
• Time to response according to 
RECIST 1.1 (TtR) and iRECIST 
(iTtR) 
• Time to progression according 
to RECIST 1.1 (TtP) and 
iRECIST (iTtP) 
• To assess the safety and 
tolerability of nanrilkefusp 
alfa in combination with 
cetuximab 
• Type, frequency, and severity of 
treatment-emergent adverse 
events according to Common 
Terminology Criteria for 
Adverse Events, version 5.0; 
safety laboratory findings; vital 
signs; electrocardiography 
findings 
• To determine the RP2D of 
nanrilkefusp alfa in 
combination with cetuximab 
• Dose-limiting toxicities 
• To characterize the 
pharmacokinetics (PK) of 
nanrilkefusp alfa in a subset 
of patients 
• Serum concentrations and 
calculated PK parameters of 
nanrilkefusp alfa 
• To determine the 
immunogenicity of 
nanrilkefusp alfa in 
combination with cetuximab 
• Incidence, titer, and time course 
of anti-drug antibodies (ADAs) 
against nanrilkefusp alfa 
Exploratory 
• To further evaluate the 
antitumor efficacy of 
• PFS on next-line anti-cancer 
treatment (PFS2) 
• Overall survival (OS) 


 
 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 16 of 83 
nanrilkefusp alfa in 
combination with cetuximab 
• To determine the status of 
immune-, molecular-, and 
disease-related biomarkers 
of potential importance 
• Assessment of Fc gamma 
receptor polymorphism or 
presence and changes in T-cell 
clonality, levels of 
inflammatory/regulatory 
cytokines or circulating tumor 
markers such as circulating 
tumor DNA at screening and 
following nanrilkefusp alfa and 
cetuximab treatment 
• To determine the impact of 
the EGFR mutational status 
on efficacy 
• Assessment of the EGFR 
mutational status at baseline and 
at disease progression 
• To characterize the PK of 
cetuximab in a subset of 
patients 
• Serum concentrations and 
calculated PK parameters of 
cetuximab 
• To determine the 
immunogenicity of 
cetuximab in combination 
with nanrilkefusp alfa 
• Incidence, titer, and time course 
of ADAs against cetuximab 
 
 
 
 
Study 
interventions 
Nanrilkefusp alfa will be administered subcutaneously on day 1 (from 
cycle 2 onwards, ±1 day), day 2 (±1 day), day 8 (±1 day), and day 9 
(±1 day) of each 21-day cycle. The dose of nanrilkefusp alfa for the 
main cohort of the study will be determined in the initial 3+3 safety 
cohorts. 
Cetuximab will be administered on day 1 (from cycle 2 onwards, 
±1 day), day 8 (±1 day), and day 15 (±1 day) of each 21-day cycle. 
The initial dose of cetuximab will be 400 mg/m2 body surface area 
administered as intravenous infusion over 120 minutes. All 
subsequent weekly doses will be 250 mg/m2 each administered as 
intravenous infusion over 60 minutes. Prior to the first infusion of 
cetuximab, patients may receive premedication with an antihistamine 
and a corticosteroid at least 1 hour prior to administration of 
cetuximab. This premedication is recommended prior to all 
subsequent infusions. On day 1 and day 8, cetuximab infusion will 
start within 30 minutes after nanrilkefusp alfa administration. 
Study population 
Patients with RAS wild-type colorectal cancer as confirmed by the 
investigational site within 3 months prior to the first administration of 
study treatment who are relapsed/refractory or intolerant to prior 
treatment with irinotecan- and oxaliplatin-containing chemotherapy 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 17 of 83 
Study duration 
The study will end one year after the last patient’s last dose of study 
treatment (nanrilkefusp alfa and/or cetuximab [whichever occurs 
later]) or 3 years after the last patient has received the first dose of 
nanrilkefusp alfa (whichever occurs earlier). 
Estimated sample 
size 
Approximately 52 patients 
Statistical 
considerations 
Interim analysis, stopping/discontinuation criteria 
An analysis for futility will be performed when the sample size is 
considered enough for such analysis. 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. 
The analysis will be based on the efficacy population. 
If 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 cetuximab treatment alone and thus the study will be 
discontinued. However, patients still on treatment can continue 
combination therapy if recommended by the IDMC. 
The criteria for conclusion of futility are defined as follows: 
• Benchmark ORR = 20%; minimal ORR = 28.8%; desired 
ORR = 36.8% 
• N = 16 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 
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, and iCBR will use the exact 
method based on the binomial distribution to derive 95% CIs. 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 DoR, iDoR, PFS, iPFS, TtR, iTtR, TtP, iTtP, PFS2, and OS. In 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 18 of 83 
case of a confirmed response or disease progression, the date of the 
first tumor assessment evaluated as response or progression will be 
used for the time-to-event variables. 
The last value of CT scan or MRI on or up to 21 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 or MRI will be 
used for the evaluation of tumor response. 
Internal safety 
committee 
Applicable only to the safety cohorts: An internal safety committee 
(ISC) will be established for the safety cohorts of this study to 
evaluate patients’ safety. The ISC will be tasked with making 
decisions based on their review to continue, modify, or stop 
recruitment or the trial based on their assessment of the safety data. 
The membership, key responsibilities, and the corresponding 
procedures will be defined in the ISC Charter. 
Independent data 
monitoring 
committee 
Applicable only to the main cohort: An independent data monitoring 
committee (IDMC) will be established for the main cohort 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. 
The IDMC will be tasked with making a recommendation to the 
sponsor based on their review to continue, modify, or stop recruitment 
or the trial based on their assessment of efficacy and safety 
information. The membership, key responsibilities, and the 
corresponding procedures will be defined in the IDMC Charter. 
 
 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 19 of 83 
1.2 Schema 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 20 of 83 
1.3 Schedule of activities 
Cycle 
Screening 
Up to 21 
days before 
day 1  
of cycle 1 
Cycle 1 
From cycle 2 onwards 
End of 
treatment* 
Within 7 (+7) days 
after the last dose 
of nanrilkefusp 
alfa and/or 
cetuximab 
(whichever occurs 
later) 
Follow
-up 
Visit 
Day 1 
 
Day 
2 
(±1 
day) 
Day 
8 
(±1 
day) 
Day 
9 
(±1 
day) 
Day 
15 
(±1 
day) 
Day 1 
(±1 day) 
Day 
2 
(±1 
day) 
Day 
8 
(±1 
day) 
Day 
9 
(±1 
day) 
Day 
15 
(±1 
day) 
Informed consent1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Cancer3 and medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
K-RAS/N-RAS 
X 
Optional at disease progression 
 
Body height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X (blood)4 
X 
(urine)5 
 
 
 
 
X (urine)5 
 
 
 
 
X (urine) 
X 
(urine)
** 
Physical examination 
X4 
 
 
 
 
 
X7 
 
 
 
 
X 
X8 
Body weight and body surface area 
X 
X9 
 
 
 
 
X9 
 
 
 
 
X 
 
Vital signs 
X 
X10 
X10 X10 X10 X11 
X10 
X10 
X10 
X10 
X11 
X 
X8 
Hematology12 
X 
X6 
X5 
X6 
X5 
X5 
X6 
 
X6 
 
X5 
X 
 
Biochemistry12 
X 
X6 
X5 
X6 
X5 
X5 
X6 
 
X6 
 
X5 
X 
 
Coagulation12 
X 
X6,13 
 
X6 
 
X5 
X6 
 
 
 
X5 
X 
 
Urinalysis 
X4 
 
 
 
 
 
X11 
 
 
 
 
X 
 
Creatinine clearance 
X 
X11 
 
 
 
 
X11 
 
 
 
 
 
 
Electrocardiography 
X 
X11 
 
 
 
 
X11 
 
 
 
 
X 
 
Echocardiography/multiple gated 
acquisition scanning 
X 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 21 of 83 
Cycle 
Screening 
Up to 21 
days before 
day 1  
of cycle 1 
Cycle 1 
From cycle 2 onwards 
End of 
treatment* 
Within 7 (+7) days 
after the last dose 
of nanrilkefusp 
alfa and/or 
cetuximab 
(whichever occurs 
later) 
Follow
-up 
Visit 
Day 1 
 
Day 
2 
(±1 
day) 
Day 
8 
(±1 
day) 
Day 
9 
(±1 
day) 
Day 
15 
(±1 
day) 
Day 1 
(±1 day) 
Day 
2 
(±1 
day) 
Day 
8 
(±1 
day) 
Day 
9 
(±1 
day) 
Day 
15 
(±1 
day) 
Eastern Cooperative Oncology Group 
performance score 
X4 
X11 
 
 
 
 
X11 
 
 
 
 
X 
X8 
Tumor assessment  
(CT/MRI) 
X14 
Every 6 weeks (±2 weeks) starting from day 1 of cycle 1 until confirmed disease progression per iRECIST, start of next-line  
anti-cancer treatment, pregnancy of the patient, withdrawal of consent by the patient, or end of the study 
Nanrilkefusp alfa administration15 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
Cetuximab administration16 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
 
Adverse events 
X 
X 
X8,17 
Concomitant medication/  
non-drug therapies 
X 
X 
X8,17 
HIV, hepatitis B and C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum for nanrilkefusp alfa 
pharmacokinetics 
See Table 1.1 
Serum for nanrilkefusp alfa anti-drug 
antibodies 
 
X11 
 
 
 
 
X11,18 
 
 
 
 
 
X8 
Serum for cetuximab pharmacokinetics 
See Table 1.1 
Serum for cetuximab anti-drug antibodies 
 
X11 
 
 
 
 
X11,18 
 
 
 
 
 
X8 
Serum for cytokines 
 
X19 
 
 
 
 
X19,20 
 
 
 
 
 
 
Whole blood for exploratory biomarkers 
 
X11,21 
 
 
 
 
X11 
 
 
 
 
 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
 
X22 
Next-line anti-cancer treatment 
 
 
 
 
 
 
 
 
 
 
 
 
X22 
Date of progression on next-line  
anti-cancer treatment 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 22 of 83 
*      Criteria for discontinuation of study interventions are listed in section 7.1. 
**    Every 30 (±2) days until 60 (±2) days after the last dose of cetuximab or 30 (±2) days after the last dose of nanrilkefusp alfa, whichever is later 
1. 
No study-specific procedures are to be performed before Informed Consent Form signature 
2. 
Age at screening and gender 
3. 
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, K-RAS/N-
RAS mutations), and the date of the latest disease progression if not coinciding with the stop date 
4. 
Within 7 days before day 1 of cycle 1 
5. 
On the day of dosing before nanrilkefusp alfa administration and/or cetuximab administration 
6. 
Sample can be taken within 24 hours before nanrilkefusp alfa and/or cetuximab administration 
7. 
Before nanrilkefusp alfa administration and afterwards as clinically required 
8. 
Follow-up visit 30 (±2) days after the last dose of nanrilkefusp alfa and/or cetuximab (whichever occurs later) 
9. 
Last body weight assessment within 3 days prior to day 1 should be used for dose calculation. 
10. Before and after nanrilkefusp alfa administration as described in section 8.2.3 
11. Before nanrilkefusp alfa and/or cetuximab administration 
12. Additional samples may be taken as clinically indicated 
13. Before nanrilkefusp alfa administration and 2 hours (±15 min) after nanrilkefusp alfa administration 
14. Tumor scans performed as part of routine clinical management are acceptable for screening if they are of acceptable diagnostic quality and performed within 21 days prior to ICF signature 
15. Time to be recorded 
16. Time to be recorded; on day 1 and day 8, cetuximab infusion will start within 30 minutes after nanrilkefusp alfa administration 
17. Contact 90 (+2) days after the last dose of nanrilkefusp alfa and/or cetuximab (whichever occurs later) 
18. To be collected up to cycle 4 
19. Before nanrilkefusp alfa administration and 6 hours (±15 min) after nanrilkefusp alfa administration 
20. Only in cycle 2 
21. Samples for Fc gamma receptor polymorphism only in cycle 1 
22. Contact 90 (+2) days after the last dose of nanrilkefusp alfa and/or cetuximab (whichever occurs later) and then at 3-month (±2 weeks) intervals until the end of the study 
 
 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 23 of 83 
Table 1.1: Pharmacokinetic sampling 
Serum samples will be collected from all patients in the initial safety cohorts and from the first 12 patients in the main cohort. All attempts should 
be made to collect the samples on time. 
Cycle, day 
Time point 
Nanrilkefusp alfa 
Cetuximab 
Cycle 1 day 1 
Pre-dose to nanrilkefusp alfa and cetuximab 
X 
X 
30 min (±5 min) 
X 
 
1 h (±5 min) 
X 
 
2 h (±15 min) 
X 
X 
4 h (±30 min) 
X 
X 
12 h (±2 h), if logistically possible 
X 
 
Cycle 1 day 2 
Pre-dose to cycle 1 day 2 nanrilkefusp alfa1 (-2 h [-15 min] to 0 h) 
X 
 
Cycle 1 day 8 
Pre-dose to cycle 1 day 8 nanrilkefusp alfa and cetuximab1 (-2 h [-15 min] to 0 h) 
X 
X 
Cycle 1 day 9 
Pre-dose to cycle 1 day 9 nanrilkefusp alfa1 (-2 h [-15 min] to 0 h) 
X 
 
 
2 h (±15 min) 
X 
 
 
4 h (±30 min) 
X 
 
Cycle 1 day 15 
Pre-dose to cycle 1 day 15 cetuximab1 (-2 h [-15 min] to 0 h) 
 
X 
Cycle 3 day 1 
Pre-dose to nanrilkefusp alfa and cetuximab1 (-2 h [-15 min] to 0 h) 
X 
X 
 
2 h (±15 min) 
X 
X 
1 Sample to be taken as early as possible when patients arrive at site 
 
 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 24 of 83 
2 INTRODUCTION 
2.1 Study rationale 
Cetuximab is a monoclonal IgG1 antibody which binds to the extracellular domain of EGFR 
and inhibits EGFR signaling, an important player in the initiation and progression of colorectal 
cancer.1,2 Cetuximab also triggers antibody-dependent cellular cytotoxicity (ADCC), an 
immune mechanism by which cells coated with IgG1 are destroyed by cells expressing CD16A 
(FcRIIIA), such as natural killer (NK) cells.3 
Nanrilkefusp alfa is a fusion protein which consists of the N-terminal domain of human 
interleukin (IL) 15 receptor  covalently coupled to human IL-15.4 In vitro, nanrilkefusp alfa 
augmented the antitumor activity of cetuximab by increasing NK cell-mediated ADCC.5 In 
clinical study SC103 (AURELIO-03; NCT04234113), nanrilkefusp alfa stimulated immune 
cell infiltration into tumors in clinically responsive patients which was accompanied by NK- 
and CD8+ T-cell activation and cytotoxicity.6 
It is hypothesized that nanrilkefusp alfa administered in combination with cetuximab can 
potentiate the tumor-directed ADCC and thus improve clinical outcomes in patients with EGFR 
positive, K-RAS/N-RAS wild-type colorectal cancer. 
2.2 Background 
Colorectal cancer is the third most commonly diagnosed cancer and a leading cause of death 
worldwide. In 2020, there were over 1.9 million new cases with an estimated 935,173 deaths.7  
EGFR signaling is one of a number of different molecular pathways involved in the 
development and progression of colorectal cancer.8 Ligand binding stimulates the tyrosine 
kinase domain of EGFR and leads to receptor dimerization and activation of several 
downstream effectors, such as K-RAS/N-RAS, that activate cell proliferation and tumor 
metastasis.1,2,9 K-RAS/N-RAS are effector molecules responsible for signal transduction from 
ligand-bound EGFR to the nucleus. Activating mutations in K-RAS/N-RAS are able to bypass 
EGFR signaling and lead to tumor progression independently of EGFR.9,10 
The choice of the optimal therapeutic strategy for each patient with metastatic colorectal cancer 
depends on a number of parameters, including clinical status, blood counts, liver and renal 
functions, measurement of tumor markers, and abdominal and thoracic CT/MRI. Patients with 
resectable disease are referred for surgery or perioperative chemotherapy to achieve complete 
resection. Patients with unresectable disease and fit for systemic treatment are treated with 
intravenous 5-fluorouracil in various combinations and schedules with irinotecan or 
oxaliplatin, oral capecitabine in combination with oxaliplatin, bevacizumab, and EGFR 
antibodies panitumumab and cetuximab.11,12 
Cetuximab, a recombinant chimeric monoclonal IgG1 antibody, binds to the extracellular 
domain of EGFR, inhibits EGFR ligand binding and dimerization, and induces EGFR 
internalization.13 Cetuximab also triggers ADCC, an immune mechanism by which cells coated 
with IgG1 are destroyed by cells expressing the activating Fc gamma receptor CD16A 
(FcRIIIA), such as NK cells.3 
Unfortunately, most patients develop resistance to cetuximab caused by increased activation of 
other receptor tyrosine kinases and downstream signaling pathways. New treatment options are 
therefore needed to prevent or overcome this resistance. 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 25 of 83 
In colorectal cancer, circulating NK cells exhibit a dysregulated phenotype compared to NK 
cells from normal human donors and demonstrate defective functionality and altered interferon 
gamma production.14 
It is hypothesized that combination treatment with a cytokine therapy that directly improves 
NK cell activity and/or functionality via increased expression of CD16 or indirectly increases 
cell fitness and activity will enhance the ADCC of cetuximab and thus may offer a new 
opportunity to better treat colorectal cancer.15 Using preclinical models, it was observed that 
IL-2 and IL-15 combined with cetuximab stimulated NK cells and improved their 
cytotoxicity.14 
Nanrilkefusp alfa is a fusion protein of the N-terminal sushi domain of human IL-15 receptor 
 covalently coupled via a linker of 20 amino acids to human IL-15.4 In vitro, nanrilkefusp alfa 
induced proliferation and expansion of both major subsets of human NK cells, CD56brightCD16- 
and CD56dimCD16+. Furthermore, nanrilkefusp alfa induced expression of the cytotoxic 
receptors NKp30 and NKG2D, whereas no upregulation of the inhibitory receptors CD158a, 
CD158b, and NKG2A was detected. Both NK cell subsets activated by nanrilkefusp alfa 
exhibited cytotoxicity towards cancer cells, and nanrilkefusp alfa augmented the antitumor 
activity of cetuximab by increasing NK cell-mediated ADCC.5 In the murine CT26 colorectal 
carcinoma model, nanrilkefusp alfa monotherapy treatment induced proliferation of NK and 
CD8+ memory T cells and significantly decreased tumor growth to about 40% on day 30.16 In 
clinical study SC103 (AURELIO-03; NCT04234113; a multicenter, open-label, phase 1/1b 
study to evaluate the safety and preliminary efficacy of nanrilkefusp alfa as monotherapy and 
in combination with pembrolizumab in patients with selected advanced/metastatic solid 
tumors), nanrilkefusp alfa stimulated immune cell infiltration into tumors in clinically 
responsive patients which was accompanied by NK and CD8+ T-cell activation and 
cytotoxicity.6 Two patients with colorectal cancer were treated in this study with nanrilkefusp 
alfa in combination with pembrolizumab; one patient at 6.0 µg/kg nanrilkefusp alfa and the 
other at 9.0 µg/kg nanrilkefusp alfa. The patient treated with 9.0 µg/kg nanrilkefusp alfa, a dose 
one dose level below the recommended phase 2 dose (RP2D), achieved confirmed stable 
disease according to iRECIST. 
Based on the above results from pre-clinical studies and preliminary results from study 
AURELIO-03, it is hypothesized that nanrilkefusp alfa administered in combination with 
cetuximab could improve NK cell activity and/or functionality via increased expression of 
CD16 or indirectly increase cell fitness and activity to enhance the ADCC of cetuximab and 
thus may offer a new opportunity to better treat K-RAS/N-RAS wild-type advanced and/or 
metastatic colorectal cancer. 
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. The majority of treatment-emergent adverse events 
(TEAEs) were of grade 1 or 2. As of 11Apr2022 (cut-off date for AURELIO-03), 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 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 26 of 83 
(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.  
The present combination nanrilkefusp alfa/cetuximab study will start with a safety cohort at 
9 µg/kg nanrilkefusp alfa, which is one dose level below the nanrilkefusp alfa RP2D of 
12 µg/kg. It is hypothesized that nanrilkefusp alfa in combination with cetuximab enhances 
tumor-directed ADCC and thus improves the clinical outcome in patients with RAS wild-type 
colorectal cancer. 
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 
the study, including patients pretreated with immune checkpoint inhibitors. Maximum 
activation of natural killer 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 cetuximab may 
be found in the Investigator’s Brochure (IB) and Erbitux’s current package insert/US 
prescribing information (for the US)17 and current summary of product characteristics (SmPC; 
for the EU).18  
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. 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 27 of 83 
3 OBJECTIVES AND ENDPOINTS 
Objective 
Endpoint(s) 
Primary 
• To estimate the antitumor 
efficacy of nanrilkefusp alfa in 
combination with cetuximab 
• Objective response rate (ORR) according to 
Response Evaluation Criteria In Solid 
Tumors version 1.1 (RECIST 1.1)19 
Secondary 
• To further evaluate the antitumor 
efficacy of nanrilkefusp alfa in 
combination with cetuximab 
• 
ORR according to RECIST for immune-
based therapeutics (iRECIST)20 (iORR) 
• 
Best overall response according to  
RECIST 1.1 (BOR) and iRECIST (iBOR) 
• 
Duration of response according to  
RECIST 1.1 (DoR) and iRECIST (iDoR) 
• 
Clinical benefit rate according to RECIST 
1.1 (CBR) and iRECIST (iCBR) 
• 
Progression-free survival (PFS) according to 
RECIST 1.1 and iRECIST (iPFS) 
• 
Time to response according to RECIST 1.1 
(TtR) and iRECIST (iTtR) 
• 
Time to progression according to RECIST 
1.1 (TtP) and iRECIST (iTtP) 
• To assess the safety and 
tolerability of nanrilkefusp alfa in 
combination with cetuximab 
• 
Type, frequency, and severity of TEAEs 
according to Common Terminology Criteria 
for Adverse Events (CTCAE), version 5.0; 
safety laboratory findings; vital signs; 
electrocardiography findings 
• To determine the RP2D of 
nanrilkefusp alfa in combination 
with cetuximab 
• Dose-limiting toxicities (DLTs) 
• To characterize the 
pharmacokinetics (PK) of 
nanrilkefusp alfa in a subset of 
patients 
• Serum concentrations and calculated PK 
parameters of nanrilkefusp alfa 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 28 of 83 
Objective 
Endpoint(s) 
• To determine the 
immunogenicity of nanrilkefusp 
alfa in combination with 
cetuximab 
• Incidence, titer, and time course of anti-drug 
antibodies (ADAs) against nanrilkefusp alfa 
Exploratory 
• To further evaluate the antitumor 
efficacy of nanrilkefusp alfa in 
combination with cetuximab 
• PFS on next-line anti-cancer treatment 
(PFS2) 
• Overall survival (OS) 
• To determine the status of 
immune-, molecular-, and 
disease-related biomarkers of 
potential importance 
• Assessment of Fc gamma receptor 
polymorphism or presence and changes in  
T-cell clonality, levels of 
inflammatory/regulatory cytokines or 
circulating tumor markers such as circulating 
tumor DNA at screening and following 
nanrilkefusp alfa and cetuximab treatment 
• To determine the impact of the 
EGFR mutational status on 
efficacy 
• Assessment of the EGFR mutational status at 
baseline and at disease progression 
• To characterize the PK of 
cetuximab in a subset of patients 
• Serum concentrations and calculated PK 
parameters of cetuximab 
• To determine the 
immunogenicity of cetuximab in 
combination with nanrilkefusp 
alfa 
• Incidence, titer, and time course of ADAs 
against cetuximab 
 
 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 29 of 83 
4 STUDY DESIGN 
4.1 Overall design 
Study SC105 (AURELIO-05) is a phase 2, open-label, single-arm, multicenter study with an 
initial safety run-in with 3+3 safety cohorts. For an overview of the study design please refer 
to section 1.2. 
4.1.1 
Study design 
First, 3 patients will be recruited sequentially so that the first administrations of nanrilkefusp 
alfa to the first and second patients will be 7 days apart and the second and third patients will 
not be dosed on the same day. These patients will be treated with cetuximab in combination 
with 9 µg/kg nanrilkefusp alfa, a dose one dose level below the RP2D as determined in study 
SC103 (AURELIO-03) which evaluated nanrilkefusp alfa at doses up to 12 µg/kg in 
combination with pembrolizumab. Please see section 6.1 for more details on administration of 
study interventions. 
After the last patient in the 9 µg/kg safety cohort completes the first treatment cycle of 21 days, 
i.e., the DLT assessment period, an internal safety committee (ISC) will review the safety data. 
If at least one patient in the initial 9 µg/kg safety cohort experiences a DLT, an additional  
3 patients will be recruited into the 9 µg/kg safety cohort. The ISC will review the safety data 
of these 3 additional patients and decide whether it is safe to increase the dose to 12 µg/kg 
nanrilkefusp alfa in combination with cetuximab in the second safety cohort or whether the 
study should proceed with 9 µg/kg nanrilkefusp alfa or with 6 µg/kg nanrilkefusp alfa. 
If there are no safety concerns in the initial 9 µg/kg safety cohort, the study will proceed to the 
second safety cohort and sequentially recruit another 3 patients who will receive 12 µg/kg 
nanrilkefusp alfa in combination with cetuximab. As in the 9 µg/kg cohort, the first 
administrations of nanrilkefusp alfa to the first and second patients will be 7 days apart and the 
second and third patients will not be dosed on the same day. Safety in the 12 µg/kg cohort will 
be evaluated by the ISC after the last patient completes the DLT assessment period (first 
treatment cycle of 21 days). 
If at least one patient in the 12 µg/kg safety cohort experiences a DLT, an additional 3 patients 
will be recruited into the 12 µg/kg safety cohort. The ISC will review the safety data of these 
3 additional patients and decide whether it is safe to proceed to the main cohort with patients 
receiving 12 µg/kg nanrilkefusp alfa in combination with cetuximab or whether the study 
should continue at a lower nanrilkefusp alfa dose. 
If there are no safety concerns in the 12 µg/kg safety cohort, the study will proceed to the main 
cohort and recruit patients who will receive 12 µg/kg nanrilkefusp alfa in combination with 
cetuximab.  
Patients in the initial 9 µg/kg safety cohort may also have a dose increase to 12 µg/kg 
nanrilkefusp alfa in the next treatment cycle at the discretion of the investigator if there are no 
safety concerns in the 12 µg/kg safety cohort. 
Patients in the safety cohorts who do not fulfill the DLT evaluability criteria (see section 4.1.3) 
for any reason other than DLT during the DLT assessment period will be replaced until at least 
3 patients per cohort have completed their DLT assessment period. 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 30 of 83 
In the main cohort of the study, patients will be treated with nanrilkefusp alfa in combination 
with cetuximab in 21-day cycles. An independent data monitoring committee (IDMC) will be 
established to review safety and efficacy data at certain time intervals, or when the interim 
analysis for futility is triggered, once the main cohort of the study starts. 
4.1.2 
DLT definition 
For the safety cohorts, DLTs will be AEs listed below, specified and graded according to 
CTCAE, version 5.0, without consideration of causality to nanrilkefusp alfa. AEs listed below 
will be considered DLTs unless clearly not related to nanrilkefusp alfa (i.e., events clearly due 
to cancer, other comorbid illness, or unequivocally related to concomitant medications).  
Every DLT in the study will be discussed with the study investigators and every effort will be 
made to ensure all clinical assessments are carried out and documented appropriately and, 
wherever possible, histological assessments are also performed to identify and understand the 
safety profile of nanrilkefusp alfa in combination with cetuximab. 
AEs that are considered DLTs 
• All grade 5 events not clearly related to disease progression or any other causes will be 
considered DLTs. 
• Any grade 3 or higher non-hematologic toxicity regardless of duration will be considered 
a DLT, with the following exceptions that are not considered DLTs: 
o Grade 3 nausea, vomiting, or diarrhea that can be controlled within 72 hours 
o Grade 3 fatigue that lasts less than 5 days 
o Grade 3 or higher correctable electrolyte abnormalities that last less than 72 hours and 
are not associated with clinical complications 
o Grade 3 or higher serum amylase or lipase not associated with clinical manifestations 
of pancreatitis 
o Grade 3 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) increase 
or grade 3 blood bilirubin increase that lasts 5 days or less 
• Hy’s law cases will be considered DLTs (see section 10.3). 
• Hematologic DLTs will include the following: 
o Grade 4 decreased neutrophil count or decreased platelet count lasting more than 7 days 
o Febrile neutropenia 
o Grade 3 or higher decreased platelet count with bleeding 
AEs that are not considered DLTs 
• Inflammatory reaction attributed to a local antitumor response (grade 3 tumor pain caused 
by acute inflammatory reaction at tumor-bearing sites, e.g., like sites of metastatic disease 
or lymph nodes) that resolves to grade 1 within 3 weeks 
• Concurrent vitiligo or alopecia of any CTCAE grade 
Other clinically significant toxicities, including a single event or multiple occurrences of the 
same event, may be considered DLTs in the safety cohorts. 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 31 of 83 
4.1.3 
DLT evaluability 
DLT evaluability is defined as follows: 
• Patient completed the first 21-day cycle (DLT assessment period of 21 days) 
• Patient received all administrations of nanrilkefusp alfa during the DLT period as per 
schedule (±1 day) 
• Patient received cetuximab as per schedule (±1 day) 
4.1.4 
Study periods 
Participation of each patient will consist of the below study periods. 
4.1.4.1 Screening 
Patients will be screened within a period of not more than 21 days, which will start when the 
Informed Consent Form (ICF) has been signed and end before day 1 of cycle 1. 
4.1.4.2 Treatment 
During the treatment period, study interventions will be administered as described in section 6 
until any of the criteria for discontinuation of study interventions is met (see section 7.1). 
After discontinuation 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 cetuximab (whichever occurs later). 
4.1.4.3 Follow-up 
All patients will come to the clinic 30 (±2) days after their last dose of nanrilkefusp alfa and/or 
cetuximab (whichever occurs later). 
Patients will be contacted 90 (+2) days after their last dose of nanrilkefusp alfa and/or 
cetuximab (whichever occurs later) and then followed up for survival at 3-month (±2 weeks) 
intervals until the end of the study defined in section 4.4. 
4.2 Scientific rationale for study design 
The AURELIO-05 study is designed as an open-label, single-arm, phase 2 proof-of-concept 
clinical trial with nanrilkefusp alfa in combination with cetuximab in patients with metastatic 
colorectal cancer. The study design represents a standard approach in early phase 2 clinical 
trials where the main aim is to investigate preliminary efficacy signals in an appropriate time 
frame to enable further clinical evaluation in a subsequent confirmatory clinical trial setting.  
The primary endpoint of this study is ORR according to RECIST 1.1. This endpoint has the 
advantage of being generally assessed earlier and with a smaller sample size compared to time-
to-event endpoints. The evaluation of ORR is generally also based on objective and quantitative 
assessments, i.e., radiological tumor assessments based on the widely accepted RECIST 1.1 
response criteria.  
In the AURELIO-05 study, the ORR of cetuximab monotherapy in patients with metastatic 
colorectal cancer with disease progression or intolerance to irinotecan-based and oxaliplatin-
based therapy was used as benchmark for the sample size calculation. The target ORR of 
approximately 37% for the nanrilkefusp alfa + cetuximab combination therapy versus 20% for 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 32 of 83 
cetuximab monotherapy21 appears to be an additional clinically relevant benefit for patients 
with metastatic colorectal cancer, as discussed and confirmed by clinical experts in the 
colorectal cancer field. 
4.3 Justification for dose 
4.3.1 
Nanrilkefusp alfa (SOT101) 
In study SC103 (AURELIO-03), 12 µg/kg of nanrilkefusp alfa was determined to be the RP2D 
for both nanrilkefusp alfa monotherapy and nanrilkefusp alfa combined with pembrolizumab. 
To ensure that it is safe to administer nanrilkefusp alfa at this RP2D together with cetuximab, 
an initial safety cohort of 3 patients will be treated with cetuximab in combination with 9 µg/kg 
nanrilkefusp alfa, a dose one dose level below the RP2D determined in study SC103 
(AURELIO-03). These 3 patients will be closely observed, and safety data collected during the 
DLT assessment period, i.e., first 21-day treatment cycle, will be evaluated by the ISC. If the 
safety of nanrilkefusp alfa at 9 µg/kg in combination with cetuximab is acceptable, another 
safety cohort of 3 patients will be treated with cetuximab in combination with 12 µg/kg 
nanrilkefusp alfa, the RP2D determined in study SC103 (AURELIO-03). Safety in the 
12 µg/kg cohort will be evaluated by the ISC after the last patient completes the DLT 
assessment period. If there are no safety concerns in the 12 µg/kg safety cohort, the study will 
proceed to the main cohort and recruit patients who will receive 12 µg/kg nanrilkefusp alfa in 
combination with cetuximab. If there are safety concerns at the 9 µg/kg and/or 12 µg/kg 
nanrilkefusp alfa safety cohorts, the ISC will decide how to proceed as described in section 
4.1.1. 
4.3.2 
Cetuximab 
Cetuximab and its required comedications will be administered as described in section 6.1. 
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 visit or contact in the study (whichever occurs later). 
The study will end one year after the last patient’s last dose of study treatment (nanrilkefusp 
alfa and/or cetuximab [whichever occurs later]) or 3 years after the last patient has received the 
first dose of nanrilkefusp alfa (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 board (IRB) 
/ independent ethics committee (IEC; in the US) or ethics committee (EC; in the EU) of the 
termination or suspension and the reason(s) for the termination or suspension. 
The investigator reserves the right to discontinue the study for his/her investigational site, 
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) and provide the sponsor and the IRB/IEC (in the US) / EC (in the EU) 
with a detailed written explanation of the termination or suspension. 
 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 33 of 83 
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. 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 
4. Life expectancy >6 months 
Disease characteristics 
5. Histologically or cytologically confirmed advanced and/or metastatic colorectal cancer  
6. RAS wild type as confirmed by: 
• locally performed US Food and Drug Administration (FDA)-approved test or an 
experienced local laboratory using validated test methods for the detection, based on 
tumor biopsy or 
• locally performed ctDNA assessment including at least mutations in exon 2 (G12D, 
G12V, G12C, G12S, G12A, G12R, G13D) and determined by a laboratory using 
validated test methods 
• samples must be taken within 3 months prior to first study administration 
7. Patients who are relapsed/refractory or intolerant to prior treatment with irinotecan- and 
oxaliplatin-containing chemotherapy 
8. Have at least one measurable lesion according to RECIST 1.1 
9. Eastern Cooperative Oncology Group (ECOG) performance score 0-2 
10. Must have recovered from all AEs due to previous therapies to grade ≤1 toxicity (excluding 
alopecia) 
Organ function 
Have adequate organ function as defined below. Specimens must be collected within 7 days 
prior to the start of study treatment. 
11. Hematology: 
11.1. Absolute neutrophil count ≥1,500/µL 
11.2. Platelets ≥100,000/µL 
11.3. Hemoglobin ≥9.0 g/dL (criteria must be met without packed red blood cell 
transfusion within the prior 2 weeks; patients can be on stable dose of erythropoietin 
[≥3 months]) 
12. Renal function: Creatinine clearance rate ≥50 mL/min as calculated using Cockcroft-Gault 
equation (see section 10.4) 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 34 of 83 
13. Hepatic function: ALT/AST ≤2.5× upper limit of normal (ULN) and total bilirubin 
≤2×ULN in patients without liver metastasis (benign hereditary hyperbilirubinemias, 
e.g., Gilbert’s syndrome, are permitted if total bilirubin <3 mg/dL). In patients with liver 
metastasis, ALT/AST ≤5×ULN is allowed but total bilirubin must be ≤2×ULN. 
14. Prothrombin time and activated partial thromboplastin time ≤1.5×ULN 
Hepatitis 
15. 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 treatments.  
16. 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). 
Special requirements for contraception 
17. A female patient is eligible to participate if she is not pregnant, not breastfeeding, and one 
of the following conditions applies: 
17.1. 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. 
17.2. A WOCBP who agrees to use a highly effective contraceptive method during the 
treatment period and for at least 60 days after the last dose of cetuximab or at least 
30 days after last dose of nanrilkefusp alfa, whichever is later. 
• WOCBP can only be included after a negative serum pregnancy test at screening 
within 7 days before day 1 of cycle 1. 
• 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 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 35 of 83 
▪ 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 60 days after the last dose 
of cetuximab or at least 30 days after 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. 
18. Male patients must agree to use a condom during the treatment period and for at least 
60 days after the last dose of cetuximab or at least 30 days after last dose of nanrilkefusp 
alfa, whichever is later. 
5.2 Exclusion criteria 
Patients will be excluded from the study if any of the following criteria apply: 
Prior/concomitant therapy 
1. Prior exposure to drugs that are agonists of IL-2 or IL-15 
2. Therapy with cetuximab within 3 months prior to ICF signature or patients who had 
progressive disease as best response to prior cetuximab-containing regimen 
3. Prior systemic anti-cancer therapies, including investigational agents before study entry 
(ICF signature): 
3.1. Less than 3 weeks or 5 half-lives (whichever shorter) for anti-cancer treatments 
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 more than 4 prior lines of systemic anticancer treatment 
5. Has received prior radiotherapy within 2 weeks of the start of study treatments. A 1-week 
radiation-free period is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-
central nervous system disease. Patients must have recovered from all radiation-related 
toxicities and not require corticosteroids. 
6. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study 
treatments 
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 3 weeks or 5 half-lives (whichever longer) before 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 36 of 83 
study entry (ICF signature). Patients who have entered the follow-up phase of an 
investigational study may participate as long as it has been 3 weeks or 
5 half-lives (whichever longer) after the last dose of the previous investigational agent. 
Medical conditions 
8. Patients with known BRAF mutations 
9. Clinically significant cardiac abnormalities including prior history of any of the following: 
9.1. Cardiomyopathy, with left ventricular ejection fraction lower than the lower limit of 
the institutional normal range at screening 
9.2. Congestive heart failure of New York Heart Association grade ≥2 
9.3. 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 treatments, and any history of coronary heart 
disease and clinically significant peripheral and/or carotid artery disease 
9.4. Prolongation of QTcF >450 msec; history or family history of congenital long QT 
syndrome 
9.5. Uncontrolled cardiac arrhythmia requiring medication 
10. 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). 
11. Has a clinical 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 treatments. 
Systemic steroid pretreatment prior to cetuximab infusion according to local guidelines is 
permitted. 
12. History of or serology positive for HIV. A locally performed HIV test is required during 
screening. 
13. 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 
(e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative 
therapy are eligible. 
14. 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 confirmed 
during screening. 
15. 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. 
16. Has an active infection requiring systemic therapy 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 37 of 83 
17. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the study, interfere with the patient’s participation for the full 
duration of the study, or is not in the best interest of the patient to participate, in the opinion 
of the treating investigator 
18. Has a known psychiatric or substance abuse disorder that would interfere with the patient’s 
ability to cooperate with the requirements of the study 
19. History of hypersensitivity to any component of cetuximab or to compounds of similar 
biological or chemical composition of nanrilkefusp alfa and/or the excipients contained in 
the study drug formulations 
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 may have adverse effects on a fetus in utero. Furthermore, it is not known if 
nanrilkefusp alfa has transient adverse effects on the composition of sperm. 
Based on findings from animal studies and its mechanism of action, cetuximab can cause fetal 
harm when administered to a pregnant woman. 
Patients should be informed that taking the study treatment may involve risks to the fetus 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 cetuximab 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). 
Patients may be rescreened once. 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 38 of 83 
5.5 Criteria for temporarily delaying enrollment/ administration of study 
intervention 
See section 6.5. 
 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 39 of 83 
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. 
Prophylactic antibiotic therapy (e.g., oral lymecycline or doxycycline) to prevent EGFR 
inhibitor-related skin toxicities are permitted according to local guidelines. 
Prior to the first infusion of cetuximab, patients may receive premedication with an 
antihistamine and a corticosteroid at least 1 hour prior to administration of cetuximab. This 
premedication is recommended prior to all subsequent infusions. 
Nanrilkefusp alfa subcutaneous injection sites will be rotated to different areas of the body 
(upper and lower extremities, each of the 4 quadrants of the abdomen) to minimize the 
summated local effects of nanrilkefusp alfa administration. 
The pharmacy manual contains specific instructions for the preparation of the nanrilkefusp alfa 
dose and cetuximab infusion and administration of nanrilkefusp alfa and cetuximab. 
Table 6.1: Study interventions 
Intervention 
name  
and type 
Dosage 
formulation 
Unit dose 
strength(s) 
Dosage 
level(s) 
Route of 
administration 
Regimen/ 
treatment period 
Sourcing 
Nanrilkefusp 
alfa 
Investigational 
intervention 
Solution for 
injection 
1.3 mg/vial See section 
4.1.1 
Subcutaneous 
Administration on 
day 1 (from cycle 
2 onwards, 
±1 day), day 2 
(±1 day), day 8 
(±1 day), and day 
9 (±1 day) of each 
21-day cycle 
Provided 
centrally  
Cetuximab 
Investigational 
intervention 
Solution for 
infusion 
5 mg/mL 
Initial dose: 
400 mg/m2 
body surface 
area as 
intravenous 
infusion over 
120 minutes 
Subsequent 
doses: 
250 mg/m2 as 
intravenous 
infusion over 
60 minutes 
Intravenous 
infusion via 
peripheral or 
central venous 
line 
Administration on 
day 1 (from cycle 
2 onwards, 
±1 day), day 8 
(±1 day), and 
day 15 (±1 day) of 
each 21-day cycle; 
on day 1 and 
day 8, cetuximab 
infusion will start 
within 30 minutes 
after nanrilkefusp 
alfa administration 
Provided 
centrally  


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 40 of 83 
6.2 Preparation, handling, storage, accountability 
The investigator or designee must confirm that 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. 
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 is a single-arm clinical trial, randomization and blinding do not apply. 
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. 
Recommendations for clinical management of cytokine release syndrome are provided in Table 
6.4. 
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 summated local effects of nanrilkefusp alfa administration. 
To minimize the risks associated with shortening of the QT interval, vital signs and 
electrocardiography (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. 
 
 
 
 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 41 of 83 
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 one 
dose level below or reduce by 
3 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 cetuximab 
Cetuximab should be reduced, delayed, or discontinued to manage adverse reactions as 
described in Table 6.3. 
Table 6.3: Recommended dose modifications of cetuximab for adverse reactions 
Adverse reaction 
Severity (CTCAE, version 5.0) Dose modification 
Infusion reactions 
Grade 1 
Reduce the infusion rate by 50%. 
Infuse under close supervision. 
Grade 2 
Reduce the infusion rate by 50%. 
Immediately administer treatment 
for symptoms. 
Grade 3 or 4 
Immediately stop infusion and 
permanently discontinue 
cetuximab. 
Dermatologic 
toxicities and 
infectious sequelae 
(e.g., acneiform rash, 
First occurrence;  
grade 3 or 4 
Delay infusion 1 to 2 weeks; if 
condition improves to grade ≤2, 
continue at 250 mg/m2. If no 
improvement, discontinue 
cetuximab permanently. 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 42 of 83 
Adverse reaction 
Severity (CTCAE, version 5.0) Dose modification 
mucocutaneous 
disease) 
Second occurrence; grade 3 or 4 
Delay infusion 1 to 2 weeks; if 
condition improves to grade ≤2, 
continue at 200 mg/m2. If no 
improvement, discontinue 
cetuximab permanently. 
Third occurrence; grade 3 or 4 
Delay infusion 1 to 2 weeks; if 
condition improves to grade ≤2, 
continue at 150 mg/m2. If no 
improvement, discontinue 
cetuximab permanently. 
Fourth occurrence; grade 3 or 4 Discontinue cetuximab 
permanently. 
Pulmonary toxicity 
Acute onset or worsening 
pulmonary symptoms 
Delay infusion 1 to 2 weeks; if 
condition improves, continue at 
the dose that was being 
administered at the time of 
occurrence. 
If no improvement in 2 weeks or 
interstitial lung disease is 
confirmed, discontinue cetuximab 
permanently. 
Ulcerative keratitis 
Confirmed diagnosis 
Interrupt or discontinue 
cetuximab permanently. 
6.5.3 
Clinical management of cytokine release syndrome 
Symptoms of cytokine release will be managed as per Table 6.4 and according to local standard 
practice and in line with published guidelines.22,23 
Recommendations for cytokine release syndrome management described in Table 6.4 can be 
modified by the individual study center as medically necessary or as appropriate without 
requiring a Protocol Amendment or being considered a Protocol deviation. 
Table 6.4: Clinical management of cytokine release syndrome24 
Grading assessment 
Treatment 
Grade 1 
• Fever, constitutional symptoms 
• Vigilant supportive care 
• Assess for infections 


 
 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 43 of 83 
Grading assessment 
Treatment 
(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 
6.5.4 
Additional diagnostic measurements 
Patients with pre-existing pulmonary diseases and patients taking concomitant chemotherapy 
known to be associated with interstitial lung disease (ILD) should be closely monitored. In the 
event of symptoms (such as dyspnoea, cough, fever) or radiographic findings suggestive of 
ILD, prompt diagnostic investigation should occur. If interstitial lung disease is diagnosed, 
cetuximab must be discontinued and the patient be treated appropriately. 
Patients presenting with signs and symptoms suggestive of keratitis such as acute or worsening: 
eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should 
be referred promptly to an ophthalmology specialist. If a diagnosis of ulcerative keratitis is 
confirmed, treatment with cetuximab should be interrupted or discontinued. If keratitis is 
diagnosed, the benefits and risks of continuing treatment should be carefully considered. 
Cetuximab should be used with caution in patients with a history of keratitis, ulcerative keratitis 
or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration. 
 


 
 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 44 of 83 
6.6 Continued access to study intervention after the end of the study 
Further supply of nanrilkefusp alfa beyond study completion will be ensured by the sponsor in 
case the investigator considers continued treatment with nanrilkefusp alfa as beneficial. 
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 cetuximab will be defined as any dose above 120% of the planned 
dose (i.e., 480 mg/m2 for the initial dose and 300 mg/m2 for subsequent doses). 
No specific information is available on the treatment of overdose of nanrilkefusp alfa and/or 
cetuximab. 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 medication will be recorded on the electronic Case Report Form (eCRF) 
including all prescription and over-the-counter products, herbal supplements, and intravenous 
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 from ICF signature to 90 days after the last dose of 
nanrilkefusp alfa and/or cetuximab (whichever occurs later) should be recorded. All 
concomitant medications administered during (S)AEs are to be recorded. SAEs are defined in 
section 8.3.1.2. 
6.8.1 
Rescue medication and supportive care 
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. 
6.8.2 
Prohibited medications 
If there is a clinical indication for any medication or vaccination specifically prohibited during 
the trial, discontinuation from study interventions 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. 
Listed below are specific restrictions for concomitant therapy or vaccination during the course 
of the study: 
• Concomitant use of drugs known to prolong the QT/QTc interval during the study should 
be avoided and only should be used if clinically indicated and in case of no other alternative. 
Some of the medications known to prolong the QT interval are:25 amiodarone, 
azithromycin, ciprofloxacin, chlorpromazine, citalopram, domperidone, donepezil, 
escitalopram, fluconazole, haloperidol, levofloxacin, levomepromazine, methadone, 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 45 of 83 
ondansetron, and sulpiride. A complete list of medications known to prolong the QT 
interval can be found at www.crediblemeds.org. 
• Administration of live or live-attenuated vaccines within 30 days prior to the first dose of 
study interventions and within 90 days after the last dose of nanrilkefusp alfa and/or 
cetuximab, whichever is later, is prohibited. Note: Killed vaccines are allowed. 
• Administration of another study intervention during treatment with nanrilkefusp alfa and 
cetuximab is prohibited. 
• Another anti-cancer therapy during treatment with nanrilkefusp alfa and cetuximab is 
prohibited. Palliative radiotherapy of, e.g., painful bone metastases not defined as indicator 
lesions is allowed. 
 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 46 of 83 
7 DISCONTINUATION OF STUDY INTERVENTION AND PATIENT 
DISCONTINUATION/WITHDRAWAL 
7.1 Discontinuation of study intervention 
Discontinuation of study treatment does not represent withdrawal from the study. 
A patient must be discontinued from study treatment for any of the following reasons: 
• Confirmed radiographic disease progression as specified in section 10.2.7. 
• Clinical disease progression (investigator’s assessment) 
• AE, namely intercurrent illness or study treatment-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 treatments 
• Pregnancy of the patient 
• Concomitant treatment with a prohibited medication 
• Initiation of new systemic anti-cancer therapy 
• Patient’s decision 
• Investigator’s decision 
After discontinuation of nanrilkefusp alfa and/or cetuximab (whichever occurs later), all 
patients will be followed up in the study as described in section 4.1.4.3. 
If nanrilkefusp alfa needs to be stopped, patients will discontinue cetuximab as well. Such 
patients will receive standard of care treatment outside the clinical trial. 
If cetuximab needs to be stopped due to an AE or the patient’s or investigator’s decision, 
nanrilkefusp alfa treatment can continue until any of the criteria for stopping or discontinuation 
of study treatment listed above is met. If cetuximab needs to be stopped for any of the reasons 
listed above except for an AE or the patient’s or investigator’s decision, nanrilkefusp alfa needs 
to be discontinued as well. 
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. 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 47 of 83 
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. 
 
 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 48 of 83 
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. 
RAS wild type at screening will be determined by using a locally performed FDA-approved 
test or an experienced local laboratory using validated test methods for the detection, based on 
tumor biopsy, or locally performed ctDNA assessment (including at least mutations in exon 2 
[G12D, G12V, G12C, G12S, G12A, G12R, G13D]), determined by a laboratory using 
validated test methods. FDA-approved tests are listed here: https://www.fda.gov/medical-
devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-
and-imaging-tools. 
Procedures conducted as part of the patient’s routine clinical management 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 
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 CT or MRI), medical 
photography, or other methods as specified in this Protocol except ultrasound which 
unacceptable for efficacy assessments. 
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 review committee. 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 and may be qualified by an independent review 
committee. 
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 


 
 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 49 of 83 
of assessing tumor scans, the term “investigator” refers to the local investigator at the site 
and/or the radiologist 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. 
Bone metastases should be assessed using an adequate method (e.g., bone scans).  
8.1.1 
Initial tumor scans 
Initial tumor scans must be performed within 21 days prior to ICF signature. The site study 
team must review screening scans to confirm the patient has measurable disease per RECIST 
1.1. 
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. 
8.1.2 
Tumor imaging 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).  
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 8.1.5. 
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 8.1.5. 
8.1.3 
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 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: 
• Confirmed disease progression per iRECIST 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 50 of 83 
• Start of next-line anti-cancer treatment 
• Pregnancy of the patient 
• Withdrawal of consent by the patient 
• End of the study 
All imaging assessments need to have confirmatory imaging using the identical method after 
at least 4 weeks. 
Patients who are clinically stable and treated past radiographic progression may continue to be 
assessed until progression is confirmed according to the rules of iRECIST, when clinically 
appropriate. 
8.1.4 
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). 
8.1.5 
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 Perform scans 4 to 8 weeks after RECIST 1.1 progression 
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 
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. 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 51 of 83 
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, and body height and body weight will be 
measured. 
8.2.2 
Vital signs 
Vital signs will include blood pressure (systolic and diastolic, after ≥5 minutes of rest), body 
temperature, and heart rate. 
8.2.3 
Special assessments on treatment days 
8.2.3.1 Nanrilkefusp alfa treatment days of cycles 1 to 3 
Patients will be observed in the hospital up to 4 hours following nanrilkefusp alfa 
administration. Vital signs (blood pressure [systolic and diastolic, after ≥5 minutes of rest], 
body temperature, and heart 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 
8.2.3.2 Nanrilkefusp alfa treatment days of cycle 4 and onwards 
Patients will be observed in the hospital up to 2 hours after nanrilkefusp alfa administration. 
Vital signs (blood pressure [systolic and diastolic, after ≥5 minutes of rest], body temperature, 
and heart 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 
Standard 12-lead ECG will be done locally. Left ventricular ejection fraction will be assessed 
using either echocardiography or nuclear medicine methodology. 


 
 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 52 of 83 
8.2.5 
Clinical safety laboratory assessments 
Clinical safety laboratory assessments are to be performed by a local laboratory. Sample 
collection, handling, storage, and shipment of samples will be performed according to local 
laboratory standards. 
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. 
8.2.5.5 Serology testing for infections 
Serology testing for infections will include testing for HIV, HBV, and HCV. 
8.2.6 
Pregnancy testing 
WOCBP will be tested for pregnancy. 
8.3 AEs, SAEs, and other safety reporting 
8.3.1 
Definitions 
8.3.1.1 AEs 
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. 
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. 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 53 of 83 
According to the US 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 SAEs 
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 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) 
8.3.1.4 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. 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 54 of 83 
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 and SAEs from the date of the patient’s signing 
the ICF until 90 days after the last dose of nanrilkefusp alfa and/or cetuximab (whichever 
occurs later). 
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 
cetuximab 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 to 60 days after the last dose of cetuximab 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 cetuximab, whichever is later. 
All SAEs 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 
nanrilkefusp alfa 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), and 
investigators. 
An investigator who receives an expedited or periodic 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 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 55 of 83 
and then file it along with the IB and will notify the IRB/IEC (in the US)/EC (in the EU), if 
appropriate according to local requirements. 
8.3.6 
Pregnancy 
Pregnancy is not considered an (S)AE unless it meets any criteria for becoming serious (see 
SAE 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 
cetuximab, the patient will be immediately discontinued from study interventions (see section 
7.1). 
Pregnancies will be monitored by the investigator to determine the outcome, including 
spontaneous abortion or voluntary termination, birth details, and the presence or absence of 
any birth defects, congenital abnormalities, or maternal or newborn complications. Every infant 
has to 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. 
8.3.7 
Assessing AEs 
Information about adverse reactions (causally related events) already known for the 
investigational medicinal products can be found in the IB and Erbitux’s current package 
insert/US prescribing information (for the US)17 and current SmPC (for the EU)18 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 
• Cetuximab 
• 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 study interventions that are known to be associated 
with the occurrence of the event 
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. 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 56 of 83 
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 National Cancer Institute’s 
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 AEs 
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). 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 57 of 83 
8.3.8.2 Documenting on eCRFs 
The reported term should be a medical diagnosis or sign/symptom of the event, not a procedure. 
Each symptom in a constellation of symptoms should be listed separately if the investigator 
has not 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 (per CTCAE, version 5.0) or a description of the AE in medical terms (not as 
reported by the patient) 
• Severity grade or intensity of the event as assessed by the investigator (1-5 per  
CTCAE, version 5.0) 
• Its causal relationship to nanrilkefusp alfa and cetuximab, 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 cetuximab due to the reported event 
• 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 
• Pregnancy of the patient or patient’s female partner 
The initial notification can be done over the 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 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 58 of 83 
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 cetuximab) or clinical trial (e.g., 
SC105 or AURELIO-05) 
4. Reason for notification/reporting (i.e., SAE or 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 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. 
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 and patients’ or partners’ pregnancies) must also be recorded in the site’s source 
documentation and on the eCRF as appropriate. 
8.4 PK 
The following serum PK parameters will be determined (nanrilkefusp alfa and cetuximab; 
cetuximab samples will be collected to be analyzed later during the course of the study if 
needed): 
• Area under the concentration-time curve (AUC; over the last measurable timepoint 
[AUClast], extrapolated to infinity [AUCinf] and over the dosing interval [AUCtau]) 
• Observed maximum concentration (Cmax) 
• Time to maximum concentration (Tmax) 
• Pre-dose concentration (Ctrough) 
• Apparent terminal elimination half-life (T1/2) 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 59 of 83 
• Apparent systemic clearance (CL) for single dose and steady state 
• Apparent volume of distribution at steady state (Vss) and during terminal phase (Vz) 
• Accumulation ratio (RAUC, RCmax) 
PK parameters will be generated by noncompartmental and/or compartmental approaches as 
appropriate. Additional PK parameters may be calculated at the discretion of the 
pharmacokineticist. 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 the 
genetic research may still participate in the study. 
Genetic research will include circulating tumor DNA analysis, assessment of Fc gamma 
receptor polymorphism, and presence and changes in T-cell clonality. 
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 
Translational research may be conducted as appropriate including but not limited to the 
assessment of Fc gamma receptor polymorphism or presence and changes in T-cell clonality, 
levels of inflammatory/regulatory cytokines or circulating tumor markers such as circulating 
tumor DNA at screening and following nanrilkefusp alfa and cetuximab treatment. 
The correlation/relationship between biomarkers and measures of clinical efficacy, safety, 
pharmacodynamic activity, and/or mechanism of action will be evaluated. 
DNA analyses are optional. Patients who do not wish to participate in this research may still 
participate in the study (also see section 8.5). 
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 analyses of biomarker 
responses to nanrilkefusp alfa in combination with cetuximab. 
EGFR mutational status and expression will be determined from the collected whole blood 
samples. 
8.7 Immunogenicity assessments 
Samples for ADAs will be collected to assess nanrilkefusp alfa immunogenicity, correlation 
with PK, and potential AEs associated with ADAs against nanrilkefusp alfa and for the 
prediction of nanrilkefusp alfa ADA production, including neutralizing ADAs. 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 60 of 83 
Samples for cetuximab 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 cetuximab. 
8.8 Health economics 
Health economics parameters will not be evaluated in this study. 
8.9 Pharmacodynamics 
Pharmacodynamic parameters will not be evaluated in this study. 
 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 61 of 83 
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 cetuximab according to RECIST 1.1 by means of ORR. Other efficacy endpoints (e.g., 
iORR, [i]BOR, [i]PFS) 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 cetuximab. 
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. 
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 cetuximab, did not violate any eligibility criteria, and did not 
have any relevant major Protocol deviations. 
9.3 Statistical analyses 
9.3.1 
General considerations 
Analyses will be descriptive (i.e., without a comparison). Safety will be analyzed as described 
in section 9.3.3.2. 
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, and iCBR will use the exact method based on the binomial 
distribution26 to derive 95% confidence intervals (CIs). Kaplan-Meier estimations and 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 62 of 83 
estimations of median (if reached) with log-log 95% CI, Q1 (25th percentile), and Q3 
(75th percentile) will be used for DoR, iDoR, PFS, iPFS, TtR, iTtR, TtP, iTtP, PFS2, and OS. 
In case of a confirmed response or disease progression, the date of the first tumor assessment 
evaluated as response or progression will be used for the time-to-event variables. 
The last value of CT scan or MRI on or up to 21 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 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 complete response according to RECIST 
1.1 (CR) or partial response according to RECIST 1.1 (PR). ORR will be analyzed and 
presented as a point estimate and a 95% CI. 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 Efficacy endpoints 
• iORR 
The iORR is defined as the proportion of patients with complete response according to 
iRECIST (iCR) or partial response according to iRECIST (iPR) and will be analyzed and 
presented as a point estimate and a 95% CI. 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. Stable disease according to RECIST 1.1 (SD) and stable disease according to 
iRECIST (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. Responders will be considered to have an ongoing response if they: i) have 
not progressed, and ii) have not started a next-line 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 in Table 
9.1. 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 63 of 83 
Table 9.1: DoR and iDoR events and censoring 
Situation 
Date of progression or censoring 
Outcome 
No progression, no death. No 
start of next-line anti-cancer 
therapy. 
Date of the last evaluable tumor 
assessment. 
Censored 
No progression, no death. Start 
of next-line anti-cancer therapy. 
Date of the last tumor assessment with 
non-progression before the start of next-
line 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. 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. 
• 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. 
Patients with missing data will be censored/considered as having an event as specified in Table 
9.2. 
Table 9.2: PFS and iPFS events and censoring 
Situation 
Date of progression or censoring 
Outcome 
Incomplete or no baseline tumor 
assessment. 
Date of first day of study treatment. 
Censored 
Start of next-line anti-cancer 
therapy. 
Date of the last tumor assessment with 
non-progression before the start of next-
line anti-cancer therapy. 
Censored 
Death before the first disease 
progression assessment. 
Date of death. 
Progressed 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 64 of 83 
Situation 
Date of progression or censoring 
Outcome 
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. Patients with missing data will be censored at the last assessment date, 
date of death, or date of eligibility (if incomplete or no baseline tumor assessments), whichever 
occurs latest. 
• TtP and iTtP 
TtP and iTtP are defined as the time from the first day of study treatment until the first date of 
radiological disease progression and will be summarized using Kaplan-Meier estimates. 
Patients with missing data will be censored/considered as having an event as specified in Table 
9.3. 
Table 9.3: TtP and iTtP events and censoring 
Situation 
Date of progression or censoring 
Outcome 
Incomplete or no baseline 
tumor assessment. 
Date of first day of study treatment. 
Censored 
Start of next-line anti-cancer 
therapy. 
Date of the last tumor assessment with non-
progression before the start of next-line 
anti-cancer therapy. 
Censored 
Death before the first disease 
progression assessment. 
Date of death. 
Censored 
Death between adequate tumor 
assessment visits. 
Date of death. 
Censored 
Death after one missed 
adequate tumor assessment. 
Date of death. 
Censored 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 65 of 83 
Situation 
Date of progression or censoring 
Outcome 
Progression after one missed 
adequate tumor assessment. 
Date of progression. 
Progressed 
Progression after more than 
one missed adequate tumor 
assessment. 
Date of the last evaluable tumor assessment. Censored 
No progression. 
Date of the last evaluable tumor assessment. Censored 
9.3.3.2 Safety endpoints 
• DLTs 
The incidence of DLTs (in DLT-evaluable patients, see section 4.1.3) by dose level will be 
summarized with counts and percentages. 
• 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 and preferred term will also be provided. 
• 
Safety laboratory findings and vital signs 
Safety laboratory findings and vital signs measurements 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 will be specified in the final statistical analysis plan 
(SAP). 
9.3.4 
Exploratory endpoint analysis 
• PFS on next-line anti-cancer treatment (PFS2) 
PFS2 is defined as the time from the first day of study treatment until the date of second 
radiological disease progression (i.e., progression on next-line anti-cancer treatment) or death 
and will be summarized using Kaplan-Meier estimates. 
Patients with missing data (i.e., without second radiological disease progression) will be 
censored at the last time known to be alive. 
• 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. Patients with missing data will be censored at 
the last time known to be alive. 


 
 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 66 of 83 
9.3.5 
Other analyses 
Other sensitivity, secondary, and exploratory analyses such as PK, immunogenicity, biomarker 
exploratory analyses, and circulating tumor DNA will be described in the final SAP. 
9.4 Interim analysis 
An analysis for futility will be performed when the sample size is considered enough for such 
analysis. Efficacy data and outputs will also be a part of the 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% CI using the exact method26 for the ORR (alpha = 0.2, alpha = 0.1 
one-sided) will be used. 
The analysis will be based on the efficacy population. 
If 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 cetuximab treatment 
alone and thus the study will be discontinued. However, patients still on treatment can continue 
combination therapy if recommended by the IDMC. 
The criteria for conclusion of futility are defined as follows: 
• Benchmark ORR = 20%21; minimal ORR = 28.8%; desired ORR = 36.8% 
• N = 16 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 
In the safety cohorts, the traditional 3+3 design dose escalation will be applied. Therefore, 3 to 
6 DLT-evaluable patients per dose level will be included in a cohort. The estimated number of 
patients is 6-12. 
The overall sample determined in this trial is 52 patients in efficacy population (see section 
9.2.3) which includes patients from the safety cohorts and the main cohort. 
The total sample size is based on a Bayesian calculation: 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, the sample size of 52 patients will ensure at 
least 80% posterior probability to achieve an effect above the minimal ORR: 
• Benchmark ORR: 20%21 
• Minimal ORR (relative increase, absolute increase): 28.8% (1.44, 8.8%) 
• Desired ORR (relative increase, absolute increase): 36.8% (1.84, 16.8%) 
 
 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 67 of 83 
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) constituted and functioning in accordance with ICH 
Guideline E6 Good Clinical Practice (GCP)27  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) 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) 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) 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) 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) to the sponsor. 
Study progress is to be reported to IRBs/IECs (in the US)/ECs (in the 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), 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) (or if regionally required, the investigator 
and the relevant IRB/IEC (in the US)/EC (in the 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) standards of practice. Upon completion of the study, the investigator or sponsor will 
provide the IRBs/IECs (in the US)/ECs (in the 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) 
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. 
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. 


 
 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 68 of 83 
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) 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 the 
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). 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) 
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 and 8.6). 
Depending on local laws and regulations, the patients might be required to provide their 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 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 69 of 83 
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 
cetuximab, 
• comparing and pooling study results, 
• establishing whether nanrilkefusp alfa in combination with cetuximab meets the 
appropriate standards of safety set by the authorities, 
• establishing whether nanrilkefusp alfa in combination with cetuximab is effective, 
• supporting the clinical development of nanrilkefusp alfa in combination with cetuximab, 
• supporting the licensing application for regulatory approval of nanrilkefusp alfa in 
combination with cetuximab anywhere in the world, 
• supporting the marketing, distribution, sale, and use of nanrilkefusp alfa in combination 
with cetuximab 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 cetuximab. 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. 
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 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 70 of 83 
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 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. 
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, 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. 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 71 of 83 
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. 
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) 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. 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 72 of 83 
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. 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. 
10.1.11 
Internal safety committee 
Applicable only to the safety cohorts: An internal safety committee (ISC) will be established 
for the safety cohorts of this study to evaluate patients’ safety. The ISC will be tasked with 
making decisions based on their review to continue, modify, or stop recruitment or the trial 
based on their assessment of the safety data. The membership, key responsibilities, and the 
corresponding procedures will be defined in the ISC Charter. 
10.1.12 
Independent data monitoring committee 
Applicable only to the main cohort: An independent data monitoring committee (IDMC) will 
be established for the main cohort 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. 
The IDMC will be tasked with making a recommendation to the sponsor based on their review 
to continue, modify, or stop recruitment or the trial based on their assessment of efficacy and 
safety information. The membership, key responsibilities, and the corresponding procedures 
will be defined in the IDMC Charter. 


 
 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 73 of 83 
10.1.13 
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.”28  
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 8.1.2. 
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. 
• 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 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 74 of 83 
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 
• 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. 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 75 of 83 
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. 
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. 
• 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) 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 76 of 83 
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.20 
 
 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 77 of 83 
10.3 Appendix 3: Hy’s law 
Drugs are likely to cause a high rate (10-50%) of fatal liver injury or need for transplant in 
patients with acute hepatocellular injury sufficient to cause jaundice. Hy’s law is a rule of 
thumb that a patient is at high risk of a fatal drug-induced liver injury if given a medication that 
causes hepatocellular injury (not cholestatic injury) with jaundice. 
Hy’s law cases have three components: 
• The drug causes hepatocellular injury, generally defined as an elevated ALT or AST by  
3-fold or greater above the ULN. Often with aminotransferases much greater (5-10×ULN). 
• Among patients showing such aminotransferase elevations, they also have elevation of their 
serum total bilirubin of greater than 2×ULN, without findings of cholestasis (defined as 
serum alkaline phosphatase (ALP) activity less than 2×ULN). 
No other reason can be found to explain the combination of increased aminotransferase and 
serum total bilirubin, such as viral hepatitis, alcohol abuse, ischemia, preexisting liver disease, 
or another drug capable of causing the observed injury.29 
10.4 Appendix 4: Cockcroft-Gault formula 
For males, creatinine clearance is estimated using the Cockcroft-Gault formula as follows: 
Creatinine clearance = [(140 − age) × weight]/(72 × serum creatinine) 
Where age is in years, weight is in kilograms, and serum creatinine is in mg/dL. Actual, not 
ideal weight is to be used. 
For females, creatinine clearance is estimated by multiplying the result of the above formula 
by 0.85. 
 
 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 78 of 83 
10.5 Appendix 3: Abbreviations 
Abbreviation 
Term 
ADA 
Anti-drug antibody 
ADCC 
Antibody-dependent cellular cytotoxicity 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ASaT 
All-subjects-as-treated 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
BOR 
Best overall response (according to RECIST 1.1) 
BRAF 
V-raf murine sarcoma viral oncogene homolog B1 
CA 
Competent authority 
CBR 
Clinical benefit rate (according to RECIST 1.1) 
CD 
Cluster of differentiation 
CFR 
Code of federal regulations 
CI 
Confidence interval 
CL 
Apparent systemic clearance 
Cmax 
Observed maximum serum concentration 
CR 
Complete response (according to RECIST 1.1) 
CRA 
Clinical research associate 
CRO 
Contract research organization 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor DNA 
Ctrough 
Pre-dose concentration 
DLT 
Dose-limiting toxicity 
DoR 
Duration of response (according to RECIST 1.1) 
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 
GCP 
Good Clinical Practice 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 79 of 83 
Abbreviation 
Term 
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 
ILD 
Interstitial lung disease 
iORR 
Objective response rate (according to iRECIST) 
iPFS 
Progression-free survival (according to iRECIST) 
iPR 
Partial response (according to iRECIST) 
IRB 
Institutional review board 
iRECIST 
Response Evaluation Criteria In Solid Tumors for immune-
based therapeutics 
ISC 
Internal safety committee 
iSD 
Stable disease (according to iRECIST) 
iTtP 
Time to progression (according to iRECIST) 
iTtR 
Time to response (according to iRECIST) 
iUPD 
Unconfirmed progressive disease (according to iRECIST) 
K-RAS 
Kirsten rat sarcoma viral oncogene homolog 
MRI 
Magnetic resonance imaging 
NK 
Natural killer 
NKG2A 
Inhibitory natural killer cell receptor 
NKG2D 
Activating natural killer cell receptor 
NKp30 
Natural killer protein 30; activating natural killer cell receptor 
N-RAS 
Neuroblastoma rat sarcoma viral oncogene homolog 
ORR 
Objective response rate (according to RECIST 1.1) 
OS 
Overall survival 
PFS 
Progression-free survival (according to RECIST 1.1) 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 80 of 83 
Abbreviation 
Term 
PFS2 
Progression-free survival on next-line anti-cancer treatment 
PK 
Pharmacokinetic(s) 
PP 
Per Protocol 
PR 
Partial response (according to RECIST 1.1) 
Q1 
25th percentile 
Q3 
75th percentile 
RAUC 
Accumulation ratio 
RAS 
Rat sarcoma viral oncogene homolog 
RCmax 
Accumulation ratio 
RECIST 1.1 
Response Evaluation Criteria In Solid Tumors version 1.1 
RP2D 
Recommended phase 2 dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease (according to RECIST 1.1) 
SmPC 
Summary of Product Characteristics 
T1/2 
Apparent terminal elimination half-life 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to maximum serum concentration 
TtP 
Time to progression (according to RECIST 1.1) 
TtR 
Time to response (according to RECIST 1.1) 
ULN 
Upper limit of normal 
Vss 
Apparent volume of distribution at steady state 
Vz 
Apparent volume of distribution during terminal phase 
WOCBP 
Woman of childbearing potential 
Abbreviations of commonly used weight, height, and volume measures are not listed 
above. 
 
 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 81 of 83 
10.6 Appendix 4: Protocol Amendment history 
The PROTOCOL AMENDMENT SUMMARY OF CHANGES for the current amendment is 
located directly before the TABLE OF CONTENTS. 
 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 82 of 83 
11 REFERENCES 
1. Ritter CA, Arteaga CL. The epidermal growth factor receptor-tyrosine kinase: a promising 
therapeutic target in solid tumors. Seminars in oncology. 2003;30(1 Suppl 1):3-11. 
2. Heinemann V, Stintzing S, Kirchner T, Boeck S, Jung A. Clinical relevance of EGFR- and 
KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed 
against the EGFR. Cancer Treat Rev. 2009;35(3):262-271. 
3. Ferris RL, Lenz HJ, Trotta AM, et al. Rationale for combination of therapeutic antibodies 
targeting tumor cells and immune checkpoint receptors: Harnessing innate and adaptive 
immunity through IgG1 isotype immune effector stimulation. Cancer Treat Rev. 
2018;63:48-60. 
4. Bessard A, Solé V, Bouchaud G, Quéméner A, Jacques Y. High antitumor activity of RLI, 
an interleukin-15 (IL-15)-IL-15 receptor alpha fusion protein, in metastatic melanoma and 
colorectal cancer. Mol Cancer Ther. 2009;8(9):2736-2745. 
5. Antosova Z, Podzimkova N, Jiratova M, et al. 562 SO-C101 induces NK cell cytotoxicity 
and potentiates antibody-dependent cell cytotoxicity and anti-tumor activity. J 
Immunother Cancer. 2020;8(Suppl 3):A339-A339. 
6. Palová L. 510 SO-C101, a high-affinity IL-15Rbg agonist, induces safe and potent anti-
tumor immune activities in patients with solid tumors and supports further clinical 
investigations. 2021;9(Suppl 2):A541-A541. 
7. Ferlay J, Ervik M, Colombet M, et al. Global Cancer Observatory: Cancer Today. 
https://gco.iarc.fr/today/home. Published 2020. Accessed February 28, 2022. 
8. Li J, Ma X, Chakravarti D, Shalapour S, DePinho RA. Genetic and biological hallmarks 
of colorectal cancer. Genes Dev. 2021;35(11-12):787-820. 
9. Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, McKinnon RA, Karapetis CS. 
Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in 
metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol. 
2015;26(1):13-21. 
10. Misale S, Yaeger R, Hobor S, et al. Emergence of KRAS mutations and acquired resistance 
to anti-EGFR therapy in colorectal cancer. Nature. 2012;486(7404):532-536. 
11. Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the 
management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27(8):1386-
1422. 
12. Benson AB, Venook AP, Al-Hawary MM, et al. Colon Cancer, Version 2.2021, NCCN 
Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer 
Network : JNCCN. 2021;19(3):329-359. 
13. Harding J, Burtness B. Cetuximab: an epidermal growth factor receptor chemeric human-
murine monoclonal antibody. Drugs of today (Barcelona, Spain : 1998). 2005;41(2):107-
127. 
14. Rocca YS, Roberti MP, Juliá EP, et al. Phenotypic and Functional Dysregulated Blood NK 
Cells in Colorectal Cancer Patients Can Be Activated by Cetuximab Plus IL-2 or IL-15. 
Front Immunol. 2016;7:413. 


 
 
 
SC105 Protocol Amendment 1, Final, 09Mar2023 
Page 83 of 83 
15. Ochoa MC, Minute L, López A, et al. Enhancement of antibody-dependent cellular 
cytotoxicity of cetuximab by a chimeric protein encompassing interleukin-15. 
Oncoimmunology. 2018;7(2):e1393597. 
16. SOTIO data on file. 
17. Erbitux 
USPI. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125084s279lbl.pdf. 
Accessed February 28, 2023. 
18. Erbitux SmPC. https://www.ema.europa.eu/en/documents/product-information/erbitux-
epar-product-information_en.pdf. Accessed February 28, 2023. 
19. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). European journal of cancer (Oxford, 
England : 1990). 2009;45(2):228-247. 
20. Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response criteria for use 
in trials testing immunotherapeutics. Lancet Oncol. 2017;18(3):e143-e152. 
21. Price TJ, Peeters M, Kim TW, et al. Panitumumab versus cetuximab in patients with 
chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer 
(ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet 
Oncol. 2014;15(6):569-579. 
22. Lee DW, Santomasso BD, Locke FL, et al. ASTCT Consensus Grading for Cytokine 
Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. 
Biology of Blood and Marrow Transplantation. 2019;25(4):625-638. 
23. Maus MV, Alexander S, Bishop MR, et al. Society for Immunotherapy of Cancer (SITC) 
clinical practice guideline on immune effector cell-related adverse events. J Immunother 
Cancer. 2020;8(2). 
24. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management 
of cytokine release syndrome. Blood. 2014;124(2):188-195. 
25. Meid AD, Bighelli I, Mächler S, et al. Combinations of QTc-prolonging drugs: towards 
disentangling pharmacokinetic and pharmacodynamic effects in their potentially additive 
nature. Ther Adv Psychopharmacol. 2017;7(12):251-264. 
26. Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometrika. 1934;26(4):404-413. 
27. International Council for Harmonisation. E6 Good Clinical Practice Guideline. 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E
6_R2__Step_4_2016_1109.pdf. Published 2016. Accessed February 28, 2023. 
28. Council of Europe Committee of Ministers. Recommendation CM/Rec (2016)6 of the 
committee of ministers to member states on research on biological materials of human 
origin. https://search.coe.int/cm/Pages/result_details.aspx?ObjectId=090000168064e8ff. 
Published 2016. Accessed February 28, 2023. 
29. U.S. Food and Drug Administration. Guidance for Industry Drug-Induced Liver Injury: 
Premarketing 
Clinical 
Evaluation. 
https://www.fda.gov/media/116737/download. 
Published 2009. Accessed February 28, 2023. 
 

SAP_001.pdf: 
Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 1 of 60 
 
 
ST-AD-008 version 06 
 
 
 
Statistical Analysis Plan  
 
 A phase 2, open-label, single-arm, multicenter study to evaluate the efficacy 
and safety of SOT101 in combination with cetuximab in patients with RAS 
wild-type colorectal cancer (AURELIO-05)  
Statistical Analysis Plan Status: Final 
Statistical Analysis Plan Version: 2.0 
Statistical Analysis Plan Date: 17MAY2023 
Study interventions:  
Product code: SOT101 (previously SO-C101, RLI-15); INN: nanrilkefusp alfa  
Cetuximab 
Protocol Reference: SC105 (AURELIO-05) 
Fortrea Study ID: 000000235712   
Sponsor: SOTIO Biotech AG 
 
Author: 
rincipal Biostatistician 
 
 
 
 
Information described herein is confidential and may be disclosed only with the express written 
permission of the sponsor. 


Statistical Analysis Plan                                                                               
Fortrea Study: 000000235712                                                        Protocol e erence: 
 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 2 of 60 
 
 
ST-AD-008 version 06 
 
 
Table of Contents 
Glossary of Abbreviations ....................................................................................................... 8 
1. Source Documents ............................................................................................................. 10 
2. Protocol Details .................................................................................................................. 11 
2.1. Overall Study Design .................................................................................................. 11 
2.1.1. Study Intervention during Treatment Period ....................................................... 12 
2.1.2. Follow-up .............................................................................................................. 13 
2.2. Study Objectives ......................................................................................................... 13 
2.2.1. Primary Objective ................................................................................................. 13 
2.2.2. Secondary Objectives ........................................................................................... 14 
2.2.3. Exploratory Objectives ......................................................................................... 14 
2.3. Sample Size and Power ............................................................................................... 14 
2.4. Primary Efficacy Variable ........................................................................................... 15 
2.5. Secondary Efficacy Variables ..................................................................................... 15 
2.6. Exploratory Efficacy Variables ................................................................................... 15 
2.7. Safety Variables .......................................................................................................... 15 
2.8. PK and Immunogenicity Variables ............................................................................. 16 
3. Analysis Populations .......................................................................................................... 17 
3.1. Screened Population .................................................................................................... 17 
3.2. Enrolled Population ..................................................................................................... 17 
3.3. All-Subjects-as-Treated Population ............................................................................ 17 
3.4. Efficacy Population ..................................................................................................... 17 
3.5. Per Protocol Population ............................................................................................... 17 
3.5.1. Important Protocol Deviations Leading to Exclusion from the PP Population..... 18 
3.6. PK Population ............................................................................................................. 18 
3.7. Special Subpopulations ............................................................................................... 18 
4. Data Handling .................................................................................................................... 19 
4.1. Time Points and Visit Windows.................................................................................. 19 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 3 of 60 
 
 
ST-AD-008 version 06 
 
4.1.1. General Definitions ............................................................................................... 19 
4.1.2. Screening Period ................................................................................................... 20 
4.1.3. Treatment Period ................................................................................................. 20 
4.1.4. Visit Windows ....................................................................................................... 20 
4.2. Handling of Dropouts, Missing Data, and Outliers ..................................................... 21 
4.2.1. Handling of Missing Efficacy Data ........................................................................ 21 
4.2.2. Handling of Missing Safety Data ........................................................................... 21 
4.2.3. Handling of Partial and Missing Dates for Adverse Events, Prior / Concomitant 
Medications/Procedures ................................................................................................ 21 
4.2.4. Handling of Partial and Missing Dates for New Anti-Cancer Therapy.................. 22 
4.2.5. Handling of Partial and Missing Death Date......................................................... 23 
4.2.6. Handling of Partial and Missing Diagnosis Date ................................................... 23 
4.2.7. Handling of Partial and Missing Laboratory Data ................................................. 23 
4.2.8. Handling of Serum PK Concentrations for Study Treatment that are Below the 
Lower Limit of Quantification ......................................................................................... 23 
5. Statistical Methods ............................................................................................................. 25 
5.1. General Principles ....................................................................................................... 25 
5.2. Patient Disposition and Data Sets Analyzed ............................................................... 26 
5.3. Protocol Deviations ..................................................................................................... 27 
5.4. Demographic and Other Baseline Characteristics ....................................................... 27 
5.4.1. Demographic Characteristics ................................................................................ 27 
5.4.2. Baseline Characteristics ........................................................................................ 28 
5.4.3. Cancer History ...................................................................................................... 28 
5.4.4. Medical History ..................................................................................................... 29 
5.4.5. Prior and Concomitant Medications .................................................................... 29 
5.4.6. Prior and Concomitant Procedures ...................................................................... 30 
5.4.7. Prior Radiation Therapy ........................................................................................ 31 
5.4.8. Prior Anti-Cancer Surgery ..................................................................................... 31 


Statistical Analysis Plan                                                                              
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 4 of 60 
 
 
ST-AD-008 version 06 
 
5.4.9. Prior Systemic Anti-Cancer Therapy ..................................................................... 31 
5.4.10. Subsequent Radiation Therapy .......................................................................... 31 
5.4.11. Subsequent Anti-Cancer Surgery ........................................................................ 31 
5.4.12. Subsequent Systemic Anti-Cancer Therapy ....................................................... 32 
5.5. Efficacy ....................................................................................................................... 32 
5.5.1. Primary Efficacy Analysis ...................................................................................... 32 
5.5.2. Sensitivity for the Primary Analyses ..................................................................... 33 
5.5.3. Secondary Efficacy Analysis .................................................................................. 33 
5.5.4. Sensitivity Analyses for the Secondary Efficacy Analysis ..................................... 41 
5.5.5. Subgroup Analysis ................................................................................................. 41 
5.5.6. Exploratory Analysis.............................................................................................. 41 
5.6. Safety ........................................................................................................................... 43 
5.6.1. Extent of Exposure and Compliance ..................................................................... 43 
5.6.2. Dose Limiting Toxicities ........................................................................................ 45 
5.6.3. Adverse Events ..................................................................................................... 46 
5.6.4. Laboratory Evaluations ......................................................................................... 50 
5.6.5. Hy’s Law for Liver Function Tests ......................................................................... 51 
5.6.6. Vital Signs .............................................................................................................. 51 
5.6.7. Body Surface Area................................................................................................. 52 
5.6.8. Electrocardiograms ............................................................................................... 52 
5.6.9. Left Ventricular Ejection Fraction (LVEF) ............................................................. 53 
5.6.10. Physical Examination .......................................................................................... 53 
5.6.11. Other Safety Variables ........................................................................................ 53 
5.6.12. Interim Analysis and Data Monitoring ............................................................... 53 
5.7. Pharmacokinetic Analysis ........................................................................................... 54 
5.7.1. Criteria for Calculation and Reporting of Area Under the Concentration-time 
Curve 55 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 5 of 60 
 
 
ST-AD-008 version 06 
 
5.7.2. Criteria for Handling Concentrations Below the Limit of Quantification or Missing 
Concentrations for Pharmacokinetic Analysis ................................................................ 56 
5.7.3. Treatment of Outliers in Pharmacokinetic Analysis ............................................. 56 
5.7.4. Presentation of Pharmacokinetic Data................................................................. 56 
5.8. Immunogenicity Assessments ..................................................................................... 57 
5.8.1. Anti-Drug Antibodies (ADAs) against nanrilkefusp alfa ........................................ 57 
5.8.2. ADAs against cetuximab ....................................................................................... 57 
5.9. Biomarkers .................................................................................................................. 57 
6. Changes in the Conduct of the Study or Planned Analysis ............................................... 58 
6.1. SD and iSD derivation................................................................................................. 58 
6.2. Duration of Follow-Up ................................................................................................ 58 
6.3. PK parameters ............................................................................................................. 58 
7. Appendices ......................................................................................................................... 59 
8. References .......................................................................................................................... 60 
 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 6 of 60 
 
 
ST-AD-008 version 06 
 
List of Tables 
 
Table 1 Study interventions ................................................................................................... 12 
Table 2 Derivation of RECIST 1.1 Disease Response from iRECIST 1.1 ............................ 32 
Table 3 Confirmation CR and PR .......................................................................................... 36 
Table 4 DoR and iDoR events and censoring ........................................................................ 37 
Table 5 PFS and iPFS events and censoring .......................................................................... 38 
Table 6 TtP and iTtP events and censoring ........................................................................... 40 
Table 7 Laboratory Tests to Be Included in Summaries........................................................ 50 
 
 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 7 of 60 
 
 
ST-AD-008 version 06 
 
Reviewers 
The following reviews of the Statistical Analysis Plan (SAP) were conducted: 
 
Name and Title  
 Role 
Version Last 
Reviewed 
Company / 
Organization 
Peer Review Statistician 
2.0 
Lead Programmer 
2.0 
Lead Project Physician 
2.0 
Lead Pharmacokineticist 2.0 
Project Statistician 
2.0 
 
 
Senior Medical Director 
2.0 
SOTIO Biotech AG 


Statistical Analysis Plan                                                                               
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 8 of 60 
 
 
ST-AD-008 version 06 
 
 
 
Glossary of Abbreviations 
 
Abbreviation 
Term 
ADA 
Anti-Drug Antibodies 
AE 
Adverse Event 
ALT 
Aspartate Aminotransferase 
ASaT 
All-Subjects-as-Treated 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Concentration-Time Curve 
AUClast 
Area Under the Concentration-Time Curve Over the Last Measurable 
Timepoint 
AUC(0-24h) 
Area Under the Concentration-Time Curve Over Time 0 to 24 hours postdose 
BLQ 
Below the Lower Limit of Quantification 
BMI 
Body Mass Index 
BOR 
Best Overall Response (according to RECIST) 
BRAF 
V-raf Murine Sarcoma Viral Oncogene Homolog B1 
BSA 
Body Surface Area 
C2h 
Observed Concentration at 2 hours postdose 
CBR 
Clinical Benefit Rate (according to RECIST) 
CI 
Confidence Interval 
Cmax 
Observed Maximum Concentration 
CR 
Complete Response 
CRF 
Case Report Form 
COVID-19 
Coronavirus Disease of 2019 
CT 
Computed Tomography 
Ctrough 
Observed Trough Concentration 
CV 
Coefficient of Variation 
DBP 
Diastolic BP 
DLT 
Dose-limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DOR 
Duration of Response (according to RECIST) 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EGFR 
Epidermal Growth Factor Receptor 
Fc 
Fragment Crystallizable 
HR 
Heart Rate 
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 
iCR 
Complete Response (according to iRECIST) 
IDMC 
Independent Data Monitoring Committee 
iDOR 
Duration of Response (according to iRECIST) 
iORR 
Objective Response Rate (according to iRECIST) 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 9 of 60 
 
 
ST-AD-008 version 06 
 
Abbreviation 
Term 
iPFS 
Progression-free Survival (according to iRECIST) 
iPR 
Partial Response (according to iRECIST) 
iRECIST 
Immune-based Therapeutics Response Evaluation Criteria in Solid Tumors 
iSD 
Stable Disease (according to iRECIST) 
iTtP 
Time to Progression (according to iRECIST) 
iTtR 
Time to Response (according to iRECIST) 
iUPD 
Unconfirmed Progressive Disease 
ISC 
Internal Safety Committee 
K-RAS 
Kirsten Rat Sarcoma Viral Oncogene Homolog 
LLN 
Lower Limit of Normal Reference Range 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
NC 
Not Calculated 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for AEs 
NE 
Not Evaluable 
N-RAS 
Neuroblastoma Rat Sarcoma Viral Oncogene Homolog 
ORR 
Objective response rate (according to RECIST) 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression-free Survival (according to RECIST) 
PFS2 
PFS on Next-line Anti-cancer Treatment 
PK 
Pharmacokinetic 
PP 
Per Protocol  
PR 
Partial Response 
PT 
Preferred Term 
QTcB 
Bazett Corrected QT Interval 
QTcF 
Fridericia Corrected QT Interval 
RC2h, RCtrough 
Accumulation Ratio of C2h or Ctrough on Cycle 3 Day 1/Cycle 1 Day 1 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious AE 
SAP 
Statistical Analysis Plan 
SBP 
Systolic BP 
SD 
Standard Deviation 
SD 
Stable Disease 
SI 
International System of Units 
SOC 
System Organ Class 
TFLs 
Tables, Figures and Listings 
Tlast 
Time of the Last Measurable Concentration 
Tmax 
Time to Maximum Concentration 
TEAE 
Treatment Emergent Adverse Event 
TESAE 
Treatment Emergent SAE 
TtP 
Time to Progression (according to RECIST) 
TtR 
Time to Response (according to RECIST) 
ULN 
Upper Limit of Normal Reference Range 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 10 of 60 
 
 
ST-AD-008 version 06 
 
1. Source Documents 
The Statistical Analysis Plan (SAP) was written based on the following documentation: 
Document 
Date 
Version 
Protocol 
09Mar2023 
Protocol Amendment 1 
eCRF 
03May2023 
3.0 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 11 of 60 
 
 
ST-AD-008 version 06 
 
2. Protocol Details 
2.1. Overall Study Design 
Study SC105 (AURELIO-05) is a phase 2, open-label, single-arm, multicenter study with an 
initial safety run-in with 3+3 safety cohorts.  
First, 3 patients will be recruited sequentially so that the first administrations of nanrilkefusp 
alfa to the first and second patients will be 7 days apart and the second and third patients will 
not be dosed on the same day. These patients will be treated with cetuximab in combination 
with 9 μg/kg nanrilkefusp alfa, a dose one dose level below the Recommended Phase 2 Dose 
(RP2D) as determined in study SC103 (AURELIO-03) which evaluated nanrilkefusp alfa at 
doses up to 12 μg/kg in combination with pembrolizumab.  
After the last patient in the 9 μg/kg safety cohort completes the first treatment cycle of 
21 days, i.e., the Dose-Limiting Toxicity (DLT) assessment period, an Internal Safety 
Committee (ISC) will review the safety data.  If at least one patient in the initial 9 μg/kg safety 
cohort experiences a DLT, an additional 3 patients will be recruited into the 9 μg/kg safety 
cohort. The ISC will review the safety data of these 3 additional patients and decide whether 
it is safe to increase the dose to 12 μg/kg nanrilkefusp alfa in combination with cetuximab in 
the second safety cohort or whether the study should proceed with 9 μg/kg nanrilkefusp alfa 
or with 6 μg/kg nanrilkefusp alfa.  
If there are no safety concerns in the initial 9 μg/kg safety cohort, the study will proceed to 
the second safety cohort and sequentially recruit another 3 patients who will receive 12 μg/kg 
nanrilkefusp alfa in combination with cetuximab. As in the 9 μg/kg cohort, the first 
administrations of nanrilkefusp alfa to the first and second patients will be 7 days apart and 
the second and third patients will not be dosed on the same day. Safety in the 12 μg/kg cohort 
will be evaluated by the ISC after the last patient completes the DLT assessment period (first 
treatment cycle of 21 days).  
If at least one patient in the 12 μg/kg safety cohort experiences a DLT, an additional 3 patients 
will be recruited into the 12 μg/kg safety cohort. The ISC will review the safety data of these 
3 additional patients and decide whether it is safe to proceed to the main cohort with patients 
receiving 12 μg/kg nanrilkefusp alfa in combination with cetuximab or whether the study 
should continue at a lower nanrilkefusp alfa dose.  
If there are no safety concerns in the 12 μg/kg safety cohort, the study will proceed to the 
main cohort and recruit patients who will receive 12 μg/kg nanrilkefusp alfa in combination 
with cetuximab.  
Patients in the initial 9 μg/kg safety cohort may also have a dose increase to 12 μg/kg 
nanrilkefusp alfa in the next treatment cycle at the discretion of the investigator if there are 
no safety concerns in the 12 μg/kg safety cohort.  


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 12 of 60 
 
 
ST-AD-008 version 06 
 
Patients in the safety cohorts who do not fulfill the DLT evaluability criteria for any reason 
other than DLT during the DLT assessment period will be replaced until at least 3 patients 
per cohort have completed their DLT assessment period.  
In the main cohort of the study patients will be treated with nanrilkefusp alfa in combination 
with cetuximab in 21-day cycles as described in the study protocol. An Independent Data 
Monitoring Committee (IDMC) will be established to review safety and efficacy data at 
certain time intervals, or when the interim analysis for futility is triggered, once the main 
cohort of the study starts.  
Study periods 
Participation of each patient will consist of the below study periods. 
2.1.1. Study Intervention during Treatment Period 
During the treatment period, study interventions will be administered as described in  
Table 1 and protocol section 6 until any of the criteria for discontinuation of study 
interventions is met. 
Table 1 Study interventions 
Intervention 
name  
and type 
Dosage 
formulation 
Unit dose 
strength(s) 
Dosage level(s) 
Route of 
administration 
Regimen/ 
treatment period 
Sourcing 
nanrilkefusp 
alfa 
Investigational 
intervention 
Solution 
for 
injection 
1.3 
mg/vial 
See section 4.1.1 of 
the protocol 
Subcutaneous Administration 
on day 1 (from 
cycle 2 onwards, 
±1 day), day 2 
(±1 day), day 8 
(±1 day), and 
day 9 (±1 day) 
of each 21-day 
cycle 
Provided 
centrally 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 13 of 60 
 
 
ST-AD-008 version 06 
 
Intervention 
name  
and type 
Dosage 
formulation 
Unit dose 
strength(s) 
Dosage level(s) 
Route of 
administration 
Regimen/ 
treatment period 
Sourcing 
Cetuximab 
Investigational 
intervention 
Solution 
for infusion 
5 mg/mL Initial dose: 
400 mg/m2 body 
surface area (BSA) 
as intravenous 
infusion over 120 
minutes 
Subsequent doses: 
250 mg/m2 as 
intravenous infusion 
over 60 minutes 
Intravenous 
infusion via 
peripheral or 
central 
venous line 
Administration 
on day 1 (from 
cycle 2 onwards, 
±1 day), day 8 
(±1 day), and 
day 15 (±1 day) 
of each 21-day 
cycle; on day 1 
and day 8, 
cetuximab 
infusion will 
start within 30 
minutes after 
nanrilkefusp alfa 
administration 
Provided 
centrally 
 
After discontinuation 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 cetuximab (whichever occurs later). 
2.1.2. Follow-up 
All patients will come to the clinic 30 (±2) days after their last dose of nanrilkefusp alfa and/or 
cetuximab (whichever occurs later). 
Patients will be contacted 90 (+2) days after their last dose of nanrilkefusp alfa and/or 
cetuximab (whichever occurs later) and then followed up for survival at 3-month (±2 weeks) 
intervals until the end of the study. 
2.2. Study Objectives 
2.2.1. Primary Objective 
The primary objective of the study is to estimate the antitumor efficacy of nanrilkefusp alfa 
in combination with cetuximab. 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 14 of 60 
 
 
ST-AD-008 version 06 
 
2.2.2. Secondary Objectives 
The secondary objectives of the study are: 
• To further evaluate the antitumor efficacy of nanrilkefusp alfa in combination with 
cetuximab 
• To assess the safety and tolerability of nanrilkefusp alfa in combination with 
cetuximab 
• To determine the RP2D of nanrilkefusp alfa in combination with cetuximab 
• To characterize the Pharmacokinetics (PK) of nanrilkefusp alfa in a subset of patients 
• To determine the immunogenicity of nanrilkefusp alfa in combination with cetuximab 
2.2.3. Exploratory Objectives 
The exploratory objectives of the study are: 
• To further evaluate the antitumor efficacy of nanrilkefusp alfa in combination with 
cetuximab 
• To determine the status of immune-, molecular-, and disease-related biomarkers of 
potential importance 
• To determine the impact of the Epidermal Growth Factor Receptor (EGFR) mutational 
status on efficacy 
• To characterize the PK of cetuximab in a subset of patients 
• To determine the immunogenicity of cetuximab in combination with nanrilkefusp alfa 
2.3. Sample Size and Power 
In the safety cohorts the traditional 3+3 design dose escalation will be applied. Therefore, 3 
to 6 DLT-evaluable patients per dose level will be included in a cohort. The estimated number 
of patients is 6-12. The overall sample determined in this trial is 52 patients in efficacy 
population which includes patients from the safety cohorts and the main cohort. 
The total sample size is based on a Bayesian calculation: Markov chain Monte Carlo has been 
used for the sample size determination. Assuming a desired Objective Response Rate (ORR) 
for the number of responses, and a uniform prior distribution between 0 and 1, the sample size 
of 52 patients will ensure at least 80% posterior probability to achieve an effect above the 
minimal ORR: 
• Benchmark ORR: 20%1 
• Minimal ORR (relative increase, absolute increase): 28.8% (1.44, 8.8%) 
• Desired ORR (relative increase, absolute increase): 36.8% (1.84, 16.8%) 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 15 of 60 
 
 
ST-AD-008 version 06 
 
2.4. Primary Efficacy Variable 
The primary efficacy variable will be the ORR according to Response Evaluation Criteria in 
Solid Tumors version 1.1 (RECIST 1.1).2 
2.5. Secondary Efficacy Variables 
The secondary efficacy variables will be: 
1. ORR according to immune-based Therapeutics RECIST (iRECIST)3 (iORR) 
2. Best Overall Response according to RECIST 1.1 (BOR) and iRECIST (iBOR) 
3. Duration of Response according to RECIST 1.1 (DoR) and iRECIST (iDoR) 
4. Clinical Benefit Rate according to RECIST 1.1 (CBR) and iRECIST (iCBR) 
5. Progression-Free Survival (PFS) according to RECIST 1.1 and iRECIST (iPFS) 
6. Time to Response according to RECIST 1.1 (TtR) and iRECIST (iTtR) 
7. Time to Progression according to RECIST 1.1 (TtP) and iRECIST (iTtP) 
2.6. Exploratory Efficacy Variables 
The exploratory efficacy variables will be: 
8. PFS on Next-line Anti-cancer Treatment (PFS2) 
9. Overall Survival (OS) 
10. Assessment of Fragment crystallizable (Fc) gamma receptor polymorphism or 
presence and changes in T-cell clonality, levels of inflammatory/regulatory cytokines 
or circulating tumor markers such as circulating tumor Deoxyribonucleic Acid (DNA) 
at screening and following nanrilkefusp alfa and cetuximab treatment 
11. Assessment of the EGFR mutational status at baseline and at disease progression 
2.7. Safety Variables 
The safety variables will be: 
• Treatment-Emergent Adverse Events (TEAEs) according to the National Cancer 
Institute-Common Terminology Criteria for AEs (NCI-CTCAE4), version 5.0 
• Safety laboratory findings  
• Vital signs  
• Electrocardiography findings 
• DLTs 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 16 of 60 
 
 
ST-AD-008 version 06 
 
2.8. PK and Immunogenicity Variables 
• Serum concentrations and calculated PK parameters of nanrilkefusp alfa and 
cetuximab  
(serum PK samples will be collected from all patients in the initial safety cohorts and 
from the first 12 patients in the main cohort) 
• Incidence, titer, and time course of Anti-drug Antibodies (ADAs) against nanrilkefusp 
alfa, including neutralizing ADAs 
• Incidence, titer, and time course of ADAs against cetuximab, including neutralizing 
ADAs 
 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 17 of 60 
 
 
ST-AD-008 version 06 
 
3. Analysis Populations 
In accordance with ICH E35 and ICH E96, the following analysis sets will be used for the 
analyses. 
3.1. Screened Population  
The Screened Population will consist of all participants who signed the ICF. 
The Screened Population will be used for the listing of screen failures and summaries of 
patient disposition and reasons for screening failures. 
 
3.2. Enrolled Population  
The enrolled population is defined as all patients who sign the main study informed consent 
form and all eligibility criteria are met as confirmed by approver during screening 
assessments.  
This population may include patients who do not receive study treatment. 
 
3.3. All-Subjects-as-Treated Population  
The All-Subjects-as-Treated (ASaT) population will consist of all patients exposed to 
nanrilkefusp alfa or cetuximab.    
All safety analyses will be performed on the ASaT population. The ASaT population will 
also be used for selected efficacy analyses.  
3.4. Efficacy Population 
The Efficacy population will consist of all patients exposed to the combination therapy for at 
least one treatment cycle. This is defined as patients with 4 doses of nanrilkefusp alfa and 3 
doses of cetuximab in Cycle 1, or patients exposed to both nanrilkefusp alfa and cetuximab 
in Cycle 1 who started Cycle 2.  
This will be the main population for the analyses of the primary endpoint and secondary 
efficacy endpoints. 
3.5. Per Protocol Population 
The Per Protocol (PP) population will consist of all patients who had at least one full treatment 
cycle of nanrilkefusp alfa and cetuximab (with 4 doses of nanrilkefusp alfa and 3 dose of 
cetuximab in Cycle 1), did not violate any eligibility criteria, and did not have any relevant 
major protocol deviations.  
Protocol deviations are defined as any change, divergence, or departure from the study design 
or procedures defined in the study protocol. Important protocol deviations are a subset of 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 18 of 60 
 
 
ST-AD-008 version 06 
 
protocol deviations which may significantly impact the correctness, accuracy, and/ or 
reliability of the study data or that may significantly affect a patient’s rights, safety, or well-
being. Section 3.5.1 details the deviations. 
3.5.1. Important Protocol Deviations Leading to Exclusion from the PP Population 
Deviations from the protocol, as defined in the protocol and/or protocol deviation plan, will 
be documented by the study monitors and project management throughout the study period. 
Only those important protocol deviations considered to have a major effect on efficacy will 
lead to complete exclusion of the patient from the PP population. For the purposes of this 
study important protocol deviations leading to exclusion from the PP population will be 
defined. Criteria which require clinical or medical monitoring interpretation will be reviewed 
prior to database lock during data review meetings. All important protocol deviations leading 
to exclusion from the PP population occurring during the study will be reviewed and approved 
by sponsor prior to database lock in a separate document. 
3.6. PK Population 
The PK population will consist of all patients who are PK-evaluable, defined as all patients 
in the ASaT who had at least 1 post-dose concentration measurement above the Lower Limit 
of Quantification (LLQ).   
3.7. Special Subpopulations 
Not Applicable. 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 19 of 60 
 
 
ST-AD-008 version 06 
 
4. Data Handling 
4.1. Time Points and Visit Windows 
4.1.1. General Definitions 
The study treatment defined is the combination of nanrilkefusp alfa 9 µg/kg or 12 µg/kg 
subcutaneously and 400 mg/m2 or 250 mg/m2 cetuximab IV infusion. 
All assessment days will be related to the first day of first dose of study treatment. Start of 
study treatment is defined as the date and time of first dose of either nanrilkefusp alfa or 
cetuximab, whichever occurs earliest. Per protocol this should be nanrilkefusp alfa.  
 
General Definition 
nanrilkefusp alfa 
Cetuximab 
Study Day 1 
Day 1 is the first dose of study treatment .  
Relative days after Day 1 are calculated as (assessment date – Day 1 date) + 1.  
Relative days prior to Day 1 are calculated as (assessment date – Day 1 date). 
The day prior to Day 1 is Day -1. Day 0 is not defined. 
Date of the First Dose 
As per Exposure CRF (First date from 
Administration date) 
As per Exposure CRF (First date 
from Administration date) 
 
Minimum of first dose of nanrilkefusp alfa and start date of the infusion for 
the first dose of cetuximab 
Date of the Last Dose 
As per Exposure CRF (Last date from 
Administration date) 
As per Exposure CRF (Last date 
from Administration date) 
 
Maximum of last dose nanrilkefusp alfa and end date of the infusion for the 
last dose of cetuximab. 
Treatment Cycle 
As per CRF 
Treatment Day 
As per CRF 
Change from baseline 
Visit value – baseline value 
Percentage change from 
baseline 
 100 * (visit value – baseline value) / baseline value 
 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 20 of 60 
 
 
ST-AD-008 version 06 
 
4.1.2. Screening Period 
For all patients, the screening period is defined as the period from time of signing ICF to the 
first dose of treatment (nanrilkefusp alfa or cetuximab) (before day 1 of cycle 1).  For some 
variables, data from more than one assessment within the screening period can be collected 
prior to the first dose of treatment (nanrilkefusp alfa or cetuximab). 
 
The baseline value is defined as the last non-missing value collected before the first dose of 
study treatment (nanrilkefusp alfa and/or cetuximab) in the screening period. However, for 
K-RAS and N-RAS parameters as well as eGFR mutation status which come from Biopsy 
performed within 3 months prior to first dose will also be considered as baseline values.  
4.1.3. Treatment Period 
Data collected at Day 1 will be assigned to the Treatment Period unless the time (HH:MM) 
of data collection and time (HH:MM) of first dose of treatment are both recorded and the data 
collection time is before the time of first dose of treatment. In this case, the assessment will 
be assigned to the screening period.  If the time (HH:MM) of data collection is not recorded 
but the protocol and/or eCRF includes an instruction to the effect that all Day 1 assessments 
are to be performed prior to the first dose of treatment, the data collected at Day 1 will be 
assigned to the screening period.  However, adverse events and medications starting on Day 
1, will be assigned to the Treatment Period. 
 
The treatment period is defined from the day of the start of study treatment to the day prior to 
the end of treatment visit , the end of study date,  or start of new anti-cancer therapy, whichever 
is earliest. Date of last contact collected on the ‘Survival Status’ eCRF where status is ‘dead 
can be after end of study if the contact was with family of subject, but the latest end of study 
date for a ‘dead’ patient is the death date of the patient.  
 
4.1.4.  Visit Windows 
All data will be analyzed using nominal study visit as defined in the Study Schedule and 
eCRF. No visit windows will be applied for summary and analysis except for tumor 
assessment. Repeated and unscheduled measurements will be included in the listings but not 
be used for statistical analyses and summaries, except for the derivation of 
minimum/maximum values post-baseline. All tumor assessments will be considered for the 
time-to-event analysis.  
Unscheduled visits will be identified with a numbering system that reflects the cycle they 
occur in by comparing the visit date against the scheduled visits and numbering in order of 
unscheduled visit e.g. Unscheduled Cycle 1 Day 1.01, Unscheduled Cycle 1 Day 8.01 etc. 
Unscheduled visits occurring on the same day as other visits will not be used in the analysis 
by timepoint.  


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 21 of 60 
 
 
ST-AD-008 version 06 
 
Visit window for the Tumor Assessment 
Additionally, for the purposes of summarizing target lesions by scheduled week, labels for 
assessments falling into the scheduled week of study will be derived e.g. ‘Week 6 assessment 
(Weeks 4 to 8)’, ‘Week 12 assessment (Weeks 10 to 14)’ etc., by assigning the assessments 
within the protocol specified window of every 6 weeks ± 2 weeks (e.g. for Week 6 : C1D1 
date + 28 <= Tumor assessment date <=C1D1 date + 56). Labels for assessments falling 
outside of the assessment windows would be labelled ‘Not Assigned’. In the case of multiple 
tumor assessments in a time window, evaluable assessments closest to the planned assessment 
time (or the closest non-evaluable assessment if all non-evaluable) will be considered the 
scheduled assessment. In the case of two assessments within a window being exactly the same 
distance from the centre of the window, the earliest assessment will be assigned as the 
scheduled assessment. Contributing assessments (e.g. target lesion assessment) should be 
labelled consistently with the overall tumor assessment.   
 
4.2. Handling of Dropouts, Missing Data, and Outliers 
4.2.1. Handling of Missing Efficacy Data 
Patients with missing data for the efficacy endpoints of ORR, iORR, CBR and iCBR will be 
classified as non-responders, if not otherwise specified.  
 
Patients with missing data for the efficacy endpoints of DoR, iDoR, PFS, iPFS, TtR, iTtR, 
TtP, iTtP, PFS2, and OS at the end of trial will be regarded as censored as described in Section 
5.5.3.  
 
4.2.2. Handling of Missing Safety Data 
In general, missing clinical laboratory data, vital signs, and Electrocardiogram (ECG) data 
will not be imputed.   Unknown or partial medication and AE date imputations are given 
below and to be used only for the assessment of prior / concomitant status for medications 
and treatment-emergent status for AEs. 
4.2.3. Handling of Partial and Missing Dates for Adverse Events, Prior / Concomitant 
Medications/Procedures 
Missing or Partial Adverse Event and Prior / Concomitant Medication/Procedure Start Dates 
Missing and / or incomplete dates for medications, procedures and AEs are imputed in a 
manner resulting in the earliest onset or the longest duration during the Treatment Period, 
whilst ensuring that the start date does not occur after the stop date.  The stop date will not be 
imputed if the medication or AE is “Ongoing”. Technically, this will be done as follows: 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 22 of 60 
 
 
ST-AD-008 version 06 
 
For a missing/incomplete start date/time the earliest date/time of the following will be 
imputed: 
• The later date of: the earliest possible start date / time, and the date / time of first dose 
of treatment. 
• The latest possible start date/time. 
• The latest possible stop date/time. 
For a missing/incomplete stop date/time the later date/time of the following will be imputed: 
• The earlier date/time of the latest possible stop date/time and the date/time of last dose 
of treatment. 
• The earliest possible stop date/time. 
• The earliest possible start date/time. 
 
Here, the earliest possible date/time is defined as: 
• The date/time itself if available. 
• The date/time of the first day of the month at 00:00hrs, if month and year are available 
but the day/time is missing. 
• The date/time of the first day of the year at 00:00hrs, if year is available but day/time 
and month are missing. 
• 00:00hrs on the day of informed consent, if the date/time is completely missing. 
 
The latest possible date/time is defined as: 
• The date/time itself if available. 
• The date/time of the last day of the month at 23:59hrs, if month and year are available 
but the day/time is missing.  
• The date/time of the last day of the year at 23:59hrs, if year is available but day/time 
and month are missing. 
• 23:59hrs on the date of last known date on the study for the patient plus one year, if 
the date/time is completely missing. 
4.2.4. Handling of Partial and Missing Dates for New Anti-Cancer Therapy 
Incomplete start dates of follow-up anti-cancer therapy will be imputed as follows: 
If only ‘day’ is missing, then impute with the first day of the month. 
If ‘day’ and ‘month’ are missing and ‘year’ is not missing and equal to year of last dose, then 
impute as date of last dose. 
Else if ‘day’ and ‘month’ are missing and ‘year’ is not missing and before year of last dose, 
then impute as 31st December of that year. 
Else if ‘day’ and ‘month’ are missing and ‘year’ is not missing and after year of last dose, 
then impute as 1st January of that year. 
 


Statistical Analysis Plan                                                                                
 
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 23 of 60 
 
 
ST-AD-008 version 06 
 
If the imputed start date is greater than the last contact date, then set to the last contact date.  
4.2.5. Handling of Partial and Missing Death Date 
Incomplete dates of death will be imputed as follows: 
If only ‘day’ is missing, then impute with the first day of the month. 
If ‘day’ and ‘month’ are missing and ‘year’ is not missing and is the same as the year of the 
last contact date, then impute as the date of the last contact +1 day. 
If ‘day’ and ‘month’ are missing and ‘year’ is not missing and is greater than the year of the 
last contact date, then impute as 1st January of that year. 
If the imputed death date is less than the last contact date, then set to the last contact date + 1 
day.  
4.2.6. Handling of Partial and Missing Diagnosis Date 
The partial start date for initial diagnosis will be assigned to 15th day of the month (if only 
day is missing) or July 1st (if both month and day are missing).  
For completely missing dates no imputation will be performed. 
4.2.7. Handling of Partial and Missing Laboratory Data 
Missing laboratory data will not be imputed. However, laboratory values of the form of “< x” 
(i.e., below the lower limit of quantification) or “> x” (i.e., above the upper limit of 
quantification) will be imputed as “x” for the purpose of calculation of summary statistics and 
comparing to normal ranges. These values will still be displayed as “< x” or “> x” in the 
listings. 
 
4.2.8. Handling of Serum PK Concentrations for Study Treatment that are Below the 
Lower Limit of Quantification 
Serum PK concentrations for Study Treatment that are Below the Lower Limit of 
Quantification (BLQ) will be handled as follows for descriptive statistics: 
• For individual data listings, values that are BLQ (add actual BLQ for nanrilkefusp alfa 
and cetuximab in ng/mL here) will be reported as < LLOQ where LLOQ will be 
replaced by the actual value for LLOQ for the specific PK assay. 
• Values that are BLQ will be set to 0 for the calculation of summary statistics by 
treatment at each scheduled time point (number of patients in analysis set (N), number 
of patients with data available (n), arithmetic mean, geometric mean, arithmetic SD, 
geometric coefficient of variation (%CV), 95% confidence interval (CI), median, min, 
and max). 
• If there are less than 3 quantifiable values in a data series, only the minimum, 
maximum and n will be presented. The other summary statistics will be denoted as not 
calculated (NC). 


Statistical Analysis Plan                                                                               
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 24 of 60 
 
 
ST-AD-008 version 06 
 
• BLQ results (treated as 0) are in a series of summarized data, geometric mean and 
CV% will be reported as NC. 
• Arithmetic mean or median values that are BLQ presented as 0. 
• If a predose concentration is missing prior to the first dose of Cycle 1 Day 1, the values 
will be set to zero. 
.  
 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 25 of 60 
 
 
ST-AD-008 version 06 
 
5. Statistical Methods 
5.1. General Principles 
All data processing, summarization and analyses will be performed using Fortrea’s SAS 
Environment / Version 9.4 (or later) of the SAS statistical software package.   
The analyses will be descriptive; no formal testing of statistical hypotheses is planned. 
Summary statistics: 
The default summary statistics for quantitative variables will be the number of observations 
(n), mean, Standard Deviation (SD), median, minimum (min) and maximum (max), for those 
patients with data. For qualitative variables, the number (n) and percentage (%) of patients 
with non-missing data per category will be the default summary presentation, and where 
appropriate and present, the number of missing values as a “Missing” category. Number of 
patients in the analysis population will be used as denominator for percentages calculation, 
unless stated otherwise in TFLs. 
Time-to-event endpoints will be summarized using Kaplan-Meier (KM) method. Estimation 
of median time and the associated 95% Confidence Interval (CI) will be provided using log-
log transformation. Number of events, number of censored patients and descriptive statistics 
[25th and 75th percentiles, minimum and maximum] for time-to-event endpoints will be also 
provided. The KM curves will be graphically displayed. 
Time conversion: 
The following conversion factors will be used to convert days into months or years:  
1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days. 
Laboratory data: 
All laboratory clinical safety and urine test results will be received from the local laboratories, 
and the results will be provided in both Standard Internal (SI) and conventional units. For the 
TFLs, the results will be summarized or presented in International System of Units (SI) units. 
Refer to Appendix of the TFLs mock shells for the SI unit corresponding to each laboratory 
test. Biomarkers, inflammatory cytokines and PK/ADA results will be received from the 
central laboratories. 
Tables, Figures, and Listings (TFLs): 
In the listings, laboratory values converted from conventional to International System of Units 
(SI) units will be reported to the same precision as values originally recorded as SI. Derived 
values for change/ percent changes in target lesions, and all safety endpoints will be rounded 
with one decimal place. 
Refer to Appendix of the TFL shells for the precision level in which each laboratory test is 
reported by the central laboratories. 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 26 of 60 
 
 
ST-AD-008 version 06 
 
Specifications for table, figures and data listing formats can be found in the TFL shells 
specifications for this study. Please refer to “2. General Format Guidelines” section within 
TFL shells for more details on presentation of results. 
 
5.2. Patient Disposition and Data Sets Analyzed 
Patient disposition will be summarized by cohort and overall, where appropriate, for the 
screening population on assigned treatment.  The following information will be reported:  
• Number and percentage of Screen Failure patients with the reason; 
• Number and percentage of patients for the following categories: 
o Enrolled , 
o Treated , 
o Not Treated , 
o Discontinued study treatment (nanrilkefusp alfa, cetuximab, or both), 
o Reasons for study treatment discontinuation, 
o Ongoing in the study, 
o Completed the study, 
o Discontinued the study, 
o Reasons for study discontinuation. 
• Number and percentage of patients included in, and excluded from efficacy 
population, PP population, and PK population together with the reasons for 
exclusion from the population; 
• Number and percentage of patients at each country/site (ASaT population using 
assigned treatment will be used for this summary); 
 
A patient will be regarded as having completed the study if the Reason for 
Completion/Discontinuation on the End of Study eCRF form is “Study completed as per 
Protocol”. A patient will be considered as having discontinued the study if Reason for 
Completion/Discontinuation is not “Study completed as per Protocol” and not Missing study 
discontinuation. Otherwise, the patient will be considered as ongoing study. The date of 'End 
of Study eCRF form' will be used for the definition of end of study date. In case a patient is 
death the date needs to be equal to Death Details eCRF form is “What was the subject’s date 
of death?”. 
A listing of all patients with their treatment and study completion status, including the 
respective reasons for treatment and study discontinuation will be presented for the enrolled 
population. 
A listing of all screen failed patients with their reasons for screen failure will be presented for 
the screening population. A separate listing of patients who failed at least one 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 27 of 60 
 
 
ST-AD-008 version 06 
 
inclusion/exclusion criteria including a text description of the criterion failed will be presented 
for the screening population. 
A listing of all patients excluded from efficacy population, PP population or pharmacokinetics 
population will be presented for the enrolled population. 
5.3. Protocol Deviations 
All important protocol deviations leading to exclusion from the PP Population (see Section 
3.5.1) will be summarized for the ASaT population overall as described below: 
• The number of unique patients with at least one important protocol deviation which 
led to exclusion from the PP Population as well as the number of patients in each 
important protocol deviation category will be presented by default descriptive 
summary statistics for categorical variables.  
 
A listing of all patients with one or more important/non important protocol deviations will be 
presented for the enrolled population.  In addition, a listing of the patients affected by 
Coronavirus Disease of 2019 (COVID-19) and the type of COVID-19 disruption will be 
provided for the enrolled population, if applicable. 
 
5.4. Demographic and Other Baseline Characteristics 
5.4.1. Demographic Characteristics 
Demographic characteristics will be summarized for the ASaT population  as described 
below. All missing data will be presented as part of a missing category, if appropriate.  
Standard descriptive statistics will be presented for the continuous variables of: 
• Age (years) 
 
Total counts and percentages of patients will be presented for the categorical variables of: 
• Age group (years): 
o < 18 
o >= 18 to < 65 
o >= 65 to < 85 
o >= 85 
• Sex 
o If female, Childbearing potential (Yes/ No) 
 If No, Reasons 
• Race 
• Ethnicity 
 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 28 of 60 
 
 
ST-AD-008 version 06 
 
Demographic Characteristics analyses will also be repeated in the Efficacy Population as well 
as the Per Protocol Population and listed for the screened population. 
 
5.4.2. Baseline Characteristics 
Baseline characteristics will be summarized for the ASaT as described below. All missing 
data will be presented as part of a missing category, if appropriate. 
Standard descriptive statistics will be presented for the continuous variables of: 
• Height (cm) at baseline 
• Weight (kg) at baseline 
• BSA (m2) at baseline 
• Body Mass Index (BMI) (kg/m²) at baseline, derived as Weight (kg) at 
baseline/Height² (cm²) at baseline 
• Eastern Cooperative Oncology Group (ECOG) at baseline 
No formal tests of statistical significance will be performed on the demographic and baseline 
characteristics data. 
Baseline Characteristics analyses will also be repeated in the Efficacy Population as well as 
the Per Protocol Population. 
Baseline characteristics will be listed for the screened population. 
5.4.3. Cancer History 
Cancer History analyses will be summarized for the ASaT. 
Standard descriptive statistics will be presented for the continuous variables of: 
• Initial diagnosis to Screening: time from initial diagnosis of cancer to screening 
defined as screening date – initial diagnosis date + 1. 
• Initial diagnosis to start of treatment: time from initial diagnosis of cancer to first dose 
defined as First dose date – initial diagnosis date + 1. 
• Metastatic diagnosis to start of treatment: time from metastatic diagnosis to first dose 
defined as First dose date – metastatic disease date + 1. 
• Latest disease progression to start of treatment: time from latest disease progression 
to first dose defined as First dose date – latest disease progression date + 1. 
• Number of previous lines of therapy  
Total counts and percentages of patients will be presented for the categorical variables of: 
• Site of primary tumor and sites of metastatic disease 
• Stage at study entry: primary tumor (T) stage, regional lymph nodes (N) stage, distant 
metastasis (M) stage, and staging  


Statistical Analysis Plan                                                                               
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 29 of 60 
 
 
ST-AD-008 version 06 
 
• Histology/ Cytology results and type 
• Prior mutation/ Expression status of Kirsten rat sarcoma viral oncogene homolog (K-
RAS), Neuroblastoma rat sarcoma viral oncogene homolog (N-RAS), V-raf murine 
sarcoma viral oncogene homolog B1 (BRAF) and EGFR  
•  Number of previous lines of therapy (continuous and categorical) 
• Previous treatment with EGFR inhibitors  
• Response of previous treatment with EGFR inhibitors  
 
Cancer History analyses will also be repeated in the Efficacy Population as well as the Per 
Protocol Population. 
Cancer History will be listed for the screened population. 
5.4.4. Medical History 
Medical history is defined as any condition, with the exception of the study indication, that 
the patient may have had prior to enrollment in the study, including any chronic conditions 
diagnosed prior to entry in the study.  
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) [most recent version at time of DB lock] and will be presented by System Organ 
Class (SOC) and Preferred Term (PT) and total. The SOCs and PTs are to be sorted by 
descending SOCs and descending PTs in the total column. 
Medical history records will be summarized for the ASaT population by overall as follows: 
• The number and percentage of patients with at least one medical history record will 
be presented.  
• The number and percentage of patients with at least one medical history record 
within each primary SOC and PT will be presented. The summary will be sorted 
using the descending order for SOC and using descending order of overall numerical 
counts for PT. Where terms tie, these will be sorted alphabetically. 
Medical history records will be listed by-patient and within-patient by medical history start 
date for the screened population. 
5.4.5. Prior and Concomitant Medications 
All medications will be coded using the Format B3G [most recent version at time of DB lock], 
Anatomical Therapeutic Chemical (ATC) Classification codes. 
Prior medications and concomitant medications are defined as follows: 
• Prior medication is defined as those taken prior to the first dose with a stop date and 
time prior to the start of the Treatment Period. 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 30 of 60 
 
 
ST-AD-008 version 06 
 
• Concomitant medications are those with a start date and time on or after the start of 
the Treatment Period, or those with a start date and time before the start of the 
Treatment Period and either a stop date and time on or the start of the Treatment 
Period, or are ongoing at the end of the study. 
See Section 4.2.3 for imputation of missing or partial dates for medication.   
Prior and concomitant medications will be summarized separately for the ASaT population 
overall as follows: 
• The number and percentage of patients with at least one prior/concomitant medication 
will be presented. 
• The number and percentage of patients with at least one prior/concomitant medication 
within each Anatomical Group (ATC Level 1), Therapeutic Subgroup (ATC Level 2), 
and preferred term will be presented. The summary will be sorted using numerical 
counts by descending order of Anatomical Group, then descending order of 
Therapeutic Subgroup, then descending order of preferred term in the total column. 
Where groups or terms tie these will be sorted alphabetically. 
Prior medications and concomitant medications will be listed separately for the enrolled 
population.  In the listings the relative start and stop day of prior/concomitant medication use 
will be calculated relative to the first dose date and time of treatment and will be presented 
for those patients who received at least one dose of treatment.  If the concomitant medication 
is “Ongoing” it will be indicated as such in the listing and the relative stop day will not be 
calculated.  Only original dates will be presented in the listing even though the relative day 
may be based on an imputed date. 
5.4.6. Prior and Concomitant Procedures 
All procedures will be coded using the MedDRA dictionary [most recent version at time of 
DB lock] and presented by System Organ Class (SOC) and Preferred Term (PT). The SOCs 
and PTs are to be sorted by descending SOCs and descending PTs. 
Prior procedures and concomitant procedures are defined as follows: 
• Prior procedure is defined as those done prior to the first dose with a stop date and 
time prior to the start of the Treatment Period. 
• Concomitant procedure are those with a start date on or after the start of the Treatment 
Period, or those with a start date before the start of the Treatment Period and either a 
stop date on or the start of the Treatment Period, or are ongoing at the end of the study. 
See Section 4.2.3 for imputation of missing or partial dates for procedure.   
Prior and concomitant procedures will be summarized separately for the ASaT population 
overall as follows: 
• The number and percentage of patients with at least one prior/concomitant procedure 
will be presented. 


Statistical Analysis Plan                                                                               
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 31 of 60 
 
 
ST-AD-008 version 06 
 
• The number and percentage of patients with at least one prior/concomitant procedure 
within each SOC and PT. 
Prior procedures and concomitant procedures will be listed separately for the enrolled 
population.  In the listings the relative start and stop day of prior/concomitant procedures use 
will be calculated relative to the first dose date of treatment and will be presented for those 
patients who received at least one dose of treatment.  If the concomitant procedure is 
“Ongoing” it will be indicated as such in the listing and the relative stop day will not be 
calculated.  Only original dates will be presented in the listing even though the relative day 
may be based on an imputed date. 
5.4.7. Prior Radiation Therapy 
Number and percentage of patients having prior radiation therapy will be summarised within 
each primary SOC and PT for the ASaT, Efficacy, and PP populations as a part of prior non-
systemic anti-cancer therapy.   
Prior radiation therapy data will be listed for the enrolled population as a part of prior non-
systemic anti-cancer therapy. 
5.4.8. Prior Anti-Cancer Surgery 
Number and percentage of patients having prior anti-cancer surgery will be summarised 
within each primary SOC and PT for the ASaT, Efficacy, and PP populations by treatment 
group and overall as a part of prior non-systemic anti-cancer therapy.   
Prior Anti-cancer surgery data will be listed for the enrolled population as a part of prior non-
systemic anti-cancer therapy. 
5.4.9. Prior Systemic Anti-Cancer Therapy 
Number and percentage of patients having prior systemic anti-cancer therapy will be 
summarised within ATC Level for the ASaT, Efficacy, and PP populations by treatment group 
and overall as a part of prior systemic anti-cancer therapy. 
Prior systemic anti-cancer therapy data will be listed for the enrolled population as a part of 
prior systemic anti-cancer therapy. 
5.4.10. Subsequent Radiation Therapy 
Subsequent Radiation therapy data will be listed for the enrolled population as a part of 
subsequent non-systemic anti-cancer therapy. 
5.4.11. Subsequent Anti-Cancer Surgery 
Subsequent Anti-Cancer Surgery data will be listed for the enrolled population as a part of 
subsequent non-systemic anti-cancer surgery. 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 32 of 60 
 
 
ST-AD-008 version 06 
 
5.4.12. Subsequent Systemic Anti-Cancer Therapy 
Subsequent Systemic Anti-Cancer therapy data will be listed for the enrolled population as a 
part of subsequent systemic anti-cancer therapy. 
5.5. Efficacy 
Only tumor assessments prior to or at the date of initiation of further-line therapy and using 
CT scan or MRI will be used for the evaluation of tumor response.  
In case of a confirmed response or disease progression, the date of the first tumor assessment 
evaluated as response or progression will be used for the time-to-event variables. 
Up to the first iUPD, the RECIST 1.1 disease response assessment will be derived from the 
iRECIST response assessment form as follows:  
Table 2 Derivation of RECIST 1.1 Disease Response from iRECIST 1.1 
iRECIST 
RECIST 1.1 
iCR 
CR 
iPR 
PR 
iSD 
SD 
iUPD 
PD 
Non-iCR/Non-iUPD 
Non-CR / Non-PD 
NE 
NE 
 
After the first iUPD, the RECIST 1.1 overall response will no longer be derived. 
All efficacy data endpoint will be listed on the enrolled population, with the exception of time 
to event analyses where the ASaT population will be used.  
Overview of Tumor Assessments with a swimmer plot per RECIST 1.1 and iRECIST 1.1 will 
be displayed graphically for ASaT population.  
5.5.1. Primary Efficacy Analysis 
The ORR is defined as the proportion of patients with Complete Response according to 
RECIST 1.1 (CR) or Partial Response according to RECIST 1.1 (PR). ORR will be analyzed 
in the efficacy population and presented as a point estimate along with 95% Clopper-Pearson 
CI. Patients with missing data will be considered as non-responders. 
To determine the ORR, the BOR (see Section 5.5.3.1) of each patient will be computed 
according to RECIST v1.1 criteria. 
ORR according to RECIST 1.1 will also be listed for enrolled population. 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 33 of 60 
 
 
ST-AD-008 version 06 
 
5.5.2. Sensitivity for the Primary Analyses 
Primary efficacy analysis will be repeated for ASaT and PP populations. 
Primary efficacy analysis will be repeated where patients with missing data will be excluded 
from the analysis. 
5.5.3. Secondary Efficacy Analysis 
5.5.3.1. BOR and iBOR 
The BOR and iBOR are defined as the best response from the start of study treatment until 
the first documented disease progression, death, or start of new anti-cancer therapy. It will be 
summarized with counts and percentages in the efficacy populationand will be repeated for 
ASaT and PP populations. 
This will also be repeated in the efficacy population where patients with missing data will be 
excluded from the analysis. 
 
Stable Disease according to RECIST 1.1 (SD) and Stable Disease according to iRECIST 
(iSD) needs to last at least 6 weeks from the start of study treatment, if not, at least one follow-
up scan is required to declare stable disease. 
BOR according to RECIST and iRECIST as well as the Overall Response will also be listed 
for enrolled population. 
For BOR each patient will be assigned one of the following categories (from best response to 
worst response): CR, PR, SD, PD, NE: 
 
Step 
Condition 
Step 1: BOR of CR 
If a BOR of CR is not determined, Step 2 
will be performed. 
At least two consecutive determinations of 
CR more than 4 weeks apart, or if not 
consecutive, with no other assessment 
between the two determinations other than 
unable to evaluate (NE), CR. 
Step 2: BOR of PR 
If a BOR of PR is not determined, Step 3 
will be performed. 
At least two consecutive determinations of 
PR or CR, more than 4 weeks apart, or if not 
consecutive, with no other assessment 
between the two determinations other than 
NE, CR, PR. 
Step 3: BOR of SD 
If a BOR of SD is not determined, Step 4 
will be performed. 
At least one SD assessment (or better), ≥ 6 
weeks (≥ 42 days) after baseline; if not, at 
least one follow-up scan (i.e., consecutive 
scan) evaluated as SD (or better) is required 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 34 of 60 
 
 
ST-AD-008 version 06 
 
to determine a BOR of SD. If not 
consecutive scans, with no other assessment 
between the two determinations other than 
NE, CR, PR, SD. 
Step 4: BOR of PD 
If a BOR of PD is not determined, Step 5 
will be performed. 
At least one (i.e., any) PD after baseline. 
Step 5: BOR of NE 
Measurable disease at baseline, but not all or 
any target lesions have been evaluated, or if 
derivation of BOR from Step 1 to 5 does not 
apply. Non-measurable disease at baseline 
will also result in BOR of NE. 
 
 
For iBOR each patient will be assigned to one of the following categories (from best to worst 
responses): iCR, iPR, immune Stable Disease (iSD), immune Confirmed Progressive Disease 
(iCPD), immune Unconfirmed Progressive disease (iUPD), or Not Evaluable (NE) at each 
timepoint: 
 
Step 
Condition 
Step 1: iBOR of iCR 
If an iBOR of iCR is not determined, Step 2 
will be performed. 
At least two consecutive determinations of 
iCR more than 4 weeks apart, or if not 
consecutive, with no other assessment 
between the two determinations other than 
unable to evaluate (NE), iCR. 
Step 2: iBOR of iPR 
If an iBOR of iPR is not determined, Step 3 
will be performed. 
At least two consecutive determinations of 
iPR or iCR, more than 4 weeks apart, or if 
not consecutive, with no other assessment 
between the two determinations other than 
NE, iCR, iPR. 
Step 3: iBOR of iSD 
If an iBOR of iSD is not determined, Step 4 
will be performed. 
At least one iSD assessment (or better), ≥ 6 
weeks (≥ 42 days) after baseline; if not, at 
least one follow-up scan (i.e., consecutive 
scan) evaluated as iSD (or better) is 
required to determine an iBOR of iSD. If 
not consecutive scans, with no other 
assessment between the two determinations 
other than NE, iCR, iPR, iSD. 
Step 4: iBOR of iCPD 
At least one (i.e., any) iCPD after baseline. 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 35 of 60 
 
 
ST-AD-008 version 06 
 
If an iBOR of iCPD is not determined, Step 
5 will be performed. 
Step 5: iBOR of iUPD 
If an iBOR of iUPD is not determined, Step 
6 will be performed. 
At least one (i.e., any) iUPD after baseline. 
Step 6: iBOR of NE 
Measurable disease at baseline, but not all 
or any target lesions have been evaluated, 
or if derivation of iBOR from Step 1 to 6 
does not apply. Non-measurable disease at 
baseline will also result in iBOR of NE 
The best overall response will be determined for all protocol specified assessments, i.e. 
scheduled assessments and also for all unscheduled assessments with non-missing 
information. 
Confirmatory scanning (Table 3) for patients who have obtained PR or CR (or respectively 
iPR or iCR) is needed and should be approximately 4 weeks after the initial response.   


Statistical Analysis Plan                                                                               
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 36 of 60 
 
 
ST-AD-008 version 06 
 
Table 3 Confirmation CR and PR  
Response: First 
Time Point 
Subsequent 
Time Point 
BOR 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR (see comment*) 
CR 
SD 
SD provided minimum criteria for SD duration met#, 
otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met#, 
otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met#, 
otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met#, 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met#, 
otherwise NE 
NE 
NE 
NE 
* Sometimes (i)CR may be claimed when subsequent scans suggest small lesions were likely still present and 
in fact the patient had (i)PR, not (i)CR at the first time point. Under these circumstances, the original (i)CR 
should be changed to (i)PR in the eCRF and the best response is (i)PR. If that is not the case, the (i)BOR of 
(i)SD will be determined considering two consecutive assessments better than (i)SD. This applies to both 
RECIST 1.1 and iRECIST..  
# At least one SD assessment (or better), ≥ 6 weeks (≥ 42 days) after baseline; if not, at least one follow-up 
scan (i.e., consecutive scan) evaluated as SD (or better) is required to determine a BOR of SD. If not 
consecutive scans, with no other assessment between the two determinations other than NE, CR, PR, SD..  
 
5.5.3.2. iORR 
The iORR is defined as the proportion of patients with iCR or iPR. iORR will be analyzed in 
the efficacy population and presented as a point estimate along with 95% Clopper-Pearson 
CI. Patients with missing data will be considered as non-responders. 
iORR analysis will be repeated for ASaT and PP populations and will be repeated in the 
efficacy population where patients with missing data will be excluded from the analysis. 
 
ORR according to iRECIST will also be listed for the enrolled population. 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 37 of 60 
 
 
ST-AD-008 version 06 
 
5.5.3.3. DoR and iDoR 
The DoR and iDoR are defined as the time until progression of disease or death for patients 
with PR, iPR or CR, iCR and will be summarized using Kaplan-Meier estimates in the 
efficacy population. Responders will be considered to have an ongoing response if they:  
• have not progressed, and  
• have not started a next-line anti-cancer therapy, and  
• have not been lost to follow-up, and  
• are alive. 
Patients with missing data will be censored/considered as having an event as specified in the 
table below.  
Table 4 DoR and iDoR events and censoring 
Situation  
Date of progression or censoring  
Outcome  
No progression, no death. No 
start of next-line anti-cancer 
therapy.  
Date of the last evaluable tumor 
assessment.  
Censored  
No progression, no death. 
Start of next-line anti-cancer 
therapy.  
Date of the last tumor assessment 
with non-progression before the 
start 
of 
next-line 
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  
 
For DOR, the start date is the date of first documented response of CR or PR (i.e. the start 
date of response, not the date when response was confirmed), and the end date is defined as 
the date of the first documented progression or death. 
For iDOR, the start date is the date of first documented response of iCR or iPR (i.e. the start 
date of response, not the date when response was confirmed), and the end date is defined as 
the date of the first documented progression according to iRECIST or death.  
The progression date to be used for calculation of iDOR should be the first date at which 
progression criteria are met (i.e, the date of iUPD) provided that iCPD is confirmed at the 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 38 of 60 
 
 
ST-AD-008 version 06 
 
next assessment. If iUPD occurs, but is disregarded because of later iSD, iPR, or iCR, that 
iUPD date should not be used as the progression event date. 
If progression is not confirmed and there is no subsequent iSD, iPR, or iCR, the iUPD date 
should still be used if: 
• the patient stops protocol treatment because they were not judged to be clinically 
stable, or 
• no further tumor assessments are done, or 
• the next timepoint responses are all iUPD, and iCPD never occurs, or 
• the patient dies from his cancer. 
DOR according to RECIST and iRECIST will be presented in a data listing for ASaT 
population. 
DOR according to RECIST and iRECIST will be presented graphically using Kaplan-meier 
plots for efficacy and ASaT populations including count for numbers of patients at risk. 
5.5.3.4. CBR and iCBR  
The CBR and iCBR are defined as the number of PR, iPR, CR, iCR, and SD, iSD and will be 
analyzed in the efficacy population and presented as a point estimate along with 95% Clopper-
Pearson CI. SD, iSD needs to last at least 6 weeks from the start of study treatment; if not, at 
least one follow-up scan is required to declare stable disease. Patients with missing data will 
be considered as non-responders.  
The analysis will be repeated for ASaT and PP populations as well as in the efficacy 
population where patients with missing data will be excluded from the analysis. 
 
CBR according to RECIST and iRECIST will be presented in a data listing for ASaT 
population. 
5.5.3.5. 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 in the efficacy population.  
Patients with missing data will be censored/considered as having an event as specified in the 
table below. 
Table 5 PFS and iPFS events and censoring 
Situation  
Date 
of 
progression 
or 
censoring  
Outcome  
Incomplete or no baseline 
tumor assessment.  
First day of study treatment 
Censored  


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 39 of 60 
 
 
ST-AD-008 version 06 
 
Start of next-line anti-cancer 
therapy.  
Date of the last tumor 
assessment 
with 
non-
progression before the start 
of 
next-line 
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  
For iPFS, the progression date to be used for calculation should be the first date at which 
progression criteria are met (i.e, the date of iUPD) provided that iCPD is confirmed at the 
next assessment. If iUPD occurs, but is disregarded because of later iSD, iPR, or iCR, that 
iUPD date should not be used as the progression event date. 
If progression is not confirmed and there is no subsequent iSD, iPR, or iCR, the iUPD date 
should still be used if: 
• the patient stops protocol treatment because they were not judged to be clinically 
stable, or 
• no further tumor assessments are done, or 
• the next timepoint responses are all iUPD, and iCPD never occurs, or 
• the patient dies from his cancer. 
PFS according to RECIST and iRECIST will be listed for ASaT population. 
PFS according to RECIST and iRECIST will be displayed graphically using Kaplan-meier 
plots for efficacy and ASaT populations including count for numbers of patients at risk. 
5.5.3.6. TtR and iTtR 
TtR and iTtR are defined as the time from the first day of study treatment until the first date 
of PR, iPR or CR, iCR and will be summarized using Kaplan-Meier estimates in the efficacy 
population.  


Statistical Analysis Plan                                                                               
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 40 of 60 
 
 
ST-AD-008 version 06 
 
Confirmed response dates will be used. Patients with missing data will be censored at the last 
assessment date, date of death, or date of eligibility (if incomplete or no baseline tumor 
assessments), whichever occurs latest. 
TTR according to RECIST and iRECIST will be listed for ASaT population. 
TTR according to RECIST and iRECIST will be displayed graphically using Kaplan-meier 
plots for efficacy and ASaT populations including count for numbers of patients at risk. 
5.5.3.7. TtP and iTtP 
TtP and iTtP are defined as the time from the first day of study treatment until the first date 
of radiological disease progression and will be summarized using Kaplan-Meier estimates in 
the efficacy population.  
Patients with missing data will be censored/considered as having an event as specified in 
Table below. 
Table 6 TtP and iTtP events and censoring 
Situation  
Date of progression or censoring  
Outcome  
Incomplete or no baseline 
tumor assessment.  
First day of study treatment 
Censored  
Start of next-line anti-
cancer therapy.  
Date of the last tumor assessment 
with non-progression before the start 
of next-line anti-cancer therapy.  
Censored  
Death before the first 
disease 
progression 
assessment.  
Date of death.  
Censored  
Death between adequate 
tumor assessment visits.  
Date of death.  
Censored  
Death after one missed 
adequate 
tumor 
assessment.  
Date of death.  
Censored 
Progression 
after 
one 
missed adequate tumor 
assessment.  
Date of progression.  
Progressed  
Progression after more 
than one missed adequate 
tumor assessment.  
Date of the last evaluable tumor 
assessment.  
Censored  
No progression.  
Date of the last evaluable tumor 
assessment.  
Censored  


Statistical Analysis Plan                                                                               
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 41 of 60 
 
 
ST-AD-008 version 06 
 
 
For iTtP, the progression date to be used for calculation should be the first date at which 
progression criteria are met (i.e, the date of iUPD) provided that iCPD is confirmed at the 
next assessment. If iUPD occurs, but is disregarded because of later iSD, iPR, or iCR, that 
iUPD date should not be used as the progression event date. 
If progression is not confirmed and there is no subsequent iSD, iPR, or iCR, the iUPD date 
should still be used if: 
• the patient stops protocol treatment because they were not judged to be clinically 
stable, or 
• no further tumor assessments are done, or 
• the next timepoint responses are all iUPD, and iCPD never occurs, or 
• the patient dies from his cancer. 
TtP according to RECIST and iRECIST will be listed for ASaT population. 
TtP according to RECIST and iRECIST will be displayed graphically using Kaplan-meier 
plots for efficacy and ASaT populations including count for numbers of patients at risk. 
5.5.4. Sensitivity Analyses for the Secondary Efficacy Analysis 
Secondary efficacy analysis will be repeated for ASaT population. 
5.5.5. Subgroup Analysis 
Not Applicable 
5.5.6. Exploratory Analysis 
5.5.6.1. PFS2 
PFS2 is defined as the time from the first day of study treatment until the date of second 
disease progression (i.e., progression on next-line anti-cancer treatment) or death and will be 
summarized using Kaplan-Meier estimates in the ASaT population. Patients with missing data 
(i.e., without second radiological disease progression) will be censored at the last time known 
to be alive.  
PFS2 data will be listed for ASaT population. 
PFS2 will be presented graphically using Kaplan-Meier plots for ASaT population. 
5.5.6.2. 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 in the ASaT population.  
Patients with missing data will be censored at the last date known to be alive. The last known 
date to be alive will be derived for patients at the analysis cutoff using the latest complete date 
among the following:  


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 42 of 60 
 
 
ST-AD-008 version 06 
 
• Patient assessment dates (blood draws [laboratory, PK], vital signs, ECOG 
performance status, ECG, tumor assessments, tumor measurement, or tumor biopsy 
dates)  
• Start and end dates of anti-cancer therapies administered after study treatment 
discontinuation  
• AE start and end dates  
• Concomitant medication start and end dates 
• Concurrent procedure date 
• Date of death collected on the ‘Death Details’ electronic Case Report Form (eCRF) 
• Date of last contact collected on the ‘Survival Status’ eCRF where status is ‘alive’; or 
date last known to be alive if status is ‘unknown’ 
• Study treatment start and end dates 
• Date of discontinuation on disposition eCRF pages (do not use if reason for 
discontinuation is lost to follow-up). 
Only dates associated with actual contact of the patient will be used in the derivation. Dates 
associated with a technical operation unrelated to patient status such as the date a blood 
sample was processed will not be used. Assessment dates after the cutoff date will not be 
applied to derive the last contact date, if applicable. 
OS data will be listed for ASaT population. 
OS will be presented graphically using Kaplan-Meier plots ASaT population. 
5.5.6.3. Duration of Follow up  
A reverse Kaplan-Meier analysis will be performed on OS in the ASaT population to estimate 
the median follow-up incorporating censoring rules and flipping event/censored events. 
Duration of Follow up data will be listed for ASaT population. 
Duration of Follow up will be presented graphically using Kaplan-Meier plots ASaT 
population. 
5.5.6.4. Assessment of the EGFR mutational status at baseline and at disease progression 
EGFR mutational status will be listed for ASaT population. 
5.5.6.5. Tumor Burden Analysis 
Absolute change from baseline and percent change from baseline for sum of target and new 
lesion diameters will be summarized in the efficacy population using descriptive statistics for 
each week of tumor assessment. The best percent change of sum of target and new target 
lesion will be presented in summary tables.  
A waterfall plot of maximum percent reduction in the sum of diameter of target lesions from 
baseline will be created  in the efficacy population. These plots will display the best 
percentage CFB in the sum of the diameter of all target lesions for each patient.  


Statistical Analysis Plan                                                                               
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 43 of 60 
 
 
ST-AD-008 version 06 
 
A spaghetti plot of percent reduction in the sum of target lesions from baseline will be created 
in the efficacy population to plot the change in tumor burden over time (in weeks from start 
of treatment) for each patient. 
Best percent change from baseline for sum of target lesion diameters is defined as the lowest 
(minimum) percent change from baseline and will be calculated with one decimal place.  
Sum of target lesion diameters will be listed for enrolled population. 
 
5.6. Safety 
5.6.1. Extent of Exposure and Compliance 
Exposure/Compliance 
nanrilkefusp alfa 
Cetuximab 
Cycle Started 
Patient received at least one dose 
of nanrilkefusp alfa in that cycle 
Patient received at least one dose 
of cetuximab in that cycle 
 
Cycle started in combination therapy is defined as patient receiving at 
least one dose of nanrilkefusp alfa and cetuximab in that cycle. 
Completed cycle 
Patient received 4 doses of nanrilkefusp alfa and 3 doses of cetuximab in 
that cycle, or patient started the next cycle. 
Duration of cycle (days) 
The day prior to the date of cycle start (day 1 in each cycle) will be 
considered as the end of the previous cycle. For the last cycle, 21 days will 
be used. 
Duration of exposure (days) 
Last dose date – Start dose date + 1 
Last dose date – Start dose date + 1 
 
Last dose date of either nanrilkefusp alfa or cetuximab, whichever is later 
– Start dose date of nanrilkefusp alfa or cetuximab, whichever is earlier + 
1 
Real dose administered 
(2 x Total volume administered) / 
patient weight (µg/kg) 
Actual dose per administration / 
BSA (mg/m²) 
Actual cumulative dose 
Sum of the real doses (µg/kg) 
administered 
Sum of the real doses (mg/m²) 
administered 
Duration of exposure (days) 
for completed cycles (*)  
Considering only completed cycles:  
End date of last completed cycle – Start dose date of nanrilkefusp alfa or 
cetuximab, whichever is earlier + 1 


Statistical Analysis Plan                                                                               
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 44 of 60 
 
 
ST-AD-008 version 06 
 
Exposure/Compliance 
nanrilkefusp alfa 
Cetuximab 
Actual dose intensity (*) 
Considering only completed cycles: 
Actual cumulative dose / Duration 
of exposure for completed cycles 
(days) in (µg/kg/day) 
Considering only completed cycles: 
Actual cumulative dose / Duration 
of exposure for completed cycles 
(days) in (mg/m²/day) 
 
Actual dose intensity by cycle 
(*) 
Considering only completed cycles: 
Actual cumulative dose in that cycle 
/ Duration of cycle (days) in 
(µg/kg/day) 
Considering only completed cycles: 
Actual cumulative dose in that cycle 
/ Duration of cycle (days) in 
(mg/m²/day) 
Intended dose intensity  
(Initial dose of nanrilkefusp alfa * 4 
doses)/ 21 day  
(As per protocol initial dosing)/ 21 
day  
Protocol initial dosing : 
900 mg/m² of BSA for cycle 1   
750 mg/m² of BSA for subsequent 
cycles 
Relative dose intensity by cycle 
(%) (*) 
Considering only completed cycles: 
100 * (Actual dose intensity by cycle 
/ Intended dose intensity) 
Considering only completed cycles: 
100 * (Actual dose intensity by 
cycle / Intended dose intensity) 
Overall relative dose intensity 
(%) (*) 
Considering only completed cycles: 
100 * (Actual dose intensity / 
Intended dose intensity) 
Considering only completed cycles: 
100 * (Actual dose intensity / 
Intended dose intensity) 
Compliance with planned dose 
(%)  
100 * (Real dose administered / 
Planned dose) at each dosing, 
taking into account per protocol 
dose changes  
100 * (Real dose administered / 
Planned dose) at each dosing, 
taking into account per protocol 
dose changes  
(*) only completed cycle as defined should be considered for derivation. 
 


Statistical Analysis Plan                                                                               
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 45 of 60 
 
 
ST-AD-008 version 06 
 
Descriptive statistics in the ASaT population and Efficacy population will be provided for: 
• Total number of cycles started 
• Total number of doses administered as well as the frequency of patients with 1, 2, 3, 4, 
5, 6, 7, 8, or ≥9 injections.  
• Duration of exposure 
• Number of patients with at least one dose adjustment 
• Actual cumulative dose 
• Actual dose intensity  
• Overall relative dose intensity  
For the combination therapy, the total number of cycles started and the duration of exposure 
will be summarized. 
Treatment compliance will be listed together with exposure for the ASaT population.  Missing 
data will not be imputed and only original data for those fields (for example, date fields) will 
be presented in the listing together with derived variables such as the calculated compliance 
(%) and exposure duration.  
Further, study treatment administration/infusion data (including total volume administered 
and dose adjustments, etc.) will be listed for the ASaT population.  
Mean of Relative Dose Intensity by Cycle will be presented graphically for ASaT population 
using bar chart. 
5.6.2. Dose Limiting Toxicities 
DLT evaluability is defined for patients in Safety cohorts as follows: 
• Patient completed the first 21-day cycle (DLT assessment period of 21 days) 
• Patient received all administrations of nanrilkefusp alfa during the DLT period as per 
schedule (±1 day) 
• Patient received cetuximab as per schedule (±1 day)  
• Patients experienced at least one DLT during the DLT assessment period, regardless 
of the number of nanrilkefusp alfa or cetuximab administrations during the DLT 
period 
DLTs will be identified in the Adverse event eCRF page with “Is the adverse event a Dose 
Limiting Toxicity?” =” Yes”.  
Patient needs to receive all administrations of nanrilkefusp alfa and cetuximab during the 
DLT period as planned per schedule. 
The incidence of DLTs by dose level will be summarized with counts and percentages by 
SOC and PT in ASaT population. 
A listing of all DLTs including the first and last dates of treatment will be presented for the 
ASaT population. 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 46 of 60 
 
 
ST-AD-008 version 06 
 
5.6.3. Adverse Events 
All AEs recorded on the eCRF will be coded using the MedDRA dictionary [most recent 
version at time of DB lock] and classified as either pre-treatment AEs or treatment–emergent 
AEs (TEAEs) as follows: 
• CRS symptoms will not be considered in the analysis to avoid duplication, as the 
diagnosis is reported instead. 
• Pre-treatment AEs are events that start prior to the start of the study treatment. 
• A TEAE is defined as an AE that started or worsened at or after the start of study 
treatment.  
• Treatment-Emergent Serious AEs (TESAEs) will be defined as TEAEs deemed by 
the investigator as Serious = “Yes”. 
• The relationship between a TEAE and nanrilkefusp alfa treatment is assessed as 
suspected or not suspected (same with cetuximab). A nanrilkefusp alfa treatment-
related TEAE will be defined as a TEAE considered by the investigator as suspected. 
A cetuximab-related TEAE will be defined as a TEAE considered by the 
investigator as suspected. 
• Assessment of AE severity/intensity will be based on the NCI-CTCAE (version 5.0). 
Severe TEAEs are defined as TEAEs assessed as being “Severe (=Grade 3)/ Grade 
4/Grade 5” in intensity. 
• TEAEs leading to dose reduction of nanrilkefusp alfa treatment are defined as 
TEAEs where “Dose reduced” is indicated as “Yes”. 
• TEAEs leading to temporary discontinuation of nanrilkefusp alfa treatment are 
defined as TEAEs where “Temporarily discontinued” is indicated as “Yes”. 
• TEAEs leading to permanent discontinuation of nanrilkefusp alfa treatment are 
defined as TEAEs where “Permanently discontinued” is indicated as “Yes”. 
• TEAEs leading to dose reduction of cetuximab treatment are defined as TEAEs 
where “Dose reduced” is indicated as “Yes”. 
• TEAEs leading to temporary discontinuation of cetuximab treatment are defined as 
TEAEs where “Temporarily discontinued” is indicated as “Yes”. 
• TEAEs leading to permanent discontinuation of cetuximab treatment are defined as 
TEAEs where “Permanently discontinued” is indicated as “Yes”. 
 
According to the eCRF, if a patient has (for example) 2 episodes of a same AE but a change 
in intensity, they will be identified using the 2 following CRF items: 
• Is this a change in severity of an already existing AE equals to “Yes” 
• If Yes, AE identifier. 


Statistical Analysis Plan                                                                               
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 47 of 60 
 
 
ST-AD-008 version 06 
 
In that case, to derive the TEAE flag, the AE identified/linked with the items above will be 
considered as the same “linked” AE but with 2 episodes. Thus, if worsening or both TEAE, 
the linked AE (both episodes) will be flagged as the TEAE.  
Linked AEs will be selected for analysis in tables based on their worst case scenario attribute 
e.g. maximum CTC grade, causal relationship, seriousness, treatment emergence and action 
taken out of all records.  
The ordering (the worst to best) for the following characteristics will be applied: 
• Action taken: permanently discontinued, temporarily discontinued, dose reduced, 
other action, no action taken. 
• Relationship: suspected, not suspected. 
• Toxicity Grade: Grade 5 to Grade 1. 
AE records within a linked AE can be given different treatment-emergence status. Treatment 
emergence for linked AEs will be established as those records in the linked AE with a 
worsening of severity from the preceding record.  
Adverse events will be summarized by default descriptive summary statistics for categorical 
variables for the ASaT population by overall as follows: 
Combination treatment related is defined as being related to either nanrilkefusp alfa or 
cetuximab (or both), and discontinuation of combination treatment means discontinuation of 
either nanrilkefusp alfa or cetuximab (or both). 
• An overview of TEAEs including the number and percentage of patients with at least 
one of each mentioned TEAE type: 
o Any TEAE 
 Leading to dose reduction of nanrilkefusp alfa  
 Leading to temporary discontinuation of nanrilkefusp alfa  
 Leading to dose reduction and temporary discontinuation of 
nanrilkefusp alfa. 
 Leading to permanent discontinuation of nanrilkefusp alfa 
 Leading to permanent discontinuation of combination treatment 
 Serious 
 Grade 1 severity (mild) 
 Grade 2 severity (moderate) 
 Grade 3 severity (severe) 
 Grade 4 severity (life-threatening or disabling) 
 Grade 5 severity (death related to TEAE) 
 ≥Grade 3 severity (severe, life-threatening, disabling, death related to 
TEAE) 
o Any nanrilkefusp alfa-related TEAE 
 Leading to permanent discontinuation of nanrilkefusp alfa 
 Leading to permanent discontinuation of combination treatment. 
 Serious 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 48 of 60 
 
 
ST-AD-008 version 06 
 
 Grade 1 severity (mild) 
 Grade 2 severity (moderate) 
 Grade 3 severity (severe) 
 Grade 4 severity (life-threatening or disabling) 
 Grade 5 severity (death related to TEAE) 
 ≥Grade 3 severity (severe, life-threatening, disabling, death related to 
TEAE) 
o Any combination-related TEAE 
 Leading to permanent discontinuation of combination treatment 
 Serious 
 Grade 1 severity (mild) 
 Grade 2 severity (moderate) 
 Grade 3 severity (severe) 
 Grade 4 severity (life-threatening or disabling) 
 Grade 5 severity (death related to TEAE) 
 ≥Grade 3 severity (severe, life-threatening, disabling, death related to 
TEAE) 
• The number and percentage of patients reporting each TEAE and the count of number 
of events will be summarized by SOC and PT for the following types of TEAEs in the 
ASaT population: 
o TEAEs 
o TEAEs occurring in ≥ 5% of patients 
o TEAEs leading to dose reduction of nanrilkefusp alfa 
o TEAEs leading to temporary discontinuation of nanrilkefusp alfa 
o TEAEs leading to dose reduction and temporary discontinuation of 
nanrilkefusp alfa  
o TEAEs leading to permanent discontinuation of nanrilkefusp alfa  
o TEAEs leading to temporary discontinuation of cetuximab 
o TEAEs leading to permanent discontinuation of cetuximab  
o TEAEs leading to permanent discontinuation of combination treatment  
o TEAEs leading to death 
o Serious TEAEs 
o Non-serious TEAEs occurring in ≥5% of patients 
o TEAEs with ≥ Grade 3 severity 
o TEAEs with ≥ Grade 3 severity occurring in ≥ 5% of patients 
o TEAEs by maximum severity grade 
o nanrilkefusp alfa-related TEAEs 
o nanrilkefusp alfa-related TEAEs leading to permanent discontinuation of 
nanrilkefusp alfa 
o nanrilkefusp alfa-related TEAEs leading to death 
o Serious nanrilkefusp alfa-related TEAEs 
o nanrilkefusp alfa-related TEAEs with ≥ Grade 3 severity 
o nanrilkefusp alfa-related TEAEs by maximum severity grade 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 49 of 60 
 
 
ST-AD-008 version 06 
 
o Combination-treatment-related TEAEs 
o Combination-treatment-related TEAEs leading to death 
o Serious combination-treatment-related TEAEs 
o Combination-treatment-related TEAEs with ≥ Grade 3 severity 
o Combination-treatment-related TEAEs by maximum severity grade 
 
• The number and percentage of patients reporting each TEAE and the count of number 
of events will be summarized by PT for the following types of TEAEs: 
o TEAEs 
o TEAEs occurring in ≥5% of patients 
o nanrilkefusp alfa-related TEAEs 
o Combination-treatment-related TEAEs 
o Serious TEAEs 
o Serious nanrilkefusp alfa-related TEAEs 
o Serious combination-treatment-related TEAEs 
• The number and percentage of patients who died will be summarized by the primary 
and secondary reason of death in the enrolled population.  
In the above summaries, patients with more than one TEAE within a particular SOC are 
counted only once for that SOC. Similarly, patients with more than one TEAE within a 
particular PT are counted only once for that PT. 
For summaries by maximum severity, patients with multiple TEAEs within a particular SOC 
or PT will be counted under the category of their most severe TEAE within that SOC or PT.    
 
Summaries by SOCs and PTs will be sorted by SOCs by their descending Order (MedDRA) 
and PTs within SOC by descending order of total incidence. Where preferred terms tie PTs 
will be sorted alphabetically. 
 
All AE data will be listed and Pre-treatment AEs and TEAEs will be presented together. 
Treatment-emergence status will be flagged in the listing. The listing will present the relative 
start and stop day of the AE calculated relative to the first dose of treatment and will be 
presented for those patients who received at least one dose of treatment. If the AE is 
“Ongoing” it will be indicated as such in the listing and the relative stop day will not be 
calculated. Only original dates will be presented in the listing even though the relative day 
may be based on an imputed date. 
 
In addition, the following listings will be presented: 
• Listing of deaths 
• Listing of AEs 
• Listing of serious TEAEs 
• Listing of TEAEs leading to temporary discontinuation of nanrilkefusp alfa  


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 50 of 60 
 
 
ST-AD-008 version 06 
 
• Listing of TEAEs leading to dose reduction of nanrilkefusp alfa  
• Listing of TEAEs leading to permanent discontinuation of cetuximab  
TEAE occurring in >= 10% of patients will be presented graphically for ASaT population. 
5.6.4. Laboratory Evaluations 
Data for the following coagulation, hematology, and biochemistry analytes received from 
local laboratory are to be measured at the scheduled visits indicated in the study flowchart.  
All parameters recorded in the study will be included in the listings, but only parameters 
defined in   
Table 7 specifies the tests that will be included in the summaries.  
Table 7 Laboratory Tests to Be Included in Summaries 
Hematology  
Test (SI unit) 
Biochemistry 
Test (SI unit) 
Coagulation 
o Hemoglobin (g/L) 
o Differential WBC (109/L and %) 
• Neutrophils 
• Lymphocytes 
o Absolute lymphocyte count 
o Platelet count (109/L)  
 
o Alanine aminotransferase (ALT) 
(U/L) 
o Aspartate aminotransferase (AST) 
(U/L) 
o Total Bilirubin (mmol/L) 
o Lactate Dehydrogenase  
o Alkaline phosphatase (U/L)  
o C-reactive protein 
o Albumin (g/L) 
o Creatinine (mmol/L) 
o Creatinine Clearance (mL/s) 
 
o D-dimer 
 
All laboratory data will be reported in SI units. All quantitative laboratory test values at each 
assessed visit will be compared with the relevant reference range in SI units and categorized 
as: 
Low: Below the lower limit of the reference range.  
Normal: Within the reference range (upper and lower limits included). 
High: Above the upper limit of the reference range.  
For analysis purposes, values preceded by a “<” or a “>” sign (i.e. those below or above the 
limits of quantification) will be considered equal to the lower or upper limit of quantification, 
respectively.  
Laboratory data will be summarized by default descriptive summary statistics for continuous 
and categorical variables for the ASaT population by overall as follows: 
•  Observed values and change from baseline at each scheduled assessed visit for each 
standard continuous laboratory parameter 


Statistical Analysis Plan                                                                               
 
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 51 of 60 
 
 
ST-AD-008 version 06 
 
Listings of all clinical laboratory data including derived change from baseline will be provided 
for the screened population. Within each listing, laboratory values outside the normal ranges 
will be flagged as either high or low for applicable laboratory assessments. 
Hematology, Coagulation and Biochemistry results for selected laboratory parameters for 
each scheduled visit will be displayed graphically using boxplots showing the summary data 
per scheduled assessment, including an overlaid mean profile line and approximate lower 
limit of normal reference range (LLN) and upper limit of normal reference range (ULN) 
reference lines indicated by overall for ASaT population. 
5.6.5. Hy’s Law for Liver Function Tests 
Hepatic function abnormality defined by an increase in AST and/or ALT to ≥3xULN 
concurrent with an increase in total bilirubin to ≥2xULN but without increase in alkaline 
phosphatase (i.e., alkaline phosphatase <2xULN) meets the criteria for Hy’s law and raises 
the concern for drug-induced liver injury when no other cause is identified. 
The summary of liver function tests will include the following categories, and the number and 
percentage of patients meeting Hy’s Law at each scheduled visit during the on-treatment 
period will be summarized for ASaT population.  
An eDISH figure displaying patients who reach 3xULN for ALT or AST, plus 2xULN for 
total bilirubin and thus are at risk for a drug induced liver injury according to Hy’s law will 
be presented for ASaT population. A listing of patients at risk will also be presented for 
screened population. 
5.6.6. Vital Signs 
The analyses described below will be conducted for the following vital signs assessments 
respectively: 
• SBP (mmHg); 
• DBP (mmHg); 
• Heart rate (bpm); 
• Body Temperature (°C) 
 
The following will be summarized by overall for the ASaT population: 
•  Observed values and change from baseline at each scheduled assessed visit for each 
standard vital sign parameter using default summary statistics for continuous 
variables 
A listing of all vital signs data including derived change from baseline will be provided for 
the screened population. 
The actual values and CFB for each scheduled study visit for selected vital signs parameters 
will be plotted at each time point using a line plot including 95% CI bars around the mean, 
this will be done by overall for ASaT population. 
 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 52 of 60 
 
 
ST-AD-008 version 06 
 
Total counts and percentages of patients will be presented for the following: 
• Maximum increase from baseline in SBP and DBP (mmHg): 
o <20 
o >=20 and <40 
o >=40 and <60 
o >=60 
• Maximum decrease from baseline in SBP and DBP (mmHg): 
o <20 
o >=20 and <40 
o >=40 and <60 
o >=60 
• Maximum increase from baseline in heart rate (bmp): 
o <30 
o >=30 
• Maximum decrease from baseline in heart rate (bmp): 
o <30 
o >=30 
• Maximum postdose heart rate (bmp) 
o <50 
o >=50 and <120 
o >=120 
5.6.7. Body Surface Area 
The analyses described below will be conducted for the following BSA assessments 
respectively: 
• Height (cm); 
• Weight (kg); 
• Body Surface Area (m2) 
A listing of all body surface area data including derived change from baseline will be provided 
for the screened population. 
 
5.6.8. Electrocardiograms 
The following ECG assessments will be taken during the study: 
• An overall investigator assessment classified as normal / abnormal, not clinically 
significant / abnormal, clinically significant / unevaluable / unknown 
• Heart rate (bpm); 
• PR interval (msec); 
• QRS interval (msec); 
• QT interval (msec); 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 53 of 60 
 
 
ST-AD-008 version 06 
 
• Bazett Corrected QT (QTcB) interval (msec);  
• Fridericia Corrected QT (QTcF) interval (msec) 
 
A listing of all ECG data will be provided for the screened population. 
 
5.6.9. Left Ventricular Ejection Fraction (LVEF) 
LVEF data will be listed for ASaT population.  
5.6.10. Physical Examination 
Physical examination data will be listed for each patient at each assessed visit for the screened 
population. 
5.6.11. Other Safety Variables 
5.6.11.1. Eastern Cooperative Oncology Group (ECOG) 
Total counts and percentages of patients will be presented for the ECOG performance status 
scores on the ASaT population.  
ECOG performance status scores will be listed for each patient at each assessed visit for the 
ASaT population. 
5.6.11.2. Pregnancy Test 
Pregnancy test results will be listed for each patient at each assessed visit for the screened 
population. 
5.6.12. Interim Analysis and Data Monitoring 
An analysis for futility will be performed when the sample size is considered enough for such 
analysis. Efficacy data and outputs will also be a part of the IDMC review.  
The futility analysis will be conducted once all patients in the efficacy population planned for 
futility analysis will have post-baseline tumor assessment data or discontinue the treatment 
before the post-baseline assessment. Patients in efficacy population who discontinue and have 
no evaluable post-baseline tumor assessment available will be considered as non-responders.  
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 method for the ORR (alpha = 
0.2, alpha = 0.1 one-sided) will be used. The analysis will be based on the efficacy population.  
If the ORR is:  
• lower than the minimal ORR, and  
• the 80% CI for the ORR does not include the minimal ORR,  


Statistical Analysis Plan                                                                               
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 54 of 60 
 
 
ST-AD-008 version 06 
 
It will be concluded that the combination treatment is futile as compared to cetuximab 
treatment alone and thus the study will be discontinued. However, patients still on treatment 
can continue combination therapy if recommended by the IDMC.  
The criteria for conclusion of futility are defined as follows:  
• Benchmark ORR = 20%; minimal ORR = 28.8%; desired ORR = 36.8%  
• N = 16 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. 
 
For the purposes of interim analyses, in the case of ongoing patients with any unconfirmed 
response and for whom a confirmatory scan is still pending: 
• Responders (PR, CR) or patients with SD that, at the time of the futility analysis, did 
not yet have a second (confirmatory) tumor assessment performed will be considered 
to have an Unconfirmed response (PR, CR) or Unconfirmed SD as BOR, respectively. 
Such BORs will be presented with “Unconfirmed” label. 
• ORR will also include Unconfirmed PR and Unconfirmed CR in the numerator. 
5.7. Pharmacokinetic Analysis  
The serum concentrations will be evaluated for nanrilkefusp alfa analyte and may or may not 
be evaluated for the cetuximab analyte (cetuximab samples will be collected to be analyzed 
later during the course of the study, if needed). Serum samples will be collected from all 
patients in the initial safety cohorts and from the first 12 patients in the main study cohort. 
The actual date and time (24-hour clock time) of each serum sample will be recorded. 
The following PK parameters will be determined where possible from the serum 
concentrations of nanrilkefusp alfa using non-compartmental methods in the validated 
software program Phoenix WinNonlin (Certara, Version 8.3.5 or higher): 
Parameter 
Definition 
AUClast 
area under the concentration-time curve over the last measurable 
concentration (Tlast)  (Cycle 1 Day 1 only) 
AUC(0-4h) 
area under the concentration-time curve over time 0 to 4 hours 
postdose (Cycle 1 Day 1 only) 
AUC(0-24h) 
area under the concentration-time curve over time 0 to 24 hours 
postdose (Cycle 1 Day 1 only) 
Cmax 
observed maximum concentration (Cycle 1 Day 1 only) 
C2h 
observed concentration at 2 hours postdose (Cycle 1 and 3 Days 1) 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 55 of 60 
 
 
ST-AD-008 version 06 
 
Parameter 
Definition 
Ctrough 
observed trough concentration (Cycle 1 Day 2 predose = Cycle 1 Day 
1 trough; Cycle 1 Day 9 predose = Cycle 1 Day 8 trough; Cycle 3 
Day 1 predose = Cycle 2 Day 9 trough)  
Tmax 
time to maximum concentration (Cycle 1 Day 1 only) 
Tlast 
time of the last measurable concentration (Cycle 1 Day 1 only) 
RC2h, and RCtrough 
Accumulation Ratio of C2h on Cycle 3 Day 1/Cycle 1 Day 1 
Accumulation Ratio of Ctrough on Cycle 2 Day 9/Cycle 1 Day 1 
 
 
For the Cycle 1 Day 1 profile, the Cycle 1 Day 2 predose concentration will be the 24 hour timepoint. 
 
If cetuximab concentrations are available, Ctrough will be reported for Cycle 1 (predose 
concentration on Day 8 and 15) and Cycle 3 (predose concentration on Day 1). 
Additional PK parameters may be determined where appropriate. 
The units of the PK parameters will be based on the concentration units provided by the 
bioanalytical laboratory and the dose units used in the study. 
Pharmacokinetic analysis will be carried out where possible using actual dose administered 
(µg for nanrilkefusp alfa) and actual postdose blood sampling times. If an actual time is 
missing, the sample concentration result will be treated as missing unless there is scientific 
justification to include the result using the nominal time.  
The parameters Cmax, Ctrough, C2h, Tlast, and Tmax will be obtained directly from the 
concentration-time profiles. If Cmax occurs at more than 1 timepoint, Tmax will be assigned to 
the first occurrence of Cmax.  
The area under the concentration-time curve (AUC) parameters will be calculated using the 
linear trapezoidal rule for increasing concentrations and the logarithmic rule for decreasing 
concentrations (linear up/log down rule). 
 
5.7.1. Criteria for Calculation and Reporting of Area Under the Concentration-time 
Curve 
The minimum requirement for the calculation of AUC will be the inclusion of at least 
3 consecutive concentrations above the lower limit of quantification. If there are only 
3 consecutive concentrations, at least 1 should follow Cmax. 


Statistical Analysis Plan                                                                               
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 56 of 60 
 
 
ST-AD-008 version 06 
 
For calculation of the partial AUC parameters, if the end interval PK sample is collected 
slightly earlier than the nominal time, the AUC parameter will be calculated using the end 
interval sample if the collection is within ± 10% of the nominal sampling time. 
5.7.2. Criteria for Handling Concentrations Below the Limit of Quantification or 
Missing Concentrations for Pharmacokinetic Analysis 
Serum concentrations below the limit of quantification (BLQ) will be assigned a value of 0 
before the first measurable concentration and thereafter BLQ concentrations will be treated 
as missing. The following rules apply to the specific situations defined below: 
● If an entire concentration-time profile is BLQ, it will be excluded from PK analysis. 
● Where 2 or more consecutive concentrations are BLQ at the end of a concentration-
time curve, the curve will be deemed to have terminated and any further quantifiable 
concentrations will be set to missing for the calculation of the PK parameters, unless 
they are considered to be a true characteristic of the profile of the drug. 
● If a predose serum concentration is missing on the first day of dosing day (Cycle 1 
Day 1), it will be set to 0 by default within Phoenix WinNonlin. 
5.7.3. Treatment of Outliers in Pharmacokinetic Analysis 
If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude the value from the PK analysis. However, the 
exclusion of any data must have strong justification and will be documented in data review 
meeting minutes. 
Any quantifiable predose concentration value on the first day of dosing (Cycle 1 Day 1) will 
be considered anomalous and set to missing which Phoenix WinNonlin will apply as 0 by 
default for the PK analysis. 
 
 
5.7.4. Presentation of Pharmacokinetic Data  
A listing of PK blood sample collection times and serum concentrations will be presented for 
evaluated analyte(s) separately for all patients for the ASaT Population.  
PK concentrations will be summarized for the PK Population by analyte, cycle, profile day, 
treatment, and protocol scheduled times using appropriate summary statistics. See Section 
4.2.8  for the handling of serum concentrations that are BLQ and the summary statistics to be 
presented.  
Individual concentrations deemed to be anomalous will be flagged in the listings and excluded 
from the summary statistics. Individual and summary concentration-time figures will be 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 57 of 60 
 
 
ST-AD-008 version 06 
 
presented on both linear and semi-logarithmic scales. PK concentrations by analyte, cycle, 
profile day, treatment, and nominal time postdose will be displayed for the PK Population 
using arithmetic mean (+ SD) figures and median figures. Overlaying individual figures and 
individual figures will be displayed using actual time postdose. For all individual and 
summary concentration-time figures: Cycle 1 Day 2 predose will be set as the 24 hour 
postdose concentration for the Cycle 1 Day 1 profile for nanrilkefusp alfa; the Cycle 1 Day 8 
predose will be set as the 168 hour postdose concentration for the Cycle 1 Day 1 profile for 
cetuximab. 
A listing of PK parameters will be presented for evaluated analyte(s) separately for all patients 
in the PK Population.  
PK parameters will be summarized for the PK Population by analyte, cycle, profile day, and 
treatment using  the summary statistics: geometric mean, CV% (inter-patient), arithmetic 
mean, SD, median, minimum, maximum, number of patients with data available (n), and 
number of patients in analysis set (N), with the exception of Tmax and Tlast where only N, n, 
minimum, median and maximum will be presented. PK parameter summary statistics will be 
calculated only if there are at least 3 evaluable data (n≥3) available, otherwise only the N, n, 
minimum and the maximum are presented and other statistics are shown as not calculated 
(NC). 
5.8. Immunogenicity Assessments  
5.8.1. Anti-Drug Antibodies (ADAs) against nanrilkefusp alfa  
Samples for ADAs will be collected to assess nanrilkefusp alfa immunogenicity, correlation 
with PK, and potential AEs associated with ADAs against nanrilkefusp alfa and for the 
prediction of nanrilkefusp alfa ADA production, including neutralizing ADAs. The 
correlation assessments will not be reported. 
The presence or absence of anti-drug antibodies, neutralizing ADA’s and titer categorizations 
will be summarized by timepoint and actual nanrilkefusp alfa dose level for the ASaT 
population. 
Immunogenicity data will be listed for the screened population. 
5.8.2. ADAs against cetuximab  
Samples for cetuximab ADAs will be collected. The decision to analyze the samples to assess 
cetuximab immunogenicity will be taken at a later date and described separately.  
5.9. Biomarkers  
Biomarker collection data from eCRF will be listed for screened population. Biomarkers 
results will be reported separately for the CSR. 


Statistical Analysis Plan                                                                               
 
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 58 of 60 
 
 
ST-AD-008 version 06 
 
6. Changes in the Conduct of the Study or Planned Analysis 
The following changes or precisions from protocol specified statistical analyses are made in 
this SAP. 
6.1. SD and iSD derivation 
SD and iSD needs to last at least 6 weeks from the start of study treatment and not weeks from 
the baseline scan as it is mentioned in protocol section 9.3.3.1. 
6.2. Duration of Follow-Up 
Duration of Follow-Up was added as a reverse Kaplan-Meier analysis on OS to estimate the 
median follow-up incorporating censoring rules and flipping event/censored events. 
6.3. PK parameters 
Adjusted PK parameters from those listed in the protocol will be derived.  The modified PK 
parameters documented in section 5.7 include only those that are calculable by non-
compartmental analysis based on the adjusted PK sampling timepoints in protocol amendment 
1. 
 
 


Statistical Analysis Plan                                                                                
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 59 of 60 
 
 
ST-AD-008 version 06 
 
7. Appendices 
Appendix 1: Document History 
Document Version, Status, Date 
Summary / Reason for Changes 
Version 1.0, Final, 19JAN2023 
Not applicable; the first version 
Version 2.0, Final, 17MAY2023 
• 
Minor updates due to protocol amendment 1 in study 
objectives 
• 
SOT101 updated to nanrilkefusp alfa 
• 
Details on the derivation and presentation of PK 
parameters by non-compartmental analysis are 
included to reflect the adjusted PK sampling 
schedule in protocol amendment 1. A separate PK 
analysis plan is no longer required. 
Version 2.0, Final, 17MAY2023 
• 
Name was changed from Labcorp Drug 
Development to Fortrea 
 


Statistical Analysis Plan                                                                               
Fortrea Study: 000000235712                                                        Protocol Reference: SC105 
                                                                                                                          (AURELIO-05) 
 
 
Sponsor Final, Version 2.0, 17MAY2023 
Page 60 of 60 
 
 
ST-AD-008 version 06 
 
8. References 
 
1Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS 
exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, 
non-inferiority phase 3 study. May 2014. Available at 
https://pubmed.ncbi.nlm.nih.gov/24739896/ 
 
2New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
January 2009. Available at https://pubmed.ncbi.nlm.nih.gov/19097774/ 
 
3iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. 
March 2017. Available at https://pubmed.ncbi.nlm.nih.gov/28271869/ 
 
4Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 
 
5ICH. Structure and Content of Clinical Study Reports, Guideline E3, 1995. Available at  
https://database.ich.org/sites/default/files/E3_Guideline.pdf 
 
6ICH. Statistical Principles for Clinical Trials, Guideline E9, 1998. Available at 
https://database.ich.org/sites/default/files/E9_Guideline.pdf