A Multicenter Open-label Phase 1/1b Study to Evaluate the Safety and Preliminary Efficacy of SO-C101 as Monotherapy and in Combination With Pembrolizumab in Patients With Selected Advanced/Metastatic Solid Tumors
Phase: PHASE1
Conditions: Thyroid Cancer, Renal Cell Carcinoma, Non Small Cell Lung Cancer, Small-cell Lung Cancer, Bladder Cancer, Melanoma, Merkel Cell Carcinoma, Skin Squamous Cell Carcinoma, Microsatellite Instability High, Triple Negative Breast Cancer, Mesothelioma, Thymic Cancer, Cervical Cancer, Biliary Tract Cancer, Hepatocellular Carcinoma, Ovarian Cancer, Gastric Cancer, Head and Neck Squamous Cell Carcinoma, Anal Cancer
Sponsor: SOTIO Biotech AG

 
 
 
Clinical Study Protocol SC103 
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1 TITLE PAGE 
Study Protocol number 
SC103 
Study Protocol title 
A multicenter open-label phase 1/1b study to evaluate the safety 
and preliminary efficacy of SO-C101 as monotherapy and in 
combination with pembrolizumab in patients with selected
advanced/metastatic solid tumors 
Sponsor 
SOTIO Biotech AG 
Hochbergerstrasse 60C 
4057 Basel 
Switzerland 
Investigational medicinal 
products 
SO-C101 
Pembrolizumab 
Indication 
Selected advanced/metastatic solid tumors 
Phase 
1/1b 
IND number 
140011 
EudraCT number 
2018-004334-15 
GCP statement 
This study will be conducted in accordance with current Good 
Clinical Practice (GCP), the provisions of International Council 
for Harmonisation (ICH) Guidelines, the Declaration of 
Helsinki and its amendments, and applicable laws and 
regulations of all countries with sites participating in the study. 
Confidentiality statement 
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. 
 
 

 
 
 
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SIGNATURES / PROTOCOL APPROVAL AND RELEASE 
We, the undersigned, have read this Protocol and its appendices and agree that they contain 
all the necessary information required for the conduct of this study. 
 
For SOTIO Biotech AG: 
 
 
 
 

 
 
 
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SIGNATURES / PROTOCOL APPROVAL AND RELEASE 
I, the undersigned, have read this Protocol and its appendices and agree that they contain all 
the necessary information required for the conduct of this study. 
 
Coordinating investigator: 
 
Prof. Aurélien Marabelle, M.D., Ph.D. 
Clinical Director  
Cancer Immunotherapy Program 
Institute Gustave Roussy 
Villejuif, France 
Signature: …………………………………… 
Date:         …………………………………… 

 
 
 
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INVESTIGATOR’S DECLARATION AND SIGNATURE 
I have read this Protocol and I agree that it contains all the necessary details for carrying out this clinical study. 
I will conduct this clinical study as described and I will complete it within the time designated. I verify that I 
am suitably qualified by education, scientific medical training, and experience to conduct this clinical study. 
Documentation of my qualifications and professional affiliations are contained in my up-to-date curriculum 
vitae. 
I will provide the supplied copies of the Protocol and all information relating to pre-clinical and previous 
clinical experience (e.g., Investigator’s Brochure) to all staff in my unit who will participate in this clinical 
study. I will discuss this material with them to ensure that they are fully conversant with the Protocol, the 
medical treatment, and the conduct of the clinical study, and that they will handle the data and information 
generated in the clinical study confidentially. 
I will conduct the clinical study in accordance with the current version of the Declaration of Helsinki (adopted 
by the 18th World Medical Association General Assembly, Helsinki, Finland, June 1964 and amended by the 
64th World Medical Association General Assembly, Fortaleza, Brazil, October 2013) and ICH guidelines on 
GCP (E6[R2] Step 4 version dated 09-Nov-2016), and the moral, ethical, and scientific principles that justify 
medical research. The clinical study will be conducted in accordance with the relevant laws and regulations 
relating to clinical studies and the protection of patients of the country in which the clinical study will be 
performed. All patients will be informed comprehensively about the nature of the clinical study and will give 
their written consent to participate before entry into the clinical study. They will be informed that they may 
withdraw from the clinical study at their discretion at any time. I will use only the information sheet and 
consent form approved by SOTIO Biotech AG (hereinafter referred to as “sponsor” or “SOTIO”) and the 
Institutional Review Board (IRB) or Ethics Committee (EC) which has reviewed this clinical study. I will 
supply SOTIO with any material written by myself (e.g., summary of clinical study) which is given to the 
IRB/EC in support of the application. 
Where applicable and required, the information contained in the electronic Case Report Forms (eCRFs) will 
be transcribed from my records, reports, and manuscripts. The eCRF may be the original source document for 
certain items. Either I or an appointed person will attest to the authenticity of the data and accuracy and 
completeness of the transcription by signing the eCRFs. I agree to the audit and monitoring procedures that 
involve verification of clinical study records against the original records by direct access. Should it be 
requested by government regulatory agencies, I will make available additional background data from my 
records, and where allowed from the hospital or institution where the clinical study was conducted. I certify 
that any laboratory, excluding the central laboratory (laboratories) appointed for the clinical study, in which 
laboratory parameters will be determined, is subject to regular external quality control. 
I consent that SOTIO and its designees can collect, process, transfer, use, and store my personal data and 
details relating to my professional activities for the purposes of this clinical study. 
I understand that the eCRFs and other data pertinent to this clinical study are the property of SOTIO and are 
confidential. I will provide SOTIO with clinical study data in a way that prevents identification of any patient. 
Investigator’s signature: 
 
        ________________________________________________ 
Date: 
 
 
 
        ________________________________________________ 
Printed name: 
 
 
        ________________________________________________ 
Street address: 
 
 
        ________________________________________________ 
Telephone number: 
 
        ________________________________________________ 
Contact information 
Sponsor’s medical monitor: 
         ________________________________________________ 
24-hr emergency telephone number:   ________________________________________________ 
Other contact information 
Full contact details for each investigational site, the sponsor, and key coordinating and operational personnel 
involved in this clinical study will be maintained in the Trial Master File and in the Investigator Site File. 

 
 
 
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2 CLINICAL PROTOCOL SYNOPSIS 
Investigational 
medicinal products 
1. SO-C101 
2. Pembrolizumab 
Protocol number 
SC103 
Study phase 
1/1b 
Study title 
A multicenter open-label phase 1/1b study to evaluate the safety and 
preliminary efficacy of SO-C101 as monotherapy and in 
combination with pembrolizumab in patients with selected 
advanced/metastatic solid tumors 
Background  
and rationale 
Over the past decade, the power of the immune system to kill 
malignant tumors using cancer immunotherapy has emerged as a 
promising approach to treat a broad range of human cancers. 
Therapy with recombinant interleukin (IL)-2, a T-cell and natural 
killer-cell growth factor, was one of the earliest forays in 
immunotherapy that yielded some successes. 
IL-15 is a member of the common γ-chain family of cytokines that 
shares functional activities with IL-2. The main nonredundant role 
of IL-15 in immune homeostasis is in the maintenance of 
long-lasting T-cell immunity by supporting the proliferation and 
survival of memory CD8+ T cells. The effects of IL-15 are mediated 
by interactions with IL-15 receptor (IL-15R) chains , ß, and . 
IL-15 can bind to the IL-15R complex of responding cells 
(cis-presentation) or complex with IL-15Rα present on accessory 
cells and bind the IL-15Rβγ complex on responding cells 
(trans-presentation). Trans-presentation represents the main route of 
IL-15 signaling. 
While initially showing promise as a cancer therapeutic, the efficacy 
of IL-15 was limited by its short in vivo half-life. More recently, 
various approaches have been developed to improve the in vivo 
half-life and efficacy of IL-15, largely by generating IL-15/IL-15Rα 
conjugates. 
In order to make use of the enhanced biological activity of the 
IL-15/IL-15R complex for the treatment of cancer and to overcome 
the need for endogenous IL-15R or coadministration of IL-15 with 
IL-15R, we engineered a fusion protein which consists of the 
N-terminal sushi domain of human IL-15R covalently coupled via 
a linker of 20 amino acids to human IL-15 (receptor-linker-IL-15 
[SO-C101]). Before being acquired by SOTIO, SO-C101 was 
referred to as RLI-15. 

 
 
 
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In vitro, SO-C101 was superior to IL-15 in driving cell proliferation 
and survival. In experiments with human T cells, SO-C101 bound 
with high affinity to IL-15Rβγ and the kinetics of SO-C101 
internalization was slower than that of IL-15. IL-15 and SO-C101 
dose-dependently activated similar signaling pathways. However, 
the kinetics and duration of these activations were markedly 
different; SO-C101-induced signaling was slower to start but lasted 
longer than signaling induced by IL-15. 
Clinical studies conducted with compounds with a similar mode of 
action; e.g., ALT-803, an IL-15/IL-15Rα complex fused to an IgG1 
Fc in which IL-15 is additionally mutated; showed that ALT-803 has 
a favorable safety profile and is able to induce a robust 
immune-stimulatory response. In addition, ALT-803 in combination 
with nivolumab showed promising clinical activity. 
This study is planned based on the encouraging results of the pre-
clinical studies with SO-C101 and the clinical unmet need for 
patients who do not respond or develop resistance to programmed 
cell death protein 1 (PD-1) and programmed cell death ligand 1 
(PD-L1) antibody treatment. The combination of SO-C101 with 
immune checkpoint inhibitors is hypothesized to extend the 
therapeutic benefit to a larger proportion of patients. 
This study will assess the safety and tolerability of SO-C101 
administered as monotherapy and in combination with an anti-PD-1 
antibody 
(pembrolizumab) 
in 
patients 
with 
selected 
relapsed/refractory advanced/metastatic solid tumors. 
SO-C101 will be administered on treatment days either as a once 
daily dose (dosing schedule 1) or twice a day as 2 divided doses 
(50%:50%) with the second dose on each treatment day being 
administered 8 hours (±15 min) after the first dose (dosing schedule 
2). 
This first-in-human (FIH) study of SO-C101 will consist of the 
following parts: 
1. Part A will assess the safety and tolerability of SO-C101 
monotherapy for dosing schedule 1 to define the maximum 
tolerated dose (MTD) and/or the recommended phase 2 dose 
(RP2D) 
2. Part A1 will assess the safety and tolerability of SO-C101 
monotherapy for dosing schedule 2 to define the MTD and/or the 
RP2D 
3. Part B will assess the safety and tolerability of SO-C101, dosing 
schedule 1, in combination with pembrolizumab and the MTD 
and/or RP2D 
4. Part B1 will assess the safety and tolerability of SO-C101, 
dosing schedule 2, in combination with pembrolizumab and the 
MTD and/or RP2D 

 
 
 
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5. Part D will be a dose expansion part at the RP2D dose level 
identified in Part A to further assess the safety, tolerability, and 
preliminary efficacy of the RP2D of SO-C101 monotherapy for 
dosing schedule 1 in selected indications 
6. Part D1 will be a dose expansion part at the RP2D dose level 
identified in Part A1 to further assess the safety, tolerability, and 
preliminary efficacy of the RP2D of SO-C101 monotherapy for 
dosing schedule 2 in selected indications 
Objectives 
PART A (SO-C101 dosing schedule 1, monotherapy, dose 
escalation) 
Primary objectives 
• To assess the safety and tolerability of SO-C101 given as 
monotherapy 
• To determine the MTD and/or RP2D of SO-C101 given as 
monotherapy 
Secondary objectives 
• To characterize the pharmacokinetics (PK) of SO-C101 
• To characterize the pharmacodynamics (PD) of SO-C101 in 
peripheral blood 
• To determine the preliminary efficacy of SO-C101 monotherapy 
as measured by objective response rate (ORR), duration of 
response (DOR), clinical benefit rate (CBR), and progression-free 
survival (PFS) according to Response Evaluation Criteria in Solid 
Tumors for immune-based therapeutics (iRECIST) 
• To determine the immunogenicity of SO-C101 given as 
monotherapy 
Exploratory objectives 
• To explore the mechanistic effects of SO-C101 on selected 
immune cell populations in tumor tissue samples 
• To assess overall survival (OS) at 6 months after the End of 
treatment (EoT) visit 
PART A1 (SO-C101 dosing schedule 2, monotherapy, dose 
escalation) 
Primary objectives 
• To assess the safety and tolerability of SO-C101 given as 
monotherapy 
• To determine the MTD and/or RP2D of SO-C101 given as 
monotherapy 
Secondary objectives 
• To characterize the PK of SO-C101 
• To characterize the PD of SO-C101 in peripheral blood 

 
 
 
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• To determine the preliminary efficacy of SO-C101 monotherapy 
as measured by ORR, DOR, CBR, and PFS according to iRECIST 
• To determine the immunogenicity of SO-C101 as monotherapy 
Exploratory objectives 
• To explore the mechanistic effects of SO-C101 on selected 
immune cell populations in tumor tissue samples 
• To assess OS at 6 months after the EoT visit 
PART B (SO-C101 dosing schedule 1, combined with 
pembrolizumab, dose escalation) 
Primary objectives 
• To assess the safety and tolerability of SO-C101 when combined 
with pembrolizumab 
• To determine the MTD and/or RP2D of SO-C101 when combined 
with pembrolizumab 
Secondary objectives 
• To characterize the PK of SO-C101 when combined with 
pembrolizumab 
• To characterize the PD of SO-C101 in peripheral blood when 
combined with pembrolizumab 
• To assess the preliminary efficacy of the combination of SO-C101 
with pembrolizumab as measured by ORR, DOR, CBR, and PFS 
according to iRECIST 
• To determine the immunogenicity of SO-C101 in combination 
with pembrolizumab 
Exploratory objectives 
• To explore the mechanistic effects of SO-C101 in combination 
with pembrolizumab on selected immune cell populations in 
tumor tissue samples 
• To assess OS at 6 months after the EoT visit 
PART B1 (SO-C101 dosing schedule 2, combined with 
pembrolizumab, dose escalation) 
Primary objectives 
• To assess the safety and tolerability of SO-C101 when combined 
with pembrolizumab 
• To determine the MTD and/or RP2D of SO-C101 when combined 
with pembrolizumab 
Secondary objectives 
• To characterize the PK of SO-C101 when combined with 
pembrolizumab 
• To characterize the PD of SO-C101 in peripheral blood when 
combined with pembrolizumab 

 
 
 
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• To assess the preliminary efficacy of the combination of SO-C101 
twice daily with pembrolizumab as measured by ORR, DOR, 
CBR, and PFS according to iRECIST 
• To determine the immunogenicity of SO-C101 in combination 
with pembrolizumab 
Exploratory objectives 
• To explore the mechanistic effects of SO-C101 in combination 
with pembrolizumab on selected immune cell populations in 
tumor tissue samples 
• To assess OS at 6 months after the EoT visit 
Part D (SO-C101 dosing schedule 1, monotherapy, dose 
expansion at the RP2D identified in Part A) 
Primary objective 
• To assess the safety and tolerability of SO-C101 
Secondary objectives 
• To characterize the PK of SO-C101 
• To characterize the PD of SO-C101 in peripheral blood 
• To assess the preliminary efficacy of SO-C101 as measured by 
ORR, DOR, CBR, and PFS according to iRECIST 
• To determine the immunogenicity of SO-C101 
Exploratory objectives 
• To explore the mechanistic effects of SO-C101 on selected 
immune cell populations in tumor tissue samples 
• To assess OS at 6 months after the EoT visit 
Part D1 (SO-C101 dosing schedule 2, monotherapy, dose 
expansion at the RP2D identified in Part A1) 
Primary objective 
• To assess the safety and tolerability of SO-C101 
Secondary objectives 
• To characterize the PK of SO-C101 
• To characterize the PD of SO-C101 in peripheral blood 
• To assess the preliminary efficacy of SO-C101 as measured by 
ORR, DOR, CBR, and PFS according to iRECIST 
• To determine the immunogenicity of SO-C101 
Exploratory objectives 
• To explore the mechanistic effects of SO-C101 on selected 
immune cell populations in tumor tissue samples 
• To assess OS at 6 months after the EoT visit 

 
 
 
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Endpoints  
PART A (SO-C101 dosing schedule 1, monotherapy, dose 
escalation) 
Primary endpoints 
• Safety and tolerability of SO-C101 as evaluated by the incidence 
of dose-limiting toxicities (DLTs), incidence of SO-C101-related 
adverse events (AEs), serious AEs (SAEs), AEs leading to 
premature discontinuation of SO-C101, deaths, and clinical 
laboratory test abnormalities 
• MTD is defined as the dose level associated with ≥33% of 
DLT-evaluable patients experiencing a DLT. If the MTD is 
reached, the RP2D will be conventionally defined as the dose 
level just below this non-tolerated dose level. If the MTD is not 
reached, the RP2D will be selected based on integrated evaluation 
of safety, tolerability, clinical benefit, PK and PD data, for all dose 
levels tested. 
Secondary endpoints 
• PK of SO-C101 
• Immune response characterized by the changes in expression of 
immune markers in peripheral blood mononuclear cells (PBMCs) 
• ORR, DOR, CBR, and PFS according to iRECIST 
• Detection of anti-drug antibodies (ADAs) 
Exploratory endpoints 
• Changes in the expression of immune biomarkers as compared to 
baseline in tumor tissue 
• OS at 6 months after the EoT visit 
PART A1 (SO-C101 dosing schedule 2, monotherapy, dose 
escalation) 
Primary endpoints 
• Safety and tolerability of SO-C101 as evaluated by the incidence 
of DLTs, incidence of SO-C101-related AEs, SAEs, AEs leading 
to premature discontinuation of SO-C101, deaths, and clinical 
laboratory test abnormalities 
• MTD is defined as the dose level associated with ≥33% of 
DLT-evaluable patients experiencing a DLT. If the MTD is 
reached, the RP2D will be conventionally defined as the dose 
level just below this non-tolerated dose level. If the MTD is not 
reached, the RP2D will be selected based on integrated evaluation 
of safety, tolerability, clinical benefit, PK and PD data, for all dose 
levels tested. 
Secondary endpoints 
• PK of SO-C101 
• Immune response characterized by the changes in expression of 
immune markers in PBMCs 

 
 
 
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• ORR, DOR, CBR, and PFS according to iRECIST 
• Detection of ADAs 
Exploratory endpoints 
• Changes in the expression of immune biomarkers as compared to 
baseline in tumor tissue 
• OS at 6 months after the EoT visit 
PART B (SO-C101 dosing schedule 1, combined with 
pembrolizumab, dose escalation) 
Primary endpoints 
• Safety 
and 
tolerability 
of 
SO-C101 
combined 
with 
pembrolizumab as evaluated by the incidence of DLTs, 
SO-C101-related AEs, SAEs, AEs leading to premature SO-C101 
discontinuation, deaths, and clinical laboratory test abnormalities 
• MTD defined as the dose level associated with ≥33% of 
DLT-evaluable patients experiencing a DLT. If the MTD is 
reached, the RP2D will be conventionally defined as the dose 
level just below this non-tolerated dose level. If the MTD is not 
reached, the RP2D will be selected based on integrated evaluation 
of safety, tolerability, clinical benefit, PK and PD data, for all dose 
levels tested. 
Secondary endpoints 
• PK of SO-C101 combined with pembrolizumab 
• Immune response after administration of SO-C101 in combination 
with pembrolizumab characterized by the changes in expression 
of immune markers in PBMCs 
• ORR, DOR, CBR, and PFS according to iRECIST 
• Detection of ADAs 
Exploratory endpoints 
• Changes in the expression of immune biomarkers after 
administration of SO-C101 in combination with pembrolizumab 
as compared to baseline in tumor tissue 
• OS at 6 months after the EoT visit 
PART B1 (SO-C101 dosing schedule 2, combined with 
pembrolizumab, dose escalation) 
Primary endpoints 
• Safety 
and 
tolerability 
of 
SO-C101 
combined 
with 
pembrolizumab as evaluated by the incidence of DLTs, 
SO-C101-related AEs, SAEs, AEs leading to premature SO-C101 
discontinuation, deaths, and clinical laboratory test abnormalities 
• MTD defined as the dose level associated with ≥33% of 
DLT-evaluable patients experiencing a DLT. If the MTD is 
reached, the RP2D will be conventionally defined as the dose 

 
 
 
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level just below this non-tolerated dose level. If the MTD is not 
reached, the RP2D will be selected based on integrated evaluation 
of safety, tolerability, clinical benefit, PK and PD data, for all dose 
levels tested. 
Secondary endpoints 
• PK of SO-C101 combined with pembrolizumab 
• Immune response after administration of SO-C101 in combination 
with pembrolizumab characterized by the changes in expression 
of immune markers in PBMCs 
• ORR, DOR, CBR, and PFS according to iRECIST 
• Detection of ADAs 
Exploratory endpoints 
• Changes in the expression of immune biomarkers after 
administration of SO-C101 in combination with pembrolizumab 
as compared to baseline in tumor tissue 
• OS at 6 months after the EoT visit 
PART D (SO-C101 dosing schedule 1, monotherapy, dose 
expansion at the RP2D identified in Part A) 
Primary endpoint 
• Safety and tolerability of SO-C101 as evaluated by the incidence 
of SO-C101-related AEs, SAEs, AEs leading to premature SO-
C101 discontinuation, deaths, and clinical laboratory test 
abnormalities 
Secondary endpoints 
• PK of SO-C101 
• Immune response after administration of SO-C101 characterized 
by the changes in expression of immune markers in PBMCs 
• ORR, DOR, CBR, and PFS according to iRECIST 
• Detection of ADAs  
Exploratory endpoints 
• Changes in the expression of immune biomarkers after 
administration of SO-C101 as compared to baseline in tumor 
tissue 
• OS at 6 months after the EoT visit 
PART D1 (SO-C101 dosing schedule 2, monotherapy, dose 
expansion at the RP2D identified in Part A1) 
Primary endpoint 
• Safety and tolerability of SO-C101 as evaluated by the incidence 
of SO-C101-related AEs, SAEs, AEs leading to premature SO-
C101 discontinuation, deaths, and clinical laboratory test 
abnormalities 

 
 
 
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Secondary endpoints 
• PK of SO-C101 
• Immune response after administration of SO-C101 characterized 
by the changes in expression of immune markers in PBMCs 
• ORR, DOR, CBR, and PFS according to iRECIST 
• Detection of ADAs 
Exploratory endpoints 
• Changes in the expression of immune biomarkers after 
administration of SO-C101 as compared to baseline in tumor 
tissue 
• OS at 6 months after the EoT visit 
Overall study 
design 
This study will assess the safety and tolerability of two 
administration schedules of SO-C101 administered as monotherapy 
(Part A, Part A1, Part D, and Part D1) and in combination with an 
anti-PD-1 antibody (pembrolizumab) (Part B and Part B1) in 
patients with selected relapsed/refractory advanced/metastatic solid 
tumors who are refractory to or intolerant of existing therapies 
known to provide clinical benefit for their condition. 
Part A, Part A1, Part B, and Part B1 will enroll patients with the 
following relapsed/refractory advanced/metastatic tumors: renal cell 
carcinoma, non-small cell lung cancer, small-cell lung cancer, 
bladder cancer, melanoma, Merkel-cell carcinoma, skin squamous-
cell carcinoma, microsatellite instability high solid tumors, triple-
negative breast cancer, mesothelioma, thyroid cancer, thymic 
cancer, cervical cancer, biliary tract cancer, hepatocellular 
carcinoma, ovarian cancer, gastric cancer, head and neck squamous-
cell carcinoma, and anal cancer. 
Part D and Part D1 will enroll patients with relapsed/refractory 
advanced/metastatic 
renal 
cell 
carcinoma, 
patients 
with 
relapsed/refractory 
advanced/metastatic 
skin 
squamous-cell 
carcinoma, 
and 
patients 
with 
relapsed/refractory 
advanced/metastatic melanoma. 
The study will have the following parts: 
• Part A will be a FIH SO-C101 monotherapy dose escalation part 
for dosing schedule 1. 
• Part A1 will be a SO-C101 monotherapy dose escalation part for 
dosing schedule 2 which will start once the RP2D of SO-C101, 
dosing schedule 1, is identified in Part A; the starting daily dose 
of Part A1 will be 1 dose level below the RP2D identified in Part 
A. The dose will be split into two identical (50%:50%) daily doses 
with the second dose on each treatment day being administered 8 
hours (±15 min) after the first dose. 
• Part B will study SO-C101 dosing schedule 1 in combination with 
pembrolizumab and will start after dose level 5 in Part A is 

 
 
 
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completed and deemed safe and will use SO-C101 monotherapy 
level 3 dose, dosing schedule 1, as the starting dose in 
combination with pembrolizumab. 
• Part B1 will study SO-C101 dosing schedule 2 in combination 
with pembrolizumab and will start once the RP2D of SO-C101, 
dosing schedule 1, in combination with pembrolizumab is 
identified in Part B; the starting daily dose of Part B1 will be 1 
dose level below the RP2D identified in Part B. The dose will be 
split into two identical (50%:50%) daily doses with the second 
dose on each treatment day being administered 8 hours (±15 min) 
after the first dose. 
• Part D will be a dose expansion part which will start once the 
RP2D of SO-C101, dosing schedule 1, is identified in Part A; SO-
C101 will be given at the Part A RP2D. 
• Part D1 will be a dose expansion part which will start once the 
RP2D of SO-C101, dosing schedule 2, is identified in Part A1; 
SO-C101 will be given at the Part A1 RP2D. 
Part A will start first with SO-C101 monotherapy dose escalation for 
dosing schedule 1 which will continue until the MTD and/or RP2D 
of SO-C101 monotherapy for dosing schedule 1 is defined. After 
this, Part A1 (dosing schedule 2) will start with the starting daily 
dose at 1 dose level below the RP2D identified in Part A and will 
continue until the MTD and/or RP2D of SO-C101 monotherapy 
given as per dosing schedule 2 is defined. 
Part B will start once monotherapy SO-C101 dose level 5 
(6.0 µg/kg) in Part A is completed and deemed safe. The starting 
dose of Part B will be Part A dose level 3 (1.5 µg/kg) which will be 
combined with a fixed dose of pembrolizumab (200 mg 
intravenously [IV] every 3 weeks). If an MTD in Part A is reached 
before dose level 5, then the starting dose of SO-C101 in Part B will 
be decided based on the review of all available safety/PD/PK data. 
After the start of Part B, the study will continue recruiting to Part A 
and Part B in parallel. The Part B SO-C101 dose will be following 
the increasing safe dose levels of monotherapy SO-C101 from Part 
A. Under no circumstances will the Part B SO-C101 dose exceed the 
highest dose deemed safe in Part A. Part B dose escalation will 
continue until the MTD and/or RP2D of SO-C101 in combination 
with pembrolizumab is defined. This approach will allow for 
combination safety/PK/PD to be tested and optimized timely and 
effectively. 
    
 
 
 
 

 
 
 
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This study is planned to allow patients to crossover from Part A and 
Part A1 to Part B or Part B1 when they have objective progressive 
disease in Part A and Part A1 and there is a dose deemed safe in Part 
B or Part B1. The investigator should also be of the opinion that 
these patients will derive benefit from combination treatment in Part 
B or Part B1. These patients will NOT be part of the dose escalation 
cohorts of Part B or Part B1; therefore, they will not be part of the 
DLT evaluation in Part B or Part B1. The crossover will only be 
allowed when all of the following criteria are met: 
• Unconfirmed progressive disease as per iRECIST in Part A and 
Part A1 
• Eligibility for Part A and Part A1 (except fresh biopsy 
requirement) still holds and patients have no known 
hypersensitivity to any of the ingredients in the pembrolizumab 
drug product (KeytrudaTM) 
• There are no safety concerns as deemed by the investigator and 
the patient should not have had a DLT in Part A and Part A1 
• A completed safe dose level identified in Part B or Part B1. If there 
are more than one safe dose levels identified, the patient will be 
allowed to be assigned to the highest dose level deemed safe. 
For each patient considered for the crossover, the investigator will 
discuss this with the sponsor’s medical monitor. 
After the RP2D of SO-C101 dosing schedule 1 in combination with 
pembrolizumab is identified in Part B, Part B1 dose escalation 
investigating SO-C101 dosing schedule 2 will start. 
Part B1 will start with the starting daily dose at 1 dose level below 
the RP2D identified in Part B until the MTD and/or RP2D of SO-
C101 dosing schedule 2 in combination with pembrolizumab is 
defined. 
Part D (dose expansion) will start after the RP2D of SO-C101 
monotherapy for dosing schedule 1 is identified in Part A. SO-C101 
will be given as per dosing schedule 1 at the RP2D identified in Part 
A. 
Part D1 (dose expansion) will start after the RP2D of SO-C101 
monotherapy for dosing schedule 2 is identified in Part A1. SO-
C101 will be given as per dosing schedule 2 at this RP2D.  
The study will recruit patients to all ongoing study parts in parallel. 
The sponsor will allocate slots for the patients to be recruited to the 
dose-escalation study parts. 
Part A  
(SO-C101 dosing 
schedule 1, 
monotherapy, dose 
escalation) 
Patients will be treated with escalating doses of SO-C101 given as 
per dosing schedule 1 via the subcutaneous (SC) route following the 
dose escalation scheme below. A starting dose of 0.25 µg/kg was 
selected in Part A of this study. If this starting dose is not tolerated, 
then a lower dose could be considered. 

 
 
 
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Dose level SO-C101 dose given once a day 
(µg/kg/administration) 
Dose increase 
1 
0.25 µg/kg 
Starting dose 
2 
0.75 µg/kg 
200% 
3 
1.5 µg/kg 
100% 
4 
3.0 µg/kg 
100% 
5 
6.0 µg/kg 
100% 
6 
9.0 µg/kg 
50% 
7 
15.0 µg/kg 
67% 
8 
12.0 µg/kg 
-20% 
Patients will be treated with SO-C101 given once a day on day 1 (±1 
day; Wednesday), day 2 (Thursday), day 8 (Wednesday), and day 9 
(Thursday) of the 21-day cycle. The start of the treatment (day 1) is 
planned to be on a Wednesday to allow biomarker sampling (fresh 
PBMCs transfer to the central laboratory) on weekdays. However, 
as long as the two doses per week are given on consecutive days (day 
1 and day 2) and the second week dosing (day 8 and day 9) takes 
place 7 days after day 1, there will be ±1 day flexibility for the day 
1 dosing to take place on a Tuesday or on a Thursday. 
SC 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 potential local effects of SO-C101 
administration. 
This dosing schedule will be revised in light of the emerging clinical 
data from initial cohorts and if these data reveal substantial 
differences from non-clinical data, adjustment of the planned dose 
levels will be considered by the Dose Escalation Committee (DEC) 
and the Independent Advisory Panel (IAP). 
This schedule should be strictly adhered to with no dose 
delays/reductions to be allowed for especially cycle 1 for maximum 
exposure for safety evaluation for DLTs. If any visits are missed for 
obtaining PK/PD/safety laboratory parameters during cycle 1, 
patients will be reviewed individually by the sponsor’s medical 
monitor and investigators for their evaluability for DLT assessment. 
SO-C101 monotherapy dose escalation for dosing schedule 1 will 
continue until the MTD and/or RP2D is reached as per the dose 
escalation schema. If the MTD is not reached at the end of the 
planned dose escalation cohorts, the recruitment will stop to assess 
RP2D. Additional doses and schedules could be opened as required 
based on the RP2D assessment results to define the optimal dose and 
schedule for further clinical studies. 

 
 
 
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Patients recruited in Part A will continue treatment at their assigned 
dose level. Intra-patient dose escalation beyond the dose initially 
assigned to a patient is not permitted during cycle 2. However, 
patients receiving treatment with SO-C101 given as per dosing 
schedule 1 beyond cycle 2 may continue treatment at the next higher 
dose level if it is assessed to be safe by the DEC and IAP and if the 
following criteria are met: 
• No safety concerns as deemed by the investigator 
• No DLT at the initial dose level assigned 
• No unacceptable AEs, defined as drug-related clinically 
meaningful, uncontrolled grade 3 or any grade 4 toxicities at the 
current dose level 
• No dose reduction at the current dose level 
• Completed at least two cycles at the assigned dose 
• The investigator should also be of the opinion that these patients 
will derive benefit from treatment at the higher dose level of 
SO-C101 given as per dosing schedule 1 
If these requirements are met, the patient can be dose escalated to 
the next dose level after discussion with the sponsor’s medical 
monitor. These patients after intra-patient dose increase will NOT 
be part of the higher dose escalation cohorts; therefore, after intra-
patient dose increase, they will not be part of the DLT evaluation. 
Intra-patient escalation up to the RP2D level is allowed and can be 
done step-by step if the patient stays at the higher dose level and 
meets the criteria for escalation as specified above. 
If treatment discontinuation is due to disease progression, crossover 
to the combination treatment (Part B or Part B1) could be 
considered. 
Patients will be discontinued from study treatment for any of the 
following events: 
• Radiographic disease progression (confirmed progressive disease 
per iRECIST [iCPD]) 
• Clinical disease progression (investigator assessment) 
• AE (intercurrent illness or study treatment-related toxicity, 
including DLTs, that would, in the judgment of the investigator, 
affect assessments of clinical status to a significant degree or 
require discontinuation of study treatment) 
• Patient may withdraw from the study at any time for any reason; 
the investigator must make every effort to determine the reason 
for this decision and record it in source documentation of the 
patient 
• Death 
• Pregnancy 

 
 
 
 
 
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• Concomitant treatment with a prohibited medication, including 
further lines of cancer therapy 
• Patient non-compliance 
• Lost to follow-up 
• Study terminated by the sponsor 
Part A1  
(SO-C101 dosing 
schedule 2, 
monotherapy, dose 
escalation) 
Patients will be treated with escalating doses of SO-C101 given as 
per dosing schedule 2 via the SC route. The starting daily dose will 
be 1 level below the RP2D identified in Part A. The dose will be 
split into two identical (50%:50%) daily doses with the second dose 
on each treatment day being administered 8 hours (±15 min) after 
the first dose. If this starting dose is not tolerated, then a lower dose 
could be considered. Further dose levels will be considered based on 
safety data and decisions taken during Dose Escalation Meetings 
(DEMs). 
Patients will be treated with SO-C101 given twice a day 8 hours (±15 
min) apart on day 1 (±1 day; Wednesday), day 2 (Thursday), day 8 
(Wednesday), and day 9 (Thursday) of the 21-day cycle. The start of 
the treatment (day 1) is planned to be on a Wednesday to allow 
biomarker sampling (fresh PBMCs transfer to the central laboratory) 
on weekdays. However, as long as the four doses per week are given 
on consecutive days (day 1 and day 2) and the second week dosing 
(day 8 and day 9) takes place 7 days after day 1, there will be ±1 day 
flexibility for the day 1 dosing to take place on a Tuesday or on a 
Thursday. 
SC 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 potential local effects of SO-C101 
administration. 
This dosing schedule will be revised in light of the emerging clinical 
data from initial cohorts and if these data reveal substantial 
differences from non-clinical data, adjustment of the planned dose 
levels will be considered by the DEC and the IAP. 
This schedule should be strictly adhered to with no dose 
delays/reductions to be allowed for especially cycle 1 for maximum 
exposure for safety evaluation for DLTs. If any visits are missed for 
obtaining PK/PD/safety laboratory parameters during cycle 1, 
patients will be reviewed individually by the sponsor’s medical 
monitor and investigators for their evaluability for DLT assessment. 
SO-C101 monotherapy dose escalation for dosing schedule 2 will 
continue until the MTD and/or RP2D is reached. If the MTD is not 
reached, the recruitment will stop to assess RP2D. Additional doses 
and schedules could be opened as required based on the RP2D 
assessment results to define the optimized dose and schedule for 
further clinical studies. 

 
 
 
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Patients recruited in Part A1 will continue treatment at their assigned 
dose level. Intra-patient dose escalation beyond the dose initially 
assigned to a patient is not permitted during cycle 2. However, 
patients receiving treatment with SO-C101 given as per dosing 
schedule 2 beyond cycle 2 may continue treatment at the next higher 
dose level if it is assessed to be safe by the DEC and IAP and if the 
following criteria are met: 
• No safety concerns as deemed by the investigator 
• No DLT at the initial dose level assigned 
• No unacceptable AEs, defined as drug-related clinically 
meaningful, uncontrolled grade 3 or any grade 4 toxicities at the 
current dose level 
• No dose reduction at the current dose level 
• Completed at least two cycles at the assigned dose 
• The investigator should also be of the opinion that these patients 
will derive benefit from treatment at the higher dose level of 
SO-C101 given as per dosing schedule 2 
If these requirements are met, the patient can be dose escalated to 
the next dose level after discussion with the sponsor’s medical 
monitor. These patients after intra-patient dose increase will NOT 
be part of the higher dose escalation cohorts; therefore, after intra-
patient dose increase, they will not be part of the DLT evaluation. 
Intra-patient escalation up to the RP2D level is allowed and can be 
done step-by step if the patient stays at the higher dose level and 
meets the criteria for escalation as specified above. 
If treatment discontinuation is due to disease progression, crossover 
to the combination treatment (Part B or Part B1) could be 
considered. 
Patients will be discontinued from study treatment for any of the 
following events: 
• Radiographic disease progression (iCPD) 
• Clinical disease progression (investigator assessment) 
• AE (intercurrent illness or study treatment-related toxicity, 
including DLTs, that would, in the judgment of the investigator, 
affect assessments of clinical status to a significant degree or 
require discontinuation of study treatment) 
• Patient may withdraw from the study at any time for any reason; 
the investigator must make every effort to determine the reason 
for this decision and record it in source documentation of the 
patient 
• Death 
• Pregnancy 
• Concomitant treatment with a prohibited medication, including 
further lines of cancer therapy 

 
 
 
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• Patient non-compliance 
• Lost to follow-up 
• Study terminated by the sponsor 
Part B  
(SO-C101 dosing 
schedule 1, 
combined with 
pembrolizumab, 
dose escalation)  
Part B treatment will consist of SO-C101 given as per dosing 
schedule 1 in combination with pembrolizumab following the dose 
escalation scheme below.  
The SO-C101 starting dose for cohort 1 of Part B, the combination 
with pembrolizumab, will be 1.5 µg/kg provided that dose level 5 
(6.0 µg/kg) in Part A is tolerated and deemed safe. If the dose level 
of 6.0 µg/kg is not deemed safe, then Part B will start at the lower 
dose level deemed safe. If this starting dose is not tolerated, then 
SO-C101 dose level -1 of Part B (0.75 µg/kg) will be tested. 
Dose 
level 
SO-C101 dose given 
once a day 
(µg/kg/administration) 
Dose 
increase 
Pembrolizumab 
-1 
0.75 µg/kg 
(-50%) 
200 mg 
1 
1.5 µg/kg 
Starting dose 
200 mg 
2 
3.0 µg/kg 
100% 
200 mg 
3 
6.0 µg/kg 
100% 
200 mg 
4 
9.0 µg/kg 
50% 
200 mg 
5 
12.0 µg/kg 
33% 
200 mg 
Patients will be treated with escalating doses of SO-C101 given once 
a day on day 1 (±1 day; Wednesday), day 2 (Thursday), day 8 
(Wednesday), and day 9 (Thursday) together with a fixed dose of 
pembrolizumab (200 mg IV every 3 weeks) given on the day 1 
administration of SO-C101. Pembrolizumab will be administered 
within 30 minutes after the first dose of SO-C101 and as outlined in 
the package insert. The start of the treatment (day 1) is planned to be 
on a Wednesday to allow biomarker sampling (fresh PBMCs 
transfer to the central laboratory) on weekdays. However, as long as 
the two doses of SO-C101 per week are given on consecutive days 
(day 1 and day 2) and the second week SO-C101 dosing (day 8 and 
day 9) takes place 7 days after day 1, there will be ±1 day flexibility. 
This schedule should be strictly adhered to with no dose 
delays/reductions to be allowed for especially in cycle 1 for 
maximum exposure for safety evaluation for DLTs. If any visits are 
missed for obtaining PK/PD/safety laboratory parameters during 
cycle 1, patients will be reviewed individually by the sponsor’s 
medical monitor and investigators for their evaluability for DLT 
assessment. 
SO-C101 combination dose escalation for dosing schedule 1 will 
continue until the MTD and/or RP2D is reached as per the dose 

 
 
 
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escalation schema. If the MTD is not reached at the end of the 
planned dose escalation cohorts, the recruitment will stop to assess 
RP2D. Additional doses and schedules could be opened as required 
based on the RP2D assessment results to define the optimal dose and 
schedule for further clinical studies. 
In case SO-C101 needs to be stopped for reasons other than disease 
progression, pembrolizumab treatment can continue for up to 1 year 
as assessed by the DEC if the patient does not progress and can 
tolerate the treatment. In case pembrolizumab needs to be stopped, 
SO-C101 treatment can continue until disease progression or 
unacceptable toxicity. 
SC 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 SO-C101 administration. 
Once Part B is open for recruitment and the first combination cohort 
is deemed safe, patients who had objective disease progression in 
Part A and Part A1 will be allowed to crossover to Part B given that 
there are no safety concerns. Patients recruited in Part B will 
continue SO-C101 given as per dosing schedule 1 and 
pembrolizumab treatment at the assigned dose level of SO-C101. 
Intra-patient dose escalation beyond the dose initially assigned to a 
patient is not permitted during cycle 2. However, patients receiving 
treatment with SO-C101 given as per dosing schedule 1 beyond 
cycle 2 may continue treatment at the next higher dose level if it is 
assessed to be safe by the DEC and IAP and if the following criteria 
are met: 
• No safety concerns as deemed by the investigator 
• No DLT at the initial dose level assigned 
• No unacceptable AEs, defined as drug-related clinically 
meaningful, uncontrolled grade 3 or any grade 4 toxicities at the 
current dose level 
• No dose reduction at the current dose level 
• Completed at least two cycles at the assigned dose 
• The investigator should also be of the opinion that these patients 
will derive benefit from treatment at the higher dose level of 
SO-C101 
If these requirements are met, the patient can be dose escalated to 
the next dose level after discussion with the sponsor’s medical 
monitor. These patients after intra-patient dose increase will NOT 
be part of the higher dose escalation cohorts; therefore, after 
intra-patient dose increase, they will not be part of the DLT 
evaluation. 
Intra-patient escalation up to the RP2D level is allowed and can be 
done step-by step if the patient stays at the higher dose level and 
meets the criteria for escalation as specified above. 

 
 
 
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Patients will be discontinued from study treatment for any of the 
following events: 
• Radiographic disease progression (iCPD) 
• Clinical disease progression (investigator assessment) 
• AE (intercurrent illness or study treatment-related toxicity, 
including DLTs, that would, in the judgment of the investigator, 
affect assessments of clinical status to a significant degree or 
require discontinuation of study treatment) 
• Patient may withdraw from the study at any time for any reason; 
the investigator must make every effort to determine the reason 
for this decision and record it in source documentation of the 
patient 
• Death 
• Pregnancy 
• Concomitant treatment with a prohibited medication, including 
further lines of cancer therapy 
• Patient non-compliance 
• Lost to follow-up 
• Study terminated by the sponsor 
Part B1  
(SO-C101 dosing 
schedule 2, 
combined with 
pembrolizumab, 
dose escalation) 
Part B1 treatment will consist of SO-C101 given as per dosing 
schedule 2 in combination with pembrolizumab. The starting daily 
dose will be 1 level below the RP2D identified in Part B. The dose 
will be split into two identical (50%:50%) daily doses with the 
second dose on each treatment day being administered 8 hours (±15 
min) after the first dose. If this starting dose is not tolerated, then a 
lower dose could be considered. Further dose levels will be 
considered based on safety data and decisions taken during DEMs. 
Patients will be treated with escalating doses of SO-C101 given 
twice a day 8 hours (±15 min) apart on day 1 (±1 day; Wednesday), 
day 2 (Thursday), day 8 (Wednesday), and day 9 (Thursday) 
together with a fixed dose of pembrolizumab (200 mg IV every 3 
weeks) given with the first administration of SO-C101 on day 1. 
Pembrolizumab will be administered within 30 minutes after the first 
dose of SO-C101 and as outlined in the package insert. The start of 
the treatment (day 1) is planned to be on a Wednesday to allow 
biomarker sampling (fresh PBMCs transfer to the central laboratory) 
on weekdays. However, as long as the four doses of SO-C101 per 
week are given on consecutive days (day 1 and day 2) and the second 
week SO-C101 dosing (day 8 and day 9) takes place 7 days after day 
1, there will be ±1 day flexibility. 
This schedule should be strictly adhered to with no dose 
delays/reductions to be allowed for especially in cycle 1 for 
maximum exposure for safety evaluation for DLTs. If any visits are 
missed for obtaining PK/PD/safety laboratory parameters during 
cycle 1, patients will be reviewed individually by the sponsor’s 

 
 
 
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medical monitor and investigators for their evaluability for DLT 
assessment. 
SO-C101 combination dose escalation for dosing schedule 2 will 
continue until the MTD and/or RP2D is reached. If the MTD is not 
reached, the recruitment will stop to assess RP2D. Additional doses 
and schedules could be opened as required based on the RP2D 
assessment results to define the optimal dose and schedule for 
further clinical studies. 
In case SO-C101 needs to be stopped for reasons other than disease 
progression, pembrolizumab treatment can continue for up to 1 year 
as assessed by the DEC if the patient does not progress and can 
tolerate the treatment. In case pembrolizumab needs to be stopped, 
SO-C101 treatment can continue until disease progression or 
unacceptable toxicity. 
SC 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 SO-C101 administration. 
Once Part B1 is open for recruitment and the first combination 
cohort is deemed safe, patients who had objective disease 
progression in Part A and Part A1 will be allowed to crossover to 
Part B1 given that there are no safety concerns. 
Patients recruited in Part B1 will continue SO-C101 given as per 
dosing schedule 2 and pembrolizumab treatment at the assigned dose 
level of SO-C101. Intra-patient dose escalation beyond the dose 
initially assigned to a patient is not permitted during cycle 2. 
However, patients receiving treatment with SO-C101 given as per 
dosing schedule 2 beyond cycle 2 may continue treatment at the next 
higher dose level if it is assessed to be safe by the DEC and IAP and 
if the following criteria are met: 
• No safety concerns as deemed by the investigator 
• No DLT at the initial dose level assigned 
• No unacceptable AEs, defined as drug-related clinically 
meaningful, uncontrolled grade 3 or any grade 4 toxicities at the 
current dose level 
• No dose reduction at the current dose level 
• Completed at least two cycles at the assigned dose 
• The investigator should also be of the opinion that these patients 
will derive benefit from treatment at the higher dose level of 
SO-C101 
If these requirements are met, the patient can be dose escalated to 
the next dose level after discussion with the sponsor’s medical 
monitor. These patients after intra-patient dose increase will NOT 
be part of the higher dose escalation cohorts; therefore, after 
intra-patient dose increase, they will not be part of the DLT 
evaluation. 

 
 
 
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Intra-patient escalation up to the RP2D level is allowed and can be 
done step-by step if the patient stays at the higher dose level and 
meets the criteria for escalation as specified above. 
Patients will be discontinued from study treatment for any of the 
following events: 
• Radiographic disease progression (iCPD) 
• Clinical disease progression (investigator assessment) 
• AE (intercurrent illness or study treatment-related toxicity, 
including DLTs, that would, in the judgment of the investigator, 
affect assessments of clinical status to a significant degree or 
require discontinuation of study treatment) 
• Patient may withdraw from the study at any time for any reason; 
the investigator must make every effort to determine the reason 
for this decision and record it in source documentation of the 
patient 
• Death 
• Pregnancy 
• Concomitant treatment with a prohibited medication, including 
further lines of cancer therapy 
• Patient non-compliance 
• Lost to follow-up 
• Study terminated by the sponsor 
Part D  
(SO-C101 dosing 
schedule 1, 
monotherapy, dose 
expansion at the 
RP2D identified in 
Part A) 
Part D treatment will consist of SO-C101 monotherapy given as per 
dosing schedule 1 at the RP2D identified in Part A. 
Patients will be treated with SO-C101 given once a day on day 1 (±1 
day; Wednesday), day 2 (Thursday), day 8 (Wednesday), and day 9 
(Thursday). The start of the treatment (day 1) is planned to be on a 
Wednesday to allow biomarker sampling (fresh PBMCs transfer to 
the central laboratory) on weekdays. However, as long as the two 
doses of SO-C101 per week are given on consecutive days (day 1 
and day 2) and the second week SO-C101 dosing (day 8 and day 9) 
takes place 7 days after day 1, there will be ±1 day flexibility for the 
day 1 dosing to take place on a Tuesday or on a Thursday. 
SC 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 SO-C101 administration. 
Patients will be discontinued from study treatment for any of the 
following events: 
• Radiographic disease progression (iCPD) 
• Clinical disease progression (investigator assessment) 
• AE (intercurrent illness or study treatment-related toxicity that 
would, in the judgment of the investigator, affect assessments of 

 
 
 
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clinical status to a significant degree or require discontinuation of 
study treatment) 
• Patient may withdraw from the study at any time for any reason; 
the investigator must make every effort to determine the reason 
for this decision and record it in source documentation of the 
patient 
• Death 
• Pregnancy 
• Concomitant treatment with a prohibited medication, including 
further lines of cancer therapy 
• Patient non-compliance 
• Lost to follow-up 
• Study terminated by the sponsor 
Part D1  
(SO-C101 dosing 
schedule 2, 
monotherapy, dose 
expansion at the 
RP2D identified in 
Part A1) 
Part D1 treatment will consist of SO-C101 monotherapy given as 
per dosing schedule 2 at the RP2D identified in Part A1. 
Patients will be treated with SO-C101 given twice a day 8 hours (±15 
min) apart on day 1 (±1 day; Wednesday), day 2 (Thursday), day 8 
(Wednesday), and day 9 (Thursday). The start of the treatment (day 
1) is planned to be on a Wednesday to allow biomarker sampling 
(fresh PBMCs transfer to the central laboratory) on weekdays. 
However, as long as the four doses of SO-C101 per week are given 
on consecutive days (day 1 and day 2) and the second week SO-
C101 dosing (day 8 and day 9) takes place 7 days after day 1, there 
will be ±1 day flexibility for the day 1 dosing to take place on a 
Tuesday or on a Thursday. 
SC 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 SO-C101 administration. 
Patients will be discontinued from study treatment for any of the 
following events: 
• Radiographic disease progression (iCPD) 
• Clinical disease progression (investigator assessment) 
• AE (intercurrent illness or study treatment-related toxicity that 
would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree or require discontinuation of 
study treatment) 
• Patient may withdraw from the study at any time for any reason; 
the investigator must make every effort to determine the reason 
for this decision and record it in source documentation of the 
patient 
• Death 
• Pregnancy 

 
 
 
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• Concomitant treatment with a prohibited medication, including 
further lines of cancer therapy 
• Patient non-compliance 
• Lost to follow-up 
• Study terminated by the sponsor 
DLT definition 
DLTs will be AEs as specified below and graded according to 
National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events version 5.0. Attribution to SO-C101 will not be used 
and the AEs listed below will be considered DLTs unless clearly not 
related to SO-C101 (i.e., events clearly due to the cancer disease, 
other comorbid illness, or unequivocally related to concomitant 
medications). The DLT evaluation period is the first treatment cycle 
of 21 days. 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 SO-C101 as 
monotherapy and in combination with pembrolizumab. 
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 exceptions below that 
are NOT considered DLTs: 
o Grade 3 nausea, vomiting, or diarrhea that can be controlled 
within 72 hours 
o Grade 3 fatigue less than 5 days 
o Grade 3 or higher correctable electrolyte abnormalities that last 
less than 72 hours and not associated with clinical 
complications 
o Grade 3 or higher amylase or lipase not associated with clinical 
manifestations of pancreatitis 
• Hy’s law cases will be considered DLTs. 
• Grade 3 aspartate transaminase (AST) or alanine transaminase 
(ALT) or grade 3 bilirubinemia that lasts more than 5 days 
• Hematologic DLTs will include the following: 
o Grade 4 neutropenia or thrombocytopenia lasting more than 
7 days 
o Febrile neutropenia 
o Grade 3 or higher thrombocytopenia with bleeding 
• Any grade 4 immune-related AEs regardless of duration 

 
 
 
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• Any grade 3 or grade 4 non-infectious pneumonitis regardless of 
duration 
• Any grade 3 immune-related AEs, excluding colitis, hepatitis, and 
pneumonitis, that do not downgrade to grade ≤2 within 3 days 
after onset of the event despite maximal supportive care including 
systemic corticosteroids or downgrade to grade 1 or baseline 
within 14 days 
• Any grade 2 pneumonitis that does not resolve to grade 1 within 
3 days of the initiation of maximal supportive care 
• Recurrent grade 2 pneumonitis in Part B and Part B1 
• Grade 3 colitis 
AEs that are NOT considered DLTs 
• Grade 3 endocrinopathy that is managed with or without systemic 
corticosteroid therapy and/or hormone replacement therapy 
• 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 AE grade 
Other clinically significant toxicities, including a single event or 
multiple occurrences of the same event, may be considered as DLTs. 
AEs occurring after treatment cycle 1 may be considered DLT-like 
events upon DEC discussion. If required, a DEM will be set up to 
assess these events. 
Observation  
of patients  
after 
administration  
of SO-C101;  
Part A, Part B,  
and Part D 
 
Cycle 1 
Dose on day 1 
In cycle 1 of Part A, Part B, and Part D, patients will be hospitalized 
for 24 hours after the first dose of SO-C101 on day 1 and will be 
closely observed for any AEs in the hospital. 
Vital signs (body temperature, heart rate, respiratory rate, and 
systolic and diastolic blood pressure) will be documented at the 
following frequency at minimum unless clinically required 
otherwise: 
• Prior to each SO-C101 dose 
• 15 minutes (±5 minutes) after dosing 
• 30 minutes (±5 minutes) after dosing 
• 60 minutes (±10 minutes) after dosing, and then 
• Every 60 minutes (±15 minutes) after dosing up until 8 hours 
following SO-C101 administration 

 
 
 
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Subsequent doses 
During observation after subsequent doses of SO-C101, vital signs 
(body temperature, heart rate, respiratory rate, and systolic and 
diastolic blood pressure) will be documented at the following 
frequency at minimum until discharge from the clinic: 
• Prior to each SO-C101 dose 
• 15 minutes (±5 minutes) after dosing 
• 30 minutes (±5 minutes) after dosing 
• 60 minutes (±10 minutes) after dosing, and then 
• Every 60 minutes (±15 minutes) after dosing up until 4-6 hours 
following SO-C101 administration 
From cycle 2 onwards 
For the subsequent cycles of Part A, Part B, and Part D, patients will 
be observed in the hospital up to 4-6 hours following SO-C101 
administration. During post-SO-C101 observation, vital signs (body 
temperature, heart rate, respiratory rate, and systolic and diastolic 
blood pressure) will be documented at the following frequency until 
discharge from the clinic: 
• Prior to each SO-C101 dose 
• 15 minutes (±5 minutes) after dosing 
• 30 minutes (±5 minutes) after dosing 
• 60 minutes (±10 minutes) after dosing, and then 
• Every 60 minutes (±15 minutes) after dosing up until 4-6 hours 
following SO-C101 administration 
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 Informed Consent Form (ICF). 
Observation  
of patients  
after 
administration  
of SO-C101;  
Part A1, Part B1, 
and Part D1 
Cycle 1 day 1 and cycle 1 day 2 
In Part A1, Part B1, and Part D1, patients will be hospitalized from 
day 1 to day 3 of cycle 1 and will be closely observed for any AEs 
in the hospital. 
Vital signs (body temperature, heart rate, respiratory rate, and 
systolic and diastolic blood pressure) will be documented at the 
following frequency at minimum unless clinically required 
otherwise: 
• Prior to the first dose of SO-C101 
• 15 minutes (±5 minutes) after dosing 
• 30 minutes (±5 minutes) after dosing 

 
 
 
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• 60 minutes (±10 minutes) after dosing, and then 
• Every 60 minutes (±15 minutes) after dosing up until 8 hours 
following SO-C101 first administration 
• Prior to the second dose of SO-C101 
• 15 minutes (±5 minutes) after the second dosing 
• Every 60 minutes (±15 minutes) after dosing up until 6 hours 
following the second SO-C101 administration (e.g., 14 hours after 
the first dose) 
Subsequent dosing days 
During observation after subsequent doses of SO-C101, vital signs 
(body temperature, heart rate, respiratory rate, and systolic and 
diastolic blood pressure) will be documented at the following 
frequency at minimum until discharge from the clinic: 
• Prior to the first dose of SO-C101 
• 15 minutes (±5 minutes) after dosing 
• 30 minutes (±5 minutes) after dosing 
• 60 minutes (±10 minutes) after dosing, and then 
• Every 60 minutes (±15 minutes) after dosing up until 4-6 
hours following the first SO-C101 administration 
• Prior to the second dose of SO-C101 at 8 hours after the first dose 
• 15 minutes (±5 minutes) after the second dosing 
• Every 60 minutes (±15 minutes) after dosing up until 4 hours 
following the second SO-C101 administration (e.g., 12 hours after 
the first dose) 
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. 
Dose escalation 
Enrollment into the dose cohorts in Part A, Part A1, Part B, and 
Part B1 
The DLT evaluation period is the first treatment cycle (21 days). 
A patient evaluable for DLT will be a patient who has completed 
cycle 1 and received all planned treatments without any treatment 
delays or interruptions: for Part A, received all 4 doses of SO-C101 
as planned; for Part A1, received all 8 doses of SO-C101 as planned; 
for Part B, received all 4 doses of SO-C101 and 1 dose of 
pembrolizumab as planned; for Part B1, received all 8 doses of SO-
C101 and 1 dose of pembrolizumab as planned. Patients who do not 
fulfill these criteria for any other reason than DLT should be 
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After completion of the DLT evaluation period with the adequate 
number of evaluable patients, all data as specified in the DEM 
Charter will be reviewed during a DEM by the DEC. The same data 
will also be reviewed by the IAP as described in the IAP Charter. 
The decision as to whether an AE should be considered as DLT 
and/or whether a dose level is to be considered intolerable will be 
made by the DEC with endorsement from the IAP. The DEC consists 
of the study investigators and the sponsor’s medical monitor. The 
IAP consists of two independent clinical experts and an independent 
statistician. 
In the event of a confirmed non-tolerable dose in any cohort, the 
sponsor will inform all sites immediately so that the patients will not 
be exposed to doses of SO-C101 that have been determined to 
exceed the MTD. Patients who will not be DLT evaluable will be 
replaced. Replaced patients can continue with study treatment. 
The dose escalation plan will follow the traditional 3+3 design as 
described by Le Tourneau et al. Initially, three patients will be 
enrolled for each dose level and if none of the three patients in a 
cohort experiences a DLT, another three patients will be treated at 
the next higher dose level. However, if one of the first three patients 
experiences a DLT, three more patients will be treated at the same 
dose level. The dose escalation continues until at least two patients 
in a cohort of three to six patients experience DLTs (i.e., ≥33% of 
patients with a DLT at that dose level). If an MTD is reached, then 
the dose escalation will be stopped. The DEC will then decide 
whether any additional patients need to be enrolled in any dose 
level(s) not exceeding the MTD to gain confidence at the dose which 
will be considered as the RP2D. 
Staggered (sentinel) dosing will be employed as described below: 
For each dose level, the first patient for the cohort will receive the 
first cycle of SO-C101 on day 1, day 2, day 8, and day 9. This patient 
will be observed for safety for 7 days afterwards, starting from day 
9. If there are no safety concerns at the end of these 7 days, the 
responsible investigator will notify the sponsor’s medical monitor 
and the second and third patients will be allowed to be dosed. The 
second and third patients will not be dosed on the same day. 
If there is a concern at the end of these 7 days of observation for 
safety of the first patient, the study investigator will notify the 
sponsor’s medical monitor as soon as possible and the sponsor will 
notify all sites and a DEM will be organized. The DEC will review, 
discuss, and decide on the next steps of the study. 
MTD and RP2D 
definitions 
If the MTD is reached, the RP2D is conventionally defined as the 
dose level just below this non-tolerated dose level. If ≤1 of 6 patients 
(or 0 of 3) in all dose cohorts experience a DLT, then the MTD will 
not have been reached. If the MTD is not reached, then the RP2D 
will be selected based on integrated evaluation of safety, tolerability, 

 
 
 
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clinical benefit, and PK and PD data for all dose levels tested. An 
expansion cohort of up to 12 patients at the RP2D could be 
considered to obtain more experience if required. The DEC will 
evaluate the data and select the RP2D according to the following 
guidelines: 
1. The RP2D will not exceed the MTD. 
2. Toxicities other than DLTs will be considered, including: AEs 
assessed as related to SO-C101 treatment but not considered 
dose limiting, the nature and frequency of toxicities, and the 
emergence of any specific category of toxicities. 
3. Evidence of clinical activity, as available 
4. Available PK/PD data 
5. If 2 or more potential RP2D dose levels cannot be distinguished 
using the criteria above, cohort expansion for optimized RP2D 
determination may take place at up to 2 dose levels to obtain data 
for up to 6 additional patients per dose level. The selection of 
RP2D will be based on this larger dataset. If serious related 
toxicities are observed in later cycles beyond cycle 1, a reduction 
of the MTD and/or RP2D may be considered. This determination 
will be made by the investigators and the sponsor’s medical 
monitor, taking into account all available data. 
Study periods 
PART A, PART A1, PART B, AND PART B1 
Screening period 
Patients will be screened within a period of not more than 21 days, 
which will start when the ICF has been signed and end on day 1 of 
cycle 1. If screening is not completed within this period, next steps 
(continue/discontinue the patient in the study) will be discussed with 
the sponsor’s medical monitor. 
Treatment periods 
DLT evaluation period 
The DLT evaluation period will be the first treatment cycle of 
21 days. 
Continued treatment period 
Patients without DLT during the DLT evaluation period will 
continue treatment with SO-C101 monotherapy or SO-C101 
together with pembrolizumab until any of the criteria for treatment 
discontinuation are met.  
Intra-patient dose escalation beyond the dose initially assigned to a 
patient is not permitted during cycle 2. However, patients receiving 
treatment with SO-C101 beyond cycle 2 may continue treatment at 
the next higher dose level if it is assessed to be safe by the DEC and 
IAP and if the criteria for intra-patient dose increase are met. These 
patients after intra-patient dose increase will NOT be part of the 
higher dose escalation cohorts; therefore, after intra-patient dose 

 
 
 
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increase, they will not be part of the DLT evaluation. Intra-patient 
escalation up to the RP2D level is allowed and can be done step-by 
step if the patient stays at the higher dose level and meets the criteria 
for escalation. 
In Part B and Part B1, in case SO-C101 needs to be discontinued for 
reasons other than disease progression, pembrolizumab treatment 
will continue for up to 1 year until any of the criteria for treatment 
discontinuation are met. If pembrolizumab needs to be discontinued 
for reasons other than disease progression, SO-C101 treatment will 
continue until any of the criteria for treatment discontinuation are 
met. 
EoT visit 
After 
termination 
of 
study 
treatments 
(SO-C101 
and/or 
pembrolizumab), patients will be evaluated at the EoT visit, which 
will be scheduled within 7 days (+7 days) after the final 
administration of SO-C101 and/or pembrolizumab (whichever 
occurs later). 
Follow-up period 
Every effort should be taken to monitor all AEs and concomitant 
medications for 90 days after the final dose of SO-C101 and/or 
pembrolizumab (whichever occurs later); all patients will come to 
the clinic 30 (±2) days, 60 (±2) days, and 90 (±2) days after the final 
dose of SO-C101 and/or pembrolizumab. 
Patients who discontinue SO-C101 therapy prior to iCPD or start of 
a new anticancer therapy will continue to have regular tumor 
assessments until: 
• iCPD, or  
• start of a new anticancer therapy, or  
• 6 months (±2 weeks) after the EoT visit, 
whichever occurs earliest, unless patients withdraw consent. 
Patients will be followed up for survival at 3 months (±2 weeks) and 
6 months (±2 weeks) after the EoT visit (end of the patients’ study 
participation). 
PART D AND PART D1 
Screening period 
Patients will be screened within a period of not more than 21 days, 
which will start when the ICF has been signed and end on day 1 of 
cycle 1. If screening is not completed within this period, next steps 
(continue/discontinue the patient in the study) will be discussed with 
the sponsor’s medical monitor. 
Treatment period 
Patients will be treated with SO-C101 until any of the criteria for 
treatment discontinuation are met. After termination of SO-C101, 

 
 
 
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patients will be evaluated at the EoT visit, which will be scheduled 
within 7 days (+7 days) after the final administration of SO-C101. 
Follow-up period 
Every effort should be taken to monitor all AEs and concomitant 
medications for 90 days after the final dose of SO-C101; all patients 
will come to the clinic 30 (±2) days, 60 (±2) days, and 90 (±2) days 
after the final dose of SO-C101. 
Patients who discontinue SO-C101 therapy prior to iCPD or start of 
a new anticancer therapy will continue to have regular tumor 
assessments until: 
• iCPD, or 
• start of a new anticancer therapy, or  
• 6 months (±2 weeks) after the EoT visit, 
whichever occurs earliest, unless patients withdraw consent. 
Patients will be followed up for survival at 3 months (±2 weeks) and 
6 months (±2 weeks) after the EoT visit (end of the patients’ study 
participation). 
End of the study 
Each study part will end when the last patient in this study part 
completes the last visit, including follow-up calls. 
The study will end when the last patient completes the last visit, 
including follow-up calls. 
Early termination 
of the study 
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) or Ethics Committee (EC) of the termination 
or suspension and the reason(s) for the termination or suspension. 
The investigator reserves the right to discontinue the study should 
his/her judgment so dictate. If the investigator terminates or 
suspends the study without prior agreement of the sponsor, the 
investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the 
IRB/EC and provide the sponsor and the IRB/EC with a detailed 
written explanation of the termination or suspension. 
Stopping rules for 
all parts 
If a patient experiences a life-threatening SAE considered by the 
investigator to be related to SO-C101 (i.e., excluding events 
unequivocally related to cancer) or if >30% of the treated patients 
discontinue because of toxicities considered by the investigator to be 
related to SO-C101, the dosing of all patients in the study will be 
temporarily stopped until the IAP (and DEC for dose escalation parts 
only) have reviewed the safety data and determined if it is safe to 
continue and at which dose. 

 
 
 
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Inclusion/ 
exclusion criteria 
INCLUSION CRITERIA 
Inclusion criteria for all study parts are the same with the exception 
of the pre-specified tumor type (inclusion criterion 2), please see 
below. 
1. Age ≥18 years 
2. Part A, Part A1, Part B, and Part B1: Patients with selected 
histologically or cytologically confirmed advanced and/or 
metastatic solid tumors (renal cell carcinoma, non-small cell 
lung cancer, small-cell lung cancer, bladder cancer, melanoma, 
Merkel-cell 
carcinoma, 
skin 
squamous-cell 
carcinoma, 
microsatellite instability high solid tumors, triple-negative breast 
cancer, mesothelioma, thyroid cancer, thymic cancer, cervical 
cancer, biliary tract cancer, hepatocellular carcinoma, ovarian 
cancer, gastric cancer, head and neck squamous-cell carcinoma, 
and anal cancer) who are refractory to or intolerant of existing 
therapies known to provide clinical benefit for their condition. 
Patients who were not previously treated with (naïve) or who 
have relapsed/refractory disease on immune checkpoint 
inhibitors are eligible. 
Part D and Part D1: Patients with histologically or cytologically 
confirmed advanced and/or metastatic renal cell carcinoma, 
patients with histologically or cytologically confirmed advanced 
and/or metastatic skin squamous-cell carcinoma, and patients 
with relapsed/refractory advanced/metastatic melanoma who are 
refractory to or intolerant of existing therapies known to provide 
clinical benefit for their condition. Patients who have 
relapsed/refractory disease on immune checkpoint inhibitors are 
eligible. 
3. Performance status: Eastern Cooperative Oncology Group 
(ECOG) performance score 0-1. Patients with ECOG 
performance score 2 will be discussed with the sponsor’s 
medical monitor to be agreed for inclusion. 
4. Immunosuppressive doses of systemic medications (such as 
steroids) or absorbed topical or inhaled steroids (doses 
≤10 mg/day of prednisone or equivalent) are allowed. Doses 
above 10 mg/day of prednisone or equivalent must be 
discontinued at least 2 weeks before investigational medicinal 
product administration. 
5. Estimated life expectancy of ≥3 months 
6. Washout periods: 4 weeks for chemotherapy, 4 weeks or 
5 half-lives (whichever shorter) for biologic agents including 
immuno-oncology therapy and 4 weeks from major surgeries, 
definitive radiotherapy and 2 weeks after palliative radiotherapy 
7. Have at least one measurable lesion per iRECIST in a non-
irradiated port. If in a previously irradiated port, must have 

 
 
 
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demonstrated progression since best response to radiation 
therapy. 
8. Have fully recovered from previous treatment to grade ≤1 
toxicity (excluding alopecia) or have stable grade 2 neuropathy 
9. Adequate organ system function: 
9.1. Left ventricular ejection fraction by echocardiogram >50% 
9.2. Patients with thyroid disease are eligible if euthyroid on 
suppressive or replacement therapy and asymptomatic 
thyroid-stimulating hormone increase to be allowed 
9.3. Creatinine clearance ≥30 mL/min using Cockcroft-Gault 
equation 
9.4. Hemoglobin at least 10 g/dL 
9.5. Prothrombin time and activated partial thromboplastin 
time ≤1.5× upper limit of normal (ULN) 
10. ALT/AST ≤2.5×ULN and total bilirubin ≤2×ULN in patients 
without liver metastasis (benign hereditary hyperbilirubinemias, 
e.g., Gilbert’s syndrome, are permitted, those patients must have 
total bilirubin <3 mg/dL). In patients with liver metastasis, 
ALT/AST ≤5×ULN is allowed but total bilirubin must be 
≤2×ULN. 
11. Negative serum pregnancy test if woman of child-bearing 
potential (WOCBP; non-childbearing is defined as greater than 
one year postmenopausal or surgically sterilized). 
WOCBP must adhere to using a medically accepted method of 
birth control and agree to continue its use during the study or be 
surgically sterilized (e.g., hysterectomy or tubal ligation) and 
males must agree to use barrier method of birth control while on 
study. WOCBP must agree to use highly effective contraception 
during treatment and for at least 30 days after SO-C101 
discontinuation (Part A, Part A1, Part D, and Part D1) or 4 
months after pembrolizumab discontinuation (Part B and Part 
B1) unless the last dose of SO-C101 is later than 4 months after 
the last pembrolizumab administration in Part B and Part B1. In 
such a case, the highly effective contraception must be used for 
at least 30 days after SO-C101 discontinuation. Highly effective 
contraception includes: 
• Placement of an intrauterine device or intrauterine 
hormone-releasing system 
• Established 
hormonal 
contraceptive 
methods: 
oral, 
intravaginal, transdermal, injectable, or implant. Females 
who are using hormonal contraceptives must have been on a 
stable dose of the same hormonal contraceptive product for at 
least 4 weeks prior to dosing and must continue to use the 
same contraceptive during the study and for 30 days after SO-
C101 discontinuation (Part A, Part A1, Part D, and Part D1) 
or 4 months after last pembrolizumab discontinuation (Part B 
and Part B1) unless the last dose of SO-C101 is later than 4 

 
 
 
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months after the last pembrolizumab administration in Part B 
and Part B1. In such a case, female patients must have been 
on a stable dose of the same hormonal contraceptive for at 
least 30 days after SO-C101 discontinuation. 
• Bilateral tubal occlusion 
Female patients exempt from this requirement are patients who 
practice total abstinence or have a sole male partner who is 
vasectomized with confirmed azoospermia. If currently 
abstinent, the patient must agree to use a double barrier method 
(condom plus diaphragm or cervical/vault cap with spermicide) 
if they become sexually active during the study, and for 30 days 
after SO-C101 discontinuation (Part A, Part A1, Part D, and Part 
D1) or 4 months after pembrolizumab discontinuation (Part B 
and Part B1) unless the last dose of SO-C101 is later than 4 
months after the last pembrolizumab administration in Part B 
and Part B1. In such a case, the patient must agree to use a 
double barrier method during treatment and for at least 30 days 
after SO-C101 discontinuation. 
Male patients must agree to use a condom during treatment and 
for 30 days after SO-C101 discontinuation (Part A, Part A1, Part 
D, and Part D1) or 4 months after pembrolizumab 
discontinuation (Part B and Part B1) unless the last dose of SO-
C101 is later than 4 months after the last pembrolizumab 
administration in Part B and Part B1. In such a case, the patient 
must agree to use a condom during treatment and for at least 30 
days after SO-C101 discontinuation. 
12. Accessible tumor tissue available for fresh biopsy 
13. Ability to understand and sign written informed consent to 
participate in the study 
EXCLUSION CRITERIA 
Exclusion criteria for all study parts 
1. Patient with untreated central nervous system metastases and/or 
leptomeningeal carcinomatosis; participants with previously 
treated stable (no progression on magnetic resonance imaging 
done 4 or more weeks apart) brain metastases are eligible 
2. Has a known additional malignancy that is progressing and/or 
requires active treatment 
3. Prior exposure to drugs that are agonists of IL-2- or IL-15-like 
but not limited to recombinant human IL-15 (NCI), ALT-803 
(ALTOR), NKTR-214 (Nektar) 
4. Patients with a history of and current interstitial lung disease or 
fibrosis and pneumonitis; patients with clinically significant or 
oxygen requiring chronic obstructive pulmonary disease or any 
chronic inflammatory disease (sarcoidosis etc.) 
5. Has received a live vaccine within 30 days of planned start of 
study therapy. Note: Seasonal influenza vaccines for injection 

 
 
 
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are generally inactivated flu vaccines and are allowed; however, 
intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated 
vaccines, and are not allowed. 
6. Absolute white blood cell count ≤2.0×109/L 
7. Absolute neutrophil count ≤1.0×109/L 
8. Platelet count ≤100×109/L 
9. Pregnant or breastfeeding women 
10. Receiving any other investigational treatment 
11. Any active autoimmune disease or a documented history of 
autoimmune disease, poorly controlled asthma, or history of 
syndrome that required systemic steroids (except the allowed 
doses) or immunosuppressive medications, except for patients 
with vitiligo or resolved childhood asthma/atopy. Patients with 
clinically controlled asthma who routinely require fixed doses 
intermittent use of bronchodilators and/or micro-doses of 
steroids are allowed. 
12. Co-morbidities: 
12.1. History of hematopoietic malignancy including chronic 
lymphocytic leukemia (excluding childhood leukemia) 
12.2. History of coronary heart disease 
12.3. Evidence of clinically active infection requiring systemic 
(any route) antibiotic therapy. All prior infections must 
have resolved following optimal therapy. 
12.4. History of or serology positive for HIV or active hepatitis 
B or C. Cured hepatitis B and hepatitis C infections are 
eligible. 
12.5. Uncontrolled hypertension (systolic >160 mm Hg and/or 
diastolic >110 mm Hg) or clinically significant (i.e., 
active) 
cardiovascular 
disease, 
cerebrovascular 
accident/stroke, or myocardial infarction within 6 months 
prior to first study medication; unstable angina; congestive 
heart failure of New York Heart Association grade 2 or 
higher; or uncontrolled cardiac arrhythmia requiring 
medication. Patients with uncontrolled hypertension 
should be medically managed on a stable regimen to 
control hypertension prior to study entry. 
12.6. Clinically significant peripheral artery disease 
12.7. Prolongation of QTcF >450 msec 
12.8. History of medical or psychiatric disease which, in the 
view of the investigator, would preclude safe treatment or 
acceptable study compliance 
13. Any ongoing toxicity from prior anti-cancer treatment that, in 
the judgment of the investigator, may interfere with study 
treatment 

 
 
 
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14. Other illness that, in the opinion of the investigator, would 
exclude the patient from participating in this study, including 
uncontrolled diabetes mellitus, cardiac disease 
Exclusion criteria for Part B and Part B1 only 
• Is hypersensitive to any of the ingredients of pembrolizumab drug 
product (KeytrudaTM) 
• History of solid organ transplantation or hematopoietic stem cell 
transplantation 
Dose escalation 
meetings 
A DEM will only take place once there are 3 or 6 DLT-evaluable 
patients to complete the cohort. A DEM will take place after the last 
patient of the cohort has completed the first cycle (21 days) with or 
without DLTs and is evaluable for DLT assessment. 
After completion of the DLT period, all available safety data will be 
reviewed by the IAP as well as the DEC. The decision as to whether 
AEs should be considered as DLTs and/or whether a dose level is to 
be considered intolerable will be made by the DEC endorsed by IAP. 
The IAP will consist of two independent clinical experts and an 
independent statistician. The working principles of the IAP will be 
defined in the IAP Charter. In the event of a confirmed non-tolerable 
dose in any cohort, the sponsor will inform all sites immediately so 
that patients will not be exposed to doses of SO-C101 that have been 
determined to exceed the MTD. 
At every DEM, all accumulating safety data from previous cohorts 
will also be reviewed and any safety issues arising during this longer 
follow-up period will be taken into consideration by the DEM panel 
as well as the IAP. 
Statistical methods 
and data analysis 
Each study part will be analyzed separately following its objectives. 
Further statistical analyses pooling data of more study parts can be 
included in the Statistical Analysis Plan (SAP). 
Safety population 
All patients exposed to SO-C101 in Part A, Part A1, Part D, and Part 
D1. All patients exposed to SO-C101 or pembrolizumab in Part B 
and Part B1. 
PK/PD population 
All PK/PD-evaluable patients. 
Efficacy population 
All patients exposed to SO-C101 (exposure for at least one treatment 
cycle) who had at least one evaluable tumor assessment per 
iRECIST after the initiation of SO-C101 treatment. 

 
 
 
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Statistical part of study design and sample size estimation 
Part A 
The traditional 3+3 design dose escalation will be applied until the 
MTD is identified. Therefore, 3 to 6 DLT-evaluable patients per 
dose level will be included in a cohort. The estimated number of 
patients is 27-54. 
Part A1 
The traditional 3+3 design dose escalation will be applied until the 
MTD is identified. Therefore, 3 to 6 DLT-evaluable patients per 
dose level will be included in a cohort. The estimated number of 
patients is 6-15. 
Part B 
The traditional 3+3 design dose escalation will be applied until the 
MTD is identified. Therefore, 3 to 6 DLT-evaluable patients per 
dose level will be included in a cohort. The estimated number of 
patients is 21-42. 
Part B1 
The traditional 3+3 design dose escalation will be applied until the 
MTD is identified. Therefore, 3 to 6 DLT-evaluable patients per 
dose level will be included in a cohort. The estimated number of 
patients is 6-15. 
Part D and Part D1 
The number of patients in Part D together with or without Part D1 
to be treated for at least one cycle is set to a maximum of 20 per 
indication (60 in total). This number of patients is deemed to be 
appropriate to provide further safety, PK, PD, and efficacy data per 
indication at the RP2D dose level identified in Part A (SO-C101, 
dosing schedule 1, monotherapy) and the RP2D dose level identified 
in Part A1 (SO-C101, dosing schedule 2, monotherapy). In case 
biomarker data in Part A1 suggest a more competitive efficacy as 
compared to once daily dosing, a switch to twice daily dosing (Part 
D1) will be made during the course of the study without affecting 
the overall number of patients enrolled. 
Analyses 
Analyses will be descriptive. Further details will be specified in the 
SAP. 
Planned duration 
It is expected that the enrollment duration will be 31-48 months 
(14-22 months Part A, 3-9 months Part A1, 11-18 months Part B, 3-
9 months Part B1, 6-12 months Part D, and 12-18 months Part D1) 
and for each patient the estimated average treatment duration will be 
12-24 weeks in Part A, Part A1, Part D, and Part D1; and 24-36 
weeks in Part B and Part B1. Patients who will respond to therapy 
will continue with treatment until any of the criteria for treatment 
discontinuation are met. 
 
 

 
 
 
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3 TABLE OF CONTENTS 
1 
TITLE PAGE ................................................................................................................. 1 
2 
CLINICAL PROTOCOL SYNOPSIS ........................................................................... 5 
3 
TABLE OF CONTENTS ............................................................................................. 40 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................. 50 
5 
ETHICS ........................................................................................................................ 53 
5.1 Institutional Review Board/ Ethics Committee ....................................................... 53 
5.2 Ethical conduct of the study .................................................................................... 53 
5.3 Patient information and informed consent ............................................................... 53 
6 
INVESTIGATORS AND SPONSOR ......................................................................... 55 
7 
INTRODUCTION ....................................................................................................... 56 
7.1 Background and rationale ........................................................................................ 56 
7.2 Nonclinical summary ............................................................................................... 57 
7.2.1 
SO-C101 monotherapy ............................................................................. 57 
7.2.2 
SO-C101 mechanism of action ................................................................. 57 
7.2.3 
SO-C101 in combination with an anti-PD-1 antibody ............................. 58 
7.2.4 
Pharmacology ........................................................................................... 58 
7.2.5 
Pharmacokinetics ...................................................................................... 59 
7.2.6 
Toxicology and safety pharmacology....................................................... 60 
7.3 Justification for the SC route as the route of administration ................................... 62 
7.4 Justification for dose scheduling ............................................................................. 62 
7.4.1 
Dosing schedule 1 ..................................................................................... 62 
7.4.2 
Dosing schedule 2 ..................................................................................... 62 
7.5 Justification for the starting dose and dose escalation steps in Part A .................... 64 
7.6 Justification for the starting dose in Part A1 ........................................................... 66 
7.7 Justification for the starting dose in Part B .............................................................. 66 
7.8 Justification for the starting dose in Part B1 ............................................................ 66 
7.9 Study design rationale .............................................................................................. 67 
8 
STUDY DESIGN AND OBJECTIVES ...................................................................... 70 
8.1 Study design ............................................................................................................. 70 
8.1.1 
Dosing schedule ........................................................................................ 72 
8.1.2 
Part A – Monotherapy SO-C101 dosing schedule 1 dose escalation ....... 72 
8.1.3 
Part A1 – Monotherapy SO-C101 dosing schedule 2 dose escalation ..... 72 

 
 
 
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8.1.4 
Part B – SO-C101 dosing schedule 1 dose escalation in combination with 
pembrolizumab........................................................................................ 72 
8.1.5 
Part B1 – SO-C101 dosing schedule 2 dose escalation in combination with 
pembrolizumab........................................................................................ 72 
8.1.6 
Part D – Monotherapy SO-C101 dosing schedule 1 dose expansion ....... 72 
8.1.7 
Part D1 – Monotherapy SO-C101 dosing schedule 2 dose expansion ..... 72 
8.1.8 
Intra-patient dose increase ........................................................................ 73 
8.1.9 
Crossover of patients from Part A and Part A1 to Part B or Part B1 ....... 73 
8.2 Objectives ................................................................................................................ 74 
8.2.1 
Part A (SO-C101 dosing schedule 1, monotherapy, dose escalation) ...... 74 
8.2.1.1 
Primary objectives .............................................................................. 74 
8.2.1.2 
Secondary objectives .......................................................................... 74 
8.2.1.3 
Exploratory objectives ........................................................................ 74 
8.2.2 
Part A1 (SO-C101 dosing schedule 2, monotherapy, dose escalation) .... 74 
8.2.2.1 
Primary objectives .............................................................................. 74 
8.2.2.2 
Secondary objectives .......................................................................... 74 
8.2.2.3 
Exploratory objectives ........................................................................ 75 
8.2.3 
Part B (SO-C101 dosing schedule 1, combined with pembrolizumab, dose 
escalation) ............................................................................................... 75 
8.2.3.1 
Primary objectives .............................................................................. 75 
8.2.3.2 
Secondary objectives .......................................................................... 75 
8.2.3.3 
Exploratory objectives ........................................................................ 75 
8.2.4 
Part B1 (SO-C101 dosing schedule 2, combined with pembrolizumab, 
dose escalation) ....................................................................................... 75 
8.2.4.1 
Primary objectives .............................................................................. 75 
8.2.4.2 
Secondary objectives .......................................................................... 75 
8.2.4.3 
Exploratory objectives ........................................................................ 76 
8.2.5 
Part D (SO-C101 dosing schedule 1, monotherapy, dose expansion at the 
RP2D identified in Part A) ...................................................................... 76 
8.2.5.1 
Primary objective................................................................................ 76 
8.2.5.2 
Secondary objectives .......................................................................... 76 
8.2.5.3 
Exploratory objectives ........................................................................ 76 
8.2.6 
Part D1 (SO-C101 dosing schedule 2, monotherapy, dose expansion at the 
RP2D identified in Part A1) .................................................................... 76 
8.2.6.1 
Primary objective................................................................................ 76 
8.2.6.2 
Secondary objectives .......................................................................... 76 
8.2.6.3 
Exploratory objectives ........................................................................ 76 

 
 
 
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9 
INVESTIGATIONAL PLAN ...................................................................................... 77 
9.1 Part A (SO-C101 dosing schedule 1, monotherapy, dose escalation) ..................... 77 
9.2 Part A1 (SO-C101 dosing schedule 2, monotherapy, dose escalation) ................... 78 
9.3 Part B (SO-C101 dosing schedule 1, combined with pembrolizumab, dose escalation)
 ……………………………………………………………………………………..80 
9.4 Part B1 (SO-C101 dosing schedule 2, combined with pembrolizumab, dose 
escalation) ................................................................................................................... 82 
9.5 Part D (SO-C101 dosing schedule 1, monotherapy, dose expansion at the RP2D 
identified in Part A)..................................................................................................... 83 
9.6 Part D1 (SO-C101 dosing schedule 2, monotherapy, dose expansion at the RP2D 
identified in Part A1)................................................................................................... 84 
9.7 Dose escalation plan and study periods ................................................................... 85 
9.7.1 
DLT definitions for Part A, Part A1, Part B, and Part B1 ........................ 87 
9.7.1.1 
AEs that are considered DLTs ............................................................ 87 
9.7.1.2 
AEs that are NOT considered DLTs .................................................. 88 
9.7.2 
Maximum tolerated dose and selection of the recommended phase 2 
dose……………………………………………………………………..88 
9.7.3 
Dose escalation meetings.......................................................................... 88 
9.7.4 
Safety monitoring beyond cycle 1 ............................................................ 89 
9.7.4.1 
Part A and Part A1 .............................................................................. 89 
9.7.4.2 
Part B and Part B1 .............................................................................. 89 
9.7.5 
Patient recruitment management .............................................................. 89 
9.7.6 
Communication plan ................................................................................ 89 
9.7.7 
Study periods in Part A, Part A1, Part B, and Part B1 ............................. 90 
9.7.7.1 
Screening period ................................................................................. 90 
9.7.7.2 
Treatment periods ............................................................................... 90 
9.7.7.2.1 
DLT evaluation period .............................................................. 90 
9.7.7.2.2 
Continued treatment period ....................................................... 90 
9.7.7.2.3 
EoT visit .................................................................................... 90 
9.7.7.3 
Follow-up period ................................................................................ 90 
9.7.8 
Study periods in Part D and Part D1......................................................... 91 
9.7.8.1 
Screening period ................................................................................. 91 
9.7.8.2 
Treatment period ................................................................................ 91 
9.7.8.3 
Follow-up period ................................................................................ 91 
9.7.9 
End of the study ........................................................................................ 91 
9.7.10 
Early termination of the study .................................................................. 92 

 
 
 
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9.7.11 
Stopping rules for all parts ....................................................................... 92 
9.8 Selection of study population .................................................................................. 92 
9.8.1 
Inclusion criteria for all study parts .......................................................... 92 
9.8.2 
Exclusion criteria ...................................................................................... 94 
9.8.2.1 
Exclusion criteria for all study parts ................................................... 94 
9.8.2.2 
Exclusion criteria for Part B and Part B1 only ................................... 95 
9.9 Treatments ............................................................................................................... 96 
9.9.1 
Treatments administered........................................................................... 96 
9.9.1.1 
SO-C101 (all study parts) ................................................................... 96 
9.9.1.2 
Pembrolizumab (Part B, Part B1) ....................................................... 96 
9.9.2 
Treatment modifications ........................................................................... 96 
9.9.3 
SO-C101 ................................................................................................... 99 
9.9.3.1 
Name, structural formula .................................................................... 99 
9.9.3.2 
Labeling for SO-C101 ........................................................................ 99 
9.9.3.3 
SO-C101 storage conditions ............................................................... 99 
9.9.4 
Pembrolizumab ....................................................................................... 100 
9.9.4.1 
Pembrolizumab description .............................................................. 100 
9.9.4.2 
Pembrolizumab identity.................................................................... 100 
9.9.4.3 
Pembrolizumab: safety information ................................................. 100 
9.9.4.4 
Pembrolizumab immunogenicity...................................................... 100 
9.9.5 
Comparator drug ..................................................................................... 100 
9.9.6 
Method of assigning patients to treatment groups .................................. 100 
9.9.7 
Selection of doses in the study ............................................................... 100 
9.9.8 
Selection and timing of dose for each patient......................................... 100 
9.9.9 
Blinding .................................................................................................. 100 
9.10 Supportive care and concomitant medication ........................................................ 101 
9.10.1 
Management of cytokine release syndrome ........................................... 101 
9.10.2 
Life-threatening toxicities....................................................................... 102 
9.10.3 
Overdosing ............................................................................................. 102 
9.10.4 
Prohibitions and restrictions during the study period ............................. 102 
9.10.4.1 Prohibited medications ..................................................................... 102 
9.10.4.2 Warnings and precautions ................................................................ 103 
9.10.4.3 Drug-drug interaction potential ........................................................ 103 
9.10.4.4 Food .................................................................................................. 103 
9.10.5 
Treatment compliance ............................................................................ 103 

 
 
 
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9.10.6 
IMP supplies and accountability............................................................. 103 
9.10.6.1 IMP supply ....................................................................................... 103 
9.10.6.2 IMP accountability ........................................................................... 104 
9.10.6.3 IMP disposal and destruction ........................................................... 104 
9.11 Study assessments .................................................................................................. 104 
9.11.1 
Demography, disease history, and other baseline assessments .............. 105 
9.11.2 
Tumor assessments ................................................................................. 105 
9.11.3 
Pharmacokinetic assessments ................................................................. 105 
9.11.4 
Pharmacodynamic and other biomarker assessments ............................. 105 
9.11.4.1 Peripheral blood................................................................................ 106 
9.11.4.1.1 
Peripheral blood mononuclear cell analysis............................ 106 
9.11.4.1.1.1 
Aim ......................................................................................... 106 
9.11.4.1.1.2 
Rationale ................................................................................. 106 
9.11.4.1.1.3 
Method .................................................................................... 106 
9.11.4.1.1.4 
Pharmacodynamic markers ..................................................... 106 
9.11.4.1.2 
Cytokine analysis .................................................................... 106 
9.11.4.2 Tumor biopsy.................................................................................... 106 
9.11.5 
Safety assessments .................................................................................. 107 
9.11.5.1 Adverse events and pregnancies ....................................................... 107 
9.11.5.1.1 
Definitions ............................................................................... 107 
9.11.5.1.1.1 
Adverse events ........................................................................ 107 
9.11.5.1.1.2 
Serious adverse events ............................................................ 107 
9.11.5.1.1.3 
Excluded events ...................................................................... 107 
9.11.5.1.1.4 
Severity/intensity vs. seriousness ........................................... 108 
9.11.5.1.1.5 
Pregnancy of study patients or their partners .......................... 108 
9.11.5.1.2 
Safety monitoring periods ....................................................... 108 
9.11.5.1.2.1 
Reporting ................................................................................ 108 
9.11.5.1.2.2 
Follow-up ................................................................................ 109 
9.11.5.1.3 
Assessing adverse events ........................................................ 109 
9.11.5.1.3.1 
Causality ................................................................................. 109 
9.11.5.1.3.2 
Severity/intensity .................................................................... 110 
9.11.5.1.3.3 
Reporting by the investigational site ...................................... 110 
9.11.5.1.3.4 
Documenting in eCRFs........................................................... 110 
9.11.5.1.3.5 
Immediately reportable events ................................................ 111 
9.11.5.1.3.6 
Minimum notification/reporting requirements ....................... 112 
9.11.5.1.3.7 
Report forms ........................................................................... 112 

 
 
 
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9.11.6 
Safety monitoring of the patients during the study................................. 112 
9.11.6.1 Physical examination and body weight and height and body surface area
 ........................................................................................................ 112 
9.11.6.2 Assessment of vital signs.................................................................. 113 
9.11.6.3 Observation of patients after administration of SO-C101 ................ 113 
9.11.6.3.1 
Part A, Part B, and Part D ....................................................... 113 
9.11.6.3.1.1 
Cycle 1 .................................................................................... 113 
9.11.6.3.1.1.1 
Dose on day 1 .......................................................... 113 
9.11.6.3.1.1.2 
Subsequent doses ..................................................... 113 
9.11.6.3.1.2 
From cycle 2 onwards ............................................................. 114 
9.11.6.3.2 
Part A1, Part B1, and Part D1 ................................................. 114 
9.11.6.3.2.1 
Cycle 1 day 1 and cycle 1 day 2 ............................................. 114 
9.11.6.3.2.2 
Subsequent dosing days .......................................................... 114 
9.11.6.4 Assessment of laboratory parameters ............................................... 115 
9.11.6.4.1 
Coagulation ............................................................................. 115 
9.11.6.4.2 
Hematology ............................................................................. 116 
9.11.6.4.3 
Biochemistry ........................................................................... 116 
9.11.6.4.4 
Urinalysis ................................................................................ 116 
9.11.6.4.5 
Thyroid function ..................................................................... 116 
9.11.6.4.6 
Pregnancy ................................................................................ 116 
9.11.6.4.7 
Cardiac function ...................................................................... 116 
9.11.6.4.8 
Kidney function....................................................................... 117 
9.11.6.4.9 
Liver and pancreatic functions ................................................ 117 
9.11.6.4.10 Adverse events ........................................................................ 117 
9.11.6.4.11 Anti-drug antibodies ............................................................... 118 
9.11.7 
Schedule of procedures/assessments ...................................................... 118 
9.11.8 
Appropriateness of measurements .......................................................... 133 
9.11.9 
Withdrawal of patients from the study ................................................... 133 
9.11.10 
Treatment discontinuation ...................................................................... 133 
9.11.11 
Guidance for continuation of study treatment beyond iRECIST-defined 
disease progression ............................................................................... 133 
9.12 Data quality assurance ........................................................................................... 134 
9.12.1 
Data collection ........................................................................................ 134 
9.12.2 
Clinical data management ...................................................................... 134 
9.13 Statistical methods ................................................................................................. 135 
9.13.1 
Study endpoints ...................................................................................... 135 

 
 
 
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9.13.1.1 Part A ................................................................................................ 135 
9.13.1.1.1 
Primary endpoints ................................................................... 135 
9.13.1.1.2 
Secondary endpoints ............................................................... 135 
9.13.1.1.3 
Exploratory endpoints ............................................................. 136 
9.13.1.2 Part A1 .............................................................................................. 136 
9.13.1.2.1 
Primary endpoints ................................................................... 136 
9.13.1.2.2 
Secondary endpoints ............................................................... 136 
9.13.1.2.3 
Exploratory endpoints ............................................................. 136 
9.13.1.3 Part B ................................................................................................ 136 
9.13.1.3.1 
Primary endpoints ................................................................... 136 
9.13.1.3.2 
Secondary endpoints ............................................................... 136 
9.13.1.3.3 
Exploratory endpoints ............................................................. 137 
9.13.1.4 Part B1 .............................................................................................. 137 
9.13.1.4.1 
Primary endpoints ................................................................... 137 
9.13.1.4.2 
Secondary endpoints ............................................................... 137 
9.13.1.4.3 
Exploratory endpoints ............................................................. 137 
9.13.1.5 Part D ................................................................................................ 137 
9.13.1.5.1 
Primary endpoint ..................................................................... 137 
9.13.1.5.2 
Secondary endpoints ............................................................... 137 
9.13.1.5.3 
Exploratory endpoints ............................................................. 138 
9.13.1.6 Part D1 .............................................................................................. 138 
9.13.1.6.1 
Primary endpoint ..................................................................... 138 
9.13.1.6.2 
Secondary endpoints ............................................................... 138 
9.13.1.6.3 
Exploratory endpoints ............................................................. 138 
9.13.2 
Definitions of analysis sets ..................................................................... 138 
9.13.2.1 Safety population .............................................................................. 138 
9.13.2.2 PK/PD population ............................................................................. 138 
9.13.2.3 Efficacy population .......................................................................... 138 
9.13.3 
Patient disposition .................................................................................. 139 
9.13.4 
Demographic and other baseline characteristics .................................... 139 
9.13.5 
Prior and concomitant therapy ................................................................ 139 
9.13.6 
Primary endpoints analyses in dose escalation parts .............................. 139 
9.13.7 
Efficacy analyses .................................................................................... 139 
9.13.8 
Pharmacokinetic analyses ....................................................................... 139 
9.13.8.1 SO-C101 PK evaluation ................................................................... 139 

 
 
 
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9.13.8.2 Pembrolizumab PK evaluation ......................................................... 140 
9.13.9 
Pharmacodynamic and other biomarker analyses .................................. 140 
9.13.10 
Safety analyses ....................................................................................... 140 
9.13.10.1 Extent of exposure ............................................................................ 140 
9.13.10.2 Adverse events.................................................................................. 140 
9.13.10.3 Vital signs ......................................................................................... 141 
9.13.11 
Determination of sample size ................................................................. 141 
9.13.11.1 Part A (SO-C101 dosing schedule 1, monotherapy, dose escalation)
 ........................................................................................................ 141 
9.13.11.2 Part A1 (SO-C101 dosing schedule 2, monotherapy, dose escalation)
 ........................................................................................................ 141 
9.13.11.3 Part B (SO-C101 dosing schedule 1, combined with pembrolizumab, 
dose escalation) .............................................................................. 141 
9.13.11.4 Part B1 (SO-C101 dosing schedule 2, combined with pembrolizumab, 
dose escalation) .............................................................................. 141 
9.13.11.5 Part D (SO-C101 dosing schedule 1, monotherapy, dose expansion at 
the RP2D identified in Part A) and Part D1 (SO-C101 dosing schedule 
2, monotherapy, dose expansion at the RP2D identified in Part A1)
 ........................................................................................................ 141 
9.13.12 
Interim analysis ...................................................................................... 141 
9.13.13 
Other statistical/analytical issues ............................................................ 141 
10 REFERENCE LIST ................................................................................................... 142 
11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES) . 146 
11.1 Changes to the Protocol ......................................................................................... 146 
11.2 Adherence to the Protocol ..................................................................................... 146 
11.3 Monitoring procedures ........................................................................................... 146 
11.4 Recording of data ................................................................................................... 146 
11.5 Identification of source data .................................................................................. 147 
11.6 Retention of records ............................................................................................... 147 
11.7 Confidentiality of personal data ............................................................................. 147 
11.8 Auditing procedures and inspection ...................................................................... 149 
11.9 Handling of IMPs .................................................................................................. 149 
11.10 Publication of results ........................................................................................... 149 
11.11 Disclosure and confidentiality of information about the study ........................... 150 
11.12 Patient insurance and indemnity.......................................................................... 150 
11.13 Future research .................................................................................................... 150 
11.14 Document history ................................................................................................ 150 

 
 
 
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11.15 Protocol amendment (version 10.0) summary of changes versus version 9.0 .... 151 
12 APPENDICES ........................................................................................................... 152 
12.1 New York Heart Association Classification .......................................................... 153 
12.2 Creatinine clearance estimation ............................................................................. 154 
12.3 Hy’s law ................................................................................................................. 155 
12.4 Assessment of performance status ......................................................................... 156 
12.5 Clinical management recommendations for HD IL-2 therapy42 ............................ 157 
12.6 Definition of MTD and RP2D as used in the study Protocol ................................ 161 
12.7 Protocol amendment history .................................................................................. 162 
12.7.1 
Version 9.0 (16-Jul-2021): Protocol changes implemented ................... 162 
12.7.2 
Version 8.0 (11-Feb-2021): Protocol changes implemented .................. 165 
12.7.3 
Version 7.0 (25-Nov-2020): Protocol changes implemented ................. 166 
12.7.4 
Version 6.1 (13-May-2020): Protocol changes implemented (note: version 
6.0 was never implemented) ................................................................. 169 
12.7.5 
Version 5.0 (05-Nov-2019): Protocol changes implemented ................. 171 
12.7.6 
Version 4.0 (10-Apr-2019): Protocol changes implemented ................. 173 
12.7.7 
Version 3.0 (20-Mar-2019): Protocol changes implemented ................. 175 
12.7.8 
Version 2.0 (17-Jan-2019) ...................................................................... 176 
12.7.8.1 Protocol changes implemented further to the initial EU VHP ......... 176 
12.7.8.2 Additional “non-VHP GNA” changes.............................................. 187 
LIST OF IN-TEXT TABLES 
Table 7.1: SO-C101 starting dose and dose escalation steps in study SC103 (Part A) .......65 
Table 9.1: SO-C101 dosing schedule 1 dose increments, Part A ........................................77 
Table 9.2: SO-C101 dosing schedule 1 dose increments in combination with 
pembrolizumab, Part B ........................................................................................................80 
Table 9.3: Guidelines for SO-C101 dose adjustments after cycle 1 ....................................96 
Table 9.4: SO-C101 modifications after cycle 1 for specific AEs – delay/hold .................97 
Table 9.5: Cardiac function assessment ............................................................................116 
Table 9.6: Schedule of procedures/assessments, Part A, Part A1, Part D, and Part D1 (SO-
C101 monotherapy) ...........................................................................................................119 
Table 9.7: Schedule of procedures/assessments, Part B and Part B1 (SO-C101 combined 
with pembrolizumab) .........................................................................................................121 
Table 9.8: Schedule of procedures/assessments, Part B and Part B1 (for patients who 
continue on pembrolizumab only after discontinuation of SO-C101) ..............................123 
Table 9.9: Blood samples collection, Part A .....................................................................124 
Table 9.10: Blood samples collection, Part A1, Part D, and Part D1 ................................125 

 
 
 
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Table 9.11: Blood samples collection, Part B ...................................................................126 
Table 9.12: Blood samples collection, Part B1 .................................................................127 
Table 9.13: Blood samples collection (Part B and Part B1; for patients who continue on 
pembrolizumab only after discontinuation of SO-C101) ..................................................128 
Table 9.14: PK sampling, Part A and Part B .....................................................................129 
Table 9.15: PK sampling, Part A1, Part B1, Part D (patients 1-5 in each indication), and Part 
D1 (patients 1-5 in each indication) ..................................................................................130 
Table 9.16: PK sampling, Part D (starting with patient 6 in each indication) ...................131 
Table 9.17: PK sampling, Part D1 (starting with patient 6 in each indication) .................132 
Table 12.1: ECOG performance status scale .....................................................................156 
LIST OF IN-TEXT FIGURES 
Figure 7.1: Structure of SO-C101 (RLI-15) ........................................................................58 
Figure 7.2: Peripheral blood cell counts of CD8+ T cells and NK cells after once-daily and 
twice-daily SO-C101 administration in cynomolgus monkeys ...........................................63 
Figure 7.3: SO-C101 serum concentrations after once-daily and twice-daily SO-C101 
administration in cynomolgus monkeys ..............................................................................63 
Figure 7.4: Dose relationship of SO-C101-mediated NK- and CD8+ T-cell activation in vitro 
and in cynomolgus monkeys ...............................................................................................65 
Figure 8.1: Overall design ...................................................................................................71 
Figure 9.1: Part A: SO-C101 dosing schedule 1 .................................................................78 
Figure 9.2: Part A1: SO-C101 dosing schedule 2 ...............................................................79 
Figure 9.3: Part B: SO-C101 dosing schedule 1 and pembrolizumab .................................81 
Figure 9.4: Part B1: SO-C101 dosing schedule 2 and pembrolizumab ...............................83 
Figure 9.5: Part D: SO-C101 dosing schedule 1 .................................................................84 
Figure 9.6: Part D1: SO-C101 dosing schedule 2 ...............................................................85 
Figure 9.7: Dose escalation flowchart (staggered dosing and 3+3 design) .........................86 
Figure 9.8: Amino acid sequence of SO-C101 ....................................................................99 
 
 
 

 
 
 
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4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALC 
Absolute lymphocyte count 
ALT 
Alanine transaminase 
ALT-803 
IL-15/IL-15Rα complex fused to an IgG1 Fc 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate transaminase 
AUC 
Area under the curve 
BCL-2 
B-cell lymphoma 2 
CA 
Competent authority 
CBR 
Clinical benefit rate  
CD 
Cluster of differentiation 
CFR 
Code of Federal Regulations 
CLS 
Capillary leak syndrome 
Cmax 
Maximum (or peak) serum concentration 
CRA 
Clinical research associate 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DEC 
Dose Escalation Committee 
DEM 
Dose Escalation Meeting 
DL 
Dose level 
DLT 
Dose-limiting toxicity 
DOR 
Duration of response  
EC 
Ethics Committee 
EC50 
Half maximal effective concentration 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EEA 
European Economic Area 
EGFR 
Epidermal growth factor receptor 
EoT 
End of treatment 
Fc 
Fragment crystallizable 
FDA 
US Food and Drug Administration 
FIH 
First-in-human 
Foxp3 
Forkhead box P3 
GCP 
Good Clinical Practice 
HbA1c 
Glycated hemoglobin  

 
 
 
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Abbreviation 
Term 
HDIL-2 
High-dose IL-2 
hs-cTnT test 
High-sensitivity cardiac troponin T test 
IAP 
Independent Advisory Panel 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
iCPD 
Confirmed progressive disease per iRECIST 
IFN 
Interferon 
Ig 
Immunoglobulin 
IL 
Interleukin 
IL-2R 
IL-2 receptor  
IL-15R 
IL-15 receptor  
IMP 
Investigational medicinal product 
IND 
Investigational new drug 
INV 
Investigator 
IRB 
Institutional Review Board 
iRECIST 
Response Evaluation Criteria In Solid Tumors for immune-based 
therapeutics 
iUPD 
Unconfirmed progressive disease per iRECIST 
IV 
Intravenous(ly) 
JAK 
Janus kinase  
KRAS 
Kirsten Ras oncogene 
MABEL 
Minimal anticipated biological effect level 
MAD 
Maximum administered dose 
MAPK 
Mitogen-activated protein kinase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
Malignant melanoma 
mRCC 
Metastatic renal cell carcinoma 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NK cell 
Natural killer cell 
NKG2D 
Natural killer group 2 member D receptor 
NKp30 
Natural cytotoxicity receptor 
NKT cell 
Natural killer T cell 
NKTR-214 
IL-2 conjugated with multiple releasable chains of polyethylene glycol 
NOAEL 
No-observed-adverse-effect level 
ORR 
Objective response rate 
OS 
Overall survival 
PAD 
Pharmacologic active dose 

 
 
 
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Abbreviation 
Term 
PBMC 
Peripheral blood mononuclear cell 
PD 
Pharmacodynamic(s) 
PD-1 
Programmed cell death protein 1 
PD-L1 
Programmed cell death ligand 1 
PFS 
Progression-free survival  
PI3K 
Phosphatidylinositol-4,5-bisphosphate 3-kinase 
PK 
Pharmacokinetic(s) 
PT 
Prothrombin time 
Q1 
25th percentile 
Q3 
75th percentile 
rhIL-15 
Recombinant human IL-15 
RLI-15 
Synonymous to SO-C101; fusion protein receptor-linker-IL-15 
RO 
Receptor occupancy 
RP2D 
Recommended phase 2 dose 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous(ly) 
SmPC 
Summary of Product Characteristics 
SOC 
System organ class 
SO-C101 
Fusion protein receptor-linker-IL-15 
SOP 
Standard Operating Procedure 
STAT  
Signal transducer and activator of transcription  
T3 
Triiodothyronine 
T4 
Thyroxine 
TC 
Teleconference 
Tmax 
Time to reach maximum concentration 
Treg 
Regulatory T cell 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WOCBP 
Woman of child-bearing potential 
*Abbreviations of commonly used weight, height, and volume measures are not listed 
above. 

 
 
 
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5 ETHICS 
5.1 
Institutional Review Board/ Ethics Committee 
The Protocol, Informed Consent Form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Ethics Committee (EC) 
constituted and functioning in accordance with International Council for Harmonisation 
(ICH) Guideline E6 Good Clinical Practice (GCP)1 and any local regulations, and by the 
competent authority (CA). Any Protocol amendment or revision to the ICF will be 
resubmitted to the IRB/EC 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/EC 
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/EC 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 investigational medicinal products (IMPs) to 
the site by the sponsor or its designee. If the IRB/EC 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/EC to the 
sponsor. 
Study progress is to be reported to IRB/ECs 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/EC, he/she 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/EC (or if regionally required, the investigator and the relevant 
IRB/EC via the head of the medical institution) and the CA of any reportable adverse events 
(AEs) per ICH guidelines and local IRB/EC standards of practice. Upon completion of the 
study, the investigator or sponsor will provide the IRB/ECs 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 IRB/EC and CA as regionally required. 
5.2 
Ethical conduct of the study 
This study will be conducted in accordance with Standard Operating Procedures (SOPs) 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 
(adopted by the 18th World Medical Association General Assembly, Helsinki, Finland, June 
1964 and amended by the 64th World Medical Association General Assembly, Fortaleza, 
Brazil, October 2013) and ICH guidelines on GCP (E6[R2] Step 4 version dated 09-Nov-
2016). 
5.3 
Patient information and informed consent 
As part of administering the informed consent document, the investigator must explain to 
each patient the nature of the study, its purpose, the procedures involved, the expected 
duration, the potential risks and benefits involved, any potential discomfort, potential 
alternative procedure(s) or course(s) of treatment available to the patient, and the extent of 
maintaining confidentiality of the patient’s records. Each patient must be informed that 

 
 
 
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participation in the study is voluntary, that he/she may withdraw from the study at any time, 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the investigator. 
This informed consent should be given by means of a standard written statement, written in 
nontechnical language. The patient should understand the statement before signing and 
dating it and will be given a copy of the signed document. 
After the ICF and any other written information to be provided to patients is read and 
explained to the patient, the patient will be asked to sign and date the ICF before any 
study-specific procedures are performed. No patient can enter the study before his/her 
informed consent has been obtained. 
The patient should be informed in a timely manner if new information becomes available 
that may be relevant to the patient’s willingness to continue participation in the study. The 
communication of this information should be documented. 
 
 

 
 
 
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6 INVESTIGATORS AND SPONSOR 
This study will be conducted by qualified investigators under the sponsorship of SOTIO 
Biotech AG (the sponsor). Some study activities can be delegated by the sponsor to vendors 
as appropriate. 
The coordinating investigator for this study is: 
Prof. Aurélien Marabelle, M.D., Ph.D. 
Clinical Director 
Cancer Immunotherapy Program 
Institute Gustave Roussy 
Villejuif, France 
 
 

 
 
 
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7 INTRODUCTION 
7.1 
Background and rationale 
Over the past decade, the power of the immune system to kill malignant tumors using cancer 
immunotherapy has emerged as a promising approach to treat a broad range of human 
cancers. The involvement of the immune system in the tumor control is well accepted and 
immunotherapy is taking a major place in the treatment of cancers recently. However, 
various mechanisms are developed by the tumor to escape from immune cell attack, and 
immunotherapy has to meet a number of challenges. To elicit an effective antitumor 
response, three steps must be achieved: 1) effective processing and presentation of tumor 
antigens by dendritic cells; 2) generation of a protective T-cell response, as well as activation 
of other immune partners such as natural killer (NK) cells, natural killer T (NKT) cells, and 
B cells; and ﬁnally 3) overcoming of the immune suppression induced by the tumor and its 
microenvironment.2 Several current cancer immunotherapies that have been investigated for 
their efficacy include cytokine therapy, adoptive cell transfer, cancer vaccines, and 
monoclonal antibodies. 
Therapy with recombinant interleukin (IL)-2, a T-cell and NK-cell growth factor, was one 
of the earliest successes in immunotherapy. IL-2 (International Nonproprietary Name: 
aldesleukin) was approved in some countries in the EU to treat metastatic renal cell 
carcinoma (mRCC) and by the US Food and Drug Administration (FDA) to treat mRCC 
and malignant melanoma (MM). The FDA approval of high-dose IL-2 (HDIL-2) for the 
treatment of mRCC and MM was based on data derived from multiple pivotal trials 
administering IL-2 of 600,000-720,000 IU/kg with up to 15 bolus infusions every 8 hours, 
based on patients’ tolerance. In 255 patients with mRCC, the objective response rate (ORR) 
was 15% with 7% complete responders.3,4 Despite the proven efﬁcacy of HDIL-2 in treating 
mRCC and MM patients, its use remains relatively restricted due to toxicity. Due to the 
short serum half-life and the need to achieve an immune-modulatory effect in the tissues, 
IL-2 must be given in high doses that induce severe systemic toxicities, including capillary 
leak syndrome (CLS), pulmonary edema, hypotension, acute renal insufﬁciency and rarely 
myocarditis. Nonetheless, this success validated the concept that stimulating T-cell and 
NK-cell responses could yield effective and durable responses. 
IL-15 is a cytokine that has many overlapping functions as IL-2 including the ability to 
promote antitumor responses but with distinct advantages over IL-2. While both IL-2 and 
IL-15 signal through the common IL-2 receptor (IL-2R) chains β and γ (IL-2Rβγ or IL-15 
receptor [IL-15R] βγ) complex, which is responsible for intracellular signaling through the 
JAK/STAT, MAPK, and PI3K pathways in T cells and NK cells, only IL-2 engages the 
high-affinity IL-2R chain α (IL-2Rα). As IL-2Rα is expressed on regulatory T cells (Tregs), 
IL-15 does not induce the expansion of these immunosuppressive cells.5-7 Because IL-15 
can engage IL-2Rβγ without engaging IL-2Rα on Tregs, it is thought to have an improved 
therapeutic index compared with IL-2.8-10 Overall, IL-15 is a T-cell growth factor that: 1) 
induces the activation and proliferation of CD8+ T cells and NK cells, 2) maintains 
long-term memory T cells with relatively less effect on Tregs, and 3) inhibits 
activation-induced cell death. These advantages led IL-15 to be ranked first among various 
novel strategies by a National Cancer Institute (NCI) immunotherapy workshop as the agent 
with the greatest potential to impact clinical oncology.11 
Despite the promising preclinical responses of recombinant IL-15,12 success in the clinical 
setting was limited by its short in vivo half-life until recently. To date, three main 
modifications of IL-15 have been made to generate more potent soluble  

 
 
 
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IL-15 agonists: 1) combining IL-15 with a soluble IL-15R chain α (IL-15Rα) or the sushi 
domain of IL-15Rα; 2) fusing IL-15Rα to the Fc portion of human IgG1; 3) mutating IL-15 
to increase its affinity to IL-2Rβγ. All formulations of IL-15 agonists have demonstrated 
increased strength and duration of IL-15R signaling and subsequent enhanced antitumor 
immunity in nonclinical studies. Recently, emerging clinical data as single agent or in 
combination with programmed cell death protein 1 (PD-1)- or programmed cell death ligand 
1 (PD-L1)-blocking antibodies showed that IL-2Rβγ agonists at doses capable of inducing 
antitumor immune responses are safe and feasible in the outpatient setting and that the 
cytokine complex might be safely combined with PD-1 immunotherapy.2 
In order to make use of the enhanced biological activity of the IL-15/IL-15Rα complex for 
the treatment of cancer and to overcome the need for endogenous IL-15Rα or 
co-administration of IL-15 with IL-15Rα, we engineered a fusion protein which consists of 
the N-terminal sushi domain of human IL-15Rα covalently coupled via a linker of 20 amino 
acids to human IL-15 (receptor-linker-IL-15 [RLI-15]; SO-C101). 
7.2 
Nonclinical summary 
The antitumor activity of SO-C101 was investigated in several syngeneic mouse tumor 
models, including subcutaneously (SC) growing as well as disseminated, metastatic tumor 
models. SO-C101 was investigated as monotherapy as well as in combination with an 
anti-PD-1 antibody. The beneficial effect of combining SO-C101 treatment with anti-PD-1 
treatment supports the clinical evaluation of this combination treatment approach. 
7.2.1 
SO-C101 monotherapy 
SO-C101 promoted mobilization, expansion, and activation of human NK and CD8+ T cells 
in humanized mice and murine NK and CD8+ T cells in syngeneic mice.13,14 
This NK- and CD8+ T-cell activation correlated with the potent anticancer therapeutic 
effects of SO-C101 in the following metastatic and solid tumor models in mice: 
• In the B16F10 metastatic melanoma model in C57BL/6 mice, SO-C101 reduced the 
number of lung metastases after intravenous (IV) injection of mouse B16F10 cells as well 
as the number of liver metastases after intrasplenic injection and increased overall 
survival (OS)15 
• In the orthotopic HCT-116 human colon tumor mouse model engrafted in the cecum of 
nude mice, systemic SO-C101 administration strongly inhibited primary tumor growth 
and metastatic dissemination to the peritoneum and other organs such as liver, lung, and 
spleen15 
• In the RENCA orthotopic tumor model, SO-C101 inhibited primary tumor growth and 
displayed a significant anti-metastatic activity in a metastatic model setting16 
7.2.2 
SO-C101 mechanism of action 
SO-C101 is a fusion protein which consists of the N-terminal sushi domain of human 
IL-15Rα covalently coupled via a linker of 20 amino acids to human IL-15 (Figure 7.1).17,18 
Before being acquired by SOTIO, SO-C101 was referred to as RLI-15. 
 
 
 

 
 
 
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Figure 7.1: Structure of SO-C101 (RLI-15) 
 
 
 
 
 
 
 
 
 
SO-C101 and IL-15 dose-dependently activate similar signaling pathways. However, the 
kinetics and duration of this activation are markedly different; SO-C101-induced signaling 
is slower to start, but lasts longer than signaling induced by IL-15.18 
7.2.3 
SO-C101 in combination with an anti-PD-1 antibody 
SO-C101 exhibited a profound synergistic effect with an anti-PD-1 antibody in several 
mouse tumor models: 
• In the CT-26 colorectal carcinoma model, SO-C101 limited primary tumor growth when 
initiated at an early time of tumor development; at a later time, combination with an 
anti-PD-1 antibody showed synergistic activity with SO-C101, but not with IL-1519 
• In the syngeneic TRAMP-C2 prostate mouse tumor model in C57BL/6 mice, treatment 
with SO-C101 alone decreased tumor growth. SO-C101 in combination with an 
anti-PD-1 antibody decreased the tumor growth more profoundly in an early treatment 
setting in comparison to the SO-C101 monotherapy; moreover, 70% of mice remained 
completely tumor-free when treated with SO-C101 in combination with anti-PD-116 
• Late therapeutic treatment of TRAMP-C2 tumors with SO-C101 and an anti-PD-1 
antibody decreased the tumor growth significantly; flow cytometry analyses showed high 
numbers of interferon (IFN)-γ-producing CD8+ T cells in splenocytes which indicated 
the induction of systemic immunity at the end of the treatment period with SO-C101 and 
the anti-PD-1 antibody16 
7.2.4 
Pharmacology 
A binding affinity of SO-C101 to IL-15R between 200 pM and 800 pM was determined. 
Binding of SO-C101 to IL-15R induced intracellular signaling, cell activation, and 
proliferation, comparable to IL-15-induced cell activation via the high affinity IL-15R. 
The half maximal effective concentration (EC50) of SO-C101 to induce cell proliferation 
was lower than its binding affinity, indicating that less than 50% of receptor occupancy (RO) 
was required to induce half maximal cell proliferation. Human NK cells were more sensitive 

 
 
 
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to SO-C101-mediated activation than CD8+ T cells as demonstrated by the difference in 
their EC50 of approximately 10 pM for NK cells and 100 pM for CD8+ T cells. 
Besides inducing cell proliferation, SO-C101 promoted the functional activation of NK and 
CD8+ T cells as demonstrated by cell surface expression of activating receptors, increased 
IFN-γ release, and cytolytic activity. Activated CD8+ T cells are known to recognize major 
histocompatibility complex-presented peptides derived from mutated or overexpressed 
proteins via their T-cell receptor on the surface of tumor cells. NKp30 and NKG2D 
expression confers cytotoxicity against induced self-proteins expressed on tumor cells by 
NK and CD8+ T cells. These SO-C101-mediated effects are in support of the activation of 
both innate and adaptive cellular immune responses against tumor cells. 
The non-human primate cynomolgus monkey (Macaca fascicularis) is regarded as the 
relevant species for in vivo studies, based on the following observations: 1) the amino acid 
sequences of human IL-15 and IL-15R show a high degree of identity to their respective 
cynomolgus monkey counterparts (IL-15: 96.3%, IL-15R 88.6%, IL-15R 94.2%, 
IL-15R: 97.6%); 2) SO-C101 activated cynomolgus NK and CD8+ T cells in vitro with 
equivalent potency to human NK and CD8+ T cells; and 3) doses promoting NK and CD8+ 
T-cell activation in vivo were 26-fold and 16-fold, respectively, lower in the cynomolgus 
monkey than in the mouse (based on allometrically scaled doses). 
Studies in rodents were used to investigate the antitumor activity of SO-C101, but not 
regarded to determine pharmacologic active and safe doses for investigations in humans. As 
mentioned above, activation of NK and CD8+ T cells correlated with antitumor activity of 
SO-C101 in several mouse tumor models, which was augmented by anti-PD-1 combination 
therapy. This positive pharmacodynamic (PD) drug-drug interaction was wanted and will 
be explored in study SC103 for its potential to increase NK- and CD8+ T-cell activation and 
tumor regression. Importantly, the combination of SO-C101 with an anti-PD-1 antibody 
produced rather additive effects, reducing the risk of an exacerbated PD response and a 
potentially associated safety concern. SO-C101 effectively activated NK and CD8+ T cells 
dose dependently at doses between 4.0 µg/kg and 25.0 µg/kg in cynomolgus monkeys. 
Consistent with in vitro and mouse in vivo studies, CD4+ T cells and regulatory 
CD4+CD25+Foxp3+ T cells were less or not significantly activated. Importantly, SC 
administration was more effective than IV infusion in activating NK and CD8+ T cells. This 
was likely caused by the difference in SO-C101 pharmacokinetics (PK); SC administration 
resulted in a longer circulation time of biologically active serum concentrations compared 
to IV administration. Two daily administrations within one week were optimal for NK- and 
CD8+ T-cell activation. Following two daily administrations on day 1 and day 2, NK- and 
CD8+ T-cell activation was comparably low on day 3, further increased until day 5 and 
resumed back to baseline by day 9. Importantly, NK- and CD8+ T-cell activation followed 
a different kinetics than the SO-C101 serum concentrations that induced this activation. 
Repeated administration over two weeks promoted the increase of lymphocyte counts and 
the number of circulating NK and CD8+ T cells. As these numbers did not further increase 
during subsequent dosing, the schedule for treatment of patients in study SC103 was 
selected accordingly. 
For more information, see the Investigator’s Brochure (IB). 
7.2.5 
Pharmacokinetics 
SO-C101 PK was mainly investigated in cynomolgus monkeys as this species is the most 
relevant for the correlation between PK and PD as well as for the assessment of SO-C101 

 
 
 
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safety. Absorption and serum kinetics following single and repeated SO-C101 
administration to cynomolgus monkeys SC or as a 15- or 60-minute IV infusion was 
investigated and an absorption, distribution, and excretion study was performed with 
[125-iodine]-SO-C101. The doses employed covered the low pharmacologic range up to 
doses resulting in toxicological findings. 
Following SC injection, maximum (or peak) serum concentration (Cmax) and area under the 
curve (AUC) increased over the entire dose range investigated. The increase of both Cmax 
and AUC was about 2-fold higher than dose-proportional at lower doses and closer to 
dose-proportional at higher doses. Cmax was observed between 1.5 and 3 hours following SC 
injection. Cmax following SC injection was between 6- to 10-fold lower, compared to IV 
infusion. The terminal half-life of SO-C101 was in the range of approximately 2 hours to 
almost 4 hours and was comparable after the SC and IV routes of administration. The 
bioavailability of SO-C101 following SC administration compared to a 60-minute IV 
infusion was at 35% to 40% relatively constant over the dose range tested. 
The volume of distribution of SO-C101 following IV infusion was low and ranged between 
37 mL/kg to 351 mL/kg between studies and groups, indicating a distribution mainly to the 
body fluid compartment. Clearance following IV administration ranged between 
81 mL/h/kg and 239 mL/h/kg, indicating that SO-C101 was not highly excreted via the liver. 
A difference in PK properties of SO-C101 between genders was not observed across all 
studies. Also, a high comparability of the SO-C101 PK was observed when SO-C101 was 
administered repeatedly and the analysis was performed on different study days. 
Accumulation of SO-C101 following repeated administration was not observed. This is in 
line with the relatively short half-life of SO-C101 and the daily administration schedule 
investigated. SO-C101 was mainly eliminated via the kidney. This is supported by the 
molecular size of SO-C101 (22 to 25 kDa) and the kidney clearance threshold above this 
molecular size. About 50% of the administered SO-C101 dose was detectable in urine 
24 hours following a single SC administration. 
For more information, see the IB. 
7.2.6 
Toxicology and safety pharmacology 
The safety of SO-C101 was investigated in three repeated dose toxicity studies performed 
in cynomolgus monkeys. These studies employed a more frequent treatment schedule (up 
to 
4 
weekly 
administrations 
for 
4 
weeks) 
than 
planned 
in 
study  
SC103 (2 administrations per week). The SC route of administration, intended for the 
treatment of patients, was investigated in a maximum tolerated dose (MTD) study and in the 
pivotal 28-day Good Laboratory Practice study at 3 dose levels. 
Immune activation was observed in the toxicity studies which is seen as the main cause for 
the effects observed. Infiltration of mononuclear cells, mostly lymphocytic, into tissues was 
a prominent result of SO-C101-mediated systemic immune activation. Tissue infiltrates of 
vascular and perivascular localization and minimal to slight intensity were observed in all 
organs analyzed. This infiltration was considered non-adverse as it did not result in 
degenerative effects in the target tissues. The SC dose of 80.0 µg/kg was described as the 
no-observed-adverse-effect level (NOAEL) and the SC dose of 100.0 µg/kg was described 
as the MTD. The symptoms leading to the definition of the MTD were hunched posture, 
reduced activity, raised hair, subdued behavior, occasional vomit, and mild tremors. This 
was accompanied by slight weight loss and transient increases in body temperature after 
SO-C101 administration. 

 
 
 
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SO-C101 produced changes in hematology and clinical chemistry parameters which were 
potentially linked to the observed systemic immune activation and tissue infiltration. Most 
evident was the dose-dependent and transient increase in C-reactive protein (CRP) levels 
after each administration. Other changes potentially indicating immune-mediated effects on 
the liver were increases in triglyceride and bilirubin as well as decreases in albumin 
(observed at the NOAEL), increases in aspartate transaminase (AST) and alanine 
transaminase (ALT) activity, and decreases in total protein, albumin:globulin ratio and 
inorganic phosphate. Creatinine and urea levels, potentially indicating the inflammation to 
the kidney, were only slightly increased in one study. 
Hematology changes, besides the increase in NK or NKT cells and CD8+ T cells, included 
a decrease in neutrophils and red blood cells, the latter accompanied by a reduction in 
hemoglobin and an increase in reticulocyte counts. The nature of these changes and how 
much the immune activation by SO-C101 contributes to these changes are unclear. Changes 
in platelet counts and coagulation parameters were not observed at the NOAEL but at the 
MTD. Fibrinogen was increased (up to 2-fold in one study), but potentially reflecting a 
marker of the underlying immune activation. 
The above described clinical chemistry and hematology changes did not reflect organ 
toxicities induced over the 4-week treatment with SO-C101. There was a dose effect 
observed with less incidence of effects and a lower magnitude at the low dose tested 
(20.0 µg/kg). Laboratory parameters returned to normal levels after the 4-week recovery 
period. The incidence and severity of mononuclear inflammatory cells infiltrates were 
decreased, indicating partial reversibility. 
SO-C101 showed the potential to induce the release of IL-6, IL-8, and IFN- from human 
whole blood cells in vitro. Consistently throughout the studies in cynomolgus monkeys 
addressing SC administration, the release of IL-6, IFN- and macrophage chemoattractant 
protein 1 was observed, possibly reflecting a direct consequence of SO-C101-mediated 
stimulation of NK and CD8+ T cells. Thus, the cytokines observed following SO-C101 
administration may contribute to the immune-mediated findings observed in the toxicology 
studies. 
The analysis of behavioral parameters as a surrogate central nervous system safety 
pharmacology parameter did not identify any SO-C101-mediated changes. Similarly, 
SO-C101-mediated effects on respiration rate were not observed. An increase in body 
temperature and heart rate was observed in a cardiac and respiratory safety pharmacology 
study approximately between 2.5 and 23 hours after SC administration which was 
accompanied with shortening of the QT interval in the 80.0 µg/kg SC group (maximal 
change by -10% to -14% following correction for heart rate). Blood pressure and other ECG 
parameters such as QP interval and QRS complex interval were generally not changed with 
biological relevance following SO-C101 administration and no heart arrhythmias were 
observed. It seems likely that QT intervals were rather indirectly affected as a response to 
increased heart rate, body temperature and the underlying immune activation stimulated by 
SO-C101. 
SC administration of SO-C101 was well tolerated. Generally, no irritation, edema, or 
erythema was observed at the sites of injection. Microscopically, vascular and perivascular 
infiltration, mainly of lymphocytes, was observed at the injection sites with minimal to slight 
intensity. 
For more information, see the IB. 

 
 
 
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7.3 
Justification for the SC route as the route of administration 
Study SC103 is planned to investigate only the SC administration of SO-C101, based on 
nonclinical PK/PD studies with SO-C101 and clinical data on agents with a similar mode of 
action. 
SO-C101 was well absorbed following SC administration and demonstrated 35% to 40% 
bioavailability compared to 60-minute infusion. Absorption following SC injection resulted 
in a relatively longer circulation time of active SO-C101 concentrations, translating into 
stronger NK- and CD8+ T-cell activation compared to IV infusion. Furthermore, Cmax was 
6- to 8-fold lower but not more variable between animals when compared to IV infusion. 
Based on these findings, the SC route is considered to be pharmacologically more effective 
than the IV route and is regarded as safe. 
Recently published clinical data on agents with a similar mode of action also support the SC 
route of administration. Studies published using the recombinant human IL-15 (rhIL-15) 
and ALT-803 (IL-15/IL-15R α complex) showed that SC dosing was safe and tolerable 
compared to IV administration due to a lower Cmax and more sustained levels of the 
compound in the circulation.20,21 The initial first-in-human (FIH) solid tumor trial of rhIL-15 
using daily IV bolus infusion for 12 consecutive days unexpectedly and severely 
demonstrated toxicities and produced diminutive immune activation and little potential for 
use as monotherapy or in combination with other agents. However, the FIH trial of SC 
administration of rhIL-15 successfully completed dose escalation cohorts and SC 
administration allowed for an MTD ≥6 times higher compared to IV bolus administration.12 
7.4 
Justification for dose scheduling 
7.4.1 
Dosing schedule 1 
Based on the PK/PD study results in cynomolgus monkeys, SO-C101 is planned to be given 
SC once daily on two consecutive days (day 1, day 2, day 8, and day 9 of a 21-day cycle) 
per week for two weeks followed by a week of rest that forms the three-weekly cycles. 
Alternative schedules of dosing may be planned after review of the patients in the first 
couple of cohorts. The schedule of two consecutive SC administrations in one week is based 
on the finding that administration on day 1 and day 2 in a treatment week resulted in optimal 
NK- and CD8+ T-cell activation in cynomolgus monkeys. A treatment period longer than 
two weeks did not further increase NK- and CD8+ T-cell numbers but rather reduced their 
cell counts. Based on these findings (see section 7.2.4), a treatment period of two weeks was 
selected for study SC103. 
7.4.2 
Dosing schedule 2 
In order to explore the potential for improving the activation and expansion of NK and 
CD8+ T cells, two alternative SC dosing schedules were investigated in cynomolgus 
monkeys: i) once-daily SO-C101 administration for 4 consecutive treatment days, and ii) 
twice-daily SO-C101 administration for 2 consecutive days (studies SO-C101-1186E and 
SO-C101-1141E). In addition, the twice-daily SO-C101 administration was investigated in 
mice and this allowed testing the anti-tumor activity (studies SO-C101-1182E and SO-
C101-1183E). 
In cynomolgus monkeys, the administration of 20 µg/kg of SO-C101 twice a day 8 hours 
apart was more effective than 40 µg/kg of SO-C101 once a day for 2 or 4 consecutive days 
in increasing the numbers of CD8+ T cells and NK cells in peripheral blood (Figure 7.2). 

 
 
 
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Notably, the increase in cell counts promoted by twice-daily SO-C101 was stronger for 
CD8+ T cells than for NK cells.  
Figure 7.2: Peripheral blood cell counts of CD8+ T cells and NK cells after once-daily 
and twice-daily SO-C101 administration in cynomolgus monkeys 
 
2D:1×40: animals were dosed once daily with 40 g/kg/dose for 2 consecutive days; 
2D:2×20: animals were dosed twice daily 8 hours apart with 20 g/kg/dose for 2 
consecutive days; 4D:1×40: animals were dosed once daily with 40 g/kg/dose for 4 
consecutive days. Administration days are indicated by arrows.  
The percentage of CD8+ T cells and NK cells was determined by flow cytometry from blood 
at pre-dose, days 5, 8, 12, and 15. Data represent means ± standard error of mean. 
The PK of SO-C101 following a single administration of 40 µg/kg promoted systemic 
concentrations above 2.5 ng/mL for about 9 hours whereas 2 doses of 20 µg/kg, 8 hours 
apart, promoted concentrations above 2.5 ng/mL for approximately 16 hours (Figure 7.3). 
The reference concentration of 2.5 ng/mL reflects the EC50 required for CD8+ T-cell 
activation. The longer exposure to SO-C101 at concentrations above 2.5 ng/mL is seen as 
the cause of the higher increase in the peripheral blood cell counts of CD8+ T cells and NK 
cells observed after twice-daily SO-C101 administration (Figure 7.2).  
Figure 7.3: SO-C101 serum concentrations after once-daily and twice-daily SO-C101 
administration in cynomolgus monkeys 
 

 
 
 
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No clinical signs were reported following the once-daily (40 µg/kg per dose) or twice-daily 
(20 µg/kg per dose) SO-C101 administration. The observed changes in hematology 
parameters were more pronounced after twice-daily SO-C101 administration than after 
once-daily SO-C101 administration. However, these changes were not clinically relevant.  
In mice, two daily administrations of the same cumulative dose of SO-C101 as used in a 
single administration per day were more effective in inducing CD8+ T-cell and NK-cell 
frequencies and were more effective in reducing the tumor volume in MC38 tumor-bearing 
mice.  
In conclusion, the preclinical observations indicate that the twice-daily SO-C101 
administration of half of the daily dose is safe and leads to a prolonged exposure to SO-
C101 at concentrations resulting in stronger PD effects as determined by an increased 
activation and proliferation of CD8+ T cells and NK cells. 
7.5 
Justification for the starting dose and dose escalation steps in Part A 
A starting dose of 0.25 µg/kg was selected for Part A. This starting dose is anticipated to 
represent a minimal active dose level. The selection of the starting dose was based on the 
activation of human NK and CD8+ T cells in vitro as well as on the responses observed in 
cynomolgus monkeys following SC administration of SO-C101 (Figure 7.4). This integrated 
approach is supported by the correlation between in vitro dose-response and the relationship 
between Cmax and NK- and CD8+ T-cell activation levels in cynomolgus monkeys. This 
allowed to determine the dose range reaching from the minimal anticipated biological effect 
level (MABEL) to the anticipated pharmacologic active dose (PAD), and the NOAEL in 
cynomolgus monkeys. These doses were translated into human doses by allometric scaling 
using 3.1 as a factor. Importantly, the pharmacologic activity of SO-C101 as shown in 
Figure 7.4 was used for determining the starting dose and the escalation steps planned for 
clinical study SC103 because this was a more sensitive approach compared to RO (see also 
section 7.2.4). 
Accordingly, a starting dose of 0.25 µg/kg was selected. This dose is expected to promote 
about 20% NK-cell activation without affecting CD8+ T cells. At an anticipated Cmax of 
0.1 ng/mL, the calculated RO would be between 0.5% and 2%, using the determined Kd 
range of 200 – 800 pM and the Hill equation.22 Based on the dose effect as shown in Figure 
7.4, the selected starting dose of 0.25 µg/kg is anticipated to represent the upper end of the 
MABEL range. 
Recent analyses of starting doses in FIH studies together with subsequent findings at higher 
doses concluded that in case of immune agonistic antibodies excluding CD3 agonists, 
generally a starting dose achieving 20% to 80% RO was considered safe.23 In the case of 
CD3-containing agonistic bispecifics, a FIH starting dose of 10% RO was not considered 
safe. Instead, a dose achieving up to 50% pharmacologic activity was acceptable with 
6 artificial dose escalations until a human MTD when a tetravalent construct with high 
affinity for CD3 was excluded.24 The selected SO-C101 starting dose of 0.25 µg/kg is 
expected to achieve below 10% RO (0.5% to 2% RO using the Kd of 200 and 800 pM) and 
20% activation of NK cells, but no T-cell activation. Furthermore, this dose is about 
100-times lower than the human equivalent of the NOAEL. Thus, the approach for selecting 
the SO-C101 starting dose is considered to be safe while reducing the number of patients 
dosed with non-active doses and is more conservative, compared to starting doses described 
in recent evaluations of immune agonistic biologics.23,24 
 

 
 
 
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Figure 7.4: Dose relationship of SO-C101-mediated NK- and CD8+ T-cell activation in 
vitro and in cynomolgus monkeys 
Data from studies with human cells in vitro and from cynomolgus monkey studies with SC 
administration of SO-C101. Activity is shown versus the in vitro SO-C101 concentration 
and the Cmax observed in vivo. Human equivalent doses were calculated by allometric 
scaling using 3.1 as a factor. MABEL: minimal anticipated biological effect level, PAD: 
pharmacologic active dose range, NOAEL: no adverse effect level, MTD: maximum 
tolerated dose. 
The subsequent dose levels as shown in Table 7.1 were selected to gradually increase 
NK-cell activation to 60% and to start inducing CD8+ T-cell activation to <10%, 
respectively, at dose level 2 and to further increase activation to 100% until dose level 6. 
Dose level 7 would still be below the human equivalent of the NOAEL (26.0 µg/kg). Dose 
escalation in study SC103 will be made dependent on the safety observed at each dose level. 
Furthermore, PK parameters as well as NK- and CD8+ T-cell activation analyzed in patients 
in each dose cohort will be considered in the dose escalation decision. 
Table 7.1: SO-C101 starting dose and dose escalation steps in study SC103 (Part A) 
Dose level 
SO-C101 dose 
Dose increase 
Expected NK 
cell activity [%] 
Expected CD8+ 
activity [%] 
1 
0.25 µg/kg 
Starting dose 
20 
0 
2 
0.75 µg/kg 
200% 
60 
<10% 
3 
1.5 µg/kg 
100% 
80 
25 
4 
3.0 µg/kg 
100% 
100 
60 

 
 
 
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Dose level 
SO-C101 dose 
Dose increase 
Expected NK 
cell activity [%] 
Expected CD8+ 
activity [%] 
5 
6.0 µg/kg 
100% 
100 
80 
6 
9.0 µg/kg 
50% 
100 
100 
7 
15.0 µg/kg 
67% 
100 
100 
8 
12.0 µg/kg* 
-20% 
100 
100 
Expected NK- and CD8+ T-cell activation was determined from Figure 7.4, based on data 
obtained in cynomolgus monkeys and the corresponding human doses, determined by 
allometric scaling. 
* Identified on 08-Jun-2021 as the RP2D for monotherapy SO-C101 administered as a once 
daily dose. 
7.6 
Justification for the starting dose in Part A1 
In Part A1, the daily dose of SO-C101 will be administered as 2 divided doses. By this 
means, maximum plasma levels of SO-C101 will be reduced whilst keeping exposure in a 
similar range but avoiding long time intervals with subtherapeutic plasma concentrations 
during the night after dosing (see section 7.4.2 and Figure 7.3).  
It is expected that the twice-daily dosing schedule will promote CD8+ T-cell and NK-cell 
expansion more effectively than the once-daily dosing schedule. The increase in CD8+ T-
cell and NK-cell counts observed in study SC103 was not linked to safety concerns. To 
reduce the likelihood of adverse effects, the daily starting dose in Part A1 will be 1 dose 
level below the recommended phase 2 dose (RP2D) identified in Part A. Thus, the daily 
starting dose will be an already proven safe daily dose. 
7.7 
Justification for the starting dose in Part B 
A starting dose of 1.5 µg/kg is selected for the combination with pembrolizumab, provided 
that dose level 5 (6.0 µg/kg) in Part A is tolerated and deemed safe. Thus, the starting dose 
in Part B will be 4-fold below the already tested dose in humans (SO-C101 monotherapy in 
Part A) which is moreover still more than 4-fold below the human equivalent of the NOAEL 
(26.0 µg/kg). If the dose level of 6.0 µg/kg in Part A is not deemed safe, then Part B will 
start at the lower dose level deemed safe from Part A. The Dose Escalation Committee 
(DEC) will review all available safety data as per the Dose Escalation Meeting (DEM) 
Charter from the first 5 cohorts of Part A before the start of Part B. The dose escalation 
scheme for Part B is shown in Table 9.2. 
7.8 
Justification for the starting dose in Part B1 
In Part B1, the daily dose of SO-C101 will be administered as 2 divided doses. By this 
means, maximum plasma levels of SO-C101 will be reduced whilst keeping exposure in a 
similar range but avoiding long time intervals with subtherapeutic plasma concentrations 
during the night after dosing (see section 7.4.2 and Figure 7.3). 
It is expected that the twice-daily dosing schedule will promote CD8+ T-cell and NK-cell 
expansion more effectively than the once-daily dosing schedule. Similarly as in Part A1, it 
is currently planned that the daily starting dose in Part B1 will be 1 dose level below the 

 
 
 
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RP2D identified in Part B if the safety profile in Part B supports this. Thus, the daily starting 
dose will be an already proven safe daily dose. 
7.9 
Study design rationale 
We hypothesize that combined checkpoint inhibition and appropriate cytokine therapy will 
lead to synergistic outcomes in the induction and/or maintenance of the antitumor responses 
by activation of both innate and adaptive cellular immune responses against tumor cells. 
The SO-C101-mediated effects overcome 1) insufficient generation of antitumor T cells;  
2) inadequate function of tumor-specific T cells; or 3) impaired formation of T-cell 
memory.25 SO-C101, besides inducing NK- and CD8+ T-cell proliferation, promotes their 
functional activation as demonstrated by cell surface expression of activating receptors, 
increased IFN-γ release, and cytolytic activity. The efficacy/safety data from clinical studies 
conducted with compounds in clinical development with a similar mode of action, e.g., 
ALT-803 (an IL-15/IL-15Rα complex fused to an IgG1 Fc) have shown a favorable safety 
profile and induction of a robust immune-stimulatory response,21,26 especially in 
combination with nivolumab. The monotherapy and combination studies indicated that new 
conjugates showed no cytokine release syndrome, CLS, hemodynamic instability, or 
systemic organ failures. The AE profile observed in these studies was anticipated, 
monitorable, and manageable. 
Increasing recognition of the potential of immunotherapeutic combinations and the fact that 
some immuno-oncology agents may yield only modest clinical activity as monotherapy yet 
be highly active in the context of a therapeutic combination have led to the deployment of 
innovative trial designs.27,28 One of these approaches integrates the combination assessment 
into the initial clinical development using the so called “bifurcated design” which is pursued 
in this study. 
In this study, SO-C101 monotherapy dose escalation for dosing schedule 1 will be executed 
first through several dose levels in Part A to allow adequate dosing and follow-up for the 
monotherapy safety to be established using the traditional 3+3 design29 (see section 9.7). 
Provided that safety is acceptable (see section 9.7), the study will “bifurcate” to two distinct 
paths (Part A and Part B) for subsequent escalation. After this point, the study will continue 
in parallel and recruit to both Part A and Part B given as per dosing schedule 1. Under no 
circumstances will the SO-C101 dose in Part B exceed the highest dose deemed safe in Part 
A (see Figure 8.1). 
After the RP2D of SO-C101 given as per dosing schedule 1 is identified in Part A, the study 
will continue to Part A1 and Part D. Part A1 will be a SO-C101 monotherapy dose escalation 
part for dosing schedule 2. The starting daily dose of SO-C101 in Part A1 will be 1 dose 
level below the RP2D identified in Part A. The dose will be split into two identical 
(50%:50%) daily doses with the second dose on each treatment day being administered 8 
hours (±15 min) after the first dose. Part D will be a dose expansion part in which SO-C101 
monotherapy will be given as per dosing schedule 1 at the Part A RP2D with the same 
schedule as in Part A. 
After the RP2D of SO-C101 given as per dosing schedule 2 is identified in Part A1, Part D1 
will start. Part D1 will be a dose expansion part in which SO-C101 monotherapy will be 
given as per dosing schedule 2 at the Part A1 RP2D with the same schedule as in Part A1.  
After the RP2D of SO-C101 given as per dosing schedule 1 in combination with 
pembrolizumab is identified in Part B, Part B1 will start. Part B1 will be a dose escalation 
part in which SO-C101 given as per dosing schedule 2 will be administered in combination 

 
 
 
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with pembrolizumab. The starting daily dose of SO-C101 in Part B1 will be 1 dose level 
below the RP2D identified in Part B. The dose will be split into two identical (50%:50%) 
daily doses with the second dose on each treatment day being administered 8 hours (±15 
min) after the first dose. 
The study will recruit patients to all ongoing study parts in parallel. The sponsor will allocate 
slots for the patients to be recruited to the dose-escalation study parts.  
The patient population for all parts will be patients who are refractory to or intolerant of 
existing therapies known to provide clinical benefit for their condition. The basis of 
selecting these tumors was to include solid tumors with known sensitivity for anti-PD-(L)1 
monotherapies also called PD-Lomas.30 PD-Lomas where ORR ≥10% was reported were 
selected to demonstrate potential efficacy signal for the effect of SO-C101 added to 
KeytrudaTM. 
Part A, Part A1, Part B, and Part B1 will enroll patients with the following 
relapsed/refractory advanced/metastatic tumors: renal cell carcinoma, non-small cell lung 
cancer, small-cell lung cancer, bladder cancer, melanoma, Merkel-cell carcinoma, skin 
squamous-cell carcinoma, microsatellite instability high solid tumors, triple-negative breast 
cancer, mesothelioma, thyroid cancer, thymic cancer, cervical cancer, biliary tract cancer, 
hepatocellular carcinoma, ovarian cancer, gastric cancer, head and neck squamous-cell 
carcinoma, and anal cancer. 
Dose escalation in Part A, Part A1, Part B, and Part B1 will continue until the MTD and/or 
RP2D of the monotherapy SO-C101 and SO-C101 in combination with pembrolizumab are 
defined. This approach will allow for combination safety/PK/PD to be tested and optimized 
timely and effectively. 
Part D and Part D1 will enroll patients with relapsed/refractory advanced/mRCC, patients 
with relapsed/refractory advanced/metastatic skin squamous-cell carcinoma, and patients 
with relapsed/refractory advanced/metastatic melanoma.  
As the monotherapy clinical activity is expected to be limited and as explained above, there 
is a clear rationale that the combination will be more efficacious, this study will allow 
patients in Part A and Part A1 to crossover to Part B or Part B1 when they have objective 
progressive disease but no safety concerns (see section 8.1.9).31 These patients will be 
allowed to crossover to Part B or Part B1 only when there is a dose level deemed safe in 
combination with pembrolizumab by the DEC during a DEM (see the DEM Charter). These 
patients will not be part of the Part B or Part B1 dose-limiting toxicity (DLT) assessment as 
they have already received SO-C101 in Part A or Part A1. This will offer an opportunity for 
patients in the monotherapy dose escalation parts (Part A, Part A1) to receive a potentially 
more effective therapy. 
In order to allow patients treated at lower dose levels of SO-C101 to receive effective 
treatment in Part A, Part A1, Part B, and Part B1, patients will be allowed to continue 
treatment at the next higher dose level if it is assessed to be safe by the DEC and an 
Independent Advisory Panel (IAP) and if the criteria listed in section 8.1.8 are met. 
After the combination RP2D of SO-C101 with pembrolizumab is identified in Part B and 
Part B1, ongoing patients in Part B and Part B1 can receive SO-C101 at the respective 
combination RP2D together with pembrolizumab if the criteria listed in section 8.1.8 are 
met. 
 

 
 
 
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The sponsor has also introduced additional safety monitoring to capture potential longer-
term side effects of monotherapy and the combination as follows: 
1. Safety monitoring beyond cycle 1: All patients will be monitored for potential late 
immune-related toxicities during the study and for 90 days after treatment 
discontinuation (see section 9.7.7.3). This will allow to capture potential late onset 
immune-mediated reactions with monotherapy SO-C101 and in combination with 
pembrolizumab such as immune-mediated pneumonitis; immune-mediated colitis, 
immune-mediated hepatitis, immune-mediated nephritis, infusion-related reactions; 
immune-mediated endocrinopathies: hypophysitis; thyroid disorders; and type 1 diabetes 
mellitus. 
2. Time period before the start of Part B: As detailed above, Part B will only start after dose 
level 5 is deemed safe in Part A. At this point, the patients at dose level 3 in Part A 
(1.5 µg/kg) will be on treatment for at least 5 cycles / minimum 4.5 months and there will 
be a minimum of 15 patients dosed at 5 dose levels (0.25, 0.75, 1.5, 3.0, and 6.0 µg/kg). 
This time period seems to be in line with the median time to onset of immune-mediated 
toxicities of pembrolizumab, although the range could be quite wide.32 
3. An IAP consisting of two experienced clinicians in immuno-oncology and an 
independent statistician will be monitoring and reviewing all safety data. 
4. Additional cardiac eligibility and safety assessments (see section 9.11.6.4.7). IL-15 was 
shown to increase hyaluronic acid secretion by endothelial cells and induce angiogenesis. 
IL-15 could be an important mediator in the progression of atherosclerosis by its 
pro-inflammatory activities.33,34 Findings from completed clinical studies with ALT-803 
have shown one patient with grade 4 congestive heart failure (monotherapy at the highest 
dose level of 20.0 µg/kg given via the SC route) and one patient with grade 3 myocardial 
infarction in combination with nivolumab.35 
Taken together, the mechanism of action of SO-C101, the results from the pre-clinical 
studies where SO-C101 in combination with PD-1 inhibitors have shown synergy, and the 
emerging encouraging clinical data with similar agents warrant SO-C101 to be studied in 
combination with an anti-PD-1 agent. Amongst potential anti-PD-1 agents, pembrolizumab 
is licensed both in frontline and in relapsed/refractory setting in many indications in the US 
and in the EU. This study aims to define the optimum RP2D of SO-C101 as monotherapy 
and in combination with pembrolizumab in a safe and efficient manner which in our view 
would be possible with the current study design. 
 

 
 
 
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8 STUDY DESIGN AND OBJECTIVES 
8.1 
Study design 
This study will assess the safety and tolerability of SO-C101 administered as monotherapy 
(Part A, Part A1, Part D, and Part D1) and in combination with an anti-PD-1 antibody 
(pembrolizumab) (Part B and Part B1) in patients with selected relapsed/refractory 
advanced/metastatic solid tumors who are refractory to or intolerant of existing therapies 
known to provide clinical benefit for their condition. Part A, Part A1, Part B, and Part B1 
will enroll patients with the following relapsed/refractory advanced/metastatic tumors: renal 
cell carcinoma, non-small cell lung cancer, small-cell lung cancer, bladder cancer, 
melanoma, Merkel-cell carcinoma, skin squamous-cell carcinoma, microsatellite instability 
high solid tumors, triple-negative breast cancer, mesothelioma, thyroid cancer, thymic 
cancer, cervical cancer, biliary tract cancer, hepatocellular carcinoma, ovarian cancer, 
gastric cancer, head and neck squamous-cell carcinoma, and anal cancer. Part D and Part 
D1 will enroll patients with relapsed/refractory advanced/mRCC, patients with 
relapsed/refractory advanced/metastatic skin squamous-cell carcinoma, and patients with 
relapsed/refractory advanced/metastatic melanoma. 
The study will have the following parts: 
• Part A will be a FIH SO-C101 monotherapy dose escalation part for dosing schedule 1. 
• Part A1 will be a SO-C101 monotherapy dose escalation part for dosing schedule 2 which 
will start once the RP2D of SO-C101 given as per dosing schedule 1 is identified in Part 
A; the starting daily dose of Part A1 will be 1 dose level below the RP2D identified in 
Part A. The dose will be split into two identical (50%:50%) daily doses with the second 
dose on each treatment day being administered 8 hours (±15 min) after the first dose. 
• Part B will be a dose escalation part which will study SO-C101 given as per dosing 
schedule 1 in combination with pembrolizumab and will start after dose level 5 in Part A 
is completed and deemed safe and will use SO-C101 monotherapy level 3 dose as the 
starting dose in combination with pembrolizumab (Figure 8.1). 
• Part B1 will be a dose escalation part which will study SO-C101 given as per dosing 
schedule 2 in combination with pembrolizumab and will start once the RP2D of SO-C101 
given as per dosing schedule 1 in combination with pembrolizumab is identified in Part 
B; the starting daily dose of Part B1 will be 1 dose level below the RP2D identified in 
Part B. The dose will be split into two identical (50%:50%) daily doses with the second 
dose on each treatment day being administered 8 hours (±15 min) after the first dose. 
• Part D will be a dose expansion part which will start once the RP2D of SO-C101 given 
as per dosing schedule 1 is identified in Part A; SO-C101 will be given at the Part A RP2D 
with the same schedule as in Part A. 
• Part D1 will be a dose expansion part which will start once the RP2D of SO-C101 given 
as per dosing schedule 2 is identified in Part A1; SO-C101 will be given at the Part A1 
RP2D with the same schedule as in Part A1. 

 
 
 
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Figure 8.1: Overall design 
 
 

 
 
 
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8.1.1 
Dosing schedule 
SO-C101 will be administered on treatment days either as a once daily dose (dosing schedule 
1) or twice a day as 2 divided doses (50%:50%) with the second dose on each treatment day 
being administered 8 hours (±15 min) after the first dose (dosing schedule 2). 
8.1.2 
Part A – Monotherapy SO-C101 dosing schedule 1 dose escalation 
Part A will start first with SO-C101 monotherapy dose escalation for dosing schedule 1 
which will continue until the MTD and/or RP2D of SO-C101 monotherapy given as per 
dosing schedule 1 is defined. 
8.1.3 
Part A1 – Monotherapy SO-C101 dosing schedule 2 dose escalation 
Part A1 will start with the starting daily dose at 1 dose level below the RP2D identified in 
Part A (which will be split into two identical [50%:50%] daily doses) until the MTD and/or 
RP2D of SO-C101 monotherapy given as per dosing schedule 2 is defined. 
8.1.4 
Part B – SO-C101 dosing schedule 1 dose escalation in combination with 
pembrolizumab 
Part B will start once monotherapy SO-C101 dose level 5 (6.0 µg/kg) in Part A is completed 
and deemed safe. The starting dose of Part B will be Part A dose level 3 (1.5 µg/kg) which 
will be combined with a fixed dose of pembrolizumab (200 mg IV every 3 weeks). If an 
MTD in Part A is reached before dose level 5, then the starting dose of SO-C101 in Part B 
will be decided based on the review of all available safety/PD/PK data. After the start of 
Part B, the study will continue recruiting to Part A and Part B in parallel. The Part B SO-
C101 dose will be following the increasing safe dose levels of monotherapy SO-C101 from 
Part A. Under no circumstances will the Part B SO-C101 dose exceed the highest dose 
deemed safe in Part A (see Figure 8.1). Part B dose escalation will continue until the MTD 
and/or RP2D of SO-C101 in combination with pembrolizumab is defined. This approach 
will allow for combination safety/PK/PD to be tested and optimized timely and effectively. 
8.1.5 
Part B1 – SO-C101 dosing schedule 2 dose escalation in combination with 
pembrolizumab 
After the RP2D of SO-C101 given as per dosing schedule 1 in combination with 
pembrolizumab is identified in Part B, Part B1 will start with the starting daily dose at 1 
dose level below the RP2D identified in Part B (which will be split into two identical 
[50%:50%] daily doses) until the MTD and/or RP2D of SO-C101 given as per dosing 
schedule 2 in combination with pembrolizumab is defined. 
8.1.6 
Part D – Monotherapy SO-C101 dosing schedule 1 dose expansion 
Part D will start after the RP2D of SO-C101 monotherapy given as per dosing schedule 1 is 
identified in Part A. SO-C101 will be given as per dosing schedule 1 at this RP2D. 
8.1.7 
Part D1 – Monotherapy SO-C101 dosing schedule 2 dose expansion 
Part D1 will start after the RP2D of SO-C101 monotherapy given as per dosing schedule 2 
is identified in Part A1. SO-C101 will be given as per dosing schedule 2 at this RP2D. 

 
 
 
 
 
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8.1.8 
Intra-patient dose increase 
Intra-patient dose escalation beyond the dose initially assigned to a patient is not permitted 
during cycle 2. However, patients receiving treatment with SO-C101 beyond cycle 2 may 
continue treatment at the next higher dose level if it is assessed to be safe by the DEC and 
IAP and if the following criteria are met: 
• No safety concerns as deemed by the investigator 
• No DLT at the initial dose level assigned 
• No unacceptable AEs, defined as drug-related clinically meaningful, uncontrolled grade 
3 or any grade 4 toxicities at the current dose level 
• No dose reduction at the current dose level 
• Completed at least two cycles at the assigned dose 
• The investigator should also be of the opinion that these patients will derive benefit from 
treatment at the higher dose level of SO-C101 
If these requirements are met, the patient can be dose escalated to the next dose level after 
discussion with the sponsor’s medical monitor. These patients after intra-patient dose 
increase will NOT be part of the higher dose escalation cohorts; therefore, after intra-patient 
dose increase, they will not be part of the DLT evaluation. 
Intra-patient escalation up to the RP2D level in Part A, Part A1, Part B, and Part B1 is 
allowed and can be done step-by step if the patient stays at the higher dose level and meets 
the criteria for escalation as specified above. 
8.1.9 
Crossover of patients from Part A and Part A1 to Part B or Part B1 
This study is planned to allow patients to crossover from Part A and Part A1 to Part B or 
Part B1 when they have objective progressive disease in Part A and Part A1 and there is a 
dose deemed safe in Part B or Part B1. The investigator should also be of the opinion that 
these patients will derive benefit from combination treatment in Part B or Part B1. These 
patients will NOT be part of the dose escalation cohorts of Part B or Part B1; therefore, they 
will not be part of the DLT evaluation in Part B or Part B1. 
The crossover will only be allowed when all of the following criteria are met: 
• Unconfirmed progressive disease (iUPD) as per Response Evaluation Criteria In Solid 
Tumors for immune-based therapeutics (iRECIST)36 in Part A and Part A1 
• Eligibility for Part A and Part A1 (except fresh biopsy requirement) still holds and 
patients have no known hypersensitivity to any of the ingredients in the pembrolizumab 
drug product (KeytrudaTM) 
• There are no safety concerns as deemed by the investigator and the patient should not 
have had a DLT in Part A and Part A1 
• A completed safe dose level identified in Part B or Part B1; if there are more than one 
safe dose levels identified, the patient will be allowed to be assigned to the highest dose 
level deemed safe 
For each patient considered for the crossover, the investigator will discuss this with the 
sponsor’s medical monitor. 
 

 
 
 
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If all of the above criteria are met, the following procedures will be applied: 
• Patient will attend the End of treatment (EoT) visit for Part A or Part A1 
• Patient will sign the ICF for Part B or Part B1 
Once a patient starts Part B or Part B1, all Part B or Part B1 study procedures starting from 
cycle 1 day 1 will be followed except: 
• PK 
• Part B or Part B1 screening biopsy (the second biopsy in cycle 2 in Part B or Part B1 is 
optional for crossover patients) 
8.2 
Objectives 
8.2.1 
Part A (SO-C101 dosing schedule 1, monotherapy, dose escalation) 
8.2.1.1 
Primary objectives 
• To assess the safety and tolerability of SO-C101 given as monotherapy 
• To determine the MTD and/or RP2D of SO-C101 given as monotherapy 
8.2.1.2 
Secondary objectives 
• To characterize the PK of SO-C101 
• To characterize the PD of SO-C101 in peripheral blood 
• To determine the preliminary efficacy of SO-C101 monotherapy as measured by ORR, 
duration of response (DOR), clinical benefit rate (CBR), and progression-free survival 
(PFS) according to iRECIST 
• To determine the immunogenicity of SO-C101 given as monotherapy 
8.2.1.3 
Exploratory objectives 
• To explore the mechanistic effects of SO-C101 on selected immune cell populations in 
tumor tissue samples 
• To assess OS at 6 months after the EoT visit  
8.2.2 
Part A1 (SO-C101 dosing schedule 2, monotherapy, dose escalation) 
8.2.2.1 
Primary objectives 
• To assess the safety and tolerability of SO-C101 given as monotherapy 
• To determine the MTD and/or RP2D of SO-C101 given as monotherapy 
8.2.2.2 
Secondary objectives 
• To characterize the PK of SO-C101 
• To characterize the PD of SO-C101 in peripheral blood 
• To determine the preliminary efficacy of SO-C101 monotherapy as measured by ORR, 
DOR, CBR, and PFS according to iRECIST 
• To determine the immunogenicity of SO-C101 as monotherapy 

 
 
 
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8.2.2.3 
Exploratory objectives 
• To explore the mechanistic effects of SO-C101 on selected immune cell populations in 
tumor tissue samples 
• To assess OS at 6 months after the EoT visit 
8.2.3 
Part B (SO-C101 dosing schedule 1, combined with pembrolizumab, dose 
escalation) 
8.2.3.1 
Primary objectives 
• To assess the safety and tolerability of SO-C101 when combined with pembrolizumab 
• To determine the MTD and/or RP2D of SO-C101 when combined with pembrolizumab 
8.2.3.2 
Secondary objectives 
• To characterize the PK of SO-C101 when combined with pembrolizumab 
• To characterize the PD of SO-C101 in peripheral blood when combined with 
pembrolizumab 
• To assess the preliminary efficacy of the combination of SO-C101 with pembrolizumab 
as measured by ORR, DOR, CBR, and PFS according to iRECIST 
• To determine the immunogenicity of SO-C101 in combination with pembrolizumab 
8.2.3.3 
Exploratory objectives 
• To explore the mechanistic effects of SO-C101 in combination with pembrolizumab on 
selected immune cell populations in tumor tissue samples 
• To assess OS at 6 months after the EoT visit 
8.2.4 
Part B1 (SO-C101 dosing schedule 2, combined with pembrolizumab, dose 
escalation) 
8.2.4.1 
Primary objectives 
• To assess the safety and tolerability of SO-C101 when combined with pembrolizumab 
• To determine the MTD and/or RP2D of SO-C101 when combined with pembrolizumab 
8.2.4.2 
Secondary objectives 
• To characterize the PK of SO-C101 when combined with pembrolizumab 
• To characterize the PD of SO-C101 in peripheral blood when combined with 
pembrolizumab 
• To assess the preliminary efficacy of the combination of SO-C101 twice daily with 
pembrolizumab as measured by ORR, DOR, CBR, and PFS according to iRECIST 
• To determine the immunogenicity of SO-C101 in combination with pembrolizumab 

 
 
 
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8.2.4.3 
Exploratory objectives 
• To explore the mechanistic effects of SO-C101 in combination with pembrolizumab on 
selected immune cell populations in tumor tissue samples 
• To assess OS at 6 months after the EoT visit 
8.2.5 
Part D (SO-C101 dosing schedule 1, monotherapy, dose expansion at the 
RP2D identified in Part A) 
8.2.5.1 
Primary objective 
• To assess the safety and tolerability of SO-C101 
8.2.5.2 
Secondary objectives 
• To characterize the PK of SO-C101 
• To characterize the PD of SO-C101 in peripheral blood 
• To assess the preliminary efficacy of SO-C101 as measured by ORR, DOR, CBR, and 
PFS according to iRECIST 
• To determine the immunogenicity of SO-C101 
8.2.5.3 
Exploratory objectives 
• To explore the mechanistic effects of SO-C101 on selected immune cell populations in 
tumor tissue samples 
• To assess OS at 6 months after the EoT visit 
8.2.6 
Part D1 (SO-C101 dosing schedule 2, monotherapy, dose expansion at the 
RP2D identified in Part A1) 
8.2.6.1 
Primary objective 
• To assess the safety and tolerability of SO-C101 
8.2.6.2 
Secondary objectives 
• To characterize the PK of SO-C101 
• To characterize the PD of SO-C101 in peripheral blood 
• To assess the preliminary efficacy of SO-C101 as measured by ORR, DOR, CBR, and 
PFS according to iRECIST 
• To determine the immunogenicity of SO-C101 
8.2.6.3 
Exploratory objectives 
• To explore the mechanistic effects of SO-C101 on selected immune cell populations in 
tumor tissue samples 
• To assess OS at 6 months after the EoT visit 
 
 

 
 
 
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9 INVESTIGATIONAL PLAN 
9.1 
Part A (SO-C101 dosing schedule 1, monotherapy, dose escalation) 
Patients will be treated with escalating doses of SO-C101 given as per dosing schedule 1 via 
the SC route following the dose escalation scheme below (Table 9.1). A starting dose of 
0.25 µg/kg was selected in Part A of this study. If this starting dose is not tolerated, then a 
lower dose will be considered. Justification for the starting dose is described in section 7.5. 
Table 9.1: SO-C101 dosing schedule 1 dose increments, Part A 
Dose level 
SO-C101 dose given once a day 
(µg/kg/administration) 
Dose increase 
1 
0.25 µg/kg 
Starting dose 
2 
0.75 µg/kg 
200% 
3 
1.5 µg/kg 
100% 
4 
3.0 µg/kg 
100% 
5 
6.0 µg/kg 
100% 
6 
9.0 µg/kg 
50% 
7 
15.0 µg/kg 
67% 
8 
12.0 µg/kg* 
-20% 
* Identified on 08-Jun-2021 as the RP2D for monotherapy SO-C101 administered as a once 
daily dose. 
Patients will be treated with SO-C101 given once a day on day 1 (±1 day; Wednesday), day 
2 (Thursday), day 8 (Wednesday), and day 9 (Thursday) of the 21-day cycle (see Figure 
9.1). The start of the treatment (day 1) is planned to be on a Wednesday to allow biomarker 
sampling (fresh peripheral blood mononuclear cells [PBMCs] transfer to the central 
laboratory) on weekdays. However, as long as the two doses per week are given on 
consecutive days (day 1 and day 2) and the second week dosing (day 8 and day 9) takes 
place 7 days after day 1, there will be ±1 day flexibility for the day 1 dosing to take place 
on a Tuesday or on a Thursday. 
SC 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 potential local effects 
of SO-C101 administration. 
This dosing schedule will be revised in light of the emerging clinical data from initial cohorts 
and if these data reveal substantial differences from non-clinical data, adjustment of the 
planned dose levels will be considered by the DEC (see the DEM Charter and section 9.7.3) 
and the IAP. 

 
 
 
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Figure 9.1: Part A: SO-C101 dosing schedule 1 
 
This schedule should be strictly adhered to with no dose delays/reductions to be allowed for 
especially cycle 1 for maximum exposure for safety evaluation for DLTs (Figure 9.1; for 
DLT evaluation, see section 9.7.1). If any visits are missed for obtaining PK/PD/safety 
laboratory parameters during cycle 1, patients will be reviewed individually by the sponsor’s 
medical monitor and investigators for their evaluability for DLT assessment (Table 9.6). 
SO-C101 dosing schedule 1 monotherapy dose escalation will continue until the MTD 
and/or RP2D is reached as per the dose escalation schema (Table 9.1). If the MTD is not 
reached at the end of the planned dose escalation cohorts, the recruitment will stop to assess 
RP2D as described in section 9.7.2. Additional doses and schedules could be opened as 
required based on the RP2D assessment results to define the optimal dose and schedule for 
further clinical studies. 
Patients recruited in Part A will continue treatment at their assigned dose level until any of 
the criteria listed in section 9.11.10 are met. Intra-patient dose escalation beyond the dose 
initially assigned to a patient is not permitted during cycle 2. However, patients receiving 
treatment with SO-C101 given as per dosing schedule 1 beyond cycle 2 may continue 
treatment at the next higher dose level if it is assessed to be safe by the DEC and IAP and if 
the criteria listed in section 8.1.8 are met. These patients after intra-patient dose increase 
will NOT be part of the higher dose escalation cohorts; therefore, after intra-patient dose 
increase, they will not be part of the DLT evaluation. Intra-patient escalation up to the RP2D 
level is allowed and can be done step-by step if the patient stays at the higher dose level and 
meets the criteria for escalation as specified in section 8.1.8. 
If a patient’s treatment discontinuation is due to disease progression, crossover to the 
combination treatment (Part B or Part B1) could be considered. See section 8.1.9. 
9.2 
Part A1 (SO-C101 dosing schedule 2, monotherapy, dose escalation) 
Patients will be treated with escalating doses of SO-C101 given as per dosing schedule 2 via 
the SC route. The starting daily dose will be 1 level below the RP2D identified in Part A. 
The dose will be split into two identical (50%:50%) daily doses with the second dose on 
each treatment day being administered 8 hours (±15 min) after the first dose. If this starting 
dose is not tolerated, then a lower dose could be considered. Further dose levels will be 

 
 
 
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considered based on safety data and decisions taken during DEMs. Justification for the 
starting dose is described in section 7.6. 
Patients will be treated with SO-C101 given twice a day 8 hours (±15 min) apart on day 1 
(±1 day; Wednesday), day 2 (Thursday), day 8 (Wednesday), and day 9 (Thursday) of the 
21-day cycle (see Figure 9.2). The start of the treatment (day 1) is planned to be on a 
Wednesday to allow biomarker sampling (fresh PBMCs transfer to the central laboratory) 
on weekdays. However, as long as the four doses per week are given on consecutive days 
(day 1 and day 2) and the second week dosing (day 8 and day 9) takes place 7 days after day 
1, there will be ±1 day flexibility for the day 1 dosing to take place on a Tuesday or on a 
Thursday. 
Figure 9.2: Part A1: SO-C101 dosing schedule 2 
 
 
 
 
 
 
 
 
 
 
 
 
SC 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 potential local effects 
of SO-C101 administration. 
This dosing schedule will be revised in light of the emerging clinical data from initial cohorts 
and if these data reveal substantial differences from non-clinical data, adjustment of the 
planned dose levels will be considered by the DEC (see the DEM Charter and section 9.7.3) 
and the IAP. 
This schedule should be strictly adhered to with no dose delays/reductions to be allowed for 
especially cycle 1 for maximum exposure for safety evaluation for DLTs (Figure 9.2; for 
DLT evaluation, see section 9.7.1). If any visits are missed for obtaining PK/PD/safety 
laboratory parameters during cycle 1, patients will be reviewed individually by the sponsor’s 
medical monitor and investigators for their evaluability for DLT assessment (Table 9.6). 
SO-C101 dosing schedule 2 monotherapy dose escalation will continue until the MTD 
and/or RP2D is reached. If the MTD is not reached, the recruitment will stop to assess RP2D. 
Additional doses and schedules could be opened as required based on the RP2D assessment 
results to define the optimal dose and schedule for further clinical studies. 
Patients recruited in Part A1 will continue treatment at their assigned dose level until any of 
the criteria listed in section 9.11.10 are met. Intra-patient dose escalation beyond the dose 
initially assigned to a patient is not permitted during cycle 2. However, patients receiving 

 
 
 
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treatment with SO-C101 given as per dosing schedule 2 beyond cycle 2 may continue 
treatment at the next higher dose level if it is assessed to be safe by the DEC and IAP and if 
the criteria listed in section 8.1.8 are met. 
These patients after intra-patient dose increase will NOT be part of the higher dose 
escalation cohorts; therefore, after intra-patient dose increase, they will not be part of the 
DLT evaluation. Intra-patient escalation up to the RP2D level is allowed and can be done 
step-by step if the patient stays at the higher dose level and meets the criteria for escalation 
as specified in section 8.1.8. 
If a patient’s treatment discontinuation is due to disease progression, crossover to the 
combination treatment (Part B or Part B1) could be considered. See section 8.1.9. 
9.3 
Part B (SO-C101 dosing schedule 1, combined with pembrolizumab, dose 
escalation) 
Part B treatment will consist of SO-C101 given as per dosing schedule 1 in combination 
with pembrolizumab following the dose escalation scheme below (Table 9.2). Justification 
for the starting dose is described in section 7.7. 
The SO-C101 starting dose for cohort 1 of Part B, the combination with pembrolizumab, 
will be 1.5 µg/kg provided that dose level 5 (6.0 µg/kg) in Part A is tolerated and deemed 
safe. If the dose level of 6.0 µg/kg is not deemed safe, then Part B will start at the lower 
dose level deemed safe. If this starting dose is not tolerated, then SO-C101 dose level -1 of 
Part B (0.75 µg/kg) will be tested. 
Table 9.2: SO-C101 dosing schedule 1 dose increments in combination with 
pembrolizumab, Part B 
Dose level 
SO-C101 dose given once a day 
(µg/kg/administration) 
Dose increase 
Pembrolizumab 
-1 
0.75 µg/kg 
(-50%) 
200 mg 
1 
1.5 µg/kg 
Starting dose 
200 mg 
2 
3.0 µg/kg 
100% 
200 mg 
3 
6.0 µg/kg 
100% 
200 mg 
4 
9.0 µg/kg 
50% 
200 mg 
5 
12.0 µg/kg 
33% 
200 mg 
Patients will be treated with escalating doses of SO-C101 given once a day on day 1 (±1 
day; Wednesday), day 2 (Thursday), day 8 (Wednesday), and day 9 (Thursday) together 
with a fixed dose of pembrolizumab (200 mg IV every 3 weeks) given on the day 1 
administration of SO-C101. Pembrolizumab will be administered within 30 minutes after 
the first dose of SO-C101 and as outlined in the package insert37,38 (see Figure 9.3). The 
start of the treatment (day 1) is planned to be on a Wednesday to allow biomarker sampling 
(fresh PBMCs transfer to the central laboratory) on weekdays. However, as long as the two 
doses of SO-C101 per week are given on consecutive days (day 1 and day 2) and the second 

 
 
 
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week SO-C101 dosing (day 8 and day 9) takes place 7 days after day 1, there will be ±1 day 
flexibility for the day 1 dosing to take place on a Tuesday or on a Thursday. 
Figure 9.3: Part B: SO-C101 dosing schedule 1 and pembrolizumab 
 
 
 
 
 
 
 
 
 
 
 
 
This schedule should be strictly adhered to with no dose delays/reductions to be allowed for 
especially cycle 1 for maximum exposure for safety evaluation for DLTs (Figure 9.3; for 
DLT evaluation, see section 9.7.1). If any visits are missed for obtaining PK/PD/safety 
laboratory parameters during cycle 1, patients will be reviewed individually by the sponsor’s 
medical monitor and investigators for their evaluability for DLT assessment (Table 9.7). 
SO-C101 combination dose escalation for dosing schedule 1 will continue until the MTD 
and/or RP2D is reached as per the dose escalation schema. If the MTD is not reached at the 
end of the planned dose escalation cohorts, the recruitment will stop to assess RP2D. 
Additional doses and schedules could be opened as required based on the RP2D assessment 
results to define the optimal dose and schedule for further clinical studies. 
Patients will continue SO-C101 given as per dosing schedule 1 and pembrolizumab 
treatment at the assigned dose level of SO-C101 until any of the criteria listed in section 
9.11.10 are met. 
Intra-patient dose escalation beyond the dose initially assigned to a patient is not permitted 
during cycle 2. However, patients receiving treatment with SO-C101 given as per dosing 
schedule 1 beyond cycle 2 may continue treatment at the next higher dose level if it is 
assessed to be safe by the DEC and IAP and if the criteria listed in section 8.1.8 are met. 
These patients after intra-patient dose increase will NOT be part of the higher dose 
escalation cohorts; therefore, after intra-patient dose increase, they will not be part of the 
DLT evaluation. 
In case SO-C101 needs to be stopped for reasons other than disease progression, 
pembrolizumab treatment can continue for up to 1 year as assessed by the DEC if the patient 
does not progress and can tolerate the treatment (see also Table 9.8 and Table 9.13). In case 
pembrolizumab needs to be stopped, SO-C101 treatment can continue until disease 
progression or unacceptable toxicity. 

 
 
 
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SC 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 SO-C101 
administration. 
Once Part B is open for recruitment and the first combination cohort is deemed safe, patients 
who had objective disease progression in Part A and Part A1 will be allowed to crossover 
to Part B given that there are no safety concerns and the criteria and procedures are followed 
as described in section 8.1.9. 
Intra-patient escalation up to the RP2D level is allowed and can be done step-by step if the 
patient stays at the higher dose level and meets the criteria for escalation as specified in 
section 8.1.8. 
9.4 
Part B1 (SO-C101 dosing schedule 2, combined with pembrolizumab, 
dose escalation) 
Part B1 treatment will consist of SO-C101 given as per dosing schedule 2 in combination 
with pembrolizumab. The starting daily dose will be 1 level below the RP2D identified in 
Part B. The dose will be split into two identical (50%:50%) daily doses with the second dose 
on each treatment day being administered 8 hours (±15 min) after the first dose. If this 
starting dose is not tolerated, then a lower dose could be considered. Further dose levels will 
be considered based on safety data and decisions taken during DEMs. Justification for the 
starting dose is described in section 7.8. 
Patients will be treated with escalating doses of SO-C101 given twice a day 8 hours (±15 
min) apart on day 1 (±1 day; Wednesday), day 2 (Thursday), day 8 (Wednesday), and day 
9 (Thursday) together with a fixed dose of pembrolizumab (200 mg IV every 3 weeks) given 
with the first administration of SO-C101 on day 1. Pembrolizumab will be administered 
within 30 minutes after the first dose of SO-C101 and as outlined in the package insert37,38 
(see Figure 9.4). The start of the treatment (day 1) is planned to be on a Wednesday to allow 
biomarker sampling (fresh PBMCs transfer to the central laboratory) on weekdays. 
However, as long as the four doses of SO-C101 per week are given on consecutive days 
(day 1 and day 2) and the second week SO-C101 dosing (day 8 and day 9) takes place 7 
days after day 1, there will be ±1 day flexibility. 
This schedule should be strictly adhered to with no dose delays/reductions to be allowed for 
especially in cycle 1 for maximum exposure for safety evaluation for DLTs (Figure 9.4; for 
DLT evaluation, see section 9.7.1). If any visits are missed for obtaining PK/PD/safety 
laboratory parameters during cycle 1, patients will be reviewed individually by the sponsor’s 
medical monitor and investigators for their evaluability for DLT assessment (Table 9.7). 
SO-C101 combination dose escalation for dosing schedule 2 will continue until the MTD 
and/or RP2D is reached. If the MTD is not reached, the recruitment will stop to assess RP2D. 
Additional doses and schedules could be opened as required based on the RP2D assessment 
results to define the optimal dose and schedule for further clinical studies. 
Patients will continue SO-C101 given as per dosing schedule 2 and pembrolizumab 
treatment at the assigned dose level of SO-C101 until any of the criteria listed in section 
9.11.10 are met. 
Intra-patient dose escalation beyond the dose initially assigned to a patient is not permitted 
during cycle 2. However, patients receiving treatment with SO-C101 given as per dosing 
schedule 2 beyond cycle 2 may continue treatment at the next higher dose level if it is 
assessed to be safe by the DEC and IAP and if the criteria listed in section 8.1.8 are met. 

 
 
 
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These patients after intra-patient dose increase will NOT be part of the higher dose 
escalation cohorts; therefore, after intra-patient dose increase, they will not be part of the 
DLT evaluation. 
Figure 9.4: Part B1: SO-C101 dosing schedule 2 and pembrolizumab 
 
 
 
 
 
 
 
 
 
 
 
 
In case SO-C101 needs to be stopped for reasons other than disease progression, 
pembrolizumab treatment can continue for up to 1 year as assessed by the DEC if the patient 
does not progress and can tolerate the treatment (see also Table 9.8 and Table 9.13). In case 
pembrolizumab needs to be stopped, SO-C101 treatment can continue until disease 
progression or unacceptable toxicity. 
SC 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 SO-C101 
administration. 
Once Part B1 is open for recruitment and the first combination cohort is deemed safe, 
patients who had objective disease progression in Part A and Part A1 will be allowed to 
crossover to Part B1 given that there are no safety concerns and the criteria and procedures 
are followed as described in section 8.1.9. 
Intra-patient escalation up to the RP2D level is allowed and can be done step-by step if the 
patient stays at the higher dose level and meets the criteria for escalation as specified in 
section 8.1.8. 
9.5 
Part D (SO-C101 dosing schedule 1, monotherapy, dose expansion at the 
RP2D identified in Part A) 
Part D treatment will consist of SO-C101 dosing schedule 1 given as monotherapy at the 
RP2D identified in Part A. 
Patients will be treated with SO-C101 given once a day on day 1 (±1 day; Wednesday), day 
2 (Thursday), day 8 (Wednesday), and day 9 (Thursday; see Figure 9.5).  
The start of the treatment (day 1) is planned to be on a Wednesday to allow biomarker 
sampling (fresh PBMCs transfer to the central laboratory) on weekdays. However, as long 
as the two doses of SO-C101 per week are given on consecutive days (day 1 and day 2) and 

 
 
 
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the second week SO-C101 dosing (day 8 and day 9) takes place 7 days after day 1, there 
will be ±1 day flexibility for the day 1 dosing to take place on a Tuesday or on a Thursday. 
Figure 9.5: Part D: SO-C101 dosing schedule 1 
 
 
 
 
 
 
 
 
 
 
 
 
This schedule should be strictly adhered to with no dose delays/reductions to be allowed for 
especially in cycle 1 for maximum exposure for safety evaluation. If any visits are missed 
for obtaining PK/PD/safety laboratory parameters during cycle 1, patients will be reviewed 
individually by the sponsor’s medical monitor and investigators. Patients will continue 
SO-C101 until any of the criteria listed in section 9.11.10 are met. 
SC 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 SO-
C101 administration. 
Data collected in Part D will be regularly reviewed by the IAP and discussed with the 
sponsor. Details will be provided in the IAP Charter. 
9.6 
Part D1 (SO-C101 dosing schedule 2, monotherapy, dose expansion at the 
RP2D identified in Part A1) 
Part D1 treatment will consist of SO-C101 given as per dosing schedule 2 as monotherapy 
at the RP2D identified in Part A1. 
Patients will be treated with SO-C101 given twice a day 8 hours (±15 min) apart on day 1 
(±1 day; Wednesday), day 2 (Thursday), day 8 (Wednesday), and day 9 (Thursday; see 
Figure 9.6). 
The start of the treatment (day 1) is planned to be on a Wednesday to allow biomarker 
sampling (fresh PBMCs transfer to the central laboratory) on weekdays. However, as long 
as the four doses of SO-C101 per week are given on consecutive days (day 1 and day 2) and 
the second week SO-C101 dosing (day 8 and day 9) takes place 7 days after day 1, there 
will be ±1 day flexibility for the day 1 dosing to take place on a Tuesday or on a Thursday. 
 
 

 
 
 
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Figure 9.6: Part D1: SO-C101 dosing schedule 2 
 
 
 
 
 
 
 
 
 
 
 
 
This schedule should be strictly adhered to with no dose delays/reductions to be allowed for 
especially in cycle 1 for maximum exposure for safety evaluation. If any visits are missed 
for obtaining PK/PD/safety laboratory parameters during cycle 1, patients will be reviewed 
individually by the sponsor’s medical monitor and investigators. Patients will continue 
SO-C101 until any of the criteria listed in section 9.11.10 are met. 
SC 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 SO-
C101 administration. 
Data collected in Part D1 will be regularly reviewed by the IAP and discussed with the 
sponsor. Details will be provided in the IAP Charter. 
9.7 
Dose escalation plan and study periods 
The DLT evaluation period is the first treatment cycle (21 days). A patient evaluable for 
DLT will be a patient who has completed cycle 1 and received all planned treatments 
without any treatment delays or interruptions: for Part A, received all 4 doses of SO-C101 
as planned; for Part A1, received all 8 doses of SO-C101 as planned; for Part B, received all 
4 doses of SO-C101 and 1 dose of pembrolizumab as planned; for Part B1, received all 8 
doses of SO-C101 and 1 dose of pembrolizumab as planned. Patients who do not fulfill these 
criteria for any other reason than DLT should be replaced. 
After completion of the DLT evaluation period with the adequate number of evaluable 
patients as defined below (see Figure 9.7), all data as specified in the DEM Charter will be 
reviewed during a DEM by the DEC. The same data will also be reviewed by the IAP as 
described in the IAP Charter. The decision as to whether an AE should be considered as 
DLT and/or whether a dose level is to be considered intolerable will be made by the DEC 
with endorsement from the IAP. The DEC consists of the study investigators and the 
sponsor’s medical monitor. The IAP consists of two independent clinical experts and an 
independent statistician. 
In the event of a confirmed non-tolerable dose in any cohort, the sponsor will inform all 
sites immediately so that the patients will not be exposed to doses of SO-C101 that have 

 
 
 
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been determined to exceed the MTD (see also the DEM Charter and sections 9.7.5 and 
9.7.6). Patients who will not be DLT evaluable will be replaced. Replaced patients can 
continue with study treatment until any of the criteria listed in section 9.11.10 are met. 
The dose escalation plan will follow the traditional 3+3 design as described by Le Tourneau 
et al.29 This Protocol uses the European and Japanese definition of MTD and RP2D; see also 
section 12.6. Initially, three patients will be enrolled for each dose level and if none of the 
three patients in a cohort experiences a DLT, another three patients will be treated at the 
next higher dose level. However, if one of the first three patients experiences a DLT, three 
more patients will be treated at the same dose level. The dose escalation continues until at 
least two patients in a cohort of three to six patients experience DLTs (i.e., ≥33% of patients 
with a DLT at that dose level). If an MTD is reached, then the dose escalation will be 
stopped. The DEC will then decide whether any additional patients need to be enrolled in 
any dose level(s) not exceeding the MTD to gain confidence at the dose which will be 
considered as the RP2D. 
Figure 9.7: Dose escalation flowchart (staggered dosing and 3+3 design) 
 
* The DEC will review, discuss, and decide on the next steps of the study endorsed by the IAP. 
**At this review meeting, the DEC will decide (with IAP endorsement) whether any additional patients need to be enrolled in any dose 
level(s) not exceeding the MTD to gain confidence at the dose which will be considered as the RP2D. 
INV: Investigator 
Staggered (sentinel) dosing will be employed as described below: 
For each dose level, the first patient for the cohort will receive the first cycle of SO-C101 
on day 1, day 2, day 8, and day 9. This patient will be observed for safety for 7 days 
afterwards, starting from day 9. If there are no safety concerns at the end of these 7 days, 
the responsible investigator will notify the sponsor’s medical monitor and the second and 
third patients will be allowed to be dosed. The second and third patients will not be dosed 
on the same day. If there is a concern at the end of these 7 days of observation for safety of 
the first patient, the study investigator will notify the sponsor’s medical monitor as soon as 
Staggered dosing 
Dose escalation flowchart for Parts A, A1, B, and B1 
0 DLT  
in 3 patients 
1 DLT  
in 3 patients 
Enroll additional  
≥3 patients to  
a total of 6 evaluable 
patients or 2 DLTs 
1 DLT  
in 6 patients 
Next higher 
dose level 
≥2 DLTs  
in 6 patients 
STOP dose 
escalation/enrollment 
DLT 
assessment  
at the end  
of the DLT 
evaluation 
period  
(21 days) 
Dose second and third patients 
at the same dose level 
Yes by INV  
No by INV 
First patient at each 
dose level deemed 
safe 7 days  
after day 9 dosing 
*Review 
safety - DEC 
(DEM)/IAP 
**Review - 
DEC/IAP 

 
 
 
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possible and the sponsor will notify all sites and a DEM will be organized. The DEC will 
review, discuss, and decide on the next steps of the study. 
9.7.1 
DLT definitions for Part A, Part A1, Part B, and Part B1 
DLTs will be AEs as specified below and graded according to the NCI’s Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. Attribution to SO-C101 
will not be used and the AEs listed below will be considered DLTs unless clearly not related 
to SO-C101 (i.e., events clearly due to the cancer disease, other comorbid illness, or 
unequivocally related to concomitant medications). The DLT evaluation period is the first 
treatment cycle of 21 days. 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 SO-C101 as monotherapy and in 
combination with pembrolizumab. 
9.7.1.1 
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 exceptions below that are NOT considered DLTs: 
o Grade 3 nausea, vomiting, or diarrhea that can be controlled within 72 hours 
o Grade 3 fatigue less than 5 days 
o Grade 3 or higher correctable electrolyte abnormalities that last less than 72 hours 
and not associated with clinical complications 
o Grade 3 or higher amylase or lipase not associated with clinical manifestations of 
pancreatitis 
• Hy’s law cases will be considered DLTs (see section 12.3) 
• Grade 3 AST or ALT or grade 3 bilirubinemia that lasts more than 5 days 
• Hematologic DLTs will include the following: 
o Grade 4 neutropenia or thrombocytopenia lasting more than 7 days 
o Febrile neutropenia 
o Grade 3 or higher thrombocytopenia with bleeding 
• Any grade 4 immune-related AEs regardless of duration 
• Any grade 3 or grade 4 non-infectious pneumonitis regardless of duration 
• Any grade 3 immune-related AEs, excluding colitis, hepatitis, and pneumonitis, that do 
not downgrade to grade ≤2 within 3 days after onset of the event despite maximal 
supportive care including systemic corticosteroids or downgrade to grade 1 or baseline 
within 14 days 
• Any grade 2 pneumonitis that does not resolve to grade 1 within 3 days of the initiation 
of maximal supportive care 
• Recurrent grade 2 pneumonitis in Part B and Part B1 
• Grade 3 colitis 

 
 
 
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9.7.1.2 
AEs that are NOT considered DLTs 
• Grade 3 endocrinopathy that is managed with or without systemic corticosteroid therapy 
and/or hormone replacement therapy 
• 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 AE grade 
Other clinically significant toxicities, including a single event or multiple occurrences of the 
same event, may be considered as DLTs. 
AEs occurring after treatment cycle 1 may be considered DLT-like events upon DEC 
discussion. If required, a DEM will be set up to assess these events. 
9.7.2 
Maximum tolerated dose and selection of the recommended phase 2 dose 
If the MTD is reached, the RP2D is conventionally defined as the dose level just below this 
non-tolerated dose level. If ≤1 of 6 patients (or 0 of 3) in all dose cohorts experience a DLT, 
then the MTD will not have been reached. If the MTD is not reached, then the RP2D will 
be selected based on integrated evaluation of safety, tolerability, clinical benefit, and PK 
and PD data for all dose levels tested. An expansion cohort of up to 12 patients at the RP2D 
could be considered to obtain more experience if required. 
The DEC will evaluate the data and select the RP2D according to the following guidelines: 
1. The RP2D will not exceed the MTD. 
2. Toxicities other than DLTs will be considered, including AEs assessed as related to 
SO-C101 treatment but not considered dose limiting, the nature and frequency of 
toxicities, and the emergence of any specific category of toxicities. 
3. Evidence of clinical activity, as available 
4. Available PK/PD data 
5. If 2 or more potential RP2D dose levels cannot be distinguished using the criteria above, 
cohort expansion for optimized RP2D determination may take place at up to 2 dose levels 
to obtain data for up to 6 additional patients per dose level. The selection of RP2D will 
be based on this larger dataset. If serious related toxicities are observed in later cycles 
beyond cycle 1, a reduction of the MTD and/or RP2D may be considered. This 
determination will be made by the investigators and the sponsor’s medical monitor, 
taking into account all available data. 
9.7.3 
Dose escalation meetings 
A DEM will only take place once there are 3 or 6 DLT-evaluable patients to complete the 
cohort. A DEM will take place after the last patient of the cohort has completed the first 
cycle (21 days) with or without DLTs and is evaluable for DLT assessment. 
After completion of the DLT period, all available safety data will be reviewed by the IAP 
as well as the DEC. The decision as to whether AEs should be considered as DLTs and/or 
whether a dose level is to be considered intolerable will be made by the DEC with 
endorsement from the IAP (for details, see the DEM Charter). The IAP will consist of two 
independent clinical experts and an independent statistician. The working principles of the 
IAP will be defined in the IAP Charter. In the event of a confirmed non-tolerable dose in 

 
 
 
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any cohort, the sponsor will inform all sites immediately so that patients will not be exposed 
to doses of SO-C101 that have been determined to exceed the MTD. 
At every DEM, all accumulated safety data from previous cohorts will also be reviewed and 
any safety issues arising during this longer follow-up period will be taken into consideration 
by the DEM panel as well as the IAP.  
9.7.4 
Safety monitoring beyond cycle 1 
9.7.4.1 
Part A and Part A1 
Starting from cycle 2, patients will be monitored for all AEs including late immune-related 
toxicities which might be associated with SO-C101 administration for 90 days after the last 
dose of SO-C101 (see section 9.7.7.3). Any late toxicities will be considered in the 
determination of the MTD/RP2D and dose schedules for Part A, Part A1, Part B, and Part 
B1. 
9.7.4.2 
Part B and Part B1 
Patients will be monitored at the same visits and assessments as specified in Part A and Part 
A1 with special attention paid to the potentiation of immune-mediated reactions during the 
combination treatment with SO-C101. 
The following immune-mediated reactions were reported in patients treated with 
pembrolizumab: 
immune-mediated 
pneumonitis; 
immune-mediated 
colitis; 
immune-mediated hepatitis; immune-mediated nephritis; infusion-related reactions; 
immune-mediated endocrinopathies: hypophysitis, thyroid disorders, and type 1 diabetes 
mellitus.37,38 
Patients will be monitored for 90 days after the last dose of SO-C101 and/or pembrolizumab 
(whichever occurs later) for any late toxicities (see section 9.7.7.3). These toxicities will be 
considered for the assessment of MTD/RP2D in Part B and Part B1. 
9.7.5 
Patient recruitment management 
Patient allocation and recruitment to all cohorts in Part A, Part A1, Part B, and Part B1 will 
be actively managed by the sponsor as described in the Cohort Management Manual. The 
study will recruit patients to all ongoing study parts in parallel. Recruitment will be based 
on pre-specified slot allocation to ensure equal chance for all sites to enroll patients into the 
study. The study investigators will be informed about available slot allocation on an ongoing 
basis by e-mails or during teleconferences (TCs) with sites. 
9.7.6 
Communication plan 
Study investigators will inform the sponsor’s medical monitor via an immediate phone 
call in case of an urgent safety signal including, but not limited to, DLTs, life-threatening 
immune reactions, and serious safety-related protocol deviations. The sponsor’s medical 
monitor will immediately inform all sites and any preventative measure will be put in place 
including stopping recruitment temporarily if required. In case of a DLT, this immediate 
phone call will be followed by submission of required information within 24 hours via 
electronic Case Report Form (eCRF) or via email. The sponsor’s medical monitor will 
immediately inform all sites and the IAP and a DEM will be planned. 
Regular study TCs will be held among study investigators (designated sub-investigators) 
and the sponsor’s medical monitor. The aim is to review potential patients for recruitment 

 
 
 
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and allow communication flow of updates on ongoing patients in the study including any 
emerging safety issues. The study investigator or designated sub-investigator will also 
inform the sponsor’s medical monitor at these regular TCs of any important toxicities or 
DLT-like events occurring in the subsequent cycles. This will allow any appropriate actions 
to be implemented. 
Ad-hoc meetings with the study investigators or designees may also be arranged to discuss 
any safety concerns during the study. 
9.7.7 
Study periods in Part A, Part A1, Part B, and Part B1 
9.7.7.1 
Screening period 
Patients will be screened within a period of not more than 21 days, which will start when 
the ICF has been signed and end on day 1 of cycle 1. If screening is not completed within 
this period, next steps (continue/discontinue the patient in the study) will be discussed with 
the sponsor’s medical monitor. 
9.7.7.2 
Treatment periods 
9.7.7.2.1 
DLT evaluation period 
The DLT evaluation period will be the first treatment cycle of 21 days. 
9.7.7.2.2 
Continued treatment period 
Patients without DLT during the DLT evaluation period will continue treatment with SO-
C101 monotherapy or SO-C101 together with pembrolizumab until any of the criteria listed 
in section 9.11.10 are met. 
Intra-patient dose escalation beyond the dose initially assigned to a patient is not permitted 
during cycle 2. However, patients receiving treatment with SO-C101 beyond cycle 2 may 
continue treatment at the next higher dose level if it is assessed to be safe by the DEC and 
IAP and if the criteria listed in section 8.1.8 are met. These patients after intra-patient dose 
increase will NOT be part of the higher dose escalation cohorts; therefore, after intra-patient 
dose increase, they will not be part of the DLT evaluation. 
Intra-patient escalation up to the RP2D level is allowed and can be done step-by step if the 
patient stays at the higher dose level and meets the criteria for escalation in section 8.1.8. 
In Part B and Part B1, in case SO-C101 needs to be discontinued for reasons other than 
disease progression, pembrolizumab treatment will continue for up to 1 year until any of the 
criteria listed in section 9.11.10 are met. If pembrolizumab needs to be discontinued for 
reasons other than disease progression, SO-C101 treatment will continue until any of the 
criteria listed in section 9.11.10 are met. 
9.7.7.2.3 
EoT visit 
After termination of study treatments (SO-C101 and/or pembrolizumab), patients will be 
evaluated at the EoT visit, which will be scheduled within 7 days (+7 days) after the final 
administration of SO-C101 and/or pembrolizumab (whichever occurs later). 
9.7.7.3 
Follow-up period 
Every effort should be taken to monitor all AEs and concomitant medications for 90 days 
after the final dose of SO-C101 and/or pembrolizumab (whichever occurs later); all patients 

 
 
 
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will come to the clinic 30 (±2) days, 60 (±2) days, and 90 (±2) days after the final dose of 
SO-C101 and/or pembrolizumab. 
Patients who discontinue SO-C101 therapy prior to confirmed progressive disease per 
iRECIST (iCPD) or start of a new anticancer therapy will continue to have regular tumor 
assessments until: 
• iCPD, or  
• start of a new anticancer therapy, or  
• 6 months (±2 weeks) after the EoT visit, 
whichever occurs earliest, unless patients withdraw consent. 
Patients will be followed up for survival at 3 months (±2 weeks) and 6 months (±2 weeks) 
after the EoT visit (end of the patients’ study participation).  
9.7.8 
Study periods in Part D and Part D1 
9.7.8.1 
Screening period 
Patients will be screened within a period of not more than 21 days, which will start when 
the ICF has been signed and end on day 1 of cycle 1. If screening is not completed within 
this period, next steps (continue/discontinue the patient in the study) will be discussed with 
the sponsor’s medical monitor. 
9.7.8.2 
Treatment period 
Patients will be treated with SO-C101 until any of the criteria for treatment discontinuation 
are met. After termination of SO-C101, patients will be evaluated at the EoT visit, which 
will be scheduled within 7 days (+7 days) after the final administration of SO-C101. 
9.7.8.3 
Follow-up period 
Every effort should be taken to monitor all AEs and concomitant medications for 90 days 
after the final dose of SO-C101; all patients will come to the clinic 30 (±2) days, 60 (±2) 
days, and 90 (±2) days after the final dose of SO-C101. 
Patients who discontinue SO-C101 therapy prior to iCPD or start of a new anticancer therapy 
will continue to have regular tumor assessments until: 
• iCPD, or 
• start of a new anticancer therapy, or 
• 6 months (±2 weeks) after the EoT visit, 
whichever occurs earliest, unless patients withdraw consent. 
Patients will be followed up for survival at 3 months (±2 weeks) and 6 months (±2 weeks) 
after the EoT visit (end of the patients’ study participation). 
9.7.9 
End of the study 
It is expected that the enrollment duration will be 31-48 months (14-22 months Part A, 3-9 
months Part A1, 11-18 months Part B, 3-9 months Part B1, 6-12 months Part D, and 12-18 
months Part D1) and for each patient the estimated average treatment duration will be 12-
24 weeks in Part A, Part A1, Part D, and Part D1; and 24-36 weeks in Part B and Part B1. 

 
 
 
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Patients who will respond to therapy will continue with treatment as specified in sections 
9.7.7 and 9.7.8. 
Each study part will end when the last patient in this study part completes the last visit, 
including follow-up calls. The study will end when the last patient completes the last visit, 
including follow-up calls. 
9.7.10 Early termination of the study 
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 IRB/ECs of the 
termination or suspension and the reason(s) for the termination or suspension. 
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate. If the investigator terminates or suspends the study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/EC and provide the 
sponsor and the IRB/EC with a detailed written explanation of the termination or 
suspension. Study records must be retained. 
9.7.11 Stopping rules for all parts 
If a patient experiences a life-threatening serious AE (SAE) considered by the investigator 
to be related to SO-C101 (i.e., excluding events unequivocally related to cancer) or if >30% 
of the treated patients discontinue because of toxicities considered by the investigator to be 
related to SO-C101, the dosing of all patients in the study will be temporarily stopped until 
the IAP (and DEC for dose escalation parts only) have reviewed the safety data and 
determined if it is safe to continue and at which dose. 
9.8 
Selection of study population 
9.8.1 
Inclusion criteria for all study parts 
Inclusion criteria for all study parts are the same with the exception of the pre-specified 
tumor type (inclusion criterion 2), please see below. 
1. Age ≥18 years 
2. Part A, Part A1, Part B, and Part B1: Patients with selected histologically or cytologically 
confirmed advanced and/or metastatic solid tumors (renal cell carcinoma, non-small cell 
lung cancer, small-cell lung cancer, bladder cancer, melanoma, Merkel-cell carcinoma, 
skin squamous-cell carcinoma, microsatellite instability high solid tumors, triple-
negative breast cancer, mesothelioma, thyroid cancer, thymic cancer, cervical cancer, 
biliary tract cancer, hepatocellular carcinoma, ovarian cancer, gastric cancer, head and 
neck squamous-cell carcinoma, and anal cancer) who are refractory to or intolerant of 
existing therapies known to provide clinical benefit for their condition. Patients who 
were not previously treated with (naïve) or who have relapsed/refractory disease on 
immune checkpoint inhibitors are eligible. 
Part D and Part D1: Patients with histologically or cytologically confirmed advanced 
and/or mRCC, patients with histologically or cytologically confirmed advanced and/or 
metastatic skin squamous-cell carcinoma, and patients with relapsed/refractory 
advanced/metastatic melanoma who are refractory to or intolerant of existing therapies 

 
 
 
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known to provide clinical benefit for their condition. Patients who have 
relapsed/refractory disease on immune checkpoint inhibitors are eligible. 
3. Performance 
status: 
Eastern 
Cooperative 
Oncology 
Group 
(ECOG)  
performance score 0-1. Patients with ECOG performance score 2 will be discussed with 
the sponsor’s medical monitor to be agreed for inclusion (see appendix 12.4). 
4. Immunosuppressive doses of systemic medications (such as steroids) or absorbed topical 
or inhaled steroids (doses ≤10 mg/day of prednisone or equivalent) are allowed. Doses 
above 10 mg/day of prednisone or equivalent must be discontinued at least 2 weeks 
before IMP administration. 
5. Estimated life expectancy of ≥3 months 
6. Washout periods: 4 weeks for chemotherapy, 4 weeks or 5 half-lives (whichever shorter) 
for biologic agents including immuno-oncology therapy and 4 weeks from major 
surgeries, definitive radiotherapy and 2 weeks after palliative radiotherapy 
7. Have at least one measurable lesion per iRECIST in a non-irradiated port. If in a 
previously irradiated port, must have demonstrated progression since best response to 
radiation therapy. 
8. Have fully recovered from previous treatment to grade ≤1 toxicity (excluding alopecia) 
or have stable grade 2 neuropathy 
9. Adequate organ system function: 
9.1. Left ventricular ejection fraction by echocardiogram >50% 
9.2. Patients with thyroid disease are eligible if euthyroid on suppressive or replacement 
therapy and asymptomatic thyroid-stimulating hormone (TSH) increase to be 
allowed 
9.3. Creatinine clearance ≥30 mL/min using Cockcroft-Gault equation (see appendix 
12.2) 
9.4. Hemoglobin at least 10 g/dL 
9.5. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) ≤1.5× 
upper limit of normal (ULN) 
10. ALT/AST ≤2.5×ULN and total bilirubin ≤2×ULN in patients without liver metastasis 
(benign hereditary hyperbilirubinemias, e.g., Gilbert’s syndrome, are permitted, those 
patients must have total bilirubin <3 mg/dL). In patients with liver metastasis, ALT/AST 
≤5×ULN is allowed but total bilirubin must be ≤2×ULN. 
11. Negative serum pregnancy test if woman of child-bearing potential (WOCBP; non-
childbearing is defined as greater than one year postmenopausal or surgically sterilized). 
WOCBP must adhere to using a medically accepted method of birth control and agree 
to continue its use during the study or be surgically sterilized (e.g., hysterectomy or tubal 
ligation) and males must agree to use barrier method of birth control while on study. 
WOCBP must agree to use highly effective contraception during treatment and for at 
least 30 days after SO-C101 discontinuation (Part A, Part A1, Part D, and Part D1) or 4 
months after pembrolizumab discontinuation (Part B and Part B1) unless the last dose 
of SO-C101 is later than 4 months after the last pembrolizumab administration in Part B 
and Part B1. In such a case, the highly effective contraception must be used for at least 
30 days after SO-C101 discontinuation. Highly effective contraception includes: 
• Placement of an intrauterine device or intrauterine hormone-releasing system 

 
 
 
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• Established hormonal contraceptive methods: oral, intravaginal, transdermal, 
injectable, or implant. Females who are using hormonal contraceptives must have 
been on a stable dose of the same hormonal contraceptive product for at least 4 weeks 
prior to dosing and must continue to use the same contraceptive during the study and 
for 30 days after SO-C101 discontinuation (Part A, Part A1, Part D, and Part D1) or 
4 months after last pembrolizumab discontinuation (Part B and Part B1) unless the 
last dose of SO-C101 is later than 4 months after the last pembrolizumab 
administration in Part B and Part B1. In such a case, female patients must have been 
on a stable dose of the same hormonal contraceptive for at least 30 days after SO-
C101 discontinuation. 
• Bilateral tubal occlusion 
Female patients exempt from this requirement are patients who practice total abstinence 
or have a sole male partner who is vasectomized with confirmed azoospermia. If 
currently abstinent, the patient must agree to use a double barrier method (condom plus 
diaphragm or cervical/vault cap with spermicide) if they become sexually active during 
the study, and for 30 days after SO-C101 discontinuation (Part A, Part A1, Part D, and 
Part D1) or 4 months after pembrolizumab discontinuation (Part B and Part B1) unless 
the last dose of SO-C101 is later than 4 months after the last pembrolizumab 
administration in Part B and Part B1. In such a case, the patient must agree to use a 
double barrier method during treatment and for at least 30 days after SO-C101 
discontinuation. 
Male patients must agree to use a condom during treatment and for 30 days after 
SO-C101 discontinuation (Part A, Part A1, Part D, and Part D1) or 4 months after 
pembrolizumab discontinuation (Part B and Part B1) unless the last dose of SO-C101 
is later than 4 months after the last pembrolizumab administration in Part B and Part 
B1. In such a case, the patient must agree to use a condom during treatment and for at 
least 30 days after SO-C101 discontinuation. 
12. Accessible tumor tissue available for fresh biopsy 
13. Ability to understand and sign written informed consent to participate in the study 
9.8.2 
Exclusion criteria 
9.8.2.1 
Exclusion criteria for all study parts 
1. Patient with untreated central nervous system metastases and/or leptomeningeal 
carcinomatosis; participants with previously treated stable (no progression on magnetic 
resonance imaging [MRI] done 4 or more weeks apart) brain metastases are eligible 
2. Has a known additional malignancy that is progressing and/or requires active treatment 
3. Prior exposure to drugs that are agonists of IL-2- or IL-15-like but not limited to rhIL-
15 (NCI), ALT-803 (ALTOR), NKTR-214 (Nektar) 
4. Patients with a history of and current interstitial lung disease or fibrosis and pneumonitis; 
patients with clinically significant or oxygen requiring chronic obstructive pulmonary 
disease or any chronic inflammatory disease (sarcoidosis etc.) 
5. Has received a live vaccine within 30 days of planned start of study therapy. Note: 
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are 
allowed; however, intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated 
vaccines, and are not allowed. 

 
 
 
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6. Absolute white blood cell (WBC) count ≤2.0×109/L 
7. Absolute neutrophil count ≤1.0×109/L 
8. Platelet count ≤100×109/L 
9. Pregnant or breastfeeding women 
10. Receiving any other investigational treatment 
11. Any active autoimmune disease or a documented history of autoimmune disease, poorly 
controlled asthma, or history of syndrome that required systemic steroids (except the 
allowed doses) or immunosuppressive medications, except for patients with vitiligo or 
resolved childhood asthma/atopy. Patients with clinically controlled asthma who 
routinely require fixed doses intermittent use of bronchodilators and/or micro-doses of 
steroids are allowed. 
12. Co-morbidities: 
12.1. History of hematopoietic malignancy including chronic lymphocytic leukemia 
(excluding childhood leukemia) 
12.2. History of coronary heart disease 
12.3. Evidence of clinically active infection requiring systemic (any route) antibiotic 
therapy. All prior infections must have resolved following optimal therapy. 
12.4. History of or serology positive for HIV or active hepatitis B or C. Cured hepatitis 
B and hepatitis C infections are eligible. 
12.5. Uncontrolled hypertension (systolic >160 mm Hg and/or diastolic >110 mm Hg) 
or clinically significant (i.e., active) cardiovascular disease, cerebrovascular 
accident/stroke, or myocardial infarction within 6 months prior to first study 
medication; unstable angina; congestive heart failure of New York Heart 
Association grade 2 or higher; or uncontrolled cardiac arrhythmia requiring 
medication. Patients with uncontrolled hypertension should be medically 
managed on a stable regimen to control hypertension prior to study entry. 
12.6. Clinically significant peripheral artery disease 
12.7. Prolongation of QTcF >450 msec39 
12.8. History of medical or psychiatric disease which, in the view of the investigator, 
would preclude safe treatment or acceptable study compliance 
13. Any ongoing toxicity from prior anti-cancer treatment that, in the judgment of the 
investigator, may interfere with study treatment 
14. Other illness that, in the opinion of the investigator, would exclude the patient from 
participating in this study, including uncontrolled diabetes mellitus, cardiac disease 
9.8.2.2 
Exclusion criteria for Part B and Part B1 only 
• Is hypersensitive to any of the ingredients of pembrolizumab drug product (KeytrudaTM) 
• History of solid organ transplantation or hematopoietic stem cell transplantation 

 
 
 
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9.9 
Treatments 
9.9.1 
Treatments administered 
9.9.1.1 
SO-C101 (all study parts) 
SO-C101 will be administered SC once a day (Part A, Part B, Part D) or twice a day 8 hours 
(±15 min) apart (Part A1, Part B1, Part D1) on day 1 (±1 day), day 2, day 8, and day 9 of 
the 21-day cycle. One treatment cycle will be 21 days (see also sections 9.1, 9.2, 9.3, 9.4, 
9.5, and 9.6). The time of administration will be recorded in the eCRF. 
SO-C101 will be supplied as solution for injection at a concentration of 2 mg/mL. See also 
section 11.9. 
9.9.1.2 
Pembrolizumab (Part B, Part B1) 
The dose of pembrolizumab will be fixed (200 mg IV every 3 weeks) and will be 
administered together with the first SO-C101 administration on day 1. See also sections 9.3, 
9.4, and 11.9. 
9.9.2 
Treatment modifications 
Any treatment-related toxicity will be managed by concomitant medication (as appropriate) 
or by treatment interruption, dose reduction, and treatment discontinuation, or a combination 
of these. 
No treatment modifications of SO-C101 will be allowed during the first cycle for all dose 
cohorts in Part A, Part A1, Part B, and Part B1 and for all patients in Part D and Part D1. In 
the following cycles, these might be allowed (for dose increase, see section 8.1.8; for 
treatment interruption, dose reduction, and treatment discontinuation, or a combination of 
these, see below). Any treatment modifications must be discussed with the sponsor’s 
medical monitor prior to administration of SO-C101 to the patient. 
Treatment modifications of pembrolizumab (Part B and Part B1) are allowed according to 
the approved label.37,38 Whenever SO-C101 is interrupted in Part B and Part B1 due to 
immune-mediated toxicity, pembrolizumab should also be interrupted. 
Patients who experience a DLT in cycle 1 in Part A, Part A1, Part B, and Part B1 may be 
allowed to continue SO-C101 at a reduced dose after discussion with the sponsor’s medical 
monitor if this is judged to be in their best interest. 
During SO-C101 treatment, SO-C101 dose interruptions and reductions due to toxicity will 
be implemented according to the instructions presented in Table 9.3 for all AEs excluding 
specific AEs as detailed in Table 9.4. 
Table 9.3: Guidelines for SO-C101 dose adjustments after cycle 1 
SO-C101-related toxicity1 During therapy 
Approximate dose adjustment 
Grade 1 
All occurrences 
Continue SO-C101 
treatment 
Maintain dose level 
Grade 2 
First occurrence 
Maintain dose level 

 
 
 
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SO-C101-related toxicity1 During therapy 
Approximate dose adjustment 
Second occurrence 
(same toxicity) 
Interrupt SO-C101 until 
resolved to grade ≤1 or 
baseline2 
Reduce by one dose level of 
starting dose 
Third occurrence 
(same toxicity) 
Reduce by two dose levels of 
starting dose 
Fourth occurrence 
(same toxicity) 
Discuss with sponsor’s medical 
monitor 
Grade 3 
First occurrence 
Interrupt SO-C101 until 
resolved to grade ≤1 or 
baseline2 
Reduce by one dose level of 
starting dose 
Second occurrence 
(same toxicity) 
Reduce by two dose levels of 
starting dose 
Third occurrence 
(same toxicity) 
Discontinue SO-C101 
treatment 
Not applicable 
Grade 4: Discontinue SO-C101 treatment3 
1. Excluding alopecia and nausea, vomiting or diarrhea not receiving adequate treatment, and AEs such as 
pneumonitis, colitis, and ALT/AST and bilirubin elevations as specified in Table 9.4 
2. Any dosage interruptions of more than 7 days should be discussed with the sponsor’s medical monitor to 
establish if longer dose interruption is needed; a delay of SO-C101 for more than 14 days due to any 
treatment-related toxicity must be discussed with the sponsor’s medical monitor before treatment can be 
resumed. If systemic corticosteroids for the treatment of immune-mediated AEs are required at doses 
above 10 mg of prednisone or equivalent for less than 4 weeks, the study drugs should be held. If systemic 
corticosteroids at doses above 10 mg of prednisone or equivalent are required for more than 4 weeks, then 
the study drugs should be discontinued. 
3. Exclude grade 4 hematologic toxicity of less than 72 hours duration 
Retreatment with SO-C101 is contraindicated in patients who have experienced grade 4 
toxicities and third occurrences of grade 3 toxicities during the study. 
The treatment modifications below apply to all SO-C101 treatment administrations (all 
study parts). Where specified as delay or hold (after cycle 1), SO-C101 will be delayed/held 
week to week. For details, see Table 9.4. 
Table 9.4: SO-C101 modifications after cycle 1 for specific AEs – delay/hold 
Event 
Grade/Severity 
SO-C101 modifications 
Kidney dysfunction 
Creatinine clearance 
<30 mL/min 
Delay the scheduled SO-C101 
treatment one week each for up to 
two weeks until a recovery is 
sufficient to resume SO-C101 
treatment, otherwise, discontinue 
SO-C101 treatment. 
Febrile neutropenia 
  
Thrombocytopenia with 
bleeding or anemia 
  
Absolute lymphocyte 
count (ALC) 
>50,000/mL 
WBC 
>60,000/mL 

 
 
 
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Event 
Grade/Severity 
SO-C101 modifications 
Systolic hypotension 
<90 mm 
Manage with bolus fluid 
administration of up to 1.5 L over 
24 hours. If systolic hypotension 
(<90 mm) of grade <3 persists at 
time of next scheduled SO-C101 
treatment, an attempt should be 
made to correct this with bolus 
fluids administration of up to 
1.5 L over 6 hours. If this 
corrects the hypotension, the 
SO-C101 treatment can be 
given. If it does not correct, 
SO-C101 treatment should be 
delayed one week each for up to 
2 weeks until recovery is 
sufficient to resume SO-C101 
treatment, otherwise discontinue 
SO-C101 treatment. 
Allergic reactions/acute 
infusion reaction 
Grade 2 with 
bronchospasm or any 
grade 3-4 
Permanently discontinue SO-
C101 treatment. 
Grade 1 or 2 (without 
bronchospasms) 
Delay SO-C101 treatment until 
symptoms subside. 
Pneumonitis 
Grade 2 
Hold SO-C101 
treatment. Resume 1 dose level 
lower once improved to grade 1 
or resolved. 
Grade 3 or 4 
Permanently discontinue 
SO-C101 treatment. 
Colitis 
Grade 2 or 3 
Hold SO-C101 
treatment. Resume 1 dose level 
lower once improved to grade 1 
or resolved. 
Grade 4 
Permanently discontinue 
SO-C101 treatment. 
ALT or AST 
Grade 2 
Hold SO-C101 treatment. 
Resume 1 dose level lower once 
improved to grade 1 or resolved. 
Grade 3 
Permanently discontinue 
SO-C101 treatment. 
Total bilirubin 
Grade 2 
Hold SO-C101 treatment. 
Resume 1 dose level lower once 
improved to grade 1 or resolved 
Grade 3 
Permanently discontinue 
SO-C101 treatment. 

 
 
 
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9.9.3 
SO-C101 
9.9.3.1 
Name, structural formula 
SO-C101 is a fusion protein. The N-terminal part of SO-C101 is comprised of 77 amino 
acids identical in sequence to the high-affinity binding site of IL-15R, referred to as the 
sushi domain. The C-terminal part is comprised of 114 amino acids identical in sequence to 
human IL-15. The two parts of SO-C101 are joined by a linker of 20 amino acids consisting 
of solely glycine and serine amino acids. 
SO-C101 is thus comprised of 211 amino acids and has a theoretical intact monoisotopic 
mass of 22,666 Da. Based on published structural information and confirmed by 
experimental data, two di-sulphide bridges are within the N-terminal sushi domain and two 
di-sulphide bridges are in the C-terminal IL-15. Additionally, two N-glycosylation sites 
were experimentally confirmed with asparagine 176 carrying the majority of the N-glycans.  
The amino acid sequence of SO-C101 is shown in Figure 9.8. 
Figure 9.8: Amino acid sequence of SO-C101 
 
 
 
 
 
In Figure 9.8, the di-sulphide bridges on the two parts of the fusion protein are shown with 
blue links between the relevant cysteines (C), the N-linked glycosylation sites are 
highlighted with a red box around the relevant asparagine (N) residues, and the linker 
between the two parts of the fusion protein is highlighted by grey shading. 
9.9.3.2 
Labeling for SO-C101 
SO-C101 will be provided by the sponsor as clinical open-labeled supply labeled in 
accordance with text that is in full regulatory compliance with each participating country. 
The primary and secondary label will be translated into the required language(s) for each of 
those countries. 
9.9.3.3 
SO-C101 storage conditions 
SO-C101 will be stored in accordance with the labeled storage conditions. Temperature 
monitoring is required at the storage location to ensure that SO-C101 is maintained within 
an established temperature range. The investigator or designee (or if regionally required, the 
head of the medical institution) is responsible for ensuring that the temperature is monitored 
throughout the total duration of the study and that records are maintained; the temperature 
should be monitored continuously by using either an in-house validated data acquisition 
system, a mechanical recording device, such as a calibrated chart recorder, or by manual 
means, such that minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. 
1 - 50
51 - 100
100 - 150
151 - 200
200 - 211
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P
A
P
R
G
G
G
S
G
G
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G
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9.9.4 
Pembrolizumab 
Pembrolizumab is commercially available. Always refer to the current/latest approved 
package insert/US prescribing information (for the US) and the Summary of Product 
Characteristics (SmPC; for the EU, available at: 
https://www.ema.europa.eu/documents/product-information/keytruda-epar-product-
information_en.pdf) for comprehensive treatment information including, but not limited to, 
treatment preparation and administration as well as full pharmacologic and safety 
information.37,38 
9.9.4.1 
Pembrolizumab description 
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between 
PD-1 and its ligands and can restore antitumor immune activity in solid tumors and 
hematologic malignancies. 
9.9.4.2 
Pembrolizumab identity 
Pembrolizumab is supplied as KeytrudaTM 1 vial of 100 mg/4 mL (25 mg/mL) – concentrate 
for solution for infusion. 
9.9.4.3 
Pembrolizumab: safety information 
Pembrolizumab is commercially available. For full safety information, please always refer 
to the current package insert/US prescribing information (for the US) and to the current 
SmPC.37,38 
9.9.4.4 
Pembrolizumab immunogenicity 
In clinical studies in patients treated with pembrolizumab 2 mg/kg every three weeks, 
200 mg every three weeks, or 10 mg/kg every two or three weeks, 36 (1.8%) of 
2034 evaluable 
patients 
tested 
positive 
for 
treatment-emergent 
antibodies 
to 
pembrolizumab, of which 9 (0.4%) patients had neutralizing antibodies against 
pembrolizumab. There was no evidence of an altered PK or safety profile with 
anti-pembrolizumab binding or neutralizing antibody development.37 
9.9.5 
Comparator drug 
Not applicable 
9.9.6 
Method of assigning patients to treatment groups 
See sections 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, and 9.7.5. 
9.9.7 
Selection of doses in the study 
See sections 9.1, 9.2, 9.3, 9.4, 9.5, and 9.6. 
9.9.8 
Selection and timing of dose for each patient 
See sections 9.1, 9.2, 9.3, 9.4, 9.5, and 9.6. 
9.9.9 
Blinding 
This is an open-label study; the treatment will not be blinded. 

 
 
 
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9.10 Supportive care and concomitant medication 
SO-C101 is to be administered in a hospital setting under supervision of the investigator. 
An intensive care facility and skilled specialists must be available. 
Supportive care can be provided based on investigator judgment according to local 
institutional guidelines. For pembrolizumab, the approved label should be followed.37,38 
SO-C101 should not be administered to the patients with significant cardiac, pulmonary, 
renal and hepatic, or central nervous system impairment. 
SC 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 SO-C101 
administration. 
The investigator should instruct patients to notify the investigational site about any new 
medications taken since screening. All medications and non-drug therapies (including 
physical therapy, pre-medications, and blood transfusions) administered after screening 
must be listed in the eCRF. See also section 9.10.4.1 for prohibited medications. 
9.10.1 Management of cytokine release syndrome 
The management intervention guidelines described in this section 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. 
SO-C101 is a fusion protein, which comprises a variant of the IL-15 molecule, which is a 
common γ-chain cytokine and shares the IL-2R β and γ chains for signaling. SO-C101 
therefore could have similar immunostimulatory properties as IL-2. SO-C101 treatment 
could potentially cause cytokine release syndrome as commercially available IL-2, although 
the risk is low. 
Cytokine release syndrome may begin immediately after treatment administration, may be 
marked by increased capillary permeability to protein and fluids, and may reduce vascular 
tone. In most patients, this will result in a concomitant drop in mean arterial blood pressure 
within 2 to 12 hours after the start of treatment. With continued treatment, clinically 
significant hypotension (defined as systolic blood pressure below 90 mm Hg or a 20 mm Hg 
drop from baseline systolic pressure) and hypoperfusion may occur. In addition, 
extravasations of protein and fluids into the extra-vascular space will lead to the formation 
of edema and creation of new effusions. Potentially life-threatening complications of 
cytokine release syndrome could include cardiac dysfunction, adult respiratory distress 
syndrome, neurologic toxicity, renal and/or hepatic failure, and disseminated intravascular 
coagulation. Of particular concern is cardiac dysfunction, which can have a rapid onset and 
be severe, but is typically reversible. 
Medical management of cytokine release syndrome begins with careful monitoring of the 
patient’s fluids and organ perfusion status. This is achieved by frequent determination of 
blood pressure and pulse, and by monitoring organ functions, which includes assessment of 
mental status and urine output. Occurrence of hypovolemia will be monitored. Flexibility in 
fluid and pressor management is essential for maintaining organ perfusion and blood 
pressure. Therefore, extreme caution should be used in treating patients with fixed 
requirements for large volumes of fluid. Administration of IV fluids, either colloid or 
crystalloid is recommended for treatment of hypovolemia. Correction of hypovolemia may 
require large volumes of IV fluids but caution is required because unrestrained fluid 
administration may exacerbate problems associated with edema formation or effusions. 

 
 
 
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With extra-vascular fluid accumulation, edema is common and ascites, pleural or pericardial 
effusions may develop. Management of these events depends on a careful balancing of the 
effects of fluid shifts so that neither the consequences of hypovolemia (e.g., impaired organ 
perfusion) nor the consequences of fluid accumulations (e.g., pulmonary edema) exceed the 
patient’s tolerance. Pulmonary edema, another manifestation of CLS, can lead to respiratory 
failure. 
For further management guidelines please refer to Proleukin that is approved in some 
countries in the EU for the treatment of mRCC40 and in the US by the FDA to treat mRCC 
and MM.41 
 For consensus guidelines on management, please also refer to “High-dose interleukin-2 
(Aldesleukin) – expert consensus on best management practices-2014”.42 See also appendix 
12.5. 
9.10.2 Life-threatening toxicities 
Life-threatening toxicities, if they are attributed to inflammatory reactions of SO-C101 in 
the judgment of the investigators, may be ameliorated by an IV administration of 
dexamethasone or other steroid-based medications. However, the use of systemic steroid 
medications may result in loss of the therapeutic effects of SO-C101. Patients receiving 
steroid medication may continue to receive the study treatment if, in the opinion of the 
investigator, there is potential clinical benefit and the patient is motivated to do so. 
9.10.3 Overdosing 
Side effects following administration of SO-C101 during the pre-clinical studies appeared 
to be dose related. Exceeding the recommended dose in the study can be associated with 
increased toxicity. Symptoms which persist after stopping the treatment with SO-C101 
should be closely monitored and treated supportively. For the life-threatening toxicities, 
IV administration of dexamethasone is recommended. 
9.10.4 Prohibitions and restrictions during the study period 
9.10.4.1 
Prohibited medications 
Concomitant use of drugs known to prolong the QT/QTc interval is prohibited during the 
study. Some of the medications known to prolong the QT interval are43: amiodarone, 
azithromycin, ciprofloxacin, chlorpromazine, citalopram, domperidone, donepezil, 
escitalopram, fluconazole, haloperidol, levofloxacin, levomepromazine, methadone, 
ondansetron, and sulpiride. A complete list of medications known to prolong the QT interval 
can be found at www.crediblemeds.org. 
Administration of live vaccines during treatment with SO-C101 (Part A, Part A1, Part D, 
Part D1) and with SO-C101 and pembrolizumab (Part B and Part B1) is prohibited. 
Administration of another IMP during treatment with SO-C101 (Part A, Part A1, Part D, 
Part D1) and with SO-C101 and pembrolizumab (Part B and Part B1) is prohibited. 
Another anticancer therapy during treatment with SO-C101 (Part A, Part A1, Part D, Part 
D1) and with SO-C101 and pembrolizumab (Part B and Part B1) is prohibited. Palliative 
radiotherapy of, e.g., painful bone metastases not defined as indicator lesions is allowed. 

 
 
 
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9.10.4.2 
Warnings and precautions 
Systemic steroid medications may result in loss of therapeutic effects of SO-C101 and 
should be avoided. However, in the event of a life-threatening inflammatory reaction to 
SO-C101, the IV administration of dexamethasone or other steroid-based medication is 
warranted. Corticosteroids have been shown to reduce cytokine-induced side effects 
including fever, renal insufficiency, hyperbilirubinemia, confusion, and dyspnea. However, 
low doses of steroids such as prednisone ≤10 mg per day or equivalent are acceptable. For 
Part B and Part B1: the approved label of pembrolizumab should be followed. If systemic 
corticosteroids for the treatment of immune-mediated AEs are required at doses above 
10 mg of prednisone or equivalent for less than 4 weeks, the study drugs should be held. If 
systemic corticosteroids at doses above 10 mg of prednisone or equivalent are required for 
more than 4 weeks, then the study drugs should be discontinued. 
Reference is made also to the Proleukin label that is approved in some countries in the EU 
for the treatment of mRCC (Proleukin UK label/SmPC at: 
https://www.medicines.org.uk/emc/ product/291) and in the US by the FDA to treat mRCC 
and MM (Proleukin US prescribing information at: 
https://www.proleukin.com/downloads/PR001I_Package%20Insert%20Clean.pdf). 
As Proleukin is a marketed medicine and an immunocytokine which may share a similar 
mechanism of action to SO-C101 albeit with an adverse safety profile, it appears reasonable 
to refer to the same warnings and precautions relating to the concurrent administration of 
medicinal products with hepatotoxic, nephrotoxic, myelotoxic, or cardiotoxic effects which 
may increase the toxicity of SO-C101 in these systems.40,41 These medications should be 
avoided during treatment with SO-C101. Beta-blockers and other antihypertensives may 
potentiate the hypotension seen with cytokine therapy. Therefore, administration of these 
medications should be avoided during SO-C101 administration but may be used at the 
discretion of the investigator. 
9.10.4.3 
Drug-drug interaction potential 
PK drug interaction studies were not carried out with SO-C101. Based on its biologic nature, 
a competition with drug-metabolizing enzymes and transporters is not expected. In addition, 
SO-C101 does not contain Ig domains such as Fc parts minimizing the risk of interference 
with concomitant monoclonal antibody therapies. 
9.10.4.4 
Food 
No food interaction is expected as the route of administration is not oral. 
9.10.5 Treatment compliance 
Treatment for each patient will be recorded during the study. CRAs will review treatment 
compliance during site visits and at the completion of the study. 
9.10.6 IMP supplies and accountability 
9.10.6.1 
IMP supply 
Study treatments must be received by designated personnel at the study site and kept in a 
secured location to which only designated site staff have access. 
The investigator will not allow the IMPs to be used other than as directed by this Protocol. 
IMPs will not be dispensed to any individual who is not enrolled in the study. 

 
 
 
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9.10.6.2 
IMP accountability 
The investigator and the study staff (or if regionally required, the head of the medical 
institution or the designated pharmacist) will be responsible for the accountability of all 
IMPs (shipment, dispensing, inventory) following the sponsor’s instructions and adherence 
to GCP guidelines as well as local or regional requirements. 
The investigator will not allow the IMPs to be used other than as directed by this Protocol. 
IMPs will not be dispensed to any individual who is not enrolled in the study. 
The site must maintain an accurate and timely record of the following: receipt of all IMPs, 
dispensing of IMPs to the patient, collection and reconciliation of unused IMPs that are not 
dispensed to patients. 
9.10.6.3 
IMP disposal and destruction 
At study close out or as appropriate during the study, the investigator will ensure return of 
reconciled IMPs (used and unused) to the sponsor, third party, or (where applicable) 
destruction of reconciled IMPs at the site. 
This includes, but may not be limited to: 
• Documentation of receipt of IMPs 
• IMP dispensing reconciliation log 
• IMP accountability log 
• Documentation of returns to the sponsor 
• Certificates of destruction for any destruction of IMPs that occurs at the site 
All forms will be provided by the sponsor. Any comparable forms that the site wishes to use 
must be approved by the sponsor. The IMP and inventory records must be made available, 
upon request, for inspection by a designated representative of the sponsor or a representative 
of a health authority (e.g., FDA). Unused IMPs/study supplies that were shipped to the site 
but not dispensed to patients are to be returned to the sponsor’s designated central or local 
depot(s) during the study or at the conclusion of the study unless provision is made by the 
sponsor for destruction of IMPs and containers at the site. Destruction at the site will only 
occur under circumstances where regulation or supply type prohibits the return of IMPs to 
the central or local depot(s). Approval for destruction to occur at the site must be provided 
by the sponsor in advance. Upon completion of IMP accountability and reconciliation 
procedures by the site’s personnel and documentation procedures by the sponsor’s 
personnel, IMPs that are to be returned to the sponsor’s designated central or local depot(s) 
must be boxed and sealed and shipped back to the central or local depot(s) following all 
local regulatory requirements. In some regions, the IMPs may be removed from the site and 
hand delivered to the central or local depot by sponsor representatives. Where IMPs are 
approved for destruction at the site, destruction will occur following the site’s standard 
procedures and certificates of destruction will be provided to the sponsor. IMP 
accountability will be reviewed during site visits and at the completion of the study. 
9.11 Study assessments 
The timing of study assessments and procedures is detailed in Table 9.6, Table 9.7, Table 
9.8, Table 9.9, Table 9.10, Table 9.11, Table 9.12, Table 9.13, Table 9.14, Table 9.15, Table 
9.16, and Table 9.17. 

 
 
 
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9.11.1 Demography, disease history, and other baseline assessments 
Demography information includes age at screening, gender, race, and ethnicity. 
All medically significant medical and surgical history must be noted in the eCRF. 
Information on history of current malignancy will be collected, including primary tumor 
location, histology/cytology, initial diagnosis date, lines of previous treatment, start and stop 
dates of the treatments prior to this study, and any prior mutations/genetic analysis (i.e., 
EGFR, KRAS mutations, BCL-2) and the date of the latest disease progression if not 
coinciding with the stop date. 
Other baseline assessments will be done as described in Table 9.6 and Table 9.7. 
9.11.2 Tumor assessments 
Tumor assessments will be performed by investigators and assessed per iRECIST for all 
tumor indications. The sponsor may request that images acquired for tumor assessments be 
sent to an imaging core laboratory for archiving and potential independent analysis. 
Disease response and disease progression will be evaluated in this study using iRECIST 
criteria by contrast enhanced computed tomography (CT) scans of the chest, abdomen, 
pelvis and/or MRI. 
The baseline disease assessment will be performed before the initiation of study treatment 
and response assessments will be performed as indicated in Table 9.6, Table 9.7, and Table 
9.8. For crossover patients, the last tumor assessment in Part A or Part A1 serves as baseline 
in Part B or Part B1. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. If there is a change in 
modality, then the study site may be asked to explain the reason for the change in the eCRF. 
A change in modality may be considered a protocol deviation. 
If a dose modification causes a delay in SO-C101 administration, the schedule of 
radiographic assessment will remain every 6 weeks (±2 weeks). 
9.11.3 Pharmacokinetic assessments 
Instructions on PK sample collection, handling, storage, and shipment of samples is detailed 
in the study-specific Laboratory Manual provided to the study site. 
The timing of PK sample collection is detailed in Table 9.14, Table 9.15, Table 9.16, and 
Table 9.17. 
9.11.4 Pharmacodynamic and other biomarker assessments 
SO-C101 activates and expands preferentially NK cells and CD8+ T cells which are the 
major effectors of SO-C101-mediated antitumor response. The assessment of the biological 
activity of SO-C101 might support the decisions for selection of monotherapy dose as well 
as combination dose with pembrolizumab during dose escalation in Part A, Part A1, Part B, 
and Part B1. PD markers will be assessed in blood PBMCs and paired tumor tissue. 

 
 
 
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9.11.4.1 
Peripheral blood 
9.11.4.1.1 
Peripheral blood mononuclear cell analysis 
9.11.4.1.1.1 
Aim 
To determine the SO-C101 dose-dependent activity on immune cell populations in 
peripheral blood 
9.11.4.1.1.2 
Rationale 
SO-C101-induced NK- and CD8+ T-cell activation and proliferation is a direct and 
immediate measure of the PD response to SO-C101 administration. The analysis will be 
used to monitor SO-C101 activity at the individual dose levels and over repeated 
administrations. 
9.11.4.1.1.3 
Method 
Flow cytometry analyses of PBMCs will be conducted from fresh blood in a volume of up 
to 9 mL delivered to central laboratory for analysis within 24 hours. 
9.11.4.1.1.4 
Pharmacodynamic markers 
Immune cells (leukocytes including NK, CD8+ and CD4+ T cells or myeloid cells) will be 
detected based on described specific markers including various subpopulations. Moreover, 
selected functional markers specific for the immune cell populations will be examined. 
9.11.4.1.2 
Cytokine analysis 
Changes in the plasma cytokine concentration of pro-inflammatory and immunosuppressive 
cytokines may correlate with the administration of SO-C101. Relevant cytokines will be 
measured in blood. 
9.11.4.2 
Tumor biopsy 
Tumor biopsies will be collected during screening and during cycle 2 to determine the 
SO-C101-dependent activation and/or expansion of immune cells to be correlated with the 
antitumor efficacy of the SO-C101 monotherapy or SO-C101 in combination with 
pembrolizumab. Additional tumor biopsy can be done at the time of a clinically significant 
event (not mandatory assessment). 
Paraffin-embedded blocks will be prepared at the sites from the tumor biopsies for 
immunohistochemistry and/or by gene profiling analyses and sent to the central laboratory 
in ambient temperature. 
Archived, fixed tumor tissue can be collected if fresh biopsy at screening is not available. 

 
 
 
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9.11.5 Safety assessments 
9.11.5.1 
Adverse events and pregnancies 
9.11.5.1.1 
Definitions 
9.11.5.1.1.1 
Adverse events 
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. 
According to the FDA (21CFR312.32), an AE means any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered drug-related. 
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. 
9.11.5.1.1.2 
Serious adverse events 
A SAE is any untoward medical occurrence that at any dose fulfills one or more of the 
following criteria: 
• Results in death 
• Is immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at immediate risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it were more severe. 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• 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 
9.11.5.1.1.3 
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) 

 
 
 
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9.11.5.1.1.4 
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. 
9.11.5.1.1.5 
Pregnancy of study patients or their partners 
Patients who are fertile must use a medically accepted birth control method during their 
participation in this clinical study and for at least 30 days after SO-C101 discontinuation 
(Part A, Part A1, Part D, and Part D1) or 4 months after pembrolizumab discontinuation 
(Part B and Part B1) unless the last dose of SO-C101 is later than 4 months after the last 
pembrolizumab administration in Part B and Part B1. In such a case, the medically accepted 
birth control method must be used for at least 30 days after SO-C101 discontinuation. 
Female patients exempt from this requirement are patients who practice total abstinence or 
have a male partner who is vasectomized with confirmed azoospermia. 
If currently abstinent, the patient must agree to use a double barrier method as described 
above if they become sexually active during the study, and for 30 days after SO-C101 
discontinuation (Part A, Part A1, Part D, and Part D1) or 4 months after pembrolizumab 
discontinuation (Part B and Part B1) unless the last dose of SO-C101 is later than 4 months 
after the last pembrolizumab administration in Part B and Part B1. In such a case, the double 
barrier method must be used for at least 30 days after SO-C101 discontinuation. See also 
section 9.8.1. 
Pregnancy is not considered an AE unless it meets any criteria for becoming serious (see the 
definitions in section 9.11.5.1.1.2). However, patients must inform the investigator of any 
newly identified pregnancy or pregnancy of their partners without delay. 
Consent to report information on the outcome of the pregnancy of male patients’ partners 
needs to be obtained from the pregnant partners. 
9.11.5.1.2 
Safety monitoring periods 
9.11.5.1.2.1 
Reporting 
Every effort should be taken to collect all (S)AEs, from the date of the patient’s signing the 
ICF until 90 days after the final administration of SO-C101 and/or pembrolizumab, 
whichever occurs later. 
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
reporting period specified above must be reported immediately to the sponsor if the event is 
considered to be causally related to the SO-C101 and/or pembrolizumab. 
In Part A, Part A1, Part D, and Part D1, pregnancies must be reported from the date of the 
patient’s signing the ICF until up to 30 days after the final administration of SO-C101. 
In Part B and Part B1, pregnancies must be reported from the date of the patient’s signing 
the ICF until up to 30 days after the final administration of SO-C101 or 4 months after the 
final administration of pembrolizumab, whichever occurs later. 

 
 
 
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9.11.5.1.2.2 
Follow-up 
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 study 
medication/procedure, interventions required to treat the event, and AE outcome. 
AEs are monitored (followed up) until resolution, stabilization (becoming a permanent 
condition), or 6 months (±2 weeks) after the EoT visit of the patient (end of the patient’s 
study participation). 
All SAEs will be followed up until the event has resolved or stabilized (permanent 
condition). 
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 and newborn complications. Every 
infant has to be followed up for 2 months after delivery. 
9.11.5.1.3 
Assessing adverse events 
Information about adverse reactions (causally related events) known for SO-C101 will be 
found in the IB or will be communicated between IB updates in the form of “Dear 
Investigator Letter”. 
9.11.5.1.3.1 
Causality 
The investigator needs to assess the causal relationship of any AE to: 
• SO-C101 
• Pembrolizumab (Part B and Part B1 only) 
• 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 IMPs 
• Disappearance or abating of symptoms when the IMP is discontinued or the dose is 
reduced 
• Reappearance of symptoms when the IMP 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 treatment 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. 
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. 

 
 
 
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For the purposes of safety reporting, ‘reasonable possibility’ means there is evidence to 
suggest a causal relationship between one of the IMPs/procedure and the AE. 
9.11.5.1.3.2 
Severity/intensity 
Severity or intensity of an AE has to be assessed according to the NCI CTCAE (v5.0). 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. 
9.11.5.1.3.3 
Reporting by the investigational site 
Any AE (including SAEs), whether or not considered to be causally related to the study 
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. 
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. 
Only clinically relevant (per investigator’s discretion) 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). 
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 the Clinical 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 eCRF 
medical history. 
Death itself is not an AE 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). 
9.11.5.1.3.4 
Documenting in 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 made a preliminary/tentative diagnosis. 
Fluctuations or re-occurrences of a condition, which are considered normal for the patient 
and are recorded in the patient’s eCRF medical history, do not need to be reported as an AE. 
However, if the condition deteriorates during the study, 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 or a description of the AE in medical terms (not as reported by the patient) 

 
 
 
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• Severity grade or intensity of the event as assessed by the investigator (1-5 per  
NCI CTCAE [v5.0]) 
• Its causal relationship to SO-C101 as assessed by the investigator (suspected; not 
suspected) 
• Its causal relationship to pembrolizumab (Part B and Part B1 only) 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 SO-C101 due to the reported event (no action taken; treatment 
interrupted; dose modified; permanently discontinued) 
• Action taken with pembrolizumab due to the reported event (no action taken; dose 
delayed; permanently discontinued) (Part B and Part B1 only) 
• Other action taken (no action taken; pharmacological treatment applied; non-
pharmacological therapy applied; other) 
• Event seriousness (non-serious or serious AE) 
• Event outcome (resolved, resolved with sequelae, not resolved, resolving, fatal, 
unknown) 
9.11.5.1.3.5 
Immediately reportable events 
The investigator or any investigational site staff must immediately (within 24 hours of 
awareness at the latest) notify/report to the Pharmacovigilance department 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 Pharmacovigilance department primarily via the eCRF system; or via: 
Email: safety@sotio.com 
Fax: +420 224 175 498 
Phone: +420 725 385 443 
Follow-up information must be sent within the same timelines using the same contact details 
as outlined above. 
Additionally, refer to Safety Reporting Instructions for Sites for information on how to 
report these events. 

 
 
 
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9.11.5.1.3.6 
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., subject identification) 
3. Concerned IMP or clinical study (e.g., SC103) 
4. Reason for notification/reporting (i.e., SAE or pregnancy) 
5. Event term 
In addition, providing the assessment of the causal relationship is necessary for 
comprehensive evaluation by the sponsor and potential regulatory submission. 
9.11.5.1.3.7 
Report forms 
The SAE Report Form is primarily completed within the eCRF system for the study and 
submitted to the Pharmacovigilance department. In case the eCRF system is not 
available/accessible, a paper SAE Report Form is filled out and sent to the 
Pharmacovigilance department (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 immediate reports from the investigational site to the Pharmacovigilance department 
(i.e., SAEs and patients’ or partners’ pregnancies) must also be recorded in the site’s source 
documentation and in the eCRF as appropriate. 
9.11.6 Safety monitoring of the patients during the study 
As this is a FIH study, patients will be closely monitored for any adverse reactions to identify 
RP2D/MTD in Part A, Part A1, Part B, and Part B1. Safety monitoring of the patients during 
the study will include assessments, examinations, and laboratory tests as described below. 
The DLT evaluation period is specified as the first treatment cycle of 21 days. During this 
first treatment cycle, each patient at every dose level will be monitored closely before and 
after each dose of SO-C101. After cycle 1, the assessments, examinations, and laboratory 
tests will continue as specified in section 9.11.7 for the assessment of cumulative effect of 
SO-C101 (all study parts) and/or overlapping immune-related reactions of SO-C101 and 
pembrolizumab (Part B and Part B1) during the study. 
9.11.6.1 
Physical examination and body weight and height and body surface area 
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, throat, neck, cardiovascular, chest/lungs, abdomen (including liver and spleen size), 
extremities, neurological, skin, and lymph nodes. For subsequent visits according to the 
protocol schedule (Table 9.6, Table 9.7, and Table 9.8), a physical examination with the 
focus on abdomen (including liver and spleen size), lymph nodes, and any other system that 

 
 
 
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may contribute to clinical disease assessments is to be done. An ECOG performance status 
will be assigned as indicated in Table 9.6, Table 9.7, and Table 9.8. 
Body height and body weight will be measured. Body height will be measured only at 
screening. Body weight will be measured before the start of each treatment cycle and as 
indicated in Table 9.6, Table 9.7, and Table 9.8. 
Body surface area will be automatically calculated using Dubois and Dubois formula.44 
9.11.6.2 
Assessment of vital signs 
Vital signs will include blood pressure (systolic and diastolic, after ≥15 minutes of rest), 
body temperature, heart rate, and respiratory rate. See also section 9.11.6.3. 
9.11.6.3 
Observation of patients after administration of SO-C101 
9.11.6.3.1 
Part A, Part B, and Part D 
9.11.6.3.1.1 
Cycle 1 
9.11.6.3.1.1.1 Dose on day 1 
In cycle 1 of Part A, Part B, and Part D, patients will be hospitalized for 24 hours after the 
first dose of SO-C101 on day 1 and will be closely observed for any AEs in the hospital. 
Vital signs (body temperature, heart rate, respiratory rate, and systolic and diastolic blood 
pressure) will be documented at the following frequency at minimum unless clinically 
required otherwise: 
• Prior to each SO-C101 dose 
• 15 minutes (±5 minutes) after dosing 
• 30 minutes (±5 minutes) after dosing 
• 60 minutes (±10 minutes) after dosing, and then 
• Every 60 minutes (±15 minutes) after dosing up until 8 hours following SO-C101 
administration 
9.11.6.3.1.1.2 Subsequent doses 
During observation after subsequent doses of SO-C101, vital signs (body temperature, heart 
rate, respiratory rate, and systolic and diastolic blood pressure) will be documented at the 
following frequency at minimum until discharge from the clinic: 
• Prior to each SO-C101 dose 
• 15 minutes (±5 minutes) after dosing 
• 30 minutes (±5 minutes) after dosing 
• 60 minutes (±10 minutes) after dosing, and then 
• Every 60 minutes (±15 minutes) after dosing up until 4-6 hours following SO-C101 
administration 

 
 
 
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9.11.6.3.1.2 
From cycle 2 onwards 
For the subsequent cycles of Part A, Part B, and Part D, patients will be observed in the 
hospital up to 4-6 hours following SO-C101 administration. 
During post-SO-C101 observation, vital signs (body temperature, heart rate, respiratory rate, 
and systolic and diastolic blood pressure) will be documented at the following frequency 
until discharge from the clinic: 
• Prior to each SO-C101 dose 
• 15 minutes (±5 minutes) after dosing 
• 30 minutes (±5 minutes) after dosing 
• 60 minutes (±10 minutes) after dosing, and then 
• Every 60 minutes (±15 minutes) after dosing up until 4-6 hours following SO-C101 
administration 
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. 
9.11.6.3.2 
Part A1, Part B1, and Part D1 
9.11.6.3.2.1 
Cycle 1 day 1 and cycle 1 day 2 
In Part A1, Part B1, and Part D1, patients will be hospitalized from day 1 to day 3 of cycle 
1 and will be closely observed for any AEs in the hospital. 
Vital signs (body temperature, heart rate, respiratory rate, and systolic and diastolic blood 
pressure) will be documented at the following frequency at minimum unless clinically 
required otherwise: 
• Prior to the first dose of SO-C101 
• 15 minutes (±5 minutes) after dosing 
• 30 minutes (±5 minutes) after dosing 
• 60 minutes (±10 minutes) after dosing, and then 
• Every 60 minutes (±15 minutes) after dosing up until 8 hours following SO-C101 first 
administration 
• Prior to the second dose of SO-C101 
• 15 minutes (±5 minutes) after the second dosing 
• Every 60 minutes (±15 minutes) after dosing up until 6 hours following the second SO-
C101 administration (e.g., 14 hours after the first dose) 
9.11.6.3.2.2 
Subsequent dosing days 
During observation after subsequent doses of SO-C101, vital signs (body temperature, heart 
rate, respiratory rate, and systolic and diastolic blood pressure) will be documented at the 
following frequency at minimum until discharge from the clinic: 
• Prior to the first dose of SO-C101 
• 15 minutes (±5 minutes) after dosing 

 
 
 
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• 30 minutes (±5 minutes) after dosing 
• 60 minutes (±10 minutes) after dosing, and then 
• Every 60 minutes (±15 minutes) after dosing up until 4-6 hours following the first SO-
C101 administration 
• Prior to the second dose of SO-C101 at 8 hours after the first dose 
• 15 minutes (±5 minutes) after the second dosing 
• Every 60 minutes (±15 minutes) after dosing up until 4 hours following the second SO-
C101 administration (e.g., 12 hours after the first dose) 
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. 
9.11.6.4 
Assessment of laboratory parameters 
The standard clinical laboratory analyses described below are to be performed by a local 
laboratory. Results from laboratory analysis performed by a local laboratory will be 
documented in the eCRF. Results from laboratory analysis performed by a central laboratory 
(see sections 9.11.3 and 9.11.4) will be provided to the sponsor or a third party. Details on 
the collection of samples and reporting of results by the laboratory/laboratories are provided 
to the investigator in the Laboratory Manual. More frequent evaluations may be performed 
at the investigator’s discretion if medically indicated; results of these additional tests should 
be recorded in eCRFs. 
The sponsor must be provided with a copy of the certification and a tabulation of the normal 
ranges for the local laboratory/laboratories. Laboratory values that are out of reference 
ranges should be evaluated for their clinical significance. Laboratory abnormalities which 
do not meet the criteria of clinical significance, as judged by the investigator, should not be 
reported as AEs. 
It should be noted that severity and seriousness are different criteria for the evaluation of 
AEs (please see more details in section 9.11.5.1.3.2). Therefore, grade 3 and grade 
4 laboratory events (evaluated per NCI CTCAE [v5.0]) do not automatically classify as 
SAEs unless they meet seriousness criteria as per definition (see section 9.11.5.1.1.2) or per 
investigator’s discretion. 
Clinically relevant laboratory abnormalities will be followed up until they return to normal, 
become stabilized (permanent condition), or until 6 months (±2 weeks) after the EoT visit 
of the patient (end of the patient’s study participation). 
The timing of the below mentioned laboratory tests to be done during the study is specified 
in Table 9.6, Table 9.7, Table 9.8, Table 9.9, Table 9.10, Table 9.11, Table 9.12, Table 9.13, 
Table 9.14, Table 9.15, Table 9.16, and Table 9.17. 
9.11.6.4.1 
Coagulation 
Coagulation tests will include PT, aPTT, international normalized ratio, D-dimer, and 
fibrinogen. 

 
 
 
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9.11.6.4.2 
Hematology 
Hematology panel will include hemoglobin, glycated hemoglobin HbA1c at study entry, 
hematocrit, red blood cell count, reticulocytes, WBC count (with full differentiation), ALC, 
and platelet count. 
9.11.6.4.3 
Biochemistry 
Blood chemistry tests will include Na, K, Cl, phosphate, Mg, Ca, albumin, total protein, 
ALT, AST, bilirubin (direct, total), alkaline phosphatase, lactate dehydrogenase, creatinine 
clearance (see appendix 12.2), creatinine, glucose (preferably fasting), urea or blood urea 
nitrogen, cholesterol, triglyceride, CRP, uric acid, amylase, and lipase. 
9.11.6.4.4 
Urinalysis 
The following parameters are to be analyzed: pH, glucose, protein, bilirubin, urobilinogen. 
Microscopic examination: red blood cell count, WBC, epithelial cells, bacteria. 
In case of proteinuria ≥100 mg/dL at screening, a 24-hour urine analysis will have to be 
performed (prior to the start of SO-C101 treatment) to document 24-hour proteinuria levels 
and a urine test will continue during the treatment period. In case of increase of proteinuria 
with ≥300 mg/dL (at any time), a 24-hour urine analysis will be performed. 
9.11.6.4.5 
Thyroid function 
Thyroid function will be monitored by means of TSH, free triiodothyronine (T3), and free 
thyroxine (T4) testing. 
9.11.6.4.6 
Pregnancy 
Premenopausal women and postmenopausal women who have been amenorrheic for less 
than 12 months will be tested for pregnancy. 
9.11.6.4.7 
Cardiac function 
During the study, patients with signs or symptoms of chest pain, murmurs, gallops, irregular 
rhythm, or palpitations must be further assessed if clinically indicated, including the need 
for hospitalization (for details, see Table 9.5). Standard 12-lead ECG will be done locally at 
the site for assessment of any change in QTcF interval and other parameters. Cardiac 
troponin T will be monitored by high-sensitivity cardiac troponin T (hs-cTnT) test during 
the study to exclude any signs of myocardial injury. Echocardiography will be performed 
for the assessment of the heart function during the study, primarily for monitoring of left 
ventricular ejection fraction and other parameters. 
Table 9.5: Cardiac function assessment 
Visit 
Assessments 
Screening 
ECG, echocardiography, and cardiac troponin T  
Cycle 1 
ECG: before each dose of SO-C101 and 4 hours (+30 min) 
after dosing (note: for schedule 2 both the first and second 
doses of SO-C101) 
Cardiac troponin T, schedule 1: days 1 and 8 before each 
dose of SO-C101 and on days 2 and 9 at least 3 hours after 
SO-C101 

 
 
 
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Visit 
Assessments 
Cardiac troponin T, schedule 2: days 1 and 8 before the first 
daily dose of SO-C101 in the morning only and on days 2 
and 9 at least 3 hours after the second daily dose of SO-
C101 
Subsequent cycles 
ECG: cycles 2 and 3: before each dose of SO-C101 and 4 
hours (+30 min) after dosing; cycle 4 onwards: on day 1 
before SO-C101 dosing and 4 hours (+30 min) after dosing 
(note: for schedule 2 both the first and second doses of SO-
C101) 
Cardiac troponin T, schedule 1: on day 1 before SO-C101 
and day 9 at least 3 hours after 
Cardiac troponin T, schedule 2: on day 1 before the first 
daily dose of SO-C101 in the morning only and on day 9 at 
least 3 hours after the second daily dose of SO-C101 
Echocardiography: from cycle 2 at the end of each second 
cycle (allowed interval from day 9 of the current cycle to 
day 2 of the next cycle) 
EoT 
ECG, echocardiography, and cardiac troponin T 
9.11.6.4.8 
Kidney function 
Kidney function will be assessed by creatinine clearance estimated by the Cockroft-Gault 
formula (see appendix 12.2) at screening and during the study and the evaluation of 
creatinine levels in serum during the study as specified in Table 9.6 and Table 9.7. 
Urine test will be done to assess levels of protein, glucose in urine, and potential urinary 
tract infections. 
9.11.6.4.9 
Liver and pancreatic functions 
Liver and pancreatic functions will be assessed by any changes in liver enzymes, amylase, 
and lipase in blood and the presence/absence of bilirubin and urobilinogen in urine. 
9.11.6.4.10 Adverse events 
Patients in Part A, Part A1, Part B, and Part B1 in cycle 1 will be closely monitored for 
potential DLTs. In the following treatment cycles, patients will be followed up closely and 
any cumulative toxicity or any DLT-like AEs will be reviewed on a continuous basis during 
every DEM. 
Patients in Part B and Part B1 will be monitored at the same visits and assessments as 
specified in SO-C101 monotherapy parts with special attention paid to the potentiation of 
immune-mediated reactions during the combination treatment with SO-C101. 
For Part B and Part B1, patient monitoring following pembrolizumab administration will 
follow the established standard of care. 
The following immune-mediated reactions were reported in patients treated with 
pembrolizumab:37,38 
immune-mediated 
pneumonitis; 
immune-mediated 
colitis, 
immune-mediated hepatitis, immune-mediated nephritis, infusion-related reactions; 

 
 
 
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immune-mediated endocrinopathies: hypophysitis, thyroid disorders, and type 1 diabetes 
mellitus. 
Pneumonitis: Patients will be monitored for new or worsening cough, chest pain, or 
shortness of breath through the assessment of vital signs and AEs. 
Colitis: Patients should be monitored for AEs, e.g., diarrhea or severe abdominal pain. 
Hepatitis: Patients should be monitored for AEs, e.g., severe nausea or vomiting, or easy 
bruising or bleeding. Patients should be monitored for changes in hepatic function. Based 
on severity of liver enzyme elevations, withhold or discontinue pembrolizumab. 
Hypophysitis: Patients should be monitored for AEs with special attention to the following: 
persistent or unusual headache, extreme weakness, dizziness or fainting, or vision changes. 
Hyperthyroidism and hypothyroidism: Patients should be monitored for changes in thyroid 
function (TSH, free T3, and free T4). 
Type 1 diabetes mellitus: Patients should be monitored for the level of glucose. 
Nephritis: Patients should be monitored for kidney function. 
Infusion-related reactions will be assessed by physical examination and AE collection and 
observation. 
In case of any immune-mediated reactions observed in Part B and Part B1 in association 
with pembrolizumab administration, please refer to instructions for treatment modifications 
as specified in section 9.9.2.  
9.11.6.4.11 Anti-drug antibodies 
Samples for anti-drug antibodies (ADAs) will be collected to assess SO-C101 and 
pembrolizumab tolerance, correlation with PK, and potential AEs associated with ADAs 
and for the prediction of ADA production. 
9.11.7 Schedule of procedures/assessments 
Table 9.6, Table 9.7, and Table 9.8 present the schedule of procedures/assessments for the 
study. Table 9.9, Table 9.10, Table 9.11, Table 9.12, Table 9.13, Table 9.14, Table 9.15, 
Table 9.16, and Table 9.17 show the timing of blood samples collection. 
All attempts should be made to collect the samples on time. Missed sample collections are 
considered protocol deviations. 

 
 
 
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Table 9.6: Schedule of procedures/assessments, Part A, Part A1, Part D, and Part D1 (SO-C101 monotherapy) 
Cycle 
 
Cycle 1 to 3* 
From cycle 4 onwards** 
End  
of treatment visit 
Within 7 (+7) days 
after the final dose of 
SO-C101 
Follow-up 
Visit 
Screening 
Up to 21 days  
before day 1  
of cycle 1 
Day 1 
Day 2 
Day 6 
Day 8 
Day 9 
Day 13 
Day 1 
Day 2 
Day 8 
Day 9 
Informed consent1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Cancer3 and medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X 
(blood) 
X (urine 
or blood) 
 
 
 
 
 
X  
(urine or 
blood) 
 
 
 
 
 
Physical examination4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X5 
Body weight and body surface area6 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
X5 
Vital signs7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X5 
Urinalysis8 
X 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
Creatinine clearance9 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
ECG 
X 
X10 
X10 
 
X10 
X10 
 
X10 
 
 
 
X 
 
Echocardiography11 
X 
End of each second cycle, starting from cycle 2  
(allowed interval from day 9 of the current cycle to day 2 of the next cycle) 
X 
 
ECOG performance score 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Tumor assessment (CT/MRI, MRI)12 
X 
Every 6 weeks (±2 weeks) 
SO-C101 administration13 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
 
Tumor biopsy14 
X 
X 
 
 
 
 
 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X5 
Concomitant medication/  
non-drug therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X5 
Survival information 
 
 
 
 
 
 
 
 
 
 
 
 
X15 
 
 
 

 
 
 
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*     Part A, Part D: All visits and dosing days will have a time window of ±1 day as long as the two doses of SO-C101 per week are given on consecutive days (day 1 and day 2) and the second week SO-C101 dosing (day 8 and day 
9) takes place 7 days after day 1, which should be strictly followed for cycle 1 and, if possible, for the following cycles. 
 
Part A1, Part D1: All visits and dosing days will have a time window of ±1 day as long as the four doses of SO-C101 per week are given on consecutive days (day 1 and day 2) and the second week SO-C101 dosing (day 8 and 
day 9) takes place 7 days after day 1, which should be strictly followed for cycle 1 and, if possible, for the following cycles. 
**   Criteria for removal from study treatment are listed in section 9.11.10 
1. No study-specific procedures are to be performed prior to ICF signature 
2. Demography implies the collection of information on age at screening, gender, race, and ethnicity 
3. Primary tumor location, histology/cytology, initial diagnosis date, lines of previous treatment, start and stop dates of the treatments prior to this study, and any prior mutations/genetic analysis (i.e., EGFR, KRAS mutations, BCL-2) 
and the date of the latest disease progression if not coinciding with the stop date 
4. To be done before SO-C101 dose and afterwards as clinically required 
5. Every 30 (±2) days until 90 (±2) days after the last dose of SO-C101 
6. To be measured before the first SO-C101 dose at day 1 of each cycle 
7. Vital signs include blood pressure (systolic and diastolic, after ≥15 minutes of rest), body temperature, heart rate, and respiratory rate. During post-SO-C101 observation, vital signs (body temperature, heart rate, respiratory rate, 
systolic and diastolic blood pressure) will be documented as described in section 9.11.6.3. 
8. Urine test will be performed prior to day 1. In case of ≥100 mg/dL proteinuria at screening, a 24-hour urine analysis will have to be performed (prior to the start of SO-C101 treatment) to document 24-hour proteinuria levels and 
a urine test will continue during the treatment period. In case of increase of proteinuria ≥300 mg/dL (at any time), a 24-hour urine analysis will be performed. 
9. From serum creatinine, calculated by the Cockcroft-Gault formula (appendix 12.2); cycles 1 and 2: days 1 and 9 prior to SO-C101 administration and on day 6; cycle 3: day 1 (prior to SO-C101 administration) and on day 6; from 
cycle 4 and onwards on days 1 and 8 prior to SO-C101 administration 
10. Before SO-C101 administration and 4 hours (+30 min) after SO-C101 administration (note: in Part A1 and Part D1 both the first and second doses of SO-C101) 
11. End of each second cycle (i.e., cycle 2, 4, 6…); allowed interval from day 9 of the current cycle to day 2 of the next cycle 
12. Until iCPD, until the start of a new anticancer therapy, or until 6 months (±2 weeks) after the EoT visit (whichever occurs earliest) unless patients withdraw consent 
13. Time to be recorded; treatment days in Part A and Part D: once a day; treatment days in Part A1 and Part D1: twice a day 8 hours (±15 min) apart 
14. Paired tumor biopsy (screening and during cycle 2) and at the time of a clinically significant event and at the time of progression or response (not mandatory); archived, fixed tumor tissue can be collected if fresh biopsy at screening 
is not available; Part A1, Part D, and Part D1: preferably/ if possible at cycle 2 day 13 (if not, will not be a deviation)  
15. At 3 months (±2 weeks) and 6 months (±2 weeks) after the EoT visit (end of the patient’s study participation) 
 
 

 
 
 
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Table 9.7: Schedule of procedures/assessments, Part B and Part B1 (SO-C101 combined with pembrolizumab) 
Cycle 
 
Cycle 1 to 3* 
From cycle 4 onwards** 
End  
of treatment visit 
Within 7 (+7) days 
after the final dose of 
SO-C101 and/or 
pembrolizumab 
Follow-up 
Visit 
Screening 
Up to 21 days  
before day 1  
of cycle 1 
Day 1 
Day 2 
Day 6 
Day 8 
Day 9 
Day 13 
Day 1 
Day 2 
Day 8 
Day 9 
Informed consent1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Cancer3 and medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X  
(blood) 
X (urine or 
blood) 
 
 
 
 
 
X  
(urine or 
blood) 
 
 
 
 
 
Physical examination4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X5 
Body weight and body surface area6 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
X5 
Vital signs7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X5 
Urinalysis8 
X 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
Creatinine clearance9 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
ECG 
X 
X10 
X10 
 
X10 
X10 
 
X10 
 
 
 
X 
 
Echocardiography11 
X 
End of each second cycle, starting from cycle 2  
(allowed interval from day 9 of the current cycle to day 2 of the next cycle) 
X 
 
ECOG performance score 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Tumor assessment (CT/MRI, MRI)12 
X 
Every 6 weeks (±2 weeks) 
SO-C101 administration13 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
 
Pembrolizumab administration14 
 
Every 3 weeks (day 1) according to the prescribing information 
 
 
Tumor biopsy15 
X 
X 
 
 
 
 
 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X5 
Concomitant medication/  
non-drug therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X5 
Survival information 
 
 
 
 
 
 
 
 
 
 
 
 
X16 
 
 
 

 
 
 
 
 
Clinical Study Protocol SC103 
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*     Part B: All visits and dosing days will have a time window of ±1 day as long as the two doses of SO-C101 per week are given on consecutive days (day 1 and day 2) and the second week SO-C101 dosing (day 8 and day 9) takes 
place 7 days after day 1. 
Part B1: All visits and dosing days will have a time window of ±1 day as long as the four doses of SO-C101 per week are given on consecutive days (day 1 and day 2) and the second week SO-C101 dosing (day 8 and day 9) takes 
place 7 days after day 1. 
** Criteria for removal from study treatment are listed in section 9.11.10 
1. No study-specific procedures are to be performed prior to ICF signature 
2. Demography implies the collection of information on age at screening, gender, race, and ethnicity 
3. Primary tumor location, histology/cytology, initial diagnosis date, lines of previous treatment, start and stop dates of the treatments prior to this study, and any prior mutations/genetic analysis (i.e., EGFR, KRAS mutations, BCL-2) 
and the date of the latest disease progression if not coinciding with the stop date 
4. To be done before SO-C101 dose and afterwards as clinically required 
5. Every 30 (±2) days until 90 (±2) days after the last dose of SO-C101 and/or pembrolizumab, whichever occurs later 
6. To be measured before the first SO-C101 dose at day 1 of each cycle 
7. Vital signs include blood pressure (systolic and diastolic, after ≥15 minutes of rest), body temperature, heart rate, and respiratory rate. During post-SO-C101 observation, vital signs (body temperature, heart rate, respiratory rate, 
systolic and diastolic blood pressure) will be documented as described in section 9.11.6.3. 
8. Urine test will be performed prior to day 1. In case of ≥100 mg/dL proteinuria at screening, a 24-hour urine analysis will have to be performed (prior to the start of SO-C101 treatment) to document 24-hour proteinuria levels and 
a urine test will continue during the treatment period. In case of increase of proteinuria ≥300 mg/dL (at any time), a 24-hour urine analysis will be performed. 
9. From serum creatinine, calculated by the Cockcroft-Gault formula (appendix 12.2); cycles 1 and 2: days 1 and 9 prior to SO-C101 administration and on day 6; cycle 3: day 1 (prior to SO-C101 administration) and on day 6; from 
cycle 4 and onwards on days 1 and 8 prior to SO-C101 administration 
10. Before SO-C101 administration and 4 hours (+30 min) after SO-C101 administration (note: in Part B1 both the first and second doses of SO-C101) 
11. End of each second cycle (i.e., cycle 2, 4, 6…); allowed interval from day 9 of the current cycle to day 2 of the next cycle 
12. Until iCPD, until the start of a new anticancer therapy, or until 6 months (±2 weeks) after the EoT visit (whichever occurs earliest) unless patients withdraw consent 
13. Time to be recorded; treatment days in Part B: once a day; treatment days in Part B1: twice a day 8 hours (±15 min) apart  
14. Time to be recorded; pembrolizumab will be administered within 30 minutes following SO-C101 administration 
15. Paired tumor biopsy (screening and during cycle 2) and at the time of a clinically significant event and at the time of progression or response (not mandatory); archived, fixed tumor tissue can be collected if fresh biopsy at screening 
is not available; Part B1: preferably/ if possible at cycle 2 day 13 (if not, will not be a deviation) 
16. At 3 months (±2 weeks) and 6 months (±2 weeks) after the EoT visit (end of the patient’s study participation) 
 
 

 
 
 
Clinical Study Protocol SC103 
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Table 9.8: Schedule of procedures/assessments, Part B and Part B1 (for patients who continue on pembrolizumab only after discontinuation of 
SO-C101) 
 
*     Criteria for removal from study treatment are listed in section 9.11.10 
1, 2, 3, and 4 to be done before pembrolizumab dose on day 1 of each cycle 
3. Vital signs include blood pressure (systolic and diastolic, after ≥15 minutes of rest), body temperature, heart rate, and respiratory rate 
4. Urine test will be performed prior pembrolizumab administration on day 1. In case of ≥100 mg/dL proteinuria at screening, a 24-hour urine analysis will have to be performed to document 24-hour proteinuria levels and a urine 
test will continue during the treatment period. In case of increase of proteinuria ≥300 mg/dL (at any time), a 24-hour urine analysis will be performed. 
5. Every 30 (±2) days until 90 (±2) days after the last dose of pembrolizumab  
6. ECG to be performed on day 1 before pembrolizumab administration  
7. Echocardiography should be done at the EoT visit 
8. Until iCPD, until the start of a new anticancer therapy, or until 6 months (±2 weeks) after the EoT visit (whichever occurs earliest) unless patients withdraw consent 
9. At 3 months (±2 weeks) and 6 months (±2 weeks) after the EoT visit (end of the patient’s study participation) 
 
 
Visit 
Day 1 of each cycle 
End of treatment visit* 
Within 7 (+7) days after the final dose of 
pembrolizumab 
Follow-up 
Pregnancy test 
X (urine or blood) 
 
 
Physical examination1 
X 
X 
X5 
Body weight and body surface area2 
X 
X 
X5 
Vital signs3 
X 
X 
X5 
Urinalysis4 
X 
X 
 
ECG6 
X 
X 
 
Echocardiography7 
 
X 
 
ECOG performance score 
X 
X 
 
Tumor assessment (CT/MRI, MRI)8 
Every 6 weeks (±2 weeks) 
Pembrolizumab administration 
Every 3 weeks (day 1) according to the prescribing 
information 
 
 
AEs 
X 
X 
X5 
Concomitant medication/  
non-drug therapies 
X 
X 
X5 
Survival information 
 
 
X9 

 
 
 
Clinical Study Protocol SC103 
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Table 9.9: Blood samples collection, Part A 
All attempts should be made to collect the samples on time. Missed sample collections are considered protocol deviations. The numbers in brackets are the expected blood 
sampling volumes in mL. 
 
Cycle 1 
Cycle 2 
Cycle 3 
From cycle 4* 
EoT 
Day 
Screening 
1 
2 
6 
8 
9 
13 
15 
1 
2 
6 
8 
9 
13 
15 
1 
2 
6 
8 
9 
13 
15 
1 
8 
9 
SO-C101 administration1 
 
X 
X 
 
X 
X 
 
 
X 
X 
 
X 
X 
 
 
X 
X 
 
X 
X 
 
 
X 
X 
X 
 
PBMCs2 
 
X (9) 
X (9) X (9) X (9) X (9) X (9) X (9) 
X (9) 
 
X (9) X (9) 
 
X (9) X (9) 
X (9) 
 
X (9) 
 
 
X (9) X (9) 
 
 
 
X (9) 
Serum (PK) 
 Please see Table 9.14 
Serum (cytokine)3 
 
X (8) 
X (8) 
 
X (8) X (8) 
 
 
X (8) 
X (8) 
 
X (8) X (8) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum (immunogenicity)4 
 
X (5) 
 
 
 
 
 
X (5) 
X (5) 
 
 
 
 
 
 
X (5) 
 
 
 
 
 
 
X (5) 
 
 
X (5) 
PBMCs (for genetic test) 
 
X (5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, hepatitis B and C 
X (5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology (full complete 
blood count incl. ALC) 
X (3) 
X (3) 
X (3) X (3) X (3) X (3) X (3) X (3) 
X (3) 
 
X (3) X (3) 
 
X (3) X (3) 
X (3) 
 
X (3) X (3) 
 
X (3) X (3) X (3) X (3) 
 
X (3) 
Biochemistry (incl. CRP) 
X (8) 
X (8) 
X (8) X (8) 
 
X (8) X (8) 
 
X (8) 
 
X (8) 
 
X (8) X (8) 
 
X (8) 
 
X (8) 
 
 
 
 
X (8) X (8) 
 
X (8) 
CRP 
 
 
 
 
X (1) 
 
 
 
 
X (1) 
 
X (1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation 
X (5) 
X (5) 
 
 
X (5) 
 
 
 
X (5) 
 
 
X (5) 
 
 
 
X (5) 
 
 
X (5) 
 
 
 
X (5) X (5) 
 
X (5) 
TSH, free T3, free T4 
X (1) 
X (1) 
 
 
 
 
 
 
X (1) 
 
 
 
 
 
 
X (1) 
 
 
 
 
 
 
X (1) 
 
 
X (1) 
Hs-cTnT test5 
X (1) 
X (1) 
X (1) 
 
X (1) X (1) 
 
 
X (1) 
 
 
 
X (1) 
 
 
X (1) 
 
 
 
X (1) 
 
 
X (1) 
 
X (1) X (1) 
Serum pregnancy 
X (5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*     Criteria for removal from study treatment are listed in section 9.11.10 
1. Time to be recorded 
2. All samples for PBMCs have to be collected before dosing (pre-dose) on the dosing day 
3. Cycle 1: day 1 and day 2 (pre-dose and 2 hours [±30 min], 4 hours [±30 min], 6 hours [±30 min] post dose), day 8 and day 9 (pre-dose and 2 hours [±30 min], 4 hours [±30 min], 6 hours [±30 min] post dose); cycle 2: day 1 and 
day 2 (pre-dose and 2 hours [±30 min], 4 hours [±30 min], 6 hours [±30 min] post dose), day 8 and day 9 (pre-dose and 2 hours [±30 min], 4 hours [±30 min], 6 hours [±30 min] post dose) 
4. Pre-dose SO-C101 on day 1 in each cycle up to cycle 12 (inclusive) and cycle 1 day 15; testing at the EoT visit to be done 
5. Hs-cTnT test (cardiac troponin T test): cycle 1: days 1 and 8 before each dose of SO-C101 and on days 2 and 9 at least 3 hours after SO-C101; subsequent cycles: on day 1 before SO-C101 and day 9 at least 3 hours after 
SO-C101 
 
 
 

 
 
 
Clinical Study Protocol SC103 
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Table 9.10: Blood samples collection, Part A1, Part D, and Part D1  
All attempts should be made to collect the samples on time. Missed sample collections are considered protocol deviations. The numbers in brackets are the expected blood 
sampling volumes in mL. 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
From cycle 5* 
EoT 
Day 
Screening 
1 
2 
6 
8 
9 
13 
15 
1 
2 
6 
8 
9 
13 
1 
2 
6 
8 
9 
13 
1 
8 
9 
1 
8 
9 
SO-C101 administration1 
 
X 
X 
 
X 
X 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
PBMCs2 
 
X (9) 
 
X (9) X (9) 
 
X (9) 
 
X(9) 
 
X(9) X(9) 
 
X(9) X (9) 
 
X (9) 
 
 
X (9) 
 
 
 
 
 
 
X (9) 
Serum (PK) 
Please see Table 9.15 
 
Serum (cytokine)3 
 
X (14) X (14) 
 
X (10) X (10) 
 
 
X 
(10) X (10) 
 
X (10) X (10) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum (immunogenicity)4 
 
X (5) 
 
 
 
 
 
X (5) X (5) 
 
 
 
 
 
X (5) 
 
 
 
 
 
X (5) 
 
 
X (5) 
 
 
X (5) 
PBMCs (for genetic test) 
 
X (5) 
 
 
 
 
 
 
 
 
 
 
 
 
X (5) 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, hepatitis B and C 
X (5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology (full complete blood 
count incl. ALC) 
X (3) 
X (3) X (3) X (3) X (3) X (3) X (3) X (3) X (3) 
 
X (3) X (3) 
 
X (3) X (3) 
 
X (3) X (3) 
 
X (3) X (3) X (3) 
 
X (3) X (3) 
 
X (3) 
Biochemistry (incl. CRP) 
X (8) 
X (8) X (8) X (8) 
 
X (8) X (8) 
 
X (8) 
 
X (8) 
 
X (8) X (8) X (8) 
 
X (8) 
 
 
 
X (8) X (8) 
 
X (8) X (8) 
 
X (8) 
CRP 
 
 
 
 
X (1) 
 
 
 
 
X (1) 
 
X (1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation 
X (5) 
X (5) 
 
 
X (5) 
 
 
 
X (5) 
 
 
X (5) 
 
 
X (5) 
 
 
X (5) 
 
 
X (5) X (5) 
 
X (5) X (5) 
 
X (5) 
TSH, free T3, free T4 
X (1) 
X (1) 
 
 
 
 
 
 
X (1) 
 
 
 
 
 
X (1) 
 
 
 
 
 
X (1) 
 
 
X (1) 
 
 
X (1) 
Hs-cTnT test5 
X (1) 
X (1) X (1) 
 
X (1) X (1) 
 
 
X (1) 
 
 
 
X (1) 
 
X (1) 
 
 
 
X (1) 
 
X (1) 
 
X (1) X (1) 
 
X (1) X (1) 
Serum pregnancy 
X (5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*     Criteria for removal from study treatment are listed in section 9.11.10 
1. Time to be recorded 
2. All samples for PBMCs have to be collected before dosing (pre-dose) on the dosing day 
3. Cycle 1: day 1 and day 2 (pre-dose and 2 hours [±30 min], 4 hours [±30 min], 6 hours [±30 min], 8 hours [±30 min], 12 hours [±30 min], 16 hours [±30 min] post dose); day 8 and day 9 (pre-dose and 4 hours [±30 min], 6 hours 
[±30 min], 8 hours [±30 min], 10 hours [±30 min] post dose); cycle 2: day 1 and day 2 (pre-dose and 4 hours [±30 min], 6 hours [±30 min], 8 hours [±30 min], 10 hours [±30 min] or 12 hours [±30 min] post dose if the patient is 
hospitalized on day 1); day 8 and day 9 (pre-dose and 4 hours [±30 min], 6 hours [±30 min], 8 hours [±30 min], 10 hours [±30 min] or 12 hours [±30 min] post dose if the patient is hospitalized on day 8); in Part A1 and Part D1, 
8 hours post dose has to be collected before the second dose of SO-C101. 
4. Pre-dose SO-C101 on day 1 in each cycle up to cycle 12 (inclusive) and cycle 1 day 15; testing at the EoT visit to be done 
5. Hs-cTnT test (cardiac troponin T test) in Part A1 and Part D1: cycle 1: days 1 and 8 before the first daily dose of SO-C101 in the morning only and on days 2 and 9 at least 3 hours after the second daily dose of SO-C101; 
subsequent cycles: on day 1 before the first daily dose of SO-C101 in the morning only and on day 9 at least 3 hours after the second daily dose of SO-C101; in Part D: cycle 1: days 1 and 8 before each dose of SO-C101 and on 
days 2 and 9 at least 3 hours after SO-C101; subsequent cycles: on day 1 before SO-C101 and day 9 at least 3 hours after SO-C101 
 
 

 
 
 
Clinical Study Protocol SC103 
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Table 9.11: Blood samples collection, Part B 
All attempts should be made to collect the samples on time. Missed sample collections are considered protocol deviations. The numbers in brackets are the expected blood 
sampling volumes in mL. 
 
Cycle 1 
Cycle 2 
Cycle 3 
From cycle 4* 
EoT 
Day 
Screening 
1 
2 
6 
8 
9 
13 
15 
1 
2 
6 
8 
9 
13 
15 
1 
2 
6 
8 
9 
13 
15 
1 
8 
9 
SO-C101 administration1 
 
X 
X 
 
X 
X 
 
 
X 
X 
 
X 
X 
 
 
X 
X 
 
X 
X 
 
 
X 
X 
X 
 
Pembrolizumab administration1 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
PBMCs2 
 
X (9) X (9) X (9) X (9) X (9) X (9) X (9) X (9) 
 
X (9) X (9) 
 
X (9) X (9) X (9) 
 
X (9) 
 
 
X (9) X (9) 
 
 
 
X (9) 
Serum (PK) 
 Please see Table 9.14 
Serum (cytokine)3 
 
X (8) X (8) 
 
X (8) X (8) 
 
 
X (8) X (8) 
 
X (8) X (8) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum (immunogenicity)4 
 
X (5) 
 
 
 
 
 
X (5) X (5) 
 
 
 
 
 
 
X (5) 
 
 
 
 
 
 
X (5) 
 
 
X (5) 
PBMCs (for genetic test) 
 
X (5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, hepatitis B and C 
X (5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology (full complete blood count 
incl. ALC) 
X (3) 
X (3) X (3) X (3) X (3) X (3) X (3) X (3) X (3) 
 
X (3) X (3) 
 
X (3) X (3) X (3) 
 
X (3) X (3) 
 
X (3) X (3) X (3) X (3) 
 
X (3) 
Biochemistry (incl. CRP) 
X (8) 
X (8) X (8) X (8) 
 
X (8) X (8) 
 
X (8) 
 
X (8) 
 
X (8) X (8) 
 
X (8) 
 
X (8) 
 
 
 
 
X (8) X (8) 
 
X (8) 
CRP 
 
 
 
 
X (1) 
 
 
 
 
X (1) 
 
X (1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation 
X (5) 
X (5) 
 
 
X (5) 
 
 
 
X (5) 
 
 
X (5) 
 
 
 
X (5) 
 
 
X (5) 
 
 
 
X (5) X (5) 
 
X (5) 
TSH, free T3, free T4 
X (1) 
X (1) 
 
 
 
 
 
 
X (1) 
 
 
 
 
 
 
X (1) 
 
 
 
 
 
 
X (1) 
 
 
X (1) 
Hs-cTnT test5 
X (1) 
X (1) X (1) 
 
X (1) X (1) 
 
 
X (1) 
 
 
 
X (1) 
 
 
X (1) 
 
 
 
X (1) 
 
 
X (1) 
 
X (1) X (1) 
Serum pregnancy 
X (5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*     Criteria for removal from study treatment are listed in section 9.11.10 
1. Time to be recorded; pembrolizumab will be administered within 30 minutes following SO-C101 administration 
2. All samples for PBMCs have to be collected before dosing (pre-dose) on the dosing day 
3. Cycle 1: day 1 and day 2 (pre-dose and 2 hours [±30 min], 4 hours [±30 min], 6 hours [±30 min] post dose), day 8 and day 9 (pre-dose and 2 hours [±30 min], 4 hours [±30 min], 6 hours [±30 min] post dose); cycle 2: day 1 and 
day 2 (pre-dose and 2 hours [±30 min], 4 hours [±30 min], 6 hours [±30 min] post dose), day 8 and day 9 (pre-dose and 2 hours [±30 min], 4 hours [±30 min], 6 hours [±30 min] post dose) 
4. Pre-dose SO-C101 on day 1 in each cycle up to cycle 12 (inclusive) and cycle 1 day 15; testing at the EoT visit to be done 
5. Hs-cTnT test (cardiac troponin T test): cycle 1: days 1 and 8 before each dose of SO-C101 and on days 2 and 9 at least 3 hours after SO-C101; subsequent cycles: on day 1 before SO-C101 and day 9 at least 3 hours after 
SO-C101 
 
 

 
 
 
Clinical Study Protocol SC103 
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Table 9.12: Blood samples collection, Part B1 
All attempts should be made to collect the samples on time. Missed sample collections are considered protocol deviations. The numbers in brackets are the expected blood 
sampling volumes in mL. 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
From cycle 5* 
EoT 
Day 
Screening 
1 
2 
6 
8 
9 
13 
15 
1 
2 
6 
8 
9 
13 
1 
2 
6 
8 
9 
13 
1 
8 
9 
1 
8 
9 
SO-C101 administration1 
 
X 
X 
 
X 
X 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Pembrolizumab administration1 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
PBMCs2 
 
X (9) 
 
X (9) X (9) 
 
X (9) 
 
X(9) 
 
X(9) X(9) 
 
X(9) X (9) 
 
X (9) 
 
 
X (9) 
 
 
 
 
 
 
X (9) 
Serum (PK) 
Please see Table 9.15 
 
Serum (cytokine)3 
 
X 
(14) 
X 
(14) 
 
X 
(10) 
X 
(10) 
 
 
X 
(10) 
X 
(10) 
 
X 
(10) 
X 
(10) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum (immunogenicity)4 
 
X (5) 
 
 
 
 
 
X (5) X (5) 
 
 
 
 
 
X (5) 
 
 
 
 
 
X (5) 
 
 
X (5) 
 
 
X (5) 
PBMCs (for genetic test) 
 
X (5) 
 
 
 
 
 
 
 
 
 
 
 
 
X (5) 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, hepatitis B and C 
X (5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology (full complete blood count incl. 
ALC) 
X (3) 
X (3) X (3) X (3) X (3) X (3) X (3) X (3) X (3) 
 
X (3) X (3) 
 
X (3) X (3) 
 
X (3) X (3) 
 
X (3) X (3) X (3) 
 
X (3) X (3) 
 
X (3) 
Biochemistry (incl. CRP) 
X (8) 
X (8) X (8) X (8) 
 
X (8) X (8) 
 
X (8) 
 
X (8) 
 
X (8) X (8) X (8) 
 
X (8) 
 
 
 
X (8) X (8) 
 
X (8) X (8) 
 
X (8) 
CRP 
 
 
 
 
X (1) 
 
 
 
 
X (1) 
 
X (1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation 
X (5) 
X (5) 
 
 
X (5) 
 
 
 
X (5) 
 
 
X (5) 
 
 
X (5) 
 
 
X (5) 
 
 
X (5) X (5) 
 
X (5) X (5) 
 
X (5) 
TSH, free T3, free T4 
X (1) 
X (1) 
 
 
 
 
 
 
X (1) 
 
 
 
 
 
X (1) 
 
 
 
 
 
X (1) 
 
 
X (1) 
 
 
X (1) 
Hs-cTnT test5 
X (1) 
X (1) X (1) 
 
X (1) X (1) 
 
 
X (1) 
 
 
 
X (1) 
 
X (1) 
 
 
 
X (1) 
 
X (1) 
 
X (1) X (1) 
 
X (1) X (1) 
Serum pregnancy 
X (5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*     Criteria for removal from study treatment are listed in section 9.11.10 
1. Time to be recorded 
2. All samples for PBMCs have to be collected before dosing (pre-dose) on the dosing day 
3. Cycle 1: day 1 and day 2 (pre-dose and 2 hours [±30 min], 4 hours [±30 min], 6 hours [±30 min], 8 hours [-30 min], 12 hours [±30 min], 16 hours [±30 min] post dose); day 8 and day 9 (pre-dose and 4 hours [±30 min], 6 hours 
[±30 min], 8 hours [-30 min], 10 hours [±30 min] post dose); cycle 2: day 1 and day 2 (pre-dose and 4 hours [±30 min], 6 hours [±30 min], 8 hours [-30 min], 10 hours [±30 min] or 12 hours [±30 min] post dose if the patient is 
hospitalized on day 1); day 8 and day 9 (pre-dose and 4 hours [±30 min], 6 hours [±30 min], 8 hours [-30 min], 10 hours [±30 min] or 12 hours [±30 min] post dose if the patient is hospitalized on day 8); 8 hours post dose has to 
be collected before the second dose of SO-C101. 
4. Pre-dose SO-C101 on day 1 in each cycle up to cycle 12 (inclusive) and cycle 1 day 15; testing at the EoT visit to be done 
5. Hs-cTnT test (cardiac troponin T test): cycle 1: days 1 and 8 before the first daily dose of SO-C101 in the morning only and on days 2 and 9 at least 3 hours after the second daily dose of SO-C101; subsequent cycles: on day 1 
before the first daily dose of SO-C101 in the morning only and on day 9 at least 3 hours after the second daily dose of SO-C101 
 
 

 
 
 
Clinical Study Protocol SC103 
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Table 9.13: Blood samples collection (Part B and Part B1; for patients who continue on pembrolizumab only after discontinuation of SO-C101) 
All attempts should be made to collect the samples on time. Missed sample collections are considered protocol deviations. The numbers in brackets are the expected blood 
sampling volumes in mL. 
 
Cycle 1 
Cycle 2 
From cycle 3* 
EoT 
Day 
1 
1 
1 
 
Pembrolizumab administration1 
X 
X 
X 
 
Hematology2 
X (3) 
X (3) 
X (3) 
X (3) 
Biochemistry3 
X (8) 
X (8) 
X (8) 
X (8) 
Coagulation4 
X (5) 
X (5) 
X (5) 
X (5) 
TSH, free T3, free T45 
X (1) 
X (1) 
X (1) 
X (1) 
 
*     Criteria for removal from study treatment are listed in section 9.11.10 
1. Time to be recorded; Part B and Part B1: pembrolizumab will be administered on day 1 
2, 3, 4, 5 Before pembrolizumab administration on day 1 in each cycle 
 
 

 
 
 
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Table 9.14: PK sampling, Part A and Part B 
All attempts should be made to collect the samples on time. Missed sample collections are 
considered protocol deviations. The numbers in brackets are the expected blood sampling volumes 
in mL. 
Cycle, day 
Time point  
(pre-dose or time after SO-C101 administration) 
SO-C101 PK 
Part A 
Part B 
Cycle 1 day 1 
Pre-dose to SO-C101 and pembrolizumab  
(as applicable) 
X (1) 
X (1) 
30 min (±5 min) 
X (1) 
X (1) 
1 h (±15 min) 
X (1) 
X (1) 
2 h (±15 min) 
X (1) 
X (1) 
4 h (Parts A, B: ±15 min) 
X (1) 
X (1) 
8 h (±15 min) 
X (1) 
X (1) 
12 h (±1 h) 
X (1) 
X (1) 
16 h (±1 h) 
X (1) 
 
20 h (±1 h) 
X (1) 
 
24 h (±6 h), pre-dose to cycle 1 day 2 
X (1) 
X (1) 
Cycle 1 day 9 
Pre-dose to SO-C101 
X (1) 
X (1) 
30 min (±5 min) 
X (1) 
X (1) 
1 h (±15 min) 
X (1) 
X (1) 
2 h (±15 min) 
X (1) 
X (1) 
4 h (±15 min) 
X (1) 
X (1) 
6 h (±15 min) 
X (1) 
X (1) 
Cycle 2 day 1 
Pre-dose to SO-C101 and pembrolizumab  
(as applicable) 
X (1) 
X (1) 
30 min (±5 min) 
X (1) 
X (1) 
1 h (±15 min) 
X (1) 
X (1) 
2 h (±15 min) 
X (1) 
X (1) 
4 h (Parts A, B: ±15 min) 
X (1) 
X (1) 
6 h (±15 min) 
X (1) 
X (1) 
Cycle 2 day 9 
Pre-dose to SO-C101 
X (1) 
X (1) 
30 min (±5 min) 
X (1) 
X (1) 
1 h (±15 min) 
X (1) 
X (1) 
2 h (±15 min) 
X (1) 
X (1) 
4 h (±15 min) 
X (1) 
X (1) 
6 h (±15 min) 
X (1) 
X (1) 
Cycle 3 day 1 
Pre-dose to SO-C101 and pembrolizumab  
(as applicable) 
X (1) 
X (1) 
30 min (±5 min) 
X (1) 
X (1) 
1 h (±15 min) 
X (1) 
X (1) 
2 h (±15 min) 
X (1) 
X (1) 
4 h (±15 min) 
X (1) 
X (1) 
6 h (±15 min) 
X (1) 
X (1) 
 
 
 

 
 
 
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Table 9.15: PK sampling, Part A1, Part B1, Part D (patients 1-5 in each indication), 
and Part D1 (patients 1-5 in each indication) 
All attempts should be made to collect the samples on time. Missed sample collections are 
considered protocol deviations. The numbers in brackets are the expected blood sampling volumes 
in mL. 
Patients will be hospitalized on PK sampling days (cycle 1 day 1, cycle 1 day 2, and cycle 3 day 1). 
Cycle, day 
Time point  
(pre-dose or time after SO-C101 administration) 
SO-C101 PK 
Cycle 1 day 1 
Pre-dose to SO-C101 and pembrolizumab (as applicable) 
X (1) 
1 h (±15 min) 
X (1) 
2 h (±15 min) 
X (1) 
4 h (±15 min) 
X (1) 
8 h (±15 min) pre-dose* 
X (1) 
9 h (±15 min) 
X (1) 
10 h (±15 min) 
X (1) 
12 h (±1 h) 
X (1) 
16 h (±1 h) 
X (1) 
20 h (±1 h) 
X (1) 
Cycle 1 day 2 
Pre-dose to SO-C101 
X (1) 
1 h (±15 min) 
X (1) 
2 h (±15 min) 
X (1) 
4 h (±15 min) 
X (1) 
8 h (±15 min) pre-dose* 
X (1) 
9 h (±15 min) 
X (1) 
10 h (±15 min) 
X (1) 
12 h (±1 h) 
X (1) 
16 h (±1 h) 
X (1) 
20 h (±1 h) 
X (1) 
24 h (±6 h) 
X (1) 
Cycle 3 day 1 
Pre-dose to SO-C101 and pembrolizumab (as applicable) 
X (1) 
1 h (±15 min) 
X (1) 
2 h (±15 min) 
X (1) 
4 h (±15 min) 
X (1) 
8 h (±15 min) pre-dose* 
X (1) 
9 h (±15 min) 
X (1) 
10 h (±15 min) 
X (1) 
12 h (±1 h) 
X (1) 
16 h (±1 h) 
X (1) 
20 h (±1 h) 
X (1) 
24 h (±6 h), pre-dose to cycle 3 day 2 
X (1) 
 
*     In Part A1, Part B1, and Part D1, 8 hours post dose must be collected before the second dose of SO-C101 
 
 

 
 
 
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Table 9.16: PK sampling, Part D (starting with patient 6 in each indication) 
All attempts should be made to collect the samples on time. Missed sample collections are 
considered protocol deviations. The numbers in brackets are the expected blood sampling volumes 
in mL. 
Cycle, day 
Time point  
(pre-dose or time after SO-C101 administration) 
SO-C101 PK 
 
Pre-dose to SO-C101 
X (1) 
Cycle 1 day 1 
1 h (±15 min) 
X (1) 
 
4 h (±15 min) 
X (1) 
 
Pre-dose to SO-C101 
X (1) 
Cycle 1 day 2 
1 h (±15 min) 
X (1) 
 
4 h (±15 min) 
X (1) 
 
Pre-dose to SO-C101  
X (1) 
Cycle 3 day 1 
1 h (±15 min) 
X (1) 
 
4 h (±15 min) 
X (1) 
 
 
 

 
 
 
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Table 9.17: PK sampling, Part D1 (starting with patient 6 in each indication) 
All attempts should be made to collect the samples on time. Missed sample collections are 
considered protocol deviations. The numbers in brackets are the expected blood sampling volumes 
in mL. 
Cycle, day 
Time point  
(pre-dose or time after SO-C101 administration) 
SO-C101 PK 
 
Pre-dose to SO-C101 
X (1) 
 
1 h (±15 min) 
X (1) 
Cycle 1 day 1 
4 h (±15 min) 
X (1) 
 
8 h (±15 min) pre-dose* 
X (1) 
 
12 h (±1 h) 
X (1) 
 
Pre-dose to SO-C101 
X (1) 
 
1 h (±15 min) 
X (1) 
Cycle 1 day 2 
4 h (±15 min) 
X (1) 
 
8 h (±15 min) pre-dose* 
X (1) 
 
12 h (±1 h) 
X (1) 
 
Pre-dose to SO-C101  
X (1) 
Cycle 3 day 1 
1 h (±15 min) 
X (1) 
 
4 h (±15 min) 
X (1) 
 
8 h (±15 min) pre-dose* 
X (1) 
 
*     8 hours post dose must be collected before the second dose of SO-C101 
 
 

 
 
 
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9.11.8 Appropriateness of measurements 
All clinical assessments are standard measurements commonly used in oncology studies. 
The safety assessments to be performed in this study, including hematology analyses, blood 
chemistry tests, urinalysis, and assessment of AEs are standard evaluations to ensure patient 
safety. 
9.11.9 Withdrawal of patients from the study 
A patient may elect to withdraw from the study at any time for any reason. All patients who 
withdraw from the study are to complete the EoT visit as indicated in Table 9.6, Table 9.7, 
and Table 9.8. 
A patient who has ceased to return for visits will be followed up by mail, phone, or other 
means to gather information such as the reason for failure to return, the status of treatment 
compliance, the presence or absence of AEs, and clinical courses of signs and symptoms. 
9.11.10 Treatment discontinuation 
Patients will be discontinued from study treatment for any of the following events: 
• Radiographic disease progression (iCPD)(see section 9.11.11 for guidance regarding the 
continuation of treatment after disease progression) 
• Clinical disease progression (investigator assessment) 
• AE (intercurrent illness or study treatment-related toxicity, including DLTs [Part A, Part 
A1, Part B, and Part B1], that would, in the judgment of the investigator, affect 
assessments of clinical status to a significant degree or require discontinuation of study 
treatment) 
• Patient may withdraw from the study at any time for any reason; the investigator must 
make every effort to determine the reason for this decision and record it in source 
documentation of the patient 
• Death 
• Pregnancy 
• Concomitant treatment with a prohibited medication, including further lines of cancer 
therapy 
• Patient non-compliance 
• Lost to follow-up 
• Study terminated by the sponsor 
See also section 9.7.11. 
9.11.11 Guidance for continuation of study treatment beyond iRECIST-defined 
disease progression 
Response will be assessed using iRECIST. As a minority of patients treated with 
immunotherapy may derive clinical benefit despite evidence of disease progression, the 
following guidance is provided for continuation of study treatment beyond iUPD.45 

 
 
 
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Patients receiving study treatment will be permitted to continue study treatment beyond 
iUPD, as assessed by the investigator, as long as they meet the following criteria: 
• Investigator-assessed clinical benefit, and do not have rapid disease progression 
• Tolerance of SO-C101 
• Tolerance of pembrolizumab (Part B and Part B1 only) 
• Stable performance status 
• Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (e.g., central nervous system metastases). 
• Investigator notifies the patient of any reasonably foreseeable risks or discomforts, or 
other alternative treatment options. 
• The decision to continue treatment beyond iUPD should be discussed with the sponsor’s 
medical monitor and documented in the study records. 
• A radiographic assessment/scan should be performed within 6 weeks (±2 weeks). The 
assessment of clinical benefit should be balanced by clinical judgment as to whether the 
patient is clinically deteriorating and unlikely to receive any benefit from continued 
treatment with study treatment. 
• If the investigator feels that the patient continues to achieve clinical benefit by continuing 
treatment, the patient should remain in the study and continue to receive monitoring 
according to the study calendar. 
• In the case of iCPD: If the investigator believes that continued treatment is appropriate, 
imaging is not required after iCPD. 
9.12 Data quality assurance 
This study will be organized, performed, and reported in compliance with the Protocol, 
SOPs, working practice documents, and applicable regulations and guidelines. Site audits 
will be made periodically by the sponsor’s or the Contract Research Organization (CRO)’s 
qualified compliance auditing team, which is an independent function from the study team 
responsible for the conduct of the study. 
9.12.1 Data collection 
Data required by the Protocol will be collected on the eCRFs, part of a validated data 
management system that is compliant with all regulatory requirements. As defined by ICH 
guidelines, the eCRF is an electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study patient. Data 
collection in the eCRF should follow the instructions described in the eCRF Completion 
Guidelines. The investigator has ultimate responsibility for the collection and reporting of 
all clinical data entered on the eCRF. The investigator or designee as identified on Form 
FDA 1572 must sign the completed eCRF to attest to its accuracy, authenticity, and 
completeness. Completed, original eCRFs are the sole property of the sponsor and should 
not be made available in any form to third parties without written permission from the 
sponsor, except for authorized representatives of the sponsor or appropriate regulatory 
authorities and IRB/ECs. 
9.12.2 Clinical data management 
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements. All 

 
 
 
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data, both eCRF and external data (e.g., laboratory data), will be entered into a clinical 
system. 
9.13 Statistical methods 
Each study part will be analyzed separately following its objectives. Part D and Part D1 are 
monotherapy parts including patients with the same indications. Therefore, data of both 
parts will be pooled for the purpose of exploratory analysis (within each indication 
separately). Further exploratory analyses including data of more study parts pooled can be 
included in the Statistical Analysis Plan (SAP).  
The analyses will be descriptive. Descriptive statistics will be performed for continuous 
variables using number, mean, standard deviation, median, Q1 (25th percentile), Q3 (75th 
percentile), minimum, and maximum, unless otherwise specified. Categorical variables will 
be summarized as number (percent) of patients. Kaplan-Meier estimations of time-to-event 
data will be performed, together with estimation of median (if reached). 
If appropriate regarding the number of patients, the descriptive statistics will be presented 
with 95% confidence intervals.  
The intra-patient increase of the SO-C101 dose is allowed from Protocol version 6.1 
onwards. The analyses are planned by dose level for all dose levels pooled. The main 
analyses are planned to be performed based on the initial dose level. However, changing the 
dose level will be also taken into account, especially in outputs presenting safety data in 
dose escalation study parts (where AEs will be presented by initial dose level and also by 
dose level administered before AE onset). Details will be specified in the SAP which will 
take into account the frequency and intensity of dose increases. 
The statistical analyses of study data are described in this section. Further details of the 
analytical plan will be provided in the SAP which will be finalized before database lock. 
Statistical analyses will be performed using SAS software or other validated statistical 
software as required. 
9.13.1 Study endpoints 
9.13.1.1 
Part A 
9.13.1.1.1 
Primary endpoints 
• Safety and tolerability of SO-C101 as evaluated by the incidence of DLTs, incidence of 
SO-C101-related AEs, SAEs, AEs leading to premature discontinuation of SO-C101, 
deaths, and clinical laboratory test abnormalities 
• MTD is defined as the dose level associated with ≥33% of DLT-evaluable patients 
experiencing a DLT. If the MTD is reached, the RP2D will be conventionally defined as 
the dose level just below this non-tolerated dose level. If the MTD is not reached, the 
RP2D will be selected based on integrated evaluation of safety, tolerability, clinical 
benefit, PK and PD data, for all dose levels tested. 
9.13.1.1.2 
Secondary endpoints 
• PK of SO-C101 
• Immune response characterized by the changes in expression of immune markers in 
PBMCs 

 
 
 
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• ORR, DOR, CBR, and PFS according to iRECIST 
• Detection of ADAs 
9.13.1.1.3 
Exploratory endpoints 
• Changes in the expression of immune biomarkers as compared to baseline in tumor tissue 
• OS at 6 months after the EoT visit 
9.13.1.2 
Part A1 
9.13.1.2.1 
Primary endpoints 
• Safety and tolerability of SO-C101 as evaluated by the incidence of DLTs, incidence of 
SO-C101-related AEs, SAEs, AEs leading to premature discontinuation of SO-C101, 
deaths, and clinical laboratory test abnormalities 
• MTD is defined as the dose level associated with ≥33% of DLT-evaluable patients 
experiencing a DLT. If the MTD is reached, the RP2D will be conventionally defined as 
the dose level just below this non-tolerated dose level. If the MTD is not reached, the 
RP2D will be selected based on integrated evaluation of safety, tolerability, clinical 
benefit, PK and PD data, for all dose levels tested. 
9.13.1.2.2 
Secondary endpoints 
• PK of SO-C101 
• Immune response characterized by the changes in expression of immune markers in 
PBMCs 
• ORR, DOR, CBR, and PFS according to iRECIST 
• Detection of ADAs 
9.13.1.2.3 
Exploratory endpoints 
• Changes in the expression of immune biomarkers as compared to baseline in tumor tissue 
• OS at 6 months after the EoT visit 
9.13.1.3 
Part B 
9.13.1.3.1 
Primary endpoints 
• Safety and tolerability of SO-C101 combined with pembrolizumab as evaluated by the 
incidence of DLTs, SO-C101-related AEs, SAEs, AEs leading to premature SO-C101 
discontinuation, deaths, and clinical laboratory test abnormalities 
• MTD defined as the dose level associated with ≥33% of DLT-evaluable patients 
experiencing a DLT. If the MTD is reached, the RP2D will be conventionally defined as 
the dose level just below this non-tolerated dose level. If the MTD is not reached, the 
RP2D will be selected based on integrated evaluation of safety, tolerability, clinical 
benefit, PK and PD data, for all dose levels tested. 
9.13.1.3.2 
Secondary endpoints 
• PK of SO-C101 combined with pembrolizumab 

 
 
 
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• Immune response after administration of SO-C101 in combination with pembrolizumab 
characterized by the changes in expression of immune markers in PBMCs 
• ORR, DOR, CBR, and PFS according to iRECIST 
• Detection of ADAs 
9.13.1.3.3 
Exploratory endpoints 
• Changes in the expression of immune biomarkers after administration of SO-C101 in 
combination with pembrolizumab as compared to baseline in tumor tissue 
• OS at 6 months after the EoT visit 
9.13.1.4 
Part B1 
9.13.1.4.1 
Primary endpoints 
• Safety and tolerability of SO-C101 combined with pembrolizumab as evaluated by the 
incidence of DLTs, SO-C101-related AEs, SAEs, AEs leading to premature SO-C101 
discontinuation, deaths, and clinical laboratory test abnormalities 
• MTD defined as the dose level associated with ≥33% of DLT-evaluable patients 
experiencing a DLT. If the MTD is reached, the RP2D will be conventionally defined as 
the dose level just below this non-tolerated dose level. If the MTD is not reached, the 
RP2D will be selected based on integrated evaluation of safety, tolerability, clinical 
benefit, PK and PD data, for all dose levels tested. 
9.13.1.4.2 
Secondary endpoints 
• PK of SO-C101 combined with pembrolizumab 
• Immune response after administration of SO-C101 in combination with pembrolizumab 
characterized by the changes in expression of immune markers in PBMCs 
• ORR, DOR, CBR, and PFS according to iRECIST 
• Detection of ADAs 
9.13.1.4.3 
Exploratory endpoints 
• Changes in the expression of immune biomarkers after administration of SO-C101 in 
combination with pembrolizumab as compared to baseline in tumor tissue 
• OS at 6 months after the EoT visit 
9.13.1.5 
Part D 
9.13.1.5.1 
Primary endpoint 
• Safety and tolerability of SO-C101 as evaluated by the incidence of SO-C101-related 
AEs, SAEs, AEs leading to premature SO-C101 discontinuation, deaths, and clinical 
laboratory test abnormalities 
9.13.1.5.2 
Secondary endpoints 
• PK of SO-C101 

 
 
 
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• Immune response after administration of SO-C101 characterized by the changes in 
expression of immune markers in PBMCs 
• ORR, DOR, CBR, and PFS according to iRECIST 
• Detection of ADAs 
9.13.1.5.3 
Exploratory endpoints 
• Changes in the expression of immune biomarkers after administration of SO-C101 as 
compared to baseline in tumor tissue 
• OS at 6 months after the EoT visit 
9.13.1.6 
Part D1 
9.13.1.6.1 
Primary endpoint 
• Safety and tolerability of SO-C101 as evaluated by the incidence of SO-C101-related 
AEs, SAEs, AEs leading to premature SO-C101 discontinuation, deaths, and clinical 
laboratory test abnormalities 
9.13.1.6.2 
Secondary endpoints 
• PK of SO-C101  
• Immune response after administration of SO-C101 characterized by the changes in 
expression of immune markers in PBMCs 
• ORR, DOR, CBR, and PFS according to iRECIST 
• Detection of ADAs 
9.13.1.6.3 
Exploratory endpoints 
• Changes in the expression of immune biomarkers after administration of SO-C101 as 
compared to baseline in tumor tissue 
• OS at 6 months after the EoT visit 
9.13.2 Definitions of analysis sets 
9.13.2.1 
Safety population 
All patients exposed to SO-C101 in Part A, Part A1, Part D, and Part D1. 
All patients exposed to SO-C101 or pembrolizumab in Part B and Part B1. 
9.13.2.2 
PK/PD population 
All PK/PD-evaluable patients. 
9.13.2.3 
Efficacy population 
All patients exposed to SO-C101 (exposure for at least one treatment cycle) who had at least 
one evaluable tumor assessment per iRECIST after the initiation of SO-C101 treatment. 

 
 
 
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9.13.3 Patient disposition 
The number (percentage) of enrolled and treated patients will be summarized as well as 
patients who completed the study/discontinued from the study and reasons for withdrawal. 
The number (percentage) of patients who completed the study treatment/discontinued from 
the study treatment and reasons for discontinuation will also be summarized by treatment 
cohort. 
9.13.4 Demographic and other baseline characteristics 
Demographic and other baseline characteristics will be summarized and listed for each 
treatment cohort. 
9.13.5 Prior and concomitant therapy 
All investigator terms (verbatim terms) for medications recorded in the eCRF will be coded 
to an 11-digit code using the World Health Organization Drug Dictionary drug codes. 
Cancer-related prior medications will be defined as medications that stopped before the first 
dose of the IMP. Concomitant medications will be defined as medications that i) started 
before the first dose of SO-C101/pembrolizumab and were continuing at the time of the first 
dose of SO-C101/pembrolizumab, or ii) started on or after the date of the first dose of 
SO-C101/pembrolizumab. Medications started after the patient’s last dose of 
SO-C101/pembrolizumab (whichever is administered last) will be labeled as post-treatment 
medications. A listing of prior, concomitant, and post-treatment medications will be 
included in the Clinical Study Report. 
9.13.6 Primary endpoints analyses in dose escalation parts 
The safety/tolerability profile of SO-C101 will be assessed. The incidence of 
treatment-emergent AEs and SAEs together with all other safety parameters will be 
summarized, by dose cohort. The incidence of DLTs (on DLT-evaluable patients, see 
section 9.7) by dose level will be tabulated. The MTD will be determined per Protocol 
definition. The RP2D will be selected as described in section 9.7.2. 
9.13.7 Efficacy analyses 
Analysis of efficacy endpoints will be descriptive as described above in section 9.13. 
Efficacy population will be used.  
Part D and Part D1 are planned to include a maximum of 60 patients (in total; up to 20 
patients treated for at least one cycle in each indication). Overview of data per indication 
will be part of efficacy evaluation.  
9.13.8 Pharmacokinetic analyses 
9.13.8.1 
SO-C101 PK evaluation 
Evaluation of PK will be performed on the PK/PD population. Serum concentrations of 
SO-C101 will be tabulated and summarized by dose level, day, and time. The following PK 
parameters will be calculated: Cmax, time to reach maximum concentration (Tmax) following 
SO-C101 administration, AUC, and if data permit, elimination half-life, total body 
clearance, volume of distribution, and accumulation ratio. 

 
 
 
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9.13.8.2 
Pembrolizumab PK evaluation 
Evaluation of PK will be performed on the PK/PD population. Serum concentrations of 
pembrolizumab will be normalized to dose 1 mg/kg and then analyzed as follows: 
Dose-normalized concentrations will be tabulated and summarized by dose level, day, and 
time. The following PK parameters will be calculated based on dose-normalized 
concentrations: Cmax, Tmax, AUC, and if data permit, elimination half-life, total body 
clearance, volume of distribution, and accumulation ratio. 
Original (measured) and dose-normalized concentrations will be listed. 
9.13.9 Pharmacodynamic and other biomarker analyses 
Evaluation of PD will be performed on the PK/PD population. PD and other biomarker 
analyses may be performed and reported separately. Details of these analyses will be 
described in a separate analysis plan. 
9.13.10 Safety analyses 
Evaluation of safety will be performed on the Safety population. Safety data to be evaluated 
include all AEs, clinical laboratory results, vital signs, ECGs, and the results of physical 
examinations.  
9.13.10.1 Extent of exposure 
The number of cycles/days on treatment, quantity of SO-C101 and pembrolizumab 
administered, and the number of patients requiring dose reductions, treatment interruption, 
and treatment discontinuation due to AEs will be summarized. 
9.13.10.2 Adverse events 
The AE verbatim descriptions (event terms as reported by the investigator from the eCRF) 
will be classified into standardized medical terminology using the Medical Dictionary for 
Regulatory Activities (MedDRA). AEs in the eCRF will be coded to the MedDRA (version 
current at the time of database lock) lower level term closest to the verbatim term. AEs will 
be presented by MedDRA preferred term nested within primary system organ class (SOC). 
A treatment-emergent AE is defined as an AE that: 
• emerges during treatment, having been absent at pretreatment (screening), or 
• reemerges during treatment, having been present at pretreatment (screening), or 
• worsens in severity during treatment relative to the pretreatment state. 
Only those AEs that were treatment emergent will be included in summary tables. All AEs, 
treatment emergent or otherwise, will be presented in patient data listings. 
The treatment-emergent AEs will be summarized by treatment cohort and their incidence 
will be reported as the number (percentage) of patients with treatment-emergent AEs by 
SOC and preferred term. A patient will be counted only once within a SOC and preferred 
term, even if the patient experienced more than one treatment-emergent AE within a specific 
SOC and preferred term. The number (percentage) of patients with treatment-emergent AEs 
will also be summarized by maximum severity (NCI CTCAE grades) and by relationship to 
SO-C101 and, in Part B and Part B1, to pembrolizumab (Suspected [related] and Not 
suspected [not related]), respectively. 

 
 
 
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9.13.10.3 Vital signs 
Descriptive statistics for vital signs parameters and changes from baseline will be presented 
by day and time after dosing and treatment cohort. 
9.13.11 Determination of sample size 
9.13.11.1 Part A (SO-C101 dosing schedule 1, monotherapy, dose escalation) 
The traditional 3+3 design dose escalation will be applied until the MTD is identified. 
Therefore, 3 to 6 DLT-evaluable patients per dose level will be included in a cohort. The 
estimated number of patients is 27-54.  
9.13.11.2 Part A1 (SO-C101 dosing schedule 2, monotherapy, dose escalation) 
The traditional 3+3 design dose escalation will be applied until the MTD is identified. 
Therefore, 3 to 6 DLT-evaluable patients per dose level will be included in a cohort. The 
estimated number of patients is 6-15. 
9.13.11.3 Part B (SO-C101 dosing schedule 1, combined with pembrolizumab, dose 
escalation) 
The traditional 3+3 design dose escalation will be applied until the MTD is identified. 
Therefore, 3 to 6 DLT-evaluable patients per dose level will be included in a cohort. The 
estimated number of patients is 21-42. 
9.13.11.4 Part B1 (SO-C101 dosing schedule 2, combined with pembrolizumab, dose 
escalation) 
The traditional 3+3 design dose escalation will be applied until the MTD is identified. 
Therefore, 3 to 6 DLT-evaluable patients per dose level will be included in a cohort. The 
estimated number of patients is 6-15. 
9.13.11.5 Part D (SO-C101 dosing schedule 1, monotherapy, dose expansion at the 
RP2D identified in Part A) and Part D1 (SO-C101 dosing schedule 2, 
monotherapy, dose expansion at the RP2D identified in Part A1) 
The number of patients in Part D together with or without Part D1 to be treated for at least 
one cycle is set to a maximum of 20 per indication (60 in total). This number of patients is 
deemed to be appropriate to provide further safety, PK, PD, and efficacy data per indication 
at the RP2D dose level identified in Part A (SO-C101, dosing schedule 1, monotherapy) and 
the RP2D dose level identified in Part A1 (SO-C101, dosing schedule 2, monotherapy). In 
case biomarker data in Part A1 suggest a more competitive efficacy as compared to once 
daily dosing, a switch to twice daily dosing (Part D1) will be made during the course of the 
study without affecting the overall number of patients enrolled. 
9.13.12 Interim analysis 
No interim analyses are planned. Data are monitored on an ongoing basis. 
9.13.13 Other statistical/analytical issues 
Not applicable 
 

 
 
 
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Cheng G, Yu A, Malek TR. T-cell tolerance and the multi-functional role of IL-2R 
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Katsanis E, Xu Z, Panoskaltsis-Mortari A, Weisdorf DJ, Widmer MB, Blazar BR. 
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Cheever MA. Twelve immunotherapy drugs that could cure cancers. Immunological 
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Huntington ND, Alves NL, Legrand N, Lim A, Strick-Marchand H, Mention J-J, 
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H, Di Santo JP. IL-15 transpresentation promotes both human T-cell reconstitution 
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Huntington ND, Legrand N, Alves NL, Jaron B, Weijer K, Plet A, Corcuff E, Mortier 
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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 
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Mortier E, Quéméner A, Vusio P, Lorenzen I, Boublik Y, Grötzinger J, Plet A, 
Jacques Y. Soluble interleukin-15 receptor alpha (IL-15R alpha)-sushi as a selective 
and potent agonist of IL-15 action through IL-15R beta/gamma. Hyperagonist IL-15 
x IL-15R alpha fusion proteins. The Journal of Biological Chemistry. 
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Bouchaud G, Garrigue-Antar L, Solé V, Quéméner A, Boublik Y, Mortier E, 
Perdreau H, Jacques Y, Plet A. The exon-3-encoded domain of IL-15ralpha 
contributes to IL-15 high-affinity binding and is crucial for the IL-15 antagonistic 
effect of soluble IL-15Ralpha. Journal of Molecular Biology. 2008;382(1):1-12. 
19. 
Desbois M, Le Vu P, Coutzac C, Marcheteau E, Béal C, Terme M, Gey A, Morisseau 
S, Teppaz G, Boselli L, Jacques Y, Béchard D, Tartour E, Cassard L, Chaput N. IL-
15 trans-signaling with the superagonist RLI promotes effector/memory CD8+ T cell 
responses and enhances antitumor activity of PD-1 antagonists. Journal of 
Immunology (Baltimore, Md: 1950). 2016;197(1):168-178. 
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Conlon KC, Lugli E, Welles HC, Rosenberg SA, Fojo AT, Morris JC, Fleisher TA, 
Dubois SP, Perera LP, Stewart DM, Goldman CK, Bryant BR, Decker JM, Chen J, 
Worthy TYA, Figg WD, Peer CJ, Sneller MC, Lane HC, Yovandich JL, Creekmore 
SP, Roederer M, Waldmann TA. Redistribution, hyperproliferation, activation of 
natural killer cells and CD8 T cells, and cytokine production during first-in-human 
clinical trial of recombinant human interleukin-15 in patients with cancer. Journal 
of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 
2015;33(1):74-82. 
21. 
Wrangle JM, Velcheti V, Patel MR, Garrett-Mayer E, Hill EG, Ravenel JG, Miller 
JS, Farhad M, Anderton K, Lindsey K, Taffaro-Neskey M, Sherman C, Suriano S, 
Swiderska-Syn M, Sion A, Harris J, Edwards AR, Rytlewski JA, Sanders CM, 
Yusko EC, Robinson MD, Krieg C, Redmond WL, Egan JO, Rhode PR, Jeng EK, 
Rock AD, Wong HC, Rubinstein MP. ALT-803, an IL-15 superagonist, in 
combination with nivolumab in patients with metastatic non-small cell lung cancer: 
a non-randomised, open-label, phase 1b trial. The Lancet Oncology. 2018;19(5):694-
704. 
22. 
Goutelle S, Maurin M, Rougier F, Barbaut X, Bourguignon L, Ducher M, Maire P. 
The Hill equation: a review of its capabilities in pharmacological modelling. 
Fundamental & Clinical Pharmacology. 2008;22(6):633-648. 

 
 
 
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23. 
Saber H, Gudi R, Manning M, Wearne E, Leighton JK. An FDA oncology analysis 
of immune activating products and first-in-human dose selection. Regulatory 
toxicology and pharmacology: RTP. 2016;81:448-456. 
24. 
Saber H, Del Valle P, Ricks TK, Leighton JK. An FDA oncology analysis of CD3 
bispecific constructs and first-in-human dose selection. Regulatory toxicology and 
pharmacology: RTP. 2017;90:144-152. 
25. 
Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired 
resistance to cancer immunotherapy. Cell. 2017;168(4):707-723. 
26. 
Bernatchez C, Haymaker C, Tannir NM, Kluger H, Tetzlaff M, Bentebibel SE, 
Jackson N, Gergel I, Tagliaferri M, Zalevsky J, Hoch U, Imperiale M, Aung S, Hwu 
P, Sznol M, Hurwitz M, Diab A. A CD122-biased agonist increases CD8+ T cells 
and natural killer cells in the tumor microenvironment; making cold tumors hot with 
NKTR-214. 
2018; 
http://www.nektar.com/application/files/7714/7887/7212/2016_SITC_NKTR-214-
clinical_poster.pdf. Accessed December 20, 2019. 
27. 
Bates SE, Berry DA, Balasubramaniam S, Bailey S, LoRusso PM, Rubin EH. 
Advancing clinical trials to streamline drug development. Clinical Cancer Research: 
An Official Journal of the American Association for Cancer Research. 
2015;21(20):4527-4535. 
28. 
Emens LA, Butterfield LH, Hodi FS, Marincola FM, Kaufman HL. Cancer 
immunotherapy trials: leading a paradigm shift in drug development. Journal for 
Immunotherapy of Cancer. 2016;4:42. 
29. 
Le Tourneau C, Lee JJ, Siu LL. Dose escalation methods in phase I cancer clinical 
trials. J Natl Cancer Inst. 2009;101(10):708-720. 
30. 
Hirsch L, Zitvogel L, Eggermont A, Marabelle A. PD-Loma: a cancer entity with a 
shared sensitivity to the PD-1/PD-L1 pathway blockade. British Journal of Cancer. 
2019;120(1):3-5. 
31. 
Ott PA, Hodi FS, Kaufman HL, Wigginton JM, Wolchok JD. Combination 
immunotherapy: a road map. Journal for Immunotherapy of Cancer. 2017;5. 
32. 
Davies M, Duffield EA. Safety of checkpoint inhibitors for cancer treatment: 
strategies for patient monitoring and management of immune-mediated adverse 
events. ImmunoTargets and Therapy. 2017;6:51-71. 
33. 
Raines EW, Ferri N. Thematic review series: The immune system and atherogenesis. 
Cytokines affecting endothelial and smooth muscle cells in vascular disease. Journal 
of Lipid Research. 2005;46(6):1081-1092. 
34. 
Wuttge DM, Eriksson P, Sirsjö A, Hansson GK, Stemme S. Expression of 
interleukin-15 in mouse and human atherosclerotic lesions. The American Journal 
of Pathology. 2001;159(2):417-423. 
35. 
Margolin K, Morishima C, Velcheti V, Miller JS, Lee SM, Silk AW, Holtan SG, 
Lacroix AM, Fling SP, Kaiser JC, Egan JO, Jones M, Rhode PR, Rock AD, Cheever 
MA, Wong HC, Ernstoff MS. Phase I trial of ALT-803, a novel recombinant IL15 
complex, in patients with advanced solid tumors. Clinical cancer research : an 
official 
journal 
of 
the 
American 
Association 
for 
Cancer 
Research. 
2018;24(22):5552-5561. 

 
 
 
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36. 
Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, Lin NU, 
Litière S, Dancey J, Chen A, Hodi FS, Therasse P, Hoekstra OS, Shankar LK, 
Wolchok JD, Ballinger M, Caramella C, de Vries EGE, group Rw. iRECIST: 
guidelines for response criteria for use in trials testing immunotherapeutics. The 
Lancet Oncology. 2017;18(3):e143-e152. 
37. 
Keytruda 
SmPC 
EU. 
 
https://www.ema.europa.eu/en/documents/product-
information/keytruda-epar-product-information_en.pdf. Accessed May 13, 2021. 
38. 
Keytruda 
US 
Prescribing 
Information.  
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125514s097lbl.pdf. 
Accessed May 13, 2021. 
39. 
U.S. Food and Drug Administration. E14 clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs: Guidance 
for 
industry. 
2018; 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio
n/Guidances/ucm073153.pdf. Accessed October 22, 2018. 
40. 
Proleukin SmPC.  https://www.medicines.org.uk/emc/product/291/smpc. Accessed 
May 11, 2021. 
41. 
Proleukin 
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Prescribing 
Information.  
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Accessed May 11, 2021. 
42. 
Dutcher JP, Schwartzentruber DJ, Kaufman HL, Agarwala SS, Tarhini AA, Lowder 
JN, Atkins MB. High dose interleukin-2 (Aldesleukin) - expert consensus on best 
management practices-2014. Journal for Immunotherapy of Cancer. 2014;2(1):26. 
43. 
Meid AD, Bighelli I, Machler S, Mikus G, Carra G, Castellazzi M, Lucii C, 
Martinotti G, Nose M, Ostuzzi G, Barbui C, Haefeli WE. Combinations of QTc-
prolonging drugs: towards disentangling pharmacokinetic and pharmacodynamic 
effects 
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additive 
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Therapeutic 
Advances 
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Psychopharmacology. 2017;7(12):251-264. 
44. 
Du Bois D, Du Bois EF. A formula to estimate the approximate surface area if height 
and weight be known. 1916. Nutrition (Burbank, Los Angeles County, Calif). 
1989;5(5):303-311; discussion 312-313. 
45. 
Yu P, Steel JC, Zhang M, Morris JC, Waldmann TA. Simultaneous blockade of 
multiple immune system inhibitory checkpoints enhances antitumor activity 
mediated by interleukin-15 in a murine metastatic colon carcinoma model. Clinical 
Cancer Research: An Official Journal of the American Association for Cancer 
Research. 2010;16(24):6019-6028. 
46. 
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. 
2016; 
https://search.coe.int/cm/Pages/result_details.aspx?ObjectId=090000168064e8ff. 
Accessed December 20, 2019. 
 
 

 
 
 
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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES) 
11.1 Changes to the Protocol 
Any change to the Protocol requires a written Protocol amendment or administrative change 
that must be approved by the sponsor before implementation. Amendments specifically 
affecting the safety of patients, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval 
by the applicable IRBs/ECs. These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all patients included in the study. If the investigator determines that an 
immediate change to or deviation from the Protocol is necessary for safety reasons to 
eliminate an immediate hazard to the patients, the sponsor’s medical monitor (or appropriate 
study team member) and the IRB/EC for the site must be notified immediately. The sponsor 
must notify the health or regulatory authority as required per local regulations. 
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/EC, but the CA and IRB/EC should 
be kept informed of such changes as required by local regulations. In these cases, the sponsor 
may be required to send a letter to the IRB/EC and the CAs detailing such changes. 
11.2 Adherence to the Protocol 
The investigator will conduct the study in strict accordance with this Protocol. 
11.3 Monitoring procedures 
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits. Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan. The investigator will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements. The eCRFs and patients’ 
corresponding original medical records (source documents) are to be fully available for 
review by the sponsor’s representatives at regular intervals. These reviews verify adherence 
to study Protocol and data accuracy in accordance with local regulations. All records at the 
site are subject to inspection by the local auditing agency and IRB/EC review. 
The investigator has to maintain source documents for each patient in the study, consisting 
of visit records (clinic, office, and hospital), laboratory data, ECG, echocardiography, 
images and the results of any other tests or assessments. The investigator must also keep 
one original signed and dated ICF (a signed and dated copy is given to the patient). 
11.4 Recording of data 
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. 

 
 
 
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11.5 Identification of source data 
All data to be recorded on the eCRF must reflect the corresponding source documents. 
11.6 Retention of records 
Notwithstanding the circumstances of completion or termination of the study, the 
investigator is responsible for retaining all study documents, including but not limited to the 
Protocol, the IB, and regulatory agency registration documents (e.g., Form FDA 1572, ICFs, 
and IRB/EC correspondence). The site should plan to retain study documents, as directed 
by the sponsor, for at least 2 years after the last approval of a marketing application in an 
ICH region and until there are no pending or contemplated marketing applications in an ICH 
region or at least 3 years have elapsed since the formal discontinuation of clinical 
development of the IMP. 
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. 
11.7 Confidentiality of personal data 
In order to ensure that personal information of each patient is kept confidential and 
protected, names and any other information that allows direct identification of a patient will 
not be in the eCRFs or included in any records or samples provided to the sponsor or 
sponsor’s authorized representatives; such information will be pseudonymised, i.e., all such 
information will be replaced by a specific code (patient number) assigned by a study doctor 
and all patients will be identified in 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 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 SO-C101 as monotherapy and in 
combination with pembrolizumab, 
• comparing and pooling study results, 
• establishing whether SO-C101 as monotherapy and in combination with pembrolizumab 
meets the appropriate standards of safety set by the authorities, 
• establishing whether SO-C101 as monotherapy and in combination with pembrolizumab 
is effective, 
• supporting the clinical development of SO-C101 as monotherapy and in combination 
with pembrolizumab, 
• supporting the licensing application for regulatory approval of SO-C101 as monotherapy 
and in combination with pembrolizumab anywhere in the world, 

 
 
 
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• supporting the marketing, distribution, sale and use of SO-C101 as monotherapy and in 
combination with pembrolizumab anywhere in the world, 
• complying with specific regulations governing clinical trials. 
Participation of patients in this study is voluntary and they may withdraw from the study at 
any time by informing the investigator. Their participation in the study will then end and the 
study personnel will stop collecting personal information from the patients, but the sponsor 
will need to retain and use the pseudonymised 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 SO-C101 as monotherapy and in 
combination with pembrolizumab. It may be necessary to retain certain aspects of 
pseudonymised (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 
pseudonymised 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), the 
United States, and other countries that are outside of the EEA. Some non-EEA countries 
may not offer the same level of privacy protection. However, the sponsor will keep personal 
information it receives as confidential as possible within the limits of the law. The sponsor 
will implement appropriate contractual measures, including the standard data protection 
contractual clauses, to ensure that the relevant recipients outside the EEA provide an 
adequate level of protection to personal information as set out in this form and as required 
by applicable law. 
The sponsor, either alone or together with other researchers, may publish or present the 
results of the study; however, personal information will not be disclosed in any publication 
or presentation. See also section 11.10. 
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 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 

 
 
 
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and personal data processed, namely the Data Protection Regulation and Incident 
Management Regulation. The organizational and technical measures introduced by the 
sponsor in relation to a protection of personal information of the patients involve the above 
mentioned pseudonymisation 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 within statutory term as 
applicable. 
11.8 Auditing procedures and inspection 
In addition to the routine monitoring procedures, audits of clinical research activities will 
be conducted in accordance with the sponsor’s SOPs to evaluate compliance with the 
principles of ICH GCP and all applicable local regulations. If a government regulatory 
authority requests an inspection during the study or after its completion, the investigator 
must inform the sponsor immediately. 
11.9 Handling of IMPs 
All IMPs will be supplied to the study sites by the sponsor. IMP supplies must be kept in an 
appropriate secure area (e.g., locked cabinet) and stored according to the conditions 
specified on the IMP labels. The investigator (or a designated pharmacist) must maintain an 
accurate record of the shipment and dispensing of the IMP in an IMP accountability ledger, 
a copy of which must be given to the sponsor at the end of the study. An accurate record of 
the date and amount of the IMP dispensed to each patient must be available for inspection 
at any time. The CRA will visit the site and review these documents along with all other 
study conduct documents at appropriate intervals once IMPs have been received by the site. 
All IMP supplies are to be used only for this study and not for any other purpose. The 
investigator (or site personnel) must not destroy any IMP labels or any partly used or unused 
IMP supply before approval to do so by the sponsor. At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all 
used and unused IMP containers, IMP labels, and a copy of the completed IMP disposition 
form to the sponsor’s CRA (or designated contractor) or, when approval is given by the 
sponsor, will destroy supplies and containers at the site. See also section 9.10.6. 
11.10 Publication of results 
All manuscripts, abstracts, or other modes of presentation arising from the results of this 
study must be reviewed and approved in writing by the sponsor in advance of submission 
pursuant to the terms and conditions set forth in the executed Clinical Trial Agreement 
between the sponsor/CRO and the institution/investigator. The review is aimed at protecting 
the sponsor’s proprietary information existing either at the date of the commencement of the 
study or generated during the study. 
The detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to the study shall be set out in the agreement 
between each investigator and the sponsor or CRO, as appropriate. 

 
 
 
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11.11 Disclosure and confidentiality of information about the study 
The contents of this Protocol and any amendments and results obtained during the study 
should be kept confidential by the investigator, the investigator’s staff, and the IRB/EC and 
will not be disclosed in whole or in part to others, or used for any purpose other than 
reviewing or performing the study, without the written consent of the sponsor. No data 
collected as part of this study will be used in any written work, including publications, 
without the written consent of the sponsor. These obligations of confidentiality and non-use 
shall in no way diminish such obligations as set forth in either the Confidentiality Agreement 
or 
Clinical 
Trial 
Agreement 
executed 
between 
the 
sponsor/CRO 
and 
the 
institution/investigator. 
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical 
Trial Agreement executed between the institution/investigator and the sponsor/CRO. 
11.12 Patient insurance and indemnity 
The sponsor will provide insurance for any patients participating in the study in accordance 
with all applicable laws and regulations. 
11.13 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”.46 
The repository will have independent monitoring that will guarantee protection of the data 
and the patients’ interests (see also section 11.7). The samples will not be transferred or 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. 
11.14 Document history 
Version 
Date 
10.0 
29-Jul-2021 (effective date 01-Nov-2021) 
9.0 
16-Jul-2021 
8.0 
11-Feb-2021 
7.0 
25-Nov-2020 
6.1 
13-May-2020 
6.0 
25-Mar-2020 (version 6.0 was never implemented) 
5.0 
05-Nov-2019 
4.0 
10-Apr-2019 
3.0 
20-Mar-2019 
2.0 
17-Jan-2019 
1.0 
12-Nov-2018 

 
 
 
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11.15 Protocol amendment (version 10.0) summary of changes versus version 
9.0 
Change 
number 
Description of change Rationale for change 
Section affected in Protocol 
version 10.0 
1 
Change of sponsorship  Change of sponsorship 
(effective date 01-Nov-2021) 
1 TITLE PAGE, 
SIGNATURES / PROTOCOL 
APPROVAL AND RELEASE, 
INVESTIGATOR’S 
DECLARATION AND 
SIGNATURE, 6 
INVESTIGATORS AND 
SPONSOR, 9.12.1 Data 
collection, 11.7 Confidentiality 
of personal data, 11.8 Auditing 
procedures and inspection 

 
 
 
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12 APPENDICES 
List of appendices 
12.1 New York Heart Association Classification ............................................................. 153 
12.2 Creatinine clearance estimation ................................................................................ 154 
12.3 Hy’s law .................................................................................................................... 155 
12.4 Assessment of performance status ............................................................................ 156 
12.5 Clinical management recommendations for HD IL-2 therapy42 ............................... 157 
12.6 Definition of MTD and RP2D as used in the study Protocol.................................... 161 
12.7 Protocol amendment history ..................................................................................... 162 
12.7.1 
Version 9.0 (16-Jul-2021): Protocol changes implemented ................... 162 
12.7.2 
Version 8.0 (11-Feb-2021): Protocol changes implemented .................. 165 
12.7.3 
Version 7.0 (25-Nov-2020): Protocol changes implemented ................. 166 
12.7.4 
Version 6.1 (13-May-2020): Protocol changes implemented (note: version 
6.0 was never implemented) ................................................................. 169 
12.7.5 
Version 5.0 (05-Nov-2019): Protocol changes implemented ................. 171 
12.7.6 
Version 4.0 (10-Apr-2019): Protocol changes implemented ................. 173 
12.7.7 
Version 3.0 (20-Mar-2019): Protocol changes implemented ................. 175 
12.7.8 
Version 2.0 (17-Jan-2019) ...................................................................... 176 
12.7.8.1 Protocol changes implemented further to the initial EU VHP ....... 176 
12.7.8.2 Additional “non-VHP GNA” changes ........................................... 187 
 
 
 

 
 
 
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12.1 New York Heart Association Classification 
Class I 
No symptoms and no limitation in ordinary physical activity, e.g., 
shortness of breath when walking, climbing stairs. 
Class II 
Mild symptoms (mild shortness of breath and/or angina) and slight 
limitation during ordinary activity. 
Class III 
Marked limitation in activity due to symptoms, even during less-than-
ordinary activity, e.g., walking short distances (20-100 m). Comfortable 
only at rest. 
Class IV 
Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound patients. 
Class V 
No class listed above or unable to determine. 
 
 

 
 
 
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12.2 Creatinine clearance estimation 
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. 
 
 

 
 
 
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12.3 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 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. 
 
 

 
 
 
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12.4 Assessment of performance status 
ECOG performance status should be documented according to Table 12.1. 
Table 12.1: ECOG performance status scale 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; 
up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled, cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
 
 

 
 
 
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12.6 Definition of MTD and RP2D as used in the study Protocol 
Since different definitions of MTD and RP2D are used in the United States compared to 
Europe and Japan, the sponsor is providing clarification on the definitions used in the study 
Protocol. 
In section 9.13.1 of the Protocol, MTD is defined “as the dose level associated with ≥33% 
of DLT-evaluable patients experiencing a DLT. If the MTD is reached, the RP2D will be 
conventionally defined as the dose level just below this non-tolerated dose level. If the MTD 
is not reached, the RP2D will be selected based on integrated evaluation of safety, 
tolerability, clinical benefit, PK and PD data, for all dose levels tested.’’ The sponsor is 
using the MTD/RP2D definition for Europe and Japan. 
According to the study Protocol, “The dose escalation plan follows the traditional 
3+3 design as described by Le Tourneau et al.” Le Tourneau et al. define MTD and RP2D 
as follows: 
• Phase I trials conducted in the United States: the highest dose level at which <33% of 
patients experience DLT. The MTD is the highest dose with ≤1 of 6 (< 33%) patients 
with DLT and is the highest tolerated dose. 
• Phase I trials conducted in Europe and Japan: the lowest dose level at which ≥33% of 
patients experience DLT (a misnomer in the sense that the MTD is actually not a tolerable 
dose). The dose escalation continues until at least 2 patients in a cohort of 3 to 6 patients 
experience DLTs (i.e., ≥33% of patients with a DLT at that dose level). 
• In phase I trials with toxicity endpoint conducted in the United States RP2D is defined 
as the MTD. 
• In phase I trials with toxicity endpoint conducted in Europe and Japan RP2D is one dose 
level below MTD. 

 
 
 
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12.7 Protocol amendment history 
The Protocol amendment (version 10.0) summary of changes versus version 9.0 for the current amendment is in section 11.15. 
12.7.1 Version 9.0 (16-Jul-2021): Protocol changes implemented 
Change 
number 
Description of change 
Rationale for change 
Section affected in Protocol version 9.0 
1 
Adjustment of the schedule of procedures/assessments to 
clarify that patients will visit the site on day 15 as follows: 
Part A: In cycles 1, 2, 3 
Part A1: In cycle 1 
Part B: In cycles 1, 2, 3 
Part B1: In cycle 1 
Part D: In cycle 1 
Part D1: In cycle 1 
To clarify that patients in study SC103 will visit the trial sites on 
day 15 only when blood sample collection is scheduled. They do 
not need to visit the site on day 15 only for AEs and concomitant 
medication/non-drug therapies recording. 
9.11.7 Schedule of 
procedures/assessments 
2 
Definition of the end of study parts  
To define that each study part will end when the last patient in 
this study part completes the last visit, including follow-up calls 
2 CLINICAL PROTOCOL SYNOPSIS, 
9.7.9 End of the study 
3 
Deletion of Part C 
Part C will be replaced by a separate trial 
2 CLINICAL PROTOCOL SYNOPSIS, 
7.9 Study design rationale, 8 STUDY 
DESIGN AND OBJECTIVES, 9 
INVESTIGATIONAL PLAN 
4 
Shortening of survival follow-up to 6 months after the EoT 
visit 
No need to observe patients for longer than 6 months after the 
EoT visit 
2 CLINICAL PROTOCOL SYNOPSIS, 
8.2 Objectives, 9.7 Dose escalation plan 
and study periods, 9.11.5.1.2 Safety 
monitoring periods, 9.11.6.4 Assessment 
of laboratory parameters, 9.11.7 Schedule 
of procedures/assessments, 9.13.1 Study 
endpoints 
5 
Cancellation of assessments (physical examination, body 
weight and surface area, vital signs, and ECOG) during 
efficacy follow-up 
Following the decision that 90 days of safety follow-up is 
enough, collection of physical examination, body weight and 
surface area, vital signs, and ECOG at efficacy follow-up visits 
will be cancelled; collection of physical examination, body 
9.11.7 Schedule of 
procedures/assessments 

 
 
 
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Description of change 
Rationale for change 
Section affected in Protocol version 9.0 
weight and surface area, and vital signs will be done during 
safety follow-up 
6 
Replacement of safety, efficacy, and survival follow-up 
periods with one follow-up period 
The three different follow-up periods were confusing to the study 
sites 
2 CLINICAL PROTOCOL SYNOPSIS, 
9.7.7 Study periods in Part A, Part A1, 
Part B, and Part B1, 9.7.8 Study periods in 
Part D and Part D1, 9.11.7 Schedule of 
procedures/assessments 
7 
Clarification until when tumor assessments are to be done 
To clarify that “until disease progression ….” in fact means 
“until iCPD or start of a new anti-cancer treatment” 
2 CLINICAL PROTOCOL SYNOPSIS, 
9.7.7 Study periods in Part A, Part A1, 
Part B, and Part B1, 9.7.8 Study periods in 
Part D and Part D1 
8 
Clarification that tumor assessments are not to be done after 
iCPD 
Not needed for the evaluation of study objectives 
9.11.7 Schedule of 
procedures/assessments, 9.11.11 Guidance 
for continuation of study treatment 
beyond iRECIST-defined disease 
progression 
9 
Update of information on the chemical structure of SO-C101  
New experimental information on the chemical structure of SO-
C101  
7.2.2 SO-C101 mechanism of action, 
9.9.3.1 Name, structural formula 
10 
Clarification that serum (immunogenicity) testing is to be 
stopped after cycle 12 (testing at the EoT visit to be done) 
Serum (immunogenicity) testing not needed beyond cycle 12 
9.11.7 Schedule of 
procedures/assessments 
11 
Change of PBMC immunomonitoring and PBMC genetic 
testing time points in Part A1, Part B1, Part D, and Part D1 
To be able to compare the two dosing schedules 
9.11.7 Schedule of 
procedures/assessments 
12 
Adjustment of the time window for serum (cytokine) sampling 
8 hours post dose in Part A1, Part D, and Part D1 from -30 
min to ±30 min 
To harmonize time windows for all serum (cytokine) sampling 
time points in Part A1, Part D, and Part D1 
9.11.7 Schedule of 
procedures/assessments 
13 
Adjustment of the time window for PK sampling 4 and 8 
hours post dose in Part A1, Part B1, Part D, and Part D1 from 
+30 min and -15 min, respectively, to ±15 min 
To harmonize time windows for all PK sampling time points in 
Part A1, Part B1, Part D, and Part D1 
9.11.7 Schedule of 
procedures/assessments 

 
 
 
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Change 
number 
Description of change 
Rationale for change 
Section affected in Protocol version 9.0 
14 
Clarification that for crossover patients, the last tumor 
assessment in Part A or Part A1 serves as baseline in Part B or 
Part B1 
To clarify baseline for tumor assessments after crossover from 
Part A or Part A1 to Part B or Part B1 
9.11.2 Tumor assessments 
15 
Wording changes in section 5.2 Ethical conduct of the study 
To improve readability and remove redundancies 
5.2 Ethical conduct of the study 
16 
Wording changes in statistical parts 
To improve readability and remove redundancies 
2 CLINICAL PROTOCOL SYNOPSIS, 
9.13 Statistical methods 
17 
Adjustment of the time window for the start of treatment (day 
1) in Part A1, Part B1, Part D, and Part D1 from +1 day to ±1 
day  
To align the time window for day 1 in Part A1, Part B1, Part D, 
and Part D1 with the time window for day 1 in Part A and Part B 
2 CLINICAL PROTOCOL SYNOPSIS, 
9.2 Part A1 (SO-C101 dosing schedule 2, 
monotherapy, dose escalation), 9.4 Part 
B1 (SO-C101 dosing schedule 2, 
combined with pembrolizumab, dose 
escalation), 9.5 Part D (SO-C101 dosing 
schedule 1, monotherapy, dose expansion 
at the RP2D identified in Part A), 9.6 Part 
D1 (SO-C101 dosing schedule 2, 
monotherapy, dose expansion at the RP2D 
identified in Part A1), 9.9.1.1 SO-C101 
(all study parts), 9.11.7 Schedule of 
procedures/ assessments 
18 
Adjustment of the sample size of Part D and Part D1 from a 
total of 20 patients per part to a total of up to 60 patients in 
total (Part D and Part D1) 
To be able to collect more safety data on the RP2D of SO-C101 
monotherapy and better characterize signals of efficacy 
2 CLINICAL PROTOCOL SYNOPSIS, 
7.9 Study design rationale, 8.1 Study 
design, 9.7.5 Patient recruitment 
management, 9.11.7 Schedule of 
procedures/ assessments, 9.13.7 Efficacy 
analyses, 9.13.11 Determination of sample 
size  
19 
Addition of information on the RP2D identified in Part A 
To update the information on the study status 
2 CLINICAL PROTOCOL SYNOPSIS, 
7.5 Justification for the starting dose and 
dose escalation steps in Part A, 7.6 
Justification for the starting dose in Part 
A1, 9.1 Part A (SO-C101 dosing schedule 

 
 
 
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Description of change 
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Section affected in Protocol version 9.0 
1, monotherapy, dose escalation), 9.3 Part 
B (SO-C101 dosing schedule 1, combined 
with pembrolizumab, dose escalation), 
12.7 Number of patients with at least one 
grade 3-4 TEAE suspected to be related to 
SO-C101 as per investigators’ judgement 
reported in study SC103 up to dose level 9 
in Part A and dose level 1 in Part B 
20 
Deletion of Senior Medical Director and change of Statistician Change of personnel 
SIGNATURES / PROTOCOL 
APPROVAL AND RELEASE 
21 
Minor wording changes and punctuation adjustments 
To improve clarity and readability 
Throughout the document 
12.7.2 Version 8.0 (11-Feb-2021): Protocol changes implemented 
Change 
number 
Description of change 
Rationale for change 
Section affected in Protocol version 8.0 
1 
Definition of stopping rules for expansion parts (Part C, Part 
D, Part D1) 
To clearly define stopping rules also for patients in Part C, Part 
D, and Part D1 
2 CLINICAL PROTOCOL SYNOPSIS; 
7.9 Study design rationale; 9.6 Part D 
(SO-C101 dosing schedule 1, 
monotherapy, dose expansion at the RP2D 
identified in Part A); 9.7 Part D1 (SO-
C101 dosing schedule 2, monotherapy, 
dose expansion at the RP2D identified in 
Part A1); 9.8.12 Stopping rules for all 
parts; 9.12.10 Treatment discontinuation 

 
 
 
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12.7.3 Version 7.0 (25-Nov-2020): Protocol changes implemented 
Change 
number 
Description of change 
Rationale for change 
Section affected in Protocol version 7.0 
1 
Addition of Part A1 and Part B1 to investigate an additional 
dosing schedule for SO-C101: administration twice a day as 2 
divided doses (instead of as 1 daily dose) with the second 
dose on each treatment day administered 8 hours (±15 min) 
after the first dose 
Based on animal PK/PD study results, the once daily dose of SO-
C101 will be administered as two divided doses and investigated 
in new study parts, Part A1and Part B1. Nonclinical studies 
demonstrated that when the total daily dose previously given as a 
once daily dose is administered as two equally divided doses 
twice daily (50% each of the once daily dose), this led to stronger 
PD activity, namely the activation of CD8+ T cells and NK cells 
as observed by their increase in absolute cell counts in 
cynomolgus monkeys (studies SO-C101-1186E, SO-C101-
1141E). This increase in immune stimulation seems to contribute 
to a reduced tumor cell growth in tumor-bearing mice. PK 
evaluations suggest that the stronger PD effect is mediated by the 
longer exposure to SO-C101 concentrations that activate CD8+ T 
cells and NK cells.  
2 CLINICAL PROTOCOL SYNOPSIS, 
7.4 Justification for dose scheduling, 
7.6 Justification for the starting dose in 
Part A1, 7.8 Justification for the starting 
dose in Part B1, 7.9 Study design 
rationale, 8.1 Study design, 
8.2 Objectives, 9.1 Part A (SO-C101 
dosing schedule 1, monotherapy, dose 
escalation), 9.2 Part A1 (SO-C101 dosing 
schedule 2, monotherapy, dose 
escalation), 9.3 Part B (SO-C101 dosing 
schedule 1, combined with 
pembrolizumab, dose escalation), 9.4 Part 
B1 (SO-C101 combined with 
pembrolizumab, dosing schedule 2, dose 
escalation), 9.8 Dose escalation plan and 
study periods, 9.9 Selection of study 
population, 9.10 Treatments, 9.11 
Supportive care and concomitant 
medication, 9.12 Study assessments, 
9.14 Statistical methods, 12.7 Number of 
patients with at least one grade 3-4 TEAE 
suspected to be related to SO-C101 as per 
investigators’ judgement reported in study 
SC103 up to dose level 9 in Part A and 
dose level 1 in Part B 
2 
Addition of Part D, a dose expansion part, testing SO-C101 
monotherapy schedule 1 RP2D from Part A in selected 
indications for additional safety and PK data 
Given the limited number of subjects in the Part A dose 
escalation population, the aim is to collect more data on the 
safety profile of the compound.  
1 TITLE PAGE, 2 CLINICAL 
PROTOCOL SYNOPSIS, 7.9 Study 
design rationale, 8.1 Study design, 
8.2 Objectives, 9.6 Part D (SO-C101 
dosing schedule 1, monotherapy, dose 
expansion at the RP2D identified in Part 

 
 
 
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A), 9.8 Dose escalation plan and study 
periods, 9.9 Selection of study population, 
9.10 Treatments, 9.11 Supportive care and 
concomitant medication, 9.12 Study 
assessments, 9.14 Statistical methods 
3 
Addition of Part D1, a dose expansion part, testing SO-C101 
monotherapy schedule 2 RP2D from Part A1 in selected 
indications for additional safety and PK data 
Given the limited number of subjects in the Part A1 dose 
escalation population, the aim is to collect more data on the 
safety profile of the compound. 
1 TITLE PAGE, 2 CLINICAL 
PROTOCOL SYNOPSIS, 7.9 Study 
design rationale, 8.1 Study design, 
8.2 Objectives, 9.7 Part D1 (SO-C101 
dosing schedule 2, monotherapy, dose 
expansion at the RP2D identified in Part 
A1), 9.8 Dose escalation plan and study 
periods, 9.9 Selection of study population, 
9.10 Treatments, 9.11 Supportive care and 
concomitant medication, 9.12 Study 
assessments, 9.14 Statistical methods 
4 
Update of dose escalation levels in Part A and Part B  
The dose escalation levels planned at the beginning of the study 
have seen some changes based on adjustments proposed, 
discussed and approved during the dose escalation meetings. The 
dose levels reflect the status at the time of this protocol 
amendment release and may require additional changes in the 
future. 
2 CLINICAL PROTOCOL SYNOPSIS, 
7.5 Justification for the starting dose and 
dose escalation steps in Part A, 9.1 Part A 
(SO-C101 dosing schedule 1, 
monotherapy, dose escalation), 9.3 Part B 
(SO-C101 dosing schedule 1, combined 
with pembrolizumab, dose escalation) 
5 
Clarification that Part C dosing schedule will be decided 
based on data about dosing schedule 1 and schedule 2 
collected in other study parts 
Clarification 
2 CLINICAL PROTOCOL SYNOPSIS, 
7.9 Study design rationale, 8.1 Study 
design, 9.10 Treatments 
6 
Clarification that all patients should have total bilirubin 
≤2×ULN (i.e., including patients with liver metastases) 
Clarification 
2 CLINICAL PROTOCOL SYNOPSIS, 
9.9 Selection of study population 
7 
Clarification that a DEM will take place after the last patient 
of the cohort has completed the first cycle (21 days) with or 
without DLTs and is evaluable for DLT assessment (this does 
Clarification 
2 CLINICAL PROTOCOL SYNOPSIS, 
9.8.3 Dose escalation meetings 

 
 
 
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not have to be within 5-7 working days as stated in previous 
versions of the protocol) 
8 
Clarification that regular study TCs will be held among study 
investigators (designated sub-investigators) and the sponsor’s 
medical monitor (this does not have to be every week as 
stated in previous versions of the protocol) 
Clarification 
9.8.5 Patient recruitment management, 
9.8.6 Communication plan 
9 
Clarification of the toxicities due to which retreatment with 
SO-C101 is contraindicated (grade 4 toxicities and third 
occurrences of grade 3 toxicities) 
Clarification 
9.10.2 Treatment modifications 
10 
Clarification that after grade 2 allergic reactions/acute 
infusion reaction with bronchospasm or any grade 3-4 allergic 
reactions/acute infusion reaction, SO-C101 is to be 
permanently discontinued 
Clarification 
9.10.2 Treatment modifications 
11 
ECG after SO-C101 administration changed from 2 hours 
after SO-C101 dosing to 4 hours after dosing 
ECG to be done close to the Cmax observed in patients 
9.12.6.4.7 Cardiac function, 
9.12.7 Schedule of 
procedures/assessments 
12 
Clarification that AEs and concomitant medications are also 
to be recorded on Day 15 
Clarification 
9.12.7 Schedule of 
procedures/assessments 
13 
Clarification that patients must be followed for AEs and 
concomitant medications 90 days after the last dose of SO-
C101 and/or pembrolizumab (as applicable), whichever 
occurs later (i.e., during efficacy follow-up or survival 
follow-up if this overlaps with safety follow-up)  
Clarification 
9.12.7 Schedule of 
procedures/assessments 
14 
Paired tumor biopsy is to be collected also at the time of 
progression or response 
To be able to collect more PK/biomarker data 
9.12.7 Schedule of 
procedures/assessments 
15 
Deletion of the sentence “Delayed sample collections will not 
be considered deviations, but the delay should be noted on the 
collection worksheet.” 
Samples not collected as per defined time matters and will be 
assessed. Protocol deviations are recorded if a sample is collected 
out of the time window. 
9.12.7 Schedule of 
procedures/assessments 

 
 
 
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Section affected in Protocol version 7.0 
16 
Addition of a 5 min time window to the 30 min PK sampling 
time point 
To prevent protocol deviations 
9.12.7 Schedule of 
procedures/assessments 
17 
Change of chief medical officer 
Change of personnel 
SIGNATURES / PROTOCOL 
APPROVAL AND RELEASE 
18 
Minor wording changes and punctuation adjustments 
To improve clarity and readability 
Throughout the document 
12.7.4 Version 6.1 (13-May-2020): Protocol changes implemented (note: version 6.0 was never implemented) 
Change 
number 
Description of change 
Rationale for change 
Section affected in Protocol version 6.1 
1 
Addition of an expansion cohort, Part C; SO-C101 combined 
with pembrolizumab at the combination RP2D identified in 
Part B or at the combination RP2D and at a lower dose of SO-
C101 (up to 20-40 patients). 
 
Ongoing patients in Part A and Part B can receive SO-C101 at 
the RP2D if specific criteria are met. Crossover of patients 
from Part A or Part B to Part C will not be allowed. 
The aim is to evaluate potential efficacy signal(s) earlier. 
CLINICAL PROTOCOL SYNOPSIS, 7.8 
Study design rationale, 8.1 Study design, 
8.1.3 Part C – SO-C101 dose expansion in 
combination with pembrolizumab, 8.1.4 
Intra-patient dose increase, 8.2.3 Part C 
(SO-C101 combined with pembrolizumab, 
dose expansion at the combination RP2D 
identified in Part B or at the combination 
RP2D and at a lower dose), 9.1 Treatment: 
Part A (SO-C101 monotherapy), 9.2 
Treatment: Part B (SO-C101 combined 
with pembrolizumab, dose escalation), 9.3 
Treatment: Part C (SO-C101 combined 
with pembrolizumab, dose expansion at 
the combination RP2D identified in Part B 
or at the combination RP2D and at a lower 
dose), 9.4.3.1 Safety monitoring beyond 
cycle 1, 9.4.7 Study periods in Part A and 
Part B, 9.4.8 Study periods in Part C, 9.4.9 
End of the study, 9.5 Selection of study 
population, 9.6.1 Treatments administered, 
9.6.2 Treatment modifications, 9.7.4.1 
Prohibited medications, 9.7.4.2 Warnings 

 
 
 
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and precautions, 9.8.5.1.1.5 Pregnancy of 
study patients or their partners, 9.8.5.1.2.1 
Reporting, 9.8.5.1.3.1 Causality, 
9.8.5.1.3.4 Documenting in eCRFs, 9.8.6 
Safety monitoring of the patients during 
the study, 9.8.6.3 Observation of patients 
after administration of SO-C101, 
9.8.6.4.10 Adverse events, 9.8.7 Schedule 
of procedures/assessments, 9.8.10 
Treatment discontinuation, 9.8.11 
Guidance for continuation of study 
treatment beyond iRECIST-defined 
disease progression, 9.10 Statistical 
methods, 9.10.1.3 Part C, 9.10.2 
Definitions of analysis sets, 9.10.10.2 
Adverse events, 9.10.11.3 Part C (SO-
C101 combined with pembrolizumab, dose 
expansion) 
2 
Addition of SO-C101 PK samples at 16 hours and 20 hours 
post-dose on cycle 1 day 1 for all patients in Part A and 12 
patients in Part C 
To be able to better describe the PK profile and calculate all PK 
parameters (current time points not sufficient to assess PK 
parameters during the elimination phase e.g. calculate tmax, t1/2…) 
9.8.7 Schedule of procedures/assessments 
3 
Addition of PK and immunogenicity analyses for 
pembrolizumab in Part C 
To be able to describe the PK profile and immunogenicity of 
pembrolizumab in combination with SO-C101 
9.8.6.4.11 Anti-drug antibodies, 9.10.8 
Pharmacokinetic analyses 
4 
Addition of an option to increase the dose of SO-C101 
administered to a patient in case this patient is in the study in 
Part A or Part B for at least 2 cycles and a higher dose of SO-
C101 is deemed safe after the Dose escalation meeting; 
possible to increase the patient’s dose of SO-C101 to this 
“new one” 
To allow patients treated at lower dose levels of SO-C101 to 
receive treatment at doses which may be more effective. 
Permitting intra-patient dose escalation is appealing because it 
gives some patients the opportunity to be treated at safe higher 
doses from which they may potentially derive more clinical 
benefit. 
CLINICAL PROTOCOL SYNOPSIS, 7.8 
Study design rationale, 8.1.4 Intra-patient 
dose increase, 9.1 Treatment: Part A (SO-
C101 monotherapy), 9.2 Treatment: Part B 
(SO-C101 combined with pembrolizumab, 
dose escalation), 9.4.7 Study periods in 
Part A and Part B, 9.6.2 Treatment 
modifications, 
9.10 Statistical methods 

 
 
 
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5 
Removal of information about a legally acceptable 
representative 
As per request from WIRB at Yale and to align with inclusion 
criterion 13 (“Ability to understand and sign written informed 
consent to participate in the study”) 
5.3 Patient information and informed 
consent 
6 
Addition of body surface area calculation 
To be able to assess the effect of body size on PK and PD of SO-
C101 to determine the appropriate dosing approach 
9.8.6.1 Physical examination, body 
weight, body surface area and height, 9.8.7 
Schedule of procedures/assessments 
7 
Archived, fixed tumor tissue can be collected if fresh biopsy at 
screening is not available 
Preferably only biopsy samples collected during the study will be 
collected and analyzed 
9.8.4.2 Tumor biopsy, 9.8.7 Schedule of 
procedures/assessments 
8 
Addition of the following coagulation parameters: D-dimer 
and fibrinogen 
Given that coagulation and inflammation are closely linked, D-
dimer and fibrinogen are added to coagulation parameters for 
dynamic monitoring of potential cytokine release syndrome 
symptoms in addition to PTT, aPTT and international normalized 
ratio 
9.8.6.4.1 Coagulation 
9 
Addition of total protein to the biochemistry panel 
Decrease in total protein can be a sign of kidney or liver function 
impairment or a sign of capillary leak associated with cytokine 
release syndrome 
9.8.6.4.3 Biochemistry 
10 
Addition of senior medical director 
Change of personnel 
SIGNATURES / PROTOCOL 
APPROVAL AND RELEASE 
11 
Minor wording and punctuation corrections 
To improve clarity and readability 
Throughout the document 
12.7.5 Version 5.0 (05-Nov-2019): Protocol changes implemented 
Change 
number 
Description of change  
Rationale for change 
Section affected in Protocol version 5.0 
1 
Revision of DLT criteria and exclusion criteria. 
 
Deletion of DLT criteria: 
- Grade 4 lymphopenia  
- Grade 3 lymphopenia lasting more than 7 days 
- Grade 3 or higher anemia 
 
Revision of DLT criteria: Lymphopenia grade 3 and lymphopenia 
grade 4 are usually not considered a toxicity that qualifies as DLT 
and are frequently part of the conglomerate clinical presentation 
of advanced malignant disease. Lymphopenia may also result 
from treatment with steroids, which is allowed to a certain extent 
in SC103. Grade 3 or higher anemia: since the protocol specifies a 
hemoglobin concentration of  
≥ 10 g/dL as eligibility criterion and the DLT period is defined to 
CLINICAL PROTOCOL SYNOPSIS, 
9.3.1.1 AEs that are considered DLTs, 
9.4.2 Exclusion criteria for both Part A and 
Part B 

 
 
 
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Deletion of "ALC ≤ 0.5×109/L" from the list of exclusion 
criteria 
be 21 days, it is highly unlikely that grade 3 or higher anemia will 
be observed during the DLT period. 
 
Deletion of “ALC ≤ 0.5×109/L” from the list of exclusion criteria: 
Recent published evidence indicates that there is no association 
between initial ALC count and response to anti-PD-1/PD-L1 in 
cancer patients in phase I (Sun et al. Eur. J. Cancer 84: 202, 2017) 
2 
Harmonization of the safety follow up period with the FDA 
requirement for 90 days follow-up. 
FDA: “The DLT evaluation period appears reasonable for the 
purposes of patient enrollment into escalating dose cohorts. 
However, continue to monitor all patients for approximately 
ninety days after treatment discontinuation for late immune-
related toxicities that have been associated with immunotherapy 
products. Any such late toxicity will need to be considered in the 
determination of the maximal tolerated dose/RP2 dose and dose 
schedule to be taken forward into part B of the study.” 
CLINICAL PROTOCOL SYNOPSIS, 7.8 
Study design rationale, 9.3.3.1.1 Part A, 
9.3.3.1.2 Part B, 9.3.6.3 Safety follow-up 
period, 9.7.5.1.2.1 Reporting, 9.7.7 
Schedule of procedures/assessments 
3 
Addition of a PK time point at 12 hours (+/- 1 hour) post dose 
at C1D1 
An additional PK sample at 12 hours post dose to be collected at 
C1D1 for PK parameter calculation. 
9.7.7 Schedule of procedures/assessments 
4 
Section 9.7.6.4.10 Adverse events: Patients in Part B will be 
monitored at the same visits and assessments as specified in 
Part 
A with the special attention to the potentiation of immune-
mediated reactions (AEs of special interest) during the 
combination treatment with SO-C101. 
 
No AESIs are monitored since DLTs cover most of the 
situation/s which might be of our interest. Therefore, we 
proposed to omit the expression ‘AEs of special interest’ from 
the current wording. 
Currently there are no AESIs defined per protocol as this is a phase 
I FIH safety study. 
9.7.6.4.10 Adverse events 
5 
biliary track tract cancer 
Correction of a typographical error 
CLINICAL PROTOCOL SYNOPSIS, 7.8 
Study design rationale, 8.1 Study design, 
9.4.1 Inclusion criteria for both Part A and 
Part B 

 
 
 
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6 
Request from the clinical site MD Anderson Cancer Center to 
clarify the definition of MTD/RP2D used for this study 
protocol, that is, to include a clarification that the sponsor is 
using the alternative EU/Japan definition of MTD/RP2D for 
this study and that this definition is a misnomer in the sense 
that the MTD is actually not a tolerable dose, as this definition 
is not the traditional definition for phase I studies in the United 
States.  
Request from the IRB of the clinical site MD Anderson Cancer 
Center 
9.3 Dose escalation plan for Part A and 
Part B, 12.6 Definition of MTD and RP2D 
as used in the study Protocol 
7 
Update of the TEAE definition in section 9.9.10.2 of the 
protocol 
Clarification of the TEAE definition 
9.9.10.2 Adverse events 
8 
Addition of a time window for ECG  
Clarification 
9.7.7 Schedule of procedures/assessments 
9 
Addition of a time window for cytokine sampling 
Clarification 
9.7.7 Schedule of procedures/assessments 
10 
Minor wording and punctuation corrections 
To improve clarity and readability  
Throughout the document 
11 
Update of contact details for AE reporting 
To reflect internal changes in the company 
9.7.5.1.3.5 Immediately reportable events, 
9.7.5.1.3.7 Report forms 
12 
For information on pembrolizumab safety refer to SmPC/US 
prescribing information 
Label updates 
9.5.4 Pembrolizumab, 9.5.4.3 
Pembrolizumab: safety information 
13 
Change of chief medical officer 
Change of personnel 
SIGNATURES / PROTOCOL 
APPROVAL AND RELEASE 
12.7.6 Version 4.0 (10-Apr-2019): Protocol changes implemented 
Change 
number 
Description of change  
Rationale for change 
Section affected in Protocol version 4.0 
1 
Monitoring of vital signs after dose 1 in cycle 1 for 8 hours 
instead of for 4-8 hours 
Need to monitor all patients after the first dose for 8 hours 
Synopsis, 9.7.6.3.1.1 Dose on day 1 
2 
Safety population in Part B to include patients exposed to SO-
C101 or pembrolizumab instead of SO-C101 only 
Usual definition of a safety population 
Synopsis, 9.9.2.1 Safety population 
3 
Introduction of a PK/PD population 
Population for PK and PD analyses  
Synopsis, 9.9.2.2 PK/PD population, 9.9.8 
Pharmacokinetic analyses, 9.9.9 
Pharmacodynamic and other biomarker 
analyses 

 
 
 
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4 
Urea or blood urea nitrogen to be tested instead of blood urea 
nitrogen only 
Need to accommodate sites’ standard practices 
9.7.6.4.3 Biochemistry 
5 
Clarification that free triiodothyronine and free thyroxine will 
be tested 
Clarification 
9.7.6.4.5 Thyroid function, 9.7.6.4.10 
Adverse events, 9.7.7 Schedule of 
procedures/assessments 
6  
ECG to be done in cycles 1- 3 before each dose of SO-C101 
and 2 hours after dosing, and from cycle 4 onwards on day 1 
before SO-C101 dosing and 2 hours after dosing; instead of on 
days 1, 2, 8, 9 in cycle 1 before each dose of SO-C101 and 2 
hours after dosing, and in subsequent cycles on day 1 before 
SO-C101 dosing  
Further to FDA comment in FDA letter dated 03-Apr-2019: 
“Specify the specific ECG collection time points with time 
matched PK samples at baseline (pre-dose), and at the 
anticipated time of maximum plasma concentration following 
administration of the first dose and following administration of 
multiple doses of SO-C101.” 
9.7.6.4.7 Cardiac function, 9.7.7 Schedule 
of procedures/assessments 
7 
Pregnancy test allowed to be done from urine or blood on day 
1 of each cycle instead of from urine only 
Need to accommodate sites’ standard practices 
9.7.7 Schedule of procedures/assessments 
8 
Serum (cytokine) volume increase from 4 to 8 mL per 
sampling 
Need to accommodate FACS analysis requirements 
9.7.7 Schedule of procedures/assessments 
9 
Renal clearance and fraction excreted will not be tested 
Renal clearance and excretion of SO-C101 will be analyzed 
following further optimization of detection methodology. Based 
on pre-clinical studies in cynomolgus monkeys, the rate of 
excretion was moderate, mean 46% of the administered 
radioactivity, recovered by 24 h post dose, main route of excretion 
was via urine with ~ 61% recovered by 72 h. Further analysis of 
urine samples by ELISA failed to detect SO-C101, likely because 
SO-C101 was contained in the urine as cleavage products that 
were not detectable by the ELISA method. For details refer to 
Investigator Brochure v.3.0 section 4.3.5 Excretion. Therefore, the 
following parameters: renal clearance and excretion fraction are 
not planned to be analyzed in this study. 
9.9.8 Pharmacokinetic analyses 
10 
Minor wording and punctuation corrections 
To improve clarity and readability  
Throughout the document 
11 
MedDRA version to be the one current at the time of database 
lock instead of version 21.1 
MedDRA version to be decided at the time of database lock 
9.9.10.2 Adverse events 
12 
Change of study statistician 
Change of personnel 
SIGNATURES / PROTOCOL 
APPROVAL AND RELEASE 

 
 
 
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1 
Clarification of the definition of dose-limiting toxicity 
Revised according to the FDA’s recommendation and grade 3 
ALT or AST and grade 3 bilirubinemia longer than 5 days have 
been included as DLT criteria grade 3 inflammatory local tumor 
reaction criteria was amended to “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.” 
Synopsis, 9.3.1.1 AEs that are considered 
DLTs, 9.3.1.2 AEs that are NOT 
considered DLTs 
2 
Clarification that whenever SO-C101 is interrupted in Part B 
due to immune-mediated toxicity, pembrolizumab should also 
be interrupted 
Revised according to the FDA’s recommendation, since in Part B 
it might be impossible to distinguish which study drug caused the 
specific toxicity. The protocol wording was adjusted for Part B as 
follows: “whenever SO-C101 treatment is interrupted for 
immune-medicated toxicity, treatment with pembrolizumab will be 
interrupted as well”.  
9.5.2 Treatment modifications  
3 
Modification of Table 9.3 Guidelines for SO-C101 dose 
adjustments beyond cycle 1 
Updated footnote #2 to Table 9.3 to reflect the Agency’s 
recommendation namely that “study drugs should be held if 
systemic corticosteroids at doses above 10 mg prednisone 
equivalent are required for any duration, and that study drug 
should be discontinued if systemic corticosteroids at doses above 
10 mg prednisone are required for > 4 weeks”. Section 9.5.2 and 
Section 9.6.4.2 were also amended in line with this change. 
9.5.2 Treatment modifications, 9.6.4.2 
Warnings and precautions 
4 
Modification of Table 9.4 SO-C101 modifications after cycle 1 
– delay/hold 
Table 9.4 has been revised to clarify SO-C101 dose modifications 
in case of grade 3 AST or ALT or grade 3 bilirubinemia with 
recommendation for dose reduction for 1 dose lower in case of 
grade 2 ALT, AST or bilirubinemia and permanent 
discontinuation of treatment with SO-C101 in case of same 
toxicities of grade 3. “Treatment modifications” of the protocol to 
give clear guidance to investigators with reference to Table 9.3 
and Table 9.4: “During SO-C101 treatment, SO-C101 dose 
interruptions and reductions due to toxicity will be implemented 
according to the instructions presented in Table 9.3 for all AEs 
excluding specific AEs as detailed in Table 9.4.” 
9.5.2 Treatment modification 

 
 
 
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5 
Clarification regarding prohibited medications and warnings 
and precautions  
Prohibited medications were clarified according to the FDA’s 
request to specify nephrotoxic, myelotoxic, cardiotoxic or 
hepatotoxic medications and specify medications known to 
prolong the QT interval.  
9.6.4.1 Prohibited medications 
6  
Clarification re use of systemic corticosteroids for immune-
mediated AEs at the doses above 10 mg of prednisone or 
equivalent  
Added a clarification about the use of systemic corticosteroids for 
treatment of immune-medicated AEs at doses above 10 mg of 
prednisone or equivalent for less than 4 weeks, the study drugs 
should be held. If systemic corticosteroids at doses above 10 mg 
of prednisone or equivalent are required for more than 4 weeks, 
then the study drug should be discontinued. 
9.5.2 Treatment modifications, 9.6.4.2 
Warnings and precautions 
12.7.8 Version 2.0 (17-Jan-2019) 
12.7.8.1 
Protocol changes implemented further to the initial EU VHP 
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1 
Part B will study SO-C101 in combination with 
pembrolizumab and will start after dose level 45 in Part A is 
completed and deemed safe (bifurcated design) and will use 
SO-C101 monotherapy level 23 dose as the starting dose in 
combination with pembrolizumab. Part B patient population 
will be the same as in Part A except that it will include 
patients who are considered relapsed/refractory with prior 
ICI therapy as well as ICI-naïve patients. 
VHP outcome (grounds for non-acceptance 17): 
According to the protocol, patients who received immune 
checkpoint inhibitors (ICI) or not (ICI naïve) will be included in 
Part B; so inclusion criterion number 2 should be amended to 
include “Part B only: Patients who were not previously treated 
with (naïve) or who have relapsed/refractory disease on ICI are 
eligible”. 
 
Response: 
The study is aimed to enroll a similar patient population in Part 
A and Part B to understand the benefit of the combination. Thus, 
inclusion criterion #2 in the protocol was written to apply for 
patients both in Part A and Part B: “Inclusion criterion #2: 
Patients who were not previously treated with (naïve) or who 
have relapsed/refractory disease on immune checkpoint 
inhibitors are eligible” However, we have noticed the 
discrepancy below in the protocol, which we believe caused the 
CLINICAL PROTOCOL SYNOPSIS, 
7.8 Study design rationale, 8.1 Study 
design 

 
 
 
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confusion in the definition of patient populations for Part A and 
Part B, and amended as follows in Synopsis, Section 7.8 and 
Section 8.1: “Part B will study SO-C101 in combination with 
pembrolizumab and will start after dose level 4 in Part A is 
completed and deemed safe (bifurcated design) and will use SO-
C101 monotherapy level 2 dose as the starting dose in 
combination with pembrolizumab. Part B patient population will 
be the same as in Part A except that it will include patients who 
are considered relapsed/refractory with prior ICI therapy as well 
as ICI-naïve patients” 
2 
11.13 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”.43 The repository will have independent 
monitoring that will guarantee protection of the data and the 
patients’ interests (see also section 11.7). The samples will not 
be transferred or 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. 
VHP outcome (grounds for non-acceptance 20): 
Regarding the possibility of samples being kept for future 
research in a Biomedical Repository, it should be provide 
information about Repository’s Policies. The policy information 
should reflect 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,” available at 
https://search.coe.int/cm/Pages/result_details.aspx?ObjectId=0900
00168064e8ff. In particular, it should specify if 1) the repository 
has independent monitoring that guarantees protection of the 
data and the patients’ interests, 2) there will be an independent 
review (ethical and scientific) of the studies that are going to be 
conducted with the samples, and 3) the samples will not be 
transfer neither sold to third parties. 
 
Response: 
Section 11.13 Future research has been added to the protocol to 
provide information about the Biomedical Repository Policies 
for future research. 
11.13 Future research 
3 
11.7 Confidentiality of personal data 
In order to ensure that personal information of each patient 
is kept confidential and protected, names and any other 
information that allows direct identification of a patient 
VHP outcome (grounds for non-acceptance 21): 
The sponsor should include a Confidentiality section in the 
protocol to ensure that confidentiality of personal data of the 
patients remain protected in accordance with Regulation (EU) 
11.7 Confidentiality of personal data 

 
 
 
 
 
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will not be in the eCRFs or included in any records or 
samples provided to the sponsor or sponsor’s authorized 
representatives; such information will be pseudonymised, 
i.e., all such information will be replaced by a specific 
code (patient number) assigned by a study doctor and all 
patients will be identified in 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 General Data Protection Regulation (EU) 2016/679 
(GDPR) 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 SO-C101 as monotherapy and in 
combination with pembrolizumab, 
• comparing and pooling study results, 
• establishing whether SO-C101 as monotherapy and in 
combination with pembrolizumab meets the appropriate 
standards of safety set by the authorities, 
• establishing whether SO-C101 as monotherapy and in 
combination with pembrolizumab is effective, 
• supporting the clinical development of SO-C101 as 
monotherapy and in combination with pembrolizumab, 
• supporting the licensing application for regulatory approval 
of SO-C101 as monotherapy and in combination with 
pembrolizumab anywhere in the world, 
• supporting the marketing, distribution, sale and use of 
SO-C101 as monotherapy and in combination with 
pembrolizumab anywhere in the world, 
• complying with specific regulations governing clinical 
2016/679 including a description of personal data protection 
measures such as patient identification code or identification code 
list, among others requirements. 
 
Response: 
Further to this request, a new section, section 11.7 Confidentiality 
of personal data, has now been added to the protocol. 

 
 
 
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trials. Participation of patients in this study is voluntary 
and they may withdraw from the study at any time by 
informing the investigator. Then the participation in the 
study will end and the study personnel will stop 
collecting personal information from the patients, but the 
sponsor will need to retain and use the pseudonymised 
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 SO-C101 as monotherapy and in combination 
with pembrolizumab. It may be necessary to retain certain 
aspects of pseudonymised (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 pseudonymised 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), the United States, and other 
countries that are outside of the EEA. Some non-EEA 
countries may not offer the same level of privacy 
protection. However, the sponsor will keep personal 
information it receives as confidential as possible within 
the limits of the law. The sponsor will implement 
appropriate contractual measures, including the standard 
data protection contractual clauses, to ensure that the 
relevant recipients outside the EEA provide an adequate 
level of protection to personal information as set out in 
this form and as required by applicable law. The sponsor, 

 
 
 
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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. See also section 11.10. 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 ethics committee 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 General Data 
Protection Regulation (EU) 2016/679 (GDPR), 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, namely the Data Protection 
Regulation and Incident Management Regulation. The 
organizational and technical measures introduced by the 
sponsor in relation to a protection of personal information 
of the patients involve the above mentioned 

 
 
 
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pseudonymisation 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 
within statutory term to the Office for Personal Data 
Protection of the Czech Republic and to all relevant study 
investigators. The sponsor has appointed a Data 
Protection Officer who can be contacted by post at 
SOTIO a.s., Jankovcova 1518/2, 170 00 Prague 7, the 
Czech Republic or via e-mail at gdpr@sotio.com. 
4 
The sponsor shall process all personal information of the 
patients in the study in accordance with the General Data 
Protection Regulation (EU) 2016/679 (GDPR), 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, namely the 
Data Protection Regulation and Incident Management 
Regulation. The organizational and technical measures 
introduced by the sponsor in relation to a protection of 
personal information of the patients involve the above 
mentioned pseudonymisation of personal information, 
appropriate controls to restrict its employees access to the 
personal information, a physical access control to any 
VHP outcome (grounds for non-acceptance 22): 
It should be provided information about Data Protection Policies 
that should reflect organizational and technical arrangements to 
avoid unauthorized access, disclosure, dissemination, alteration or 
loss of information and personal data processed; moreover, it 
should specify the measures that will be implemented in case of 
data security breach. 
 
Response: 
In the newly created section 11.7 in the protocol, information 
about Data Protection Policies that reflects organizational and 
technical arrangement is provided: 
“The sponsor shall process all personal information of the 
patients in the study in accordance with the General Data 
11.7 Confidentiality of personal data 

 
 
 
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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 within statutory term to the Office for Personal Data 
Protection of the Czech Republic and to all relevant study 
investigator. 
Protection Regulation (EU) 2016/679 (GDPR), 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, namely the 
Data Protection Regulation and Incident Management 
Regulation. The organizational and technical measures 
introduced by the sponsor in relation to a protection of personal 
information of the patients involve the above mentioned 
pseudonymisation 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 within statutory term to the Office for Personal 
Data Protection of the Czech Republic and to all relevant study 
investigator.” 
5 
Reduction of the starting dose from 0.5 µg/kg to 0.25 µg/kg 
and increase of the number of cohorts from 8 to 9 in Part A 
VHP outcome (grounds for non-acceptance 25): 
As activation of NK cells occurs at lower doses, please consider 
a starting dose which confers around 25% activation of NK 
cells. Indeed, as mentioned in the meeting minutes, the sponsor 
use a PAD approach based only on the activation of CD8+ T cell 
while the NK activation should be taken into consideration. 
 
Response: 
The sponsor revised the starting dose, based on the Agencies 
comments and Question 25. The starting dose in Part A was 
CLINICAL PROTOCOL SYNOPSIS, 
7.6 Justification for the starting dose and 
dose escalation steps in Part A, 
Justification for the starting dose in Part 
B, Study design rationale, 8.1.2 Part B – 
SO-C101 dose escalation in combination 
with pembrolizumab, 9.1 Treatment: Part 
A (SO- C101 monotherapy), 9.2 
Treatment: Part B (SO- C101 combined 
with pembrolizumab), 9.3.7 End of the 

 
 
 
 
 
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reduced from 0.5 µg/kg to 0.25 µg/kg. This revised starting dose 
is anticipated to promote 20% NK cell activation, while not 
affecting CD8 T cell activation. The receptor occupancy (RO) 
was calculated to be at 0.5% to 6%. The sponsor considers this 
new starting dose as safe for Part A of the planned clinical study 
SC-103. The subsequent dose levels were accordingly revised. 
The revised starting doses and the dose escalation steps as well 
as their justification are described in sections 7.6 and 7.7 of the 
SC-103 clinical study protocol. 
study, Table 9.3: Guidelines for SO- 
C101 dose adjustments beyond cycle 1, 
9.9.11 Determination of sample size 
6 
For each dose level, firstly one patient will be enrolled and 
will receive the first two four doses of SO-C101 (day 1, and 
day 2, day 8, and day 9). This patient will be observed for 
safety for 7 days after the fourth dose, starting from day 19. 
If there are no safety concerns at the end of these first 7 days, 
the responsible investigator will notify the sponsor’s medical 
monitor and the second and third patients will be allowed to 
be dosed. The second and third patients will not be dosed on 
the same day. 
VHP outcome (grounds for non-acceptance 26): 
Sponsor should amend the protocol to modify staggered 
(sentinel) dosing approach regarding first dose administration of 
second patient in order to let enough time to observed any delay 
effect of the IMP. Therefore, the second patient should be dosed 
7 days after the 4th administration (Day 9) of the first patient 
instead of the 7 days after the 1st administration (Day 1) of the 
first patient. 
 
Response: 
The study protocol has been amended per the recommendation 
above, and the new amended text is provided below: 
“For each dose level, the first patient will be enrolled and will 
receive the first four doses of SO-C101 (day 1, day 2, day 8, and 
day 9). This patient will be observed for safety for 7 days after 
the fourth dose, starting from day 9. If there are no safety 
concerns at the end of those 7 days, the responsible investigator 
will notify the sponsor’s medical monitor and the second and 
third patients will be allowed to be dosed. The second and third 
patients will not be dosed on the same day.” 
CLINICAL PROTOCOL SYNOPSIS, 
9.3 Dose escalation plan for Part A and 
Part B, Figure 9.3: Dose escalation 
flowchart (staggered dosing and 3 + 3 
design) 
7 
9.6.1 Management of cytokine release syndrome 
The management intervention guidelines described in this 
section can be modified by the individual study center as 
medically necessary or as appropriate without requiring a 
protocol amendment or being considered a protocol 
VHP outcome (grounds for non-acceptance 27): 
The sponsor is required to add to the protocol the management 
in case of patients experiencing a cytokine release syndrome as 
the risk cannot be excluded even if it is low. 
 
9.6.1 Management of cytokine release 
syndrome, 12.5 Clinical management 
recommendations for HD IL-2 therapy 

 
 
 
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deviation. SO-C101 is a fusion protein, which comprises a 
variant of the IL-15 molecule, which is a common γ-chain 
cytokine and shares the IL-2 receptor β and γ chains for 
signaling. SO-C101 therefore could have similar 
immunostimulatory properties as IL-2. SO-C101 treatment 
could potentially cause cytokine release syndrome as 
commercially available IL- 2, although the risk is low. 
Cytokine release syndrome may begin immediately after 
treatment administration and may be marked by increased 
capillary permeability to protein and fluids and reduces 
vascular tone. In most patients, this will result in a 
concomitant drop in mean arterial blood pressure within 2 to 
12 hours after the start of treatment. With continued 
treatment, clinically significant hypotension (defined as 
systolic blood pressure below 90 mm Hg or a 20 mm Hg 
drop from baseline systolic pressure) and hypoperfusion may 
occur. In addition, extravasations of protein and fluids into 
the extra-vascular space will lead to the formation of edema 
and creation of new effusions. Potentially life-threatening 
complications of CRS could include cardiac dysfunction, 
adult respiratory distress syndrome, neurologic toxicity, renal 
and/or hepatic failure, and disseminated intravascular 
coagulation. Of particular concern is cardiac dysfunction, 
which can be rapid onset and severe, but is typically 
reversible. Medical management of cytokine release 
syndrome begins with carefully monitoring of the patient’s 
fluids and organ perfusion status. This is achieved by 
frequent determination of blood pressure and pulse, and by 
monitoring organ functions, which includes assessment of 
mental status and urine output. Occurrence of hypovolemia 
will be monitored. Flexibility in fluid and pressor 
management is essential for maintaining organ perfusion and 
blood pressure. Therefore, extreme caution should be used in 
treating patients with fixed requirements for large volumes of 
fluid. Administration of IV fluids, either colloid or 
Response: 
New section 9.6.1 Management of cytokine release syndrome 
has been added to the Protocol. 

 
 
 
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crystalloid is recommended for treatment of hypovolemia. 
Correction of hypovolemia may require large volumes of IV 
fluids but caution is required because unrestrained fluid 
administration may exacerbate problems associated with 
edema formation or effusions. With extra-vascular fluid 
accumulation, edema is common and ascites, pleural or 
pericardial effusions may develop. Management of these 
events depends on a careful balancing of the effects of fluid 
shifts so that neither the consequences of hypovolemia (e.g., 
impaired organ perfusion) nor the consequences of fluid 
accumulations (e.g., pulmonary edema) exceed the patient’s 
tolerance. Pulmonary edema, another manifestation of 
capillary leak syndrome, can lead to respiratory failure. For 
further management guidelines please refer to Proleukin that 
is approved in some countries in the EU for the treatment of 
mRCC39 and in the US by the FDA to treat mRCC and 
malignant melanoma.40 For consensus guidelines on 
management, please also refer to “High-dose interleukin-2 
(Aldesleukin) – expert consensus on best management 
practices-2014”.41 See also appendix 12.5. 
8 
10. Alanine transaminase (ALT)/ aspartate transaminase 
(AST) ≤2.5×ULN and total bilirubin ≤2×ULN in patients 
without liver metastasis (benign hereditary 
hyperbilirubinemias, e.g., Gilbert’s syndrome, are permitted, 
those patients must have total bilirubin <3 mg/dL). In patients 
with liver metastasis, ALT/AST ≤5×ULN is allowed. 
VHP outcome (grounds for non-acceptance 28): 
The sponsor is required to amend inclusion criterion number 11 
to specify bilirubin upper limit of normal (ULN) in patients 
with Gilbert’s syndrome. 
 
Response: 
The inclusion criteria for patients with Gilbert’s syndrome 
has been modified and upper limit of total bilirubin 
<3 mg/dL has been specified. 
CLINICAL PROTOCOL SYNOPSIS, 
9.4.1 Inclusion criteria 
9 
13.10. Part B only: History of solid organ transplantation or 
hematopoietic stem cell transplantation 
VHP outcome (grounds for non-acceptance 29): 
The sponsor is required to amend the protocol to add the history 
of solid organ transplantation or HSCT as exclusion criterion to 
avoid the risks of immuno-associated events of pembrolizumab 
(SmPC of Keytruda). 
CLINICAL PROTOCOL SYNOPSIS, 
9.4.2 Exclusion criteria 

 
 
 
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Response: 
The protocol exclusion criteria has been amended to follow this 
recommendation and Exclusion criterion #13.10 has been added 
to the protocol as follows for Part B: Part B only: History of 
solid organ transplantation or HSCT 
10 
Removal of distinction between non-immune-related and 
immune-related DLTs 
VHP outcome (grounds for non-acceptance 30): 
The sponsor is required to clarify what is implied by “non-
immune-related AEs that are considered DLTs” (section 9.3.1.1) 
as both IMPs are involved in immune mechanisms. The sponsor 
should clarify how it will be distinguished between DLTs that 
are considered non-immune-related grade ≥3 liver toxicity and 
immune-related grade ≥3 liver toxicity. 
 
Response: 
The sponsor revised the wording for the DLT criteria in the 
protocol in light of this questions and removed the “non-
immune- related DLT” or “immune-related DLT” distinction as 
highlighted by the agency as both IMPs are involved in immune 
mechanisms. 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 as well as wherever possible histological 
assessments are also performed to identify and understand the 
safety profile of the SO-C101 as monotherapy and in 
combination with pembrolizumab. 
CLINICAL PROTOCOL SYNOPSIS, 
9.3.1 DLT definitions Part A and Part B 
11 
The treatment modifications below apply to all study 
treatment visits (Part A and Part B) when SO-C101 or 
pembrolizumab are is given. Where specified as delay or 
hold (after cycle 1), the study treatment (pembrolizumab 
and/or SO-C101) will be delayed/held week to week. For 
details, see Table 9.4. 
 
In Table 9.4: SO-C101 Study treatment 
VHP outcome (grounds for non-acceptance 31): 
The sponsor is required to clarify the protocol to specify if table 
9.4 provides for doses modifications of Keytruda as this table 
does not follow Keytruda SmPC recommendations (especially 
for grade 3 recurrent colitis and liver toxicity). However, it is 
specify in section 9.5.2 that “treatment modifications of 
pembrolizumab are allowed according to the approved label”. 
 
9.5.2 Treatment modifications, Table 
9.4: SO-C101Treatment modifications 
after cycle 1 – delay/hold 

 
 
 
 
 
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Response: 
Table 9.4 was meant to be related to SO-C101 dose 
modifications only; however, the title of the table was 
misleading. This table is now modified to refer to dose 
modification for SO-C101 administration and this has been 
clarified in the protocol. For Keytruda administration, the 
Keytruda SmPC recommendations must be followed. 
12 
 
 
 
 
 
 
 
 
 
VHP outcome (grounds for non-acceptance 32): 
The sponsor is required to add to Table 9.9 “blood sample 
collection” the expected blood sampling volumes since many 
samples are planned in addition to the usual management of 
patients (pharmacokinetics, cytokines, PBMC). 
 
Response: 
The corresponding blood volume for each sample has been 
added into Tables 9.9 and 9.10 of the protocol. 
Table 9.9: Blood samples collection (Part 
A and Part B), Table 9.10: Blood 
samples collection (Part B; for patients 
who continue on pembrolizumab only 
after discontinuation of SO- C101) 
12.7.8.2 
Additional “non-VHP GNA” changes 
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1 
Özlem Ataman, M.D., Ph.D. 
Head of Translational Research and Early Clinical 
Development Acting Chief Medical Officer 
Job title changed 
SIGNATURES / PROTOCOL 
APPROVAL AND RELEASE 
2 
Revision of the solid tumor indications to include solid tumors 
of renal cell carcinoma, non-small cell lung cancer, small-cell 
lung cancer, bladder cancer, melanoma, Merkel-cell 
carcinoma, skin squamous-cell carcinoma, microsatellite 
instability high solid tumors, triple-negative breast cancer, 
mesothelioma, thyroid cancer, thymic cancer, cervical cancer, 
biliary track cancer, hepatocellular carcinoma, ovarian cancer, 
gastric cancer, head and neck squamous-cell carcinoma, and 
anal cancer 
Tumor indications to be included in the study has been revised to 
include solid tumors with known sensitivity for anti-PD-(L)1 
monotherapies among the so called “PD- Lomas”. PD-Lomas 
where ORR ≥10% was reported were selected to demonstrate 
potential efficacy signal for the effect of SO- C101 added to 
Keytruda. 
1 TITLE PAGE, CLINICAL PROTOCOL 
SYNOPSIS, 7.8 Study design rationale, 
8.1 Study design, 9.4.1 Inclusion criteria, 
9.7.2 Efficacy assessments, 9.7.2.1 
Radiologic evaluation of disease 

 
 
 
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3 
Addition of a signature page for the coordinating investigator To show approval of the Protocol by the coordinating investigator SIGNATURES / PROTOCOL 
APPROVAL AND RELEASE 
4 
- Grade 3 or higher leukocytosis 
To align the synopsis with the body of the 
Protocol 
CLINICAL PROTOCOL 
SYNOPSIS 
5 
The coordinating investigator for this trial is: Prof. Aurélien 
Marabelle, M.D., Ph.D. Clinical Director 
Cancer Immunotherapy Program Institute Gustave Roussy 
Villejuif, France 
To mention the coordinating investigator in the Protocol 
6 INVESTIGATORS AND SPONSOR 
6 
Clarification of the required time of observation of patients 
after SO- C101 administration 
To clarify further the time period of the observation after SO-
C101 administration 
CLINICAL PROTOCOL SYNOPSIS, 
9.7.6.3 Observation of patients after 
administration of SO-C101 
7 
Addition of creatinine clearance calculation in addition to 
serum creatinine evaluation as follows: 
- cycles 1 and 2: days 1 and 9 prior to SO-C101 administration 
and on day 6; - - cycle 3: day 1 (prior to SO-C101 
administration) and on day 6; 
- from cycle 4 and onwards on days 1 and 8 prior to SO-C101 
administration. 
To add creatinine clearance calculation in addition to serum 
creatinine evaluation 
9.7.6.4.8 Kidney function, Table 9.6: 
Schedule of procedures/assessments, Part 
A (SO-C101 monotherapy) 
8 
Deletion of information about posting of summary of study 
results to https://www.clinicaltrialsregister.eu/ and 
https://clinicaltrials.gov/. 
Not mandatory/required 
11.10 Publication of results 
9 
Minor wording corrections and clarifications 
To improve readability and clarify ambiguities 
Throughout the Protocol