A Phase 2, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Setanaxib, When Administered With Pembrolizumab, in Patients With Recurrent or Metastatic SCCHN
Phase: PHASE2
Conditions: Squamous Cell Carcinoma of Head and Neck
Sponsor: Calliditas Therapeutics Suisse SA

CLINICAL STUDY PROTOCOL 
 
Title: 
A Phase 2, Randomised, Double-Blind, Placebo-Controlled, 
Proof-of-Concept Study to Evaluate the Efficacy, Safety, and 
Tolerability, and Effects on Tumour Biomarkers of the 
NOX1/4 Inhibitor Setanaxib, when Administered with the PD-
1 Inhibitor Pembrolizumab, in Patients with Recurrent or 
Metastatic Squamous Cell Carcinoma of the Head and Neck 
(SCCHN) 
NCT number:  
NCT05323656 
Unique Protocol ID:  
GSN000400 
Document Date:  
25 April 2023 
 

Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000400 
Protocol Version and Date: Version 4.0 (25 April 2023)  
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Confidential 
 
 
CLINICAL STUDY PROTOCOL 
Title: 
A Phase 2, Randomised, Double-Blind, Placebo-Controlled, 
Proof-of-Concept Study to Evaluate the Efficacy, Safety, and 
Tolerability, and Effects on Tumour Biomarkers of the 
NOX1/4 Inhibitor Setanaxib, when Administered with the 
PD-1 Inhibitor Pembrolizumab, in Patients with Recurrent or 
Metastatic Squamous Cell Carcinoma of the Head and Neck 
(SCCHN) 
Short title:  
A Phase 2, Randomised Study of Setanaxib Co-
Administered with Pembrolizumab in Patients with 
Recurrent or Metastatic SCCHN  
Protocol number:  
GSN000400 
Study phase:  
Phase 2  
Test product:  
Setanaxib 
Regulatory agency 
identifier numbers: 
Investigational New Drug number: 158611 
EudraCT (European Drug Regulating Authorities Clinical 
Trials) number: 2021-004627-33 
Sponsor:  
Calliditas Therapeutics Suisse SA, 
Chemin des Aulx 16, 
1228 Plan-les-Ouates, 
Switzerland 
Calliditas Therapeutics Suisse SA is a subsidiary of 
Calliditas Therapeutics AB  
Contract research 
organisation:  
ICON Clinical Research Limited, 
South County Business Park, 
Leopardstown, Dublin 18, 
D18 X5R3, 
Ireland 
Phone: +353 (1) 291 2000 
Fax: +353 (1) 247 6260 
ICON is a corporate affiliate of PRA 
Protocol version and 
date:  
Version 4.0 (25 April 2023) incorporating Global 
Amendments 1 and 2 
This study will be performed in compliance with the principles of International Council 
for Harmonisation guidelines on Good Clinical Practice. 
This document is a confidential communication of the sponsor. Acceptance of this 
document constitutes agreement by the recipient that no unpublished information 

Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000400 
Protocol Version and Date: Version 4.0 (25 April 2023)  
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Confidential 
 
 
contained herein shall be published or disclosed without prior written approval, except 
that this document will be disclosed to the appropriate Institutional Review 
Board(s)/Independent Ethics Committee(s) under the condition that they keep it 
confidential. 

Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000400 
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Confidential 
 
 
PROTOCOL SIGNATURE PAGE – SPONSOR 
This protocol has been reviewed and approved by the representatives listed below. Any 
modification of the protocol must be agreed upon by the sponsor and the investigator and 
must be documented in writing. 
Sponsor representatives: 
 
 
 
Chief Medical Officer 
Print Name 
 
 
Title 
 
 
 
 
Signature 
 
Date 
 
 
 
Statistician 
Print Name 
 
 
Title 
 
 
 
 
Signature 
 
Date 
 

Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000400 
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PROTOCOL SIGNATURE PAGE – CONTRACT RESEARCH 
ORGANISATION 
This protocol has been reviewed and approved by the representatives listed below. Any 
modification of the protocol must be agreed upon by the sponsor and the investigator and 
must be documented in writing. 
ICON representative: 
 
 
 
Medical Director 
Print Name 
 
 
Title 
 
 
 
 
Signature 
 
Date 
 

Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000400 
Protocol Version and Date: Version 4.0 (25 April 2023)  
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Confidential 
 
 
PROTOCOL SIGNATURE PAGE – INVESTIGATOR 
I have read this protocol, which has been agreed by the sponsor and given 
approval/favourable opinion by the Institutional Review Board (IRB)/Independent Ethics 
Committee(IEC), and I agree that it contains all necessary details for my staff and I to 
conduct this study as described. I will provide copies of the protocol and any 
amendments to all study personnel under my supervision and provide access to all 
information provided by the sponsor or their specified designees. I will discuss the 
material with the study personnel to ensure that they are fully informed about the study. 
I understand that information contained in or pertaining to this protocol is confidential 
and should not be disclosed, other than to those directly involved in the execution or the 
ethical review of the study, without written authorisation from the sponsor. It is, however, 
permissible to provide information to a patient in order to obtain consent. 
I agree to conduct this study according to this protocol and to comply with its 
requirements, subject to ethical and safety considerations and guidelines, and to conduct 
the study in accordance with the Declaration of Helsinki, International Council for 
Harmonisation guidelines on Good Clinical Practice (ICH GCP), and applicable regional 
regulatory requirements. 
I agree to comply with the procedures described for data recording and reporting and to 
permit monitoring and auditing by the sponsor (or designee), and inspection by the 
appropriate regulatory authorities. 
I agree to make my patients’ study records available to sponsor’s personnel, their 
representatives and relevant regulatory authorities in order to verify data that I have 
entered into the electronic case report forms (eCRFs). I will retain the study-related 
essential documents until the sponsor indicates that they are no longer needed. I am 
aware of my responsibilities as per ICH GCP, local regulations, the study protocol, and 
the clinical trial agreement. 
I understand that to the sponsor may decide to suspend or prematurely terminate the study 
at any time for whatever reason; such a decision will be communicated to me in writing. 
Conversely, should I decide to withdraw from execution of the study, I will communicate 
my intention immediately in writing to the sponsor (or designee). 

Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000400 
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Confidential 
 
 
PROTOCOL SIGNATURE PAGE – INVESTIGATOR (continued) 
Investigator: 
 
 
 
 
Print Name 
 
 
Title 
 
Institution 
 
 
 
Signature 
 
Date 
 

Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000400 
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Confidential 
 
 
SERIOUS ADVERSE EVENT, ADVERSE EVENTS OF SPECIAL 
INTEREST, PREGNANCY, AND OVERDOSE CONTACT 
INFORMATION 
In the event of a serious adverse event (SAE), the investigator will send a safety report 
form within 24 hours of becoming aware of the SAE to the contact details below. 
Any adverse events of special interest (AESIs), pregnancies, or overdoses will also be 
reported within 24 hours of becoming aware of the event to the contact details below. 
 
Contract Research Organisation 
In Europe, Asia-Pacific, and Africa (EAPA): 
SPM2 
Fax 
+49 (0)621 570 5971 
Email patient.safety@calliditas.com 
 
In the Americas: 
SPM2 
Fax 
+1 978-338-0668 
Email patient.safety@calliditas.com 

Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000400 
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Confidential 
 
 
PRODUCT COMPLAINTS 
Product complaints will be collected if they occur in the study. A product complaint is 
any alleged deficiency related to the identity or quality of a study drug, after it is released 
for distribution to a site or to a patient. This includes all components distributed with the 
drug, such as packaging, drug containers, labelling, and inserts. 
Examples include: 
• 
Packaging that is damaged or broken 
• 
Missing or illegible labelling 
• 
Inability of customer to administer the product 
• 
Product with an unexpected colour, appearance (eg, broken tablets), or taste 
Product complaints should be reported by filling out the Product Complaint Report Form 
and emailing it to CADSCCSX-SCCSXBnetmb@prahs.com. 
Any adverse events (AEs) that are associated with a product complaint should be 
reported per instructions for AE Reporting in Section 7.3. 

Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000400 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
 
Version 4.0, 25 April 2023 
Global Amendment 2 (substantial) 
Description of change and rationale for change: 
To ensure having approximately 50 patients with evaluable Week 9 biomarker and 
imaging data and mitigate risks from a higher than expected number of patients 
discontinuing study early or declining to have imaging or biopsies at Week 9, this 
protocol amendment allows flexibility in increasing the sample size up to 70 patients if 
needed. 
In addition, a number of minor errors have been corrected along with editorial changes 
to ensure consistency of terminology throughout. 
 
Version 3.0, 13 May 2022 
Global Amendment 1 (substantial) 
Description of change and rationale for change: 
The following revisions and corrections have been incorporated in the protocol and 
protocol summary where applicable: 
1. Genkyotex Suisse SA has been renamed Calliditas Therapeutics Suisse SA 
effective 01 April 2022. 
2. Some of the changes implemented in the local UK, French, and German revised 
protocols have been incorporated in the global amendment. 
3. Background Section 1.1 includes minor revisions to align with the Investigator 
Brochure, Edition 12.0. 
4. Concomitant Medication and Procedures Section 6.8 has been amended to align 
with the Investigator Brochure, Edition 12.0 
5. The Screening Period has been extended for 1 week to facilitate screening 
activities. 
6. Study Follow-up assessments have been clarified. 
7. The sample size has been reduced to 50 patients. 
8. An exploratory objective/endpoint has been added for assessment of circulating 
biomarkers, involving collection of additional blood samples.  
 
Version 2.0, 20 October 2021 
The protocol has been generated to implement changes mandated by US FDA. 

Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000400 
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Version 1.0, 31 August 2021 
Initial creation 

Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000400 
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PROTOCOL SUMMARY 
Protocol number: GSN000400 
Protocol title: A Phase 2, Randomised, Double-Blind, Placebo-Controlled, Proof-of-Concept Study to 
Evaluate the Efficacy, Safety, and Tolerability, and Effects on Tumour Biomarkers of the NOX1/4 
Inhibitor Setanaxib, when Administered with the PD-1 Inhibitor Pembrolizumab, in Patients with 
Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN) 
Short title: A Phase 2 Study of Setanaxib Co-Administered with Pembrolizumab in Patients with 
Recurrent or Metastatic SCCHN 
Sponsor: Calliditas Therapeutics Suisse SA 
Study phase: Phase 2 
Study sites: It is planned to recruit approximately 35 investigational centres in North America and 
Europe. 
Objectives and Endpoints: 
Primary Objective 
Primary Endpoint 
• To compare the change in tumour size per 
Response Evaluation Criteria in Solid 
Tumours Version 1.1 (RECIST v1.1) in 
recurrent or metastatic SCCHN patients 
treated with setanaxib and pembrolizumab 
versus patients treated with placebo and 
pembrolizumab 
• Best percentage change in tumour size, 
defined as the best percentage change from 
Baseline in the sum of diameters of target 
lesions, as assessed by RECIST v1.1  
Key Secondary Objectives  
Key Secondary Endpoints 
• To compare the progression-free survival 
(PFS) per RECIST v1.1 in recurrent or 
metastatic SCCHN patients treated with 
setanaxib and pembrolizumab versus patients 
treated with placebo and pembrolizumab 
• PFS, defined as time from randomisation to 
the first documented disease progression per 
RECIST v1.1 or death due to any cause, 
whichever occurs first. PFS at 3, 6, and 12 
months and median PFS will be summarised 
• To compare the change from Baseline in 
cancer-associated fibroblasts (CAFs) level in 
tumour tissue from recurrent or metastatic 
SCCHN patients treated with setanaxib and 
pembrolizumab versus patients treated with 
placebo and pembrolizumab 
• Change from Baseline in CAFs level in 
tumour tissue 
• To compare the change from Baseline in the 
number of cluster of differentiation 8 (CD8+) 
tumour-infiltrating lymphocytes (TILs) and 
regulatory T-cells in tumour tissue from 
recurrent or metastatic SCCHN patients 
treated with setanaxib and pembrolizumab 
versus patients treated with placebo and 
pembrolizumab 
• Change from Baseline in the number of 
CD8+ TILs and regulatory T-cells in tumour 
tissue 
Other Secondary Objectives  
Other Secondary Endpoints 
• To assess the overall response rate (ORR), 
the duration of response (DoR) and disease 
control rate (DCR) per RECIST v1.1 in 
recurrent or metastatic SCCHN patients 
treated with setanaxib and pembrolizumab 
• ¨Proportion of the patients who have a 
complete response (CR) or partial response 
(PR) per RECIST v1.1 will be used to assess 
ORR 

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versus patients treated with placebo and 
pembrolizumab 
• The minimum time when CR or PR is first 
observed to the time of progression of disease 
(PD) or death will be used to assess DoR 
• Proportion of the patients in whom the best 
overall response is determined as CR, PR, or 
stable disease (SD) per RECIST v1.1 will be 
used to assess DCR 
• To assess the overall survival (OS) in 
recurrent or metastatic SCCHN patients 
treated with setanaxib and pembrolizumab 
versus patients treated with placebo and 
pembrolizumab 
• OS, defined as the time from Randomisation 
to death due to any cause. Patients without 
documented death at the time of the final 
analysis will be censored at the date of the 
last follow-up 
• To evaluate the safety and tolerability profile 
of setanaxib and pembrolizumab, versus 
placebo and pembrolizumab, in recurrent or 
metastatic SCCHN patients 
• Adverse events (AEs): monitoring for AEs at 
all visits 
• AEs of special interest (AESIs): 
o 
Anaemia 
o 
Hypothyroidism 
• Vital signs: pulse rate, systolic blood pressure 
(SBP), and diastolic blood pressure (DBP) 
• 12-lead electrocardiogram (ECG): clinically 
significant abnormalities 
• Physical examination: abnormal findings 
• Laboratory tests: 
o 
Haematology 
o 
Biochemistry 
o 
Urinalysis 
o 
Thyroid function test 
• To compare the change from Baseline in 
programmed cell death ligand 1 (PD-L1) 
expression in tumour tissue from recurrent or 
metastatic SCCHN patients treated with 
setanaxib and pembrolizumab versus patients 
treated with placebo and pembrolizumab 
• Levels of PD-L1 expression in tumour tissue 
• To compare the change from Baseline in 
patterns of gene expression and differential 
gene expression in tumour tissue from 
recurrent or metastatic SCCHN patients 
treated with setanaxib and pembrolizumab 
versus patients treated with placebo and 
pembrolizumab, using RNA sequencing 
• Gene expression quantification and analysis 
of patterns of gene activation for CAFs, 
CD8+ TILs, and regulatory T-cells 
• To assess the plasma exposure of setanaxib 
and its metabolite GKT138184 
• Pre-dose and post-dose plasma 
concentrations of setanaxib and GKT138184: 
o 
Area under the concentration-time curve 
over the last 24-h dosing interval at 
steady state (AUC[0-24]-ss) 
o 
Minimum plasma concentration at 
steady state (Cmin-ss) 
o 
Maximum plasma concentration at 
steady state (Cmax-ss) 
Exploratory Objectives 
Exploratory Endpoints 
• To assess the relationship between setanaxib 
and GKT138184 plasma exposure and 
response, if data permits 
• Where data permit, the pharmacokinetics 
(PK) (setanaxib and GKT138184 plasma 
exposure)/pharmacodynamics (PD) (eg, 

Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000400 
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changes in biomarkers, efficacy, and safety 
parameters) relationship may be explored 
graphically and/or using appropriate PK/PD 
modelling techniques 
• To compare the change from Baseline in 
patterns of gene expression and differential 
gene expression in tumour tissue from 
recurrent or metastatic SCCHN patients 
treated with setanaxib and pembrolizumab 
versus patients treated with placebo and 
pembrolizumab, using RNA sequencing 
• Gene expression quantification and analysis 
of patterns of gene activation for relevant 
immuno-oncology, inflammatory and other 
relevant gene signatures 
• To compare changes in circulating 
biomarkers detectable in peripheral blood in 
recurrent or metastatic SCCHN patients 
treated with setanaxib and pembrolizumab 
versus patients treated with placebo and 
pembrolizumab 
 
• Evaluations of pre-, on-treatment, and 
progression peripheral blood samples for 
circulating biomarkers which may include 
but will not be limited to panels of cytokines, 
chemokines and other soluble biomarkers; T-
cell receptor repertoire analysis; and analysis 
of gene expression biomarkers associated 
with immunomodulatory effects 
Study design: 
This is a randomised, double-blind, placebo-controlled, proof-of-concept, Phase 2 study assessing 
setanaxib co-administered with pembrolizumab in patients with recurrent or metastatic SCCHN. The 
safety and efficacy of setanaxib 800 mg twice daily [BID] will be assessed against matching placebo 
over up to 105 weeks of treatment. 
The study design is outlined in Figure 1 (Study Schematic), and the visit schedule and planned 
assessments at each visit are detailed in Table 1. 
The study will consist of an up to 35-day Screening Period, an up to 24-month Treatment Period (Day 1 
to Week 105), and a 28-day Safety Follow-up Period. The total duration of the study for patients 
remaining in the study until their final follow-up assessment will be up to approximately 114 weeks 
(approximately 2 years and 2 months). 
Patients will be assessed for eligibility during the Screening Period. Patients will attend the Screening 
Visit within 35 days of Day 1, such that all of the results of the screening tests will be available at the 
time that patient eligibility is reconfirmed prior to dosing. If serum pregnancy (see Footnote ‘d’ of Table 
1) retest is required, it should be repeated within 7 days prior to randomisation. 
Patients who are screen failures may undergo full rescreening once at the discretion of the investigator 
and medical monitor if there is a reasonable expectation that the patient is potentially eligible for the 
study. 
As part of eligibility criteria, tumour tissue CAFs level must be assessed by a central laboratory and an 
elevated tumour CAFs level demonstrated. For Baseline biomarker determination and determination of 
eligibility, a fresh tumour biopsy will be required from all patients before dosing in the study (unless 
there is tumour material available from a biopsy taken within 30 days prior to the Screening Visit, which 
can be used for the Baseline biomarker analysis). 
In addition, for patients with a suitable archival tumour biopsy sample available, the archival sample 
may be used to assess CAFs level and determine eligibility (Note: this can only be performed after the 
patient has provided signed informed consent). This will not dispense from the need for a recent pre-
study tumour biopsy, collected during or within 30 days prior to the Screening Period, for patients 
eligible for the study. To be considered suitable for determination of CAF levels, the archival biopsy 
must have been collected within 6 months prior to the Screening Visit (Visit 1), and the patient must 
have received no further anti-cancer therapy since then. 
Eligible patients will be randomised to the investigational medicinal product (IMP) setanaxib tablets 800 
mg BID, or placebo, according to a 1:1 randomisation ratio, stratified by human papillomavirus (HPV) 
status. Treatment with pembrolizumab will be initiated on the same day (Day 1) as the first dose of IMP, 

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and will be administered according to current clinical guidelines and labelling, ie, 200-mg IV infusion 
every 3 weeks (q3w). 
Treatment with pembrolizumab will continue until: RECIST v1.1-defined disease progression as 
determined by the investigator, unacceptable toxicity, or a maximum of 24 months. If progression is 
suspected, but not confirmed, study treatment may continue until confirmation of radiological 
progression. 
Treatment with setanaxib or placebo will continue throughout the period of pembrolizumab therapy. 
When pembrolizumab is discontinued, blinded study treatment will be discontinued at the same time. 
Baseline assessments will be performed on Day 1 (Visit 2). Post-Baseline assessments will be performed 
every 3 weeks up to pembrolizumab discontinuation. Following permanent IMP discontinuation at any 
time during the study, patients will undergo an End-of-Treatment (EoT) Visit as soon as possible and a 
Safety Follow-up Visit at 28 days after the last dose. Tumour assessments will be conducted from the 
date of randomisation and continue until RECIST v1.1-defined disease progression, irrespective of 
treatment discontinuation. Efficacy Follow-up for PFS and survival will continue until at least 38 
progression events have occurred. AEs will be recorded up to 28 days after study treatment 
discontinuation, while any further anti-cancer medication will be recorded until progression. 
Throughout the study, particular attention will be given to the detection and management of potential 
cases of anaemia and potential cases of hypothyroidism. 
Safety and tolerability data will be regularly reviewed by an unblinded Independent Data Monitoring 
Committee (IDMC), with the first assessment after approximately 12 patients (6 per treatment group) 
have had the opportunity to complete at least 1 cycle of pembrolizumab +/- setanaxib, followed by 
periodic assessments at a frequency defined in the IDMC Charter. The IDMC may recommend change(s) 
to the setanaxib dose regimen or study conduct based on the safety data reviews, as defined in the IDMC 
Charter. 
After approximately 12 patients (6 per treatment group) have completed their Baseline and post-
treatment biopsy, initial gene expression and biomarker data in tumour tissue may be reviewed by the 
sponsor, who will remain masked to randomised treatment assignment. A second review may be 
performed, if required. 
Study duration: 
The start of the study will be the date on which the first patient provides informed consent, and the end 
of the study will be the last patient’s last assessment. 
The maximum study duration for an individual patient is up to approximately 114 weeks (approximately 
2 years and 2 months): An up to 35-day Screening Period, an up to 24-month Treatment Period (Day 1 to 
Week 105), followed by an EoT Visit as soon as possible and a Safety Follow-up Visit at 28 days after 
the last IMP dose. 
Planned number of patients: It is planned to randomise approximately 50 patients; however, depending 
on the number of patients providing evaluable Week 9 biopsy and imaging data, an additional up to 20 
patients (making a maximum of 70 patients) may be randomised to ensure an adequate amount of data is 
available for the efficacy and biomarker analyses.  
Target population: 
Patients aged ≥18 years with recurrent or metastatic SCCHN who are eligible for treatment with 
pembrolizumab monotherapy. 
Inclusion criteria: 
1. Male or female patients aged ≥18 years, inclusive, at the time of informed consent. 
2. Willing and able to give informed consent and to comply with the requirements of the study. 
3. Histologically- or cytologically-confirmed diagnosis of SCCHN (ie, primary tumour arising from 
the oral cavity [including tongue], nasal cavity, paranasal sinuses, oropharynx, hypopharynx, or 
larynx) that is recurrent or metastatic (including both HPV+ve and HPV-ve SCCHN), with or 
without nodal involvement, and with or without metastatic spread, and is not eligible for surgical 
resection. 

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4. Candidates for first-line treatment for pembrolizumab for recurrent or metastatic SCCHN, at the 
discretion of the investigator. 
5. A positive CAFs level (defined as CAFs level in tumours ≥5%), performed at a central laboratory, 
with a fresh tumour biopsy taken during or within 30 days prior to the Screening Period. If 
available, suitable archival tissue (taken within 6 months prior to the Screening Visit and where 
the patient has received no further anti-cancer therapy during this 6-month period) can be used to 
assess tumour CAFs level and determine patient eligibility (Note: patients found to have low CAF 
levels in archival tissue material should not proceed to have further biopsies or screening 
activities). 
6. Measurable disease, in accordance with RECIST v1.1, and with tumour accessible and of 
sufficient volume for pre-treatment and on-treatment biopsy. 
7. Combined positive score (CPS) ≥1, as determined on the archival or fresh tumour biopsy taken 
during or within 30 days prior to the Screening Period. 
8. HPV status known at randomisation. 
9. Life expectancy of at least 6 months in the judgment of the investigator. 
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
11. Adequate organ and bone marrow function within 35 days of starting study treatment. Criteria 
“a” to “c” cannot be met in patients with ongoing or recent (within 14 days of screening test) 
transfusions or who require ongoing growth factor support: 
a. 
Absolute neutrophil count ≥1,000/mm3 (≥1.0×109/L). 
b. 
Platelet count ≥100,000/mm3 (≥100×109/L). 
c. 
Haemoglobin ≥9 g/dL, in the absence of transfusions for at least 2 weeks. Patients 
requiring ongoing transfusions or growth factor support to maintain haemoglobin ≥ 
9g/dL are not eligible. 
d. 
Total bilirubin ≤1.5×upper limit of normal (ULN) (if associated with liver metastases or 
Gilbert's disease, ≤3×ULN). 
e. 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3×ULN. 
f. 
Serum creatinine ≤2.0 mg/dL or creatinine clearance ≥40 mL/min (measured or 
calculated according to the method of Cockcroft and Gault). 
12. Female patients of childbearing potential must use a highly effective method of contraception to 
prevent pregnancy for ≥4 weeks before randomisation and must agree to continue strict 
contraception up to 120 days after the last dose of IMP or pembrolizumab, whichever is the later. 
a. 
For the purposes of this study, women of childbearing potential are defined as “fertile, 
following menarche and until becoming postmenopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and 
bilateral oophorectomy.” 
b. 
Postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. In female patients who are not using hormonal contraception or hormonal 
replacement therapy but with suspected menopause and less than 12 months of 
amenorrhea, a high follicle stimulating hormone (FSH) level in the postmenopausal 
range will be required at Screening to confirm a postmenopausal state. Confirmation 
with more than one FSH measurement is required. 
c. 
Highly effective contraception is defined as methods that can achieve a failure rate of 
less than 1% per year when used consistently and correctly. These methods are: 
(1) Combined (oestrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal) 
(2) Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, or implantable) 
(3) Intrauterine device 
(4) Intrauterine hormone-releasing system 
(5) Bilateral tubal occlusion 

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(6) Vasectomised partner 
(7) 
Sexual abstinence (refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments). The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical study 
and the preferred and usual lifestyle of the patient.  
Periodic abstinence (calendar, symptothermal, post-ovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method are not acceptable methods of contraception).. 
13. Female patients of childbearing potential must have a negative serum pregnancy test at Screening 
and a negative urine pregnancy test at Baseline/Randomisation before dosing. 
14. Male patients with female partners of childbearing potential must be willing to use a condom and 
require their partner to use a highly effective contraceptive method (as defined in the list in item 
12c). Female condom and male condom should not be used together. This requirement begins at 
the time of informed consent and ends 120 days after receiving the last dose of IMP or 
pembrolizumab, whichever is the later. 
15. Male patients must refrain from donating sperm, and female patients must refrain from donating 
eggs, from Baseline until 120 days after the last dose of IMP or pembrolizumab, whichever is the 
later. 
Exclusion criteria: 
1. Diagnosis of immunosuppression or receiving systemic steroid therapy or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study treatment, with the 
exception of intranasal and inhaled corticosteroids or systemic corticosteroids at doses not to 
exceed 10 mg/day of prednisone or equivalent. Steroids as premedication for hypersensitivity 
reactions due to radiographic contrast agents are allowed. 
2. Anti-cancer monoclonal antibody treatment within 4 weeks prior to study Day 1. 
3. Chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to 
study Day 1 (radiation therapy can be allowed for palliative therapy of bone metastasis only). 
4. Not recovered from AEs Grade 2 or greater (except for alopecia) due to previously administered 
agents. 
5. Treatment with any investigational agent within 12 weeks of Screening Visit or 5 half-lives of 
the IMP (if known), whichever is longer, or current enrolment in an interventional clinical study. 
6. Prior treatment with setanaxib or participation in a previous setanaxib clinical study. 
7. Prior treatment with pembrolizumab. 
8. Known additional malignancy that is progressing or requires active treatment excepting basal cell 
carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer that has 
undergone potentially curative therapy, or malignancy treated with curative intent and with no 
known active disease ≥2 years before the first dose of IMP and of low potential risk for 
recurrence. 
9. Known active central nervous system metastases and/or carcinomatous meningitis. 
10. Active autoimmune disease requiring systemic treatment within the past 3 months or documented 
history of clinically severe autoimmune disease, or syndrome that requires systemic steroids or 
immunosuppressive agents. The following are exceptions to this criterion: 
a. 
Patients with vitiligo or alopecia. 
b. 
Any chronic skin condition that does not require systemic therapy. 
c. 
Patients with coeliac disease controlled by diet alone. 
11. Any evidence of current interstitial lung disease or pneumonitis, or a prior history of interstitial 
lung disease or non-infectious pneumonitis requiring high-dose glucocorticoids. 
12. Active infection requiring systemic therapy. 
13. Known human immunodeficiency virus (HIV) infection or acute or chronic hepatitis B or C 
infection. Patients with a past or resolved hepatitis B virus infection (defined as the presence of 
hepatitis B core antibody [HBcAb] and absence of hepatitis B surface antigen [HBsAg]) are 

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eligible provided the hepatitis virus DNA test is negative. Patients positive for hepatitis C 
antibody are eligible only if polymerase chain reaction (PCR) is negative for hepatitis C virus 
RNA. Patients with ongoing anti-viral therapy with potent inhibitors of cytochrome P450 (CYP) 
3A4 are not eligible. Testing for HIV is only required if clinically indicated and is not mandatory 
for this study. 
14. Serious chronic gastrointestinal conditions associated with diarrhoea. 
15. History of significant haematological problems, such as blood dyscrasias requiring treatment, 
aplastic anaemia, myelodysplastic syndrome, or leukaemia. 
16. Surgery (eg, stomach bypass) or medical condition that might significantly affect absorption of 
medicines (as judged by the investigator). 
17. A positive pregnancy test or breastfeeding for female patients. 
18. Evidence of any of the following cardiac conduction abnormalities: a QTc Fredericia interval 
>450 milliseconds for male patients or >470 milliseconds for female patients. Patients with a 
second- or third-degree atrioventricular block are to be excluded. 
19. TSH >ULN at Screening. 
20. Unstable cardiovascular disease as defined by any of the following: 
a. 
Unstable angina within 6 months prior to Screening 
b. 
Myocardial infarction, coronary artery bypass graft surgery, or coronary angioplasty 
within 6 months prior to Screening 
c. 
Cerebrovascular accident within 6 months prior to Screening 
d. 
New York Heart Association Class III or IV heart failure 
21. Presence of any laboratory abnormality or condition that, in the opinion of the investigator, could 
interfere with or compromise a patient’s treatment, assessment, or compliance with the protocol 
and/or study procedures. 
22. Any other condition that, in the opinion of the investigator, constitutes a risk or contraindication 
for the participation of the patient in the study, or that could interfere with the study objectives, 
conduct, or evaluation. 
23. Use of medications known to be potent CYP3A4 inhibitors or inducers, or potent uridine 
diphosphate (UDP)-glucuronosyltransferase 1A9 (UGT1A9) inhibitors or inducers, within 21 
days prior to IMP administration. 
24. Legal incapacity or limited legal capacity. 
25. Psychiatric illness/social situations that would limit compliance with study requirement, 
substantially increase risk of incurring AEs or compromise the ability of the patient to give written 
informed consent. 
26. Patients who are unable to provide informed consent, are incarcerated or unable to follow protocol 
requirements`` 
27. Previous randomisation in this study. 
Test product: 
Name: Setanaxib 
Setanaxib tablets will contain 400 mg setanaxib powder formulated with excipients and will be provided 
to each patient in high-density polyethylene (HDPE) bottles. 
Dose: 800 mg BID for up to 105 weeks. 
Mode of administration: Patients will self-administer 2 tablets of setanaxib 400 mg in the morning and 
2 tablets of setanaxib 400 mg in the evening (ie, 800 mg BID). Patients will self-administer setanaxib with 
food or up to 30 minutes after a meal. 
Patients will receive setanaxib in combination with pembrolizumab, administered as 200-mg intravenous 
(IV) infusion q3w. 
Control product: 

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Name: Placebo 
Matching placebo tablets, containing only excipients, will also be provided in HDPE bottles. 
Placebo tablets are visually identical to setanaxib tablets. 
Dose: 2 tablets of matching placebo BID 
Mode of administration: Patients will self-administer 2 tablets of matching placebo in the morning and 
2 tablets of matching placebo in the evening. Patients will self-administer matching placebo with food or 
up to 30 minutes after a meal. 
Patients will receive placebo in combination with pembrolizumab, administered as 200-mg IV infusion 
q3w. 
Statistical methods: 
Sample size 
An overall sample size of approximately 50 patients (25 per treatment group) is considered sufficient to 
assess the primary endpoint of the best percentage change in tumour size following treatment with 
setanaxib when administered with pembrolizumab, versus placebo when administered with 
pembrolizumab, in patients with recurrent or metastatic SCCHN. With 25 patients per treatment group, 
using a 2-sided t-test, there will be 85% power to detect a 20% mean difference between the treatment 
groups in best percentage change in tumour size, with an estimated standard deviation of 30% and a 2-
sided alpha of 20%. To mitigate risks from a higher than expected number of patients discontinuing the 
study early or declining to have imaging or biopsies at Week 9, an additional up to 20 patients (making a 
maximum of 70 patients) may be randomised.  
The key secondary endpoints of numbers of CAFs, CD8+ TILs, and regulatory T-cells in tumour tissue, 
and gene expression analysis in tumour tissue will be used to determine proof-of-concept. With 25 
patients per treatment group, there will be 90% power to detect a limit fold change (LFC) of more than 
1.5 in gene sequencing endpoints measured in tumour tissue, assuming at least 20 patients have an 
evaluable Baseline and post-Baseline tissue sample. 
For the key secondary endpoint of PFS, if the true hazard ratio for PFS is 0.5, at least 38 progression 
events as defined by RECIST v1.1 will be required to have >80% power to demonstrate a statistically 
significant difference in PFS with 2-sided p<0.2. 

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For qualitative variables, the population size (N for sample size and n for available data) and the percentage 
(of available data) for each class of the variable will be presented. Quantitative variables will be 
summarised using descriptive statistics, including n, mean, standard deviation (SD), median, minimum, 
and maximum values. Graphical presentations of the data will be produced to aid interpretation. 
An initial data cut-off will occur approximately 9 weeks after completion of enrolment, when all patients 
are expected to have had at least 3 cycles of pembrolizumab, at least one post-treatment scan, and the 
opportunity for a post-treatment tumour biopsy. At this point, the primary endpoint of best percentage 
change in tumour size and some secondary endpoints will be analysed. An updated analysis may be 
performed after 38 progression events have been reported. During ongoing review of the overall 
progression event count, if the predicted timing of the initial and updated analyses are expected to be close 
in proximity, one analysis may be performed. Investigators and patients will continue to be blinded to 
randomised study treatment after initial unblinding of data for the primary analysis until the final database 
lock. 
For the primary endpoint of best percentage change in tumour size, the absolute values at Baseline and 
Week 9 and best percentage change in target lesion tumour size will be summarised using descriptive 
statistics and presented by treatment group in summary tables and waterfall plots. The primary endpoint 
will be used to assess the effect of the setanaxib + pembrolizumab versus placebo + pembrolizumab. The 
primary efficacy analysis will be based on the Full Analysis Set (FAS) and will evaluate the effect of 
setanaxib on best percentage change in tumour size from an analysis of covariance (ANCOVA) model 
including a term for the best percentage change tumour size, a covariate for Baseline tumour size and a 
term for treatment. The number of patients, unadjusted mean, and adjusted least-square means (lsmeans) 
for each treatment group will be presented, together with the difference in adjusted lsmeans, 80% 
confidence interval, and corresponding p-value from the fitted ANCOVA model. 
The key secondary endpoint of PFS will be summarised by Kaplan-Meier plots presented by treatment 
groups. Median PFS and the proportion of patients who are progression-free at 3, 6, and 12 months will 
be summarised along with 80% confidence intervals presented for each treatment group. Patients who 
have not progressed by the time of the data cut-off for the updated analysis will be censored. The 
comparison between the treatment groups of PFS will be performed by fitting a Cox proportional hazard 
model with treatment group as the only covariate. The hazard ratio for PFS, based on the profile partial 
likelihood from the fitted using Cox proportional hazards model, will be calculated as a measure of the 
treatment effect along with the respective 95% Wald confidence interval and the asymptotic p-value from 
the Wald test for the difference in the log hazards in the fitted model. 
The secondary endpoint of OS will not be formally compared between the groups but will be 
summarised in a Kaplan-Meier plot together with descriptive statistics, as described for PFS. 
The secondary endpoints of ORR, DoR, and DCR will be summarised using descriptive statistics for each 
treatment group and associated 90% Agresti-Coull confidence interval. 
For the key secondary endpoints of numbers of CAFs, CD8+ TILs, and regulatory T-cells, and the 
secondary endpoint of PD-L1 expression analysis in tumour tissue, it is hypothesised based on the mode 
of action of setanaxib that there will be a reduction in CAFs level and an increase in the number of CD8+ 
TILs. Data will be summarised descriptively and will be graphically presented by boxplots displayed for 
each treatment group and individual patient profiles displaying pre- and post-doses counts. Changes 
within treatment groups (ie, across paired tissue samples) and between treatment groups will be 
summarised. An ANCOVA model will be used to assess for significant differences after adjustment for 
Baseline differences. The treatment effect from the fitted ANCOVA model will estimate the treatment 
difference based on mean score. A logarithmic transformation will be applied prior to analysis, if 
appropriate. 
For the secondary endpoint of changes in patterns of gene expression and differential gene expression in 
tumour tissue, data will be displayed graphically and will be assessed by principal components analysis 
to identify distinction between clusters of genes. 
Changes in tumour biomarkers will be correlated with change in tumour size and other efficacy 
parameters. 

Sponsor Name: Calliditas Therapeutics Suisse SA 
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Protocol Version and Date: Version 4.0 (25 April 2023)  
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Safety Analysis: 
The Safety Analysis Set will be used for the analysis of safety data (AEs, including AESIs, clinical 
laboratory tests, vital signs, 12-lead ECGs, and physical examination). The safety data will be presented 
descriptively and not formally analysed.  
Protocol version and date: Version 4.0 (25 April 2023)  
 

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STUDY SCHEMATIC 
Figure 1 
Study Schematic 
 
AE=adverse event; CAFs=cancer-associated fibroblasts; IV=intravenously; PFS=progression-free survival; 
PO=per os (orally, or via either a feeding tube or a percutaneous endoscopic gastrostomy device in case 
patients are unable to swallow tablets); q3w=every 3 weeks; R=randomisation; RECIST v1.1=response 
evaluation criteria in solid tumours version 1.1 
* For patients with a suitable archival tumour biopsy sample available, the archival sample may be used to 
assess CAFs level and determine eligibility (Note: this can only be performed after the patient has provided 
signed informed consent). This will not dispense from the need for a recent pre-study tumour biopsy. 
** Or earlier if progression occurs before 9 weeks. 
 
 
Screening 
Treatment 
Follow-up 
Randomised, double-blind 
Setanaxib 800 mg PO, twice daily 
Matching placebo 
All enrolled patients 
Pembrolizumab 200 mg IV, q3w 
28 days for AEs 
No treatment 
Tumour biopsy 
9 weeks** 
(±1 week) 
≤35 days 
Biopsy of 
tumour* 
CAFs level 
in tumour 
No 
treatment 
R 
Until at least 38 
progression 
events for PFS and 
survival 
Until RECIST v1.1 
defined disease 
progression for 
tumour response 

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SCHEDULE OF ASSESSMENTS 
Table 1 
Schedule of Assessments 
 
Study Period Screening 
Double-blind Treatment Period 
EoTa 
Follow-upa 
Study Weeks: 
-5 to -1 
BL 
3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 
63, 66, 69, 72, 75, 78, 81, 84, 87, 90, 93, 96, 99, 102 
105 
EoT 
Visit 
Last IMP 
Dose+28 
(±7 days) 
Refer to 
Footnote 
‘L’l 
Study Days 
(Visit Window): -35 to -1 
1 
Every 21 days 
(±5) 
735 
(±3) 
Visit: 
1 
2 
3 to 36 
37 
EoT 
Safety 
Follow-up 
Efficacy 
Follow-up 
Informed consent 
X 
 
 
 
 
 
 
Determination of eligibilityb 
X 
Xb 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
Demographics, ECOG performance 
status, and relevant medical history 
X 
X 
 
 
 
 
 
Height  
X 
 
 
 
 
 
 
Body weight 
X 
 
X 
X 
X 
X 
 
Body temperature 
X 
X 
X 
X 
X 
X 
 
Physical examination / symptoms-
directed physical examinationc 
X 
X 
X 
X 
X 
X 
 
Pulse rate, SBP, and DBP 
X 
X 
X 
X 
X 
X 
 
12-lead ECGd 
X 
X 
X 
X 
X 
X 
 
Blood sampling: 
 
 
 
 
 
 
 
  Pregnancy test (serum)e 
Xe 
 
 
 
 
 
 
  Haematology and biochemistryf 
X 
X 
X 
X 
X 
X 
 
  Thyroid function testf 
 
X 
X 
X 
X 
X 
 

Sponsor Name: Calliditas Therapeutics Suisse SA 
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Table 1 
Schedule of Assessments 
 
Study Period Screening 
Double-blind Treatment Period 
EoTa 
Follow-upa 
Study Weeks: 
-5 to -1 
BL 
3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 
63, 66, 69, 72, 75, 78, 81, 84, 87, 90, 93, 96, 99, 102 
105 
EoT 
Visit 
Last IMP 
Dose+28 
(±7 days) 
Refer to 
Footnote 
‘L’l 
Study Days 
(Visit Window): -35 to -1 
1 
Every 21 days 
(±5) 
735 
(±3) 
Visit: 
1 
2 
3 to 36 
37 
EoT 
Safety 
Follow-up 
Efficacy 
Follow-up 
  PKg 
 
X 
X (at Week 3, at time of second tumour biopsy [ie, 9 weeks after the 
start of study treatment, or earlier if progression occurs before 9 
weeks], at Week 24, and at Week 51) 
X 
X 
 
 
  Exploratory circulating biomarker 
blood samplesh 
 
X 
X (9 weeks [±1 week] after the start of study treatment, or earlier if 
progression occurs before 9 weeks) 
 
 
 
 
Urine collection: 
 
 
 
 
 
 
 
  Urinalysisi 
X 
 
 
X 
X 
X 
 
  Pregnancy test (urine)j 
 
X 
X 
X 
X 
X 
 
Tumour biopsyk 
X 
 
X (9 weeks [±1 week] after the start of study treatment, or earlier if 
progression occurs before 9 weeks) 
 
 
 
 
Tumour assessment 
X 
 
Xl 
 
 
Xm 
Xm 
Survival assessmentn 
 
 
X 
X 
X 
X 
X 
Treatment dispensation 
 
 
 
 
 
 
 
  Pembrolizumabo 
 
X 
X 
 
 
 
 
  IMP (setanaxib/placebo)p 
 
X 
X 
 
 
 
 
Prior and concomitant medicationsq,r 
X 
X 
X 
X 
X 
X 
X 
Recording of AEsr 
X 
X 
X 
X 
X 
Xs 
Xs 
AE=adverse event; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BID=twice daily; BL=Baseline; CAFs=cancer-associated 
fibroblasts; CT=computed tomography; DBP=diastolic blood pressure; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EoT=End-of-Treatment; 
GGT=gamma glutamyl transpeptidase; IMP=investigational medicinal product; INR=international normalised ratio; MRI=magnetic resonance imaging; PD1-L1=programmed 

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Table 1 
Schedule of Assessments 
 
Study Period Screening 
Double-blind Treatment Period 
EoTa 
Follow-upa 
Study Weeks: 
-5 to -1 
BL 
3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 
63, 66, 69, 72, 75, 78, 81, 84, 87, 90, 93, 96, 99, 102 
105 
EoT 
Visit 
Last IMP 
Dose+28 
(±7 days) 
Refer to 
Footnote 
‘L’l 
Study Days 
(Visit Window): -35 to -1 
1 
Every 21 days 
(±5) 
735 
(±3) 
Visit: 
1 
2 
3 to 36 
37 
EoT 
Safety 
Follow-up 
Efficacy 
Follow-up 
cell death-1 ligand 1; PK=pharmacokinetics; RBC=red blood cell; RECIST v1.1=response evaluation criteria in solid tumours version 1.1; SAE=serious adverse event; 
SBP=systolic blood pressure; T4=thyroxine; TILs=tumour-infiltrating lymphocytes; TSH=thyroid-stimulating hormone; WBC=white blood cell 
a Patients who permanently discontinue IMP prior to completion of the 105-week Double-blind Treatment Period will have an EoT Visit as soon as possible and a Safety 
Follow-up Visit at 28 days after the last IMP dose. Efficacy assessments will continue beyond this 28-day follow-up until disease progression. 
b Eligibility to enter the Double-blind Treatment Period will be determined during Visit 1, with a final check before randomisation on Day 1.  
c A complete physical examination, including assessments of the standard physical examination items (general appearance, skin, eyes, ears, nose, throat, head and neck, heart, 
chest and lungs, abdomen, extremities, lymph nodes, musculoskeletal, neurological, and other body systems, if applicable, for describing the status of the patient’s health), 
will be performed during Screening Visit 1 and at the Week 105 Visit (Visit 37). Patients who permanently discontinue IMP prior to or at the Week 105 Visit will have a 
complete physical examination at the EoT Visit. For Visits 2 to 36, when applicable, a symptoms-directed physical examination will be performed. 
d At Visit 2 (Study Day 1) and Visit 3, 12-lead ECG will be recorded pre-dose and 2 hours (± 30 minutes) post setanaxib/placebo dosing. From Visit 4 onwards, 12-lead ECG 
are only required before setanaxib/placebo dosing; additional ECGs may be recorded as clinically indicated. 
e A blood sample for the serum pregnancy test must be taken within 7 days of Day 1 (female patients of childbearing potential only). Therefore, if Screening Visit is performed 
more than 7 days prior to Day 1, the serum pregnancy test must be repeated within 7 days of Day 1. 
f Haematology: haematocrit, haemoglobin, absolute and relative reticulocyte counts, RBC count, WBC count, differential WBC count, platelet count, 
absolute neutrophil count, mean cell volume, and INR (INR only at Screening). 
Biochemistry: ALP, ALT, AST, amylase, total and conjugated bilirubin, GGT, glucose, total protein, albumin, creatinine, urea, total cholesterol, triglycerides, sodium, 
potassium, and chloride. 
Thyroid function test: TSH and free T4 
g Blood samples for PK assessment will be collected just before the start of pembrolizumab infusion and before the IMP morning dose at Day 1, Week 3, Week 24, Week 51, 
and Week 105, and PK samples may be collected at any time on the day of the second biopsy and at EoT Visit. 
h Blood samples (20 mL whole blood) will be collected for analysis of exploratory circulating biomarkers before commencing study treatment, during treatment (at Week 9) 
and at progression. 
i Qualitative tests will be performed using urine dipsticks. 
j Urine pregnancy test, for females of childbearing potential only, will be performed at each visit before dosing.  

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Table 1 
Schedule of Assessments 
 
Study Period Screening 
Double-blind Treatment Period 
EoTa 
Follow-upa 
Study Weeks: 
-5 to -1 
BL 
3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 
63, 66, 69, 72, 75, 78, 81, 84, 87, 90, 93, 96, 99, 102 
105 
EoT 
Visit 
Last IMP 
Dose+28 
(±7 days) 
Refer to 
Footnote 
‘L’l 
Study Days 
(Visit Window): -35 to -1 
1 
Every 21 days 
(±5) 
735 
(±3) 
Visit: 
1 
2 
3 to 36 
37 
EoT 
Safety 
Follow-up 
Efficacy 
Follow-up 
k A fresh tumour biopsy will be taken during or within 30 days prior to the Screening Period for assessment of tumour biomarkers (CAFs, CD8+ TILs, regulatory T-cells, and 
PD1-L1) and gene expression analysis. A second biopsy of tumour for assessment of tumour biomarkers and gene expression analysis will be performed 9 weeks (±1 week) 
after the start of study treatment, or earlier if progression occurs before 9 weeks. A third optional tumour biopsy can be performed at disease progression (only for patients 
who had their second biopsy at 9 weeks, and who consented to having a third sample). 
l Tumour response will be assessed on CT/MRI scan using RECIST v1.1 at Visit 5 (Week 9 ±1 week), and then every 6 weeks (±1 week) through the first year, and every 9 
weeks (±1 week) thereafter until RECIST v1.1-defined disease progression.  
m Tumour assessments will be conducted from the date of randomisation and continue until RECIST v1.1-defined disease progression, irrespective of treatment discontinuation. 
n Survival will be followed until at least 38 progression events. 
o Pembrolizumab 200 mg will be administered intravenously every 3 weeks 
p Setanaxib 800 mg BID or matching placebo will be administered orally (or via either a feeding tube or a percutaneous endoscopic gastrostomy device in case patients are 
unable to swallow tablets). 
q Prior medication will be recorded during Screening only. 
r AEs and changes to concomitant medications will be recorded at each visit. For patients who discontinued study treatment but remain followed for tumour assessment until 
RECIST v1.1-defined disease progression, AEs will be recorded up to 28 days after study treatment discontinuation, while any further anti-cancer medication will be recorded 
until progression.  
s Only SAEs with an onset after the EoT Visit that are considered related to IMP will be reported at the Safety/Efficacy Follow-up Visits. 
 

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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ...................................................................................1 
PROTOCOL SIGNATURE PAGE – SPONSOR ...........................................................3 
PROTOCOL SIGNATURE PAGE – CONTRACT RESEARCH 
ORGANISATION ..............................................................................................................4 
PROTOCOL SIGNATURE PAGE – INVESTIGATOR ...............................................5 
SERIOUS ADVERSE EVENT, ADVERSE EVENTS OF SPECIAL 
INTEREST, PREGNANCY, AND OVERDOSE CONTACT 
INFORMATION ................................................................................................................7 
PRODUCT COMPLAINTS ..............................................................................................8 
PROTOCOL AMENDMENT SUMMARY OF CHANGES .........................................9 
PROTOCOL SUMMARY ..............................................................................................11 
STUDY SCHEMATIC ....................................................................................................21 
SCHEDULE OF ASSESSMENTS .................................................................................22 
TABLE OF CONTENTS ................................................................................................26 
LIST OF TABLES ...........................................................................................................29 
LIST OF FIGURES .........................................................................................................29 
LIST OF ABBREVIATIONS .........................................................................................30 
1 
INTRODUCTION AND RATIONALE .................................................................35 
1.1 
Background ..........................................................................................................35 
1.1.1 
Squamous Cell Carcinoma of the Head and Neck ......................................35 
1.1.2 
Setanaxib (Investigational Medicinal Product) ...........................................36 
1.1.3 
Pembrolizumab ..............................................................................................38 
1.2 
Study Rationale ....................................................................................................40 
1.3 
Benefit/Risk Assessment ......................................................................................42 
2 
STUDY OBJECTIVES AND ENPOINTS .............................................................50 
2.1 
Primary Objective and Endpoint .......................................................................50 
2.2 
Secondary Objectives and Endpoints.................................................................50 
2.3 
Exploratory Objectives and Endpoints ..............................................................52 
3 
STUDY PLAN ...........................................................................................................54 
3.1 
Overall Study Design and Plan ...........................................................................54 
3.2 
Discussion of Study Design ..................................................................................56 
3.3 
End of Study .........................................................................................................59 
3.4 
Stopping Rules ......................................................................................................59 
4 
STUDY POPULATION ...........................................................................................60 
4.1 
Inclusion Criteria .................................................................................................60 
4.2 
Exclusion Criteria ................................................................................................62 
4.3 
Screen Failures .....................................................................................................65 
4.3.1 
Premature Discontinuation of Investigational Medicinal Product ...........65 
4.3.2 
Premature Discontinuation from the Study ................................................66 
4.3.3 
Lost to Follow-up ...........................................................................................67 
5 
DESCRIPTION OF STUDY ASSESSMENTS ......................................................68 
5.1 
Demographics and Other Screening Assessments ............................................68 

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5.1.1 
Demographics .................................................................................................69 
5.1.2 
Eastern Cooperative Oncology Group Performance Status ......................69 
5.1.3 
Medical History ..............................................................................................69 
5.2 
Efficacy Assessments ...........................................................................................69 
5.2.1 
Tumour Imaging and Assessment of Disease ..............................................69 
5.2.1.1 
Initial Tumour Imaging ...........................................................................70 
5.2.1.2 
Tumour Imaging During the Study........................................................70 
5.2.2 
Tumour Biopsy ...............................................................................................71 
5.2.3 
Peripheral Blood for Circulating Biomarkers Analysis .............................73 
5.3 
Safety Assessments ...............................................................................................73 
5.3.1 
Adverse Events ...............................................................................................73 
5.3.2 
Clinical Laboratory Evaluations ..................................................................74 
5.3.2.1 
Detection and Management of Anaemia ................................................75 
5.3.2.2 
Detection and Management of Hypothyroidism ...................................76 
5.3.3 
Pregnancy .......................................................................................................76 
5.3.4 
Breastfeeding ..................................................................................................78 
5.3.5 
12-lead Electrocardiogram ............................................................................78 
5.3.6 
Vital Signs .......................................................................................................78 
5.3.7 
Physical Examination, Including Height and Body Weight ......................79 
5.4 
Pharmacokinetics .................................................................................................79 
6 
TREATMENTS ........................................................................................................80 
6.1 
Investigational Medicinal Product .....................................................................80 
6.1.1 
Description of Investigational Medicinal Product ......................................80 
6.1.2 
Preparation, Handling, and Storage ............................................................80 
6.1.3 
Labelling and Shipment ................................................................................81 
6.2 
Blinding .................................................................................................................81 
6.3 
Method of Assigning Treatment .........................................................................82 
6.4 
Dose and Administration .....................................................................................83 
6.4.1 
Dose Modification ..........................................................................................84 
6.4.2 
Dechallenge and Rechallenge ........................................................................84 
6.4.3 
Intervention After the End of the Study ......................................................84 
6.5 
Precautions and/or Lifestyle Considerations.....................................................84 
6.6 
Prior Medication ..................................................................................................84 
6.7 
Background Treatment .......................................................................................85 
6.8 
Concomitant Medication .....................................................................................85 
6.9 
Overdose ...............................................................................................................87 
6.10 
Compliance ...........................................................................................................88 
6.11 
Accountability ......................................................................................................88 
7 
ADVERSE EVENTS ................................................................................................89 
7.1 
Definitions .............................................................................................................89 
7.1.1 
Adverse Events ...............................................................................................89 
7.1.2 
Serious Adverse Events .................................................................................89 
7.1.3 
Suspected Unexpected Serious Adverse Reactions .....................................90 

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7.1.4 
Clinical Laboratory Abnormalities and Other Abnormal 
Assessments ....................................................................................................91 
7.1.5 
Adverse Events of Special Interest ...............................................................91 
7.2 
Assessment of Adverse Events ............................................................................91 
7.2.1 
Severity............................................................................................................91 
7.2.2 
Causality .........................................................................................................92 
7.3 
Documenting and Reporting Adverse Events ...................................................93 
7.4 
Reporting of Serious Adverse Events .................................................................94 
7.5 
Adverse Event and Serious Adverse Event Follow-up .....................................94 
7.6 
Safety Reporting Oversight .................................................................................94 
8 
STATISTICS .............................................................................................................96 
8.1 
General Procedures .............................................................................................96 
8.2 
Analysis Populations ............................................................................................97 
8.3 
Sample Size ...........................................................................................................97 
8.4 
Statistical Methods ...............................................................................................98 
8.4.1 
Statistical Hypothesis .....................................................................................98 
8.4.2 
Primary Endpoint ..........................................................................................98 
8.4.3 
Secondary Endpoints ...................................................................................100 
8.4.4 
Sensitivity Analysis ......................................................................................101 
8.4.5 
Supportive Analysis .....................................................................................102 
8.4.6 
Analysis of Safety .........................................................................................102 
8.4.7 
Pharmacokinetic Endpoints ........................................................................103 
8.4.8 
Handling of Missing Values ........................................................................104 
9 
ETHICS AND RESPONSIBILITIES ...................................................................105 
9.1 
Good Clinical Practice .......................................................................................105 
9.2 
Institutional Review Board/Independent Ethics Committee .........................105 
9.3 
Informed Consent ..............................................................................................105 
9.4 
Independent Data Monitoring Committee ......................................................107 
9.5 
Financing and Insurance ...................................................................................107 
9.5.1 
Contractual and Financial Details ..............................................................107 
9.5.2 
Insurance, Indemnity, and Compensation.................................................108 
9.5.3 
Financial Disclosure .....................................................................................108 
10 RECORDS MANAGEMENT................................................................................109 
10.1 
Source Documentation.......................................................................................110 
10.2 
Electronic Case Report Form Completion and Data Management ..............110 
10.3 
Study Files and Record Retention ....................................................................111 
11 AUDITING AND MONITORING ........................................................................112 
11.1 
Risk and Quality Tolerance Limits ..................................................................112 
11.2 
Protocol Adherence and Deviations .................................................................113 
12 AMENDMENTS .....................................................................................................114 
13 STUDY REPORT AND PUBLICATIONS ..........................................................115 
14 STUDY START AND TERMINATION ..............................................................116 
15 CONFIDENTIALITY ............................................................................................117 
16 REFERENCES .......................................................................................................118 

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17 APPENDICES .........................................................................................................123 
17.1 
APPENDIX I – Study Administrative Structure ............................................123 
17.2 
APPENDIX II – Eastern Cooperative Oncology Group Performance 
Status ...................................................................................................................125 
17.3 
APPENDIX III – Medications or Substances to Be Avoided or Used 
with Caution During Treatment with Setanaxib ............................................126 
17.4 
APPENDIX IV – RECIST v1.1 Methodology .................................................134 
LIST OF TABLES 
Table 1 
Schedule of Assessments ..........................................................................22 
Table 2 
Risk Assessment .......................................................................................44 
Table 3 
Calculation of Safety Margins Based on 39-Week Repeat Dose Study 
in Dogs .......................................................................................................58 
Table 4 
Type of Concomitant Medications to Avoid or Use with Caution with 
Setanaxib .................................................................................................126 
Table 5 
Use with Caution – Concomitant Medications with Known Risk of QT 
Interval Prolongation or Increased Risk of Torsades de Pointes ......128 
Table 6 
Avoid Usage – Guidance on Specific Concomitant Medications to 
Avoid with Setanaxib .............................................................................129 
Table 7 
Use with Caution – Sensitive CYP2C9, CYP2C19, CYP2B6, OAT3, 
BCRP, and P-gp Substrates ..................................................................131 
LIST OF FIGURES 
Figure 1 
Study Schematic .......................................................................................21 

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LIST OF ABBREVIATIONS 
ADL 
activities of daily living 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC(0-24)-ss 
area under the concentration-time curve over the last 24-h dosing 
interval at steady state 
BID 
twice daily 
CAF 
cancer-associated fibroblast 
CCl4 
carbon tetrachloride 
CD8 
cluster of differentiation 8 
Cmax-ss 
maximum plasma concentration at steady state 
Cmin-ss 
minimum plasma concentration at steady state  
CPS 
combined positive score 
CR 
complete response 
CRO 
contract research organisation 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA4 
cytotoxic T-lymphocyte antigen 4 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DBP 
diastolic blood pressure 
DCR 
disease control rate 
DoR 
duration of response 
EAPA 
Europe, Asia-Pacific, and Africa 
ECG 
electrocardiogram 

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ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form  
EGFR 
epidermal growth factor receptor 
EoT 
end-of-treatment 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FAS 
Full Analysis Set 
FoxP3 
forkhead box P3 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltransferase 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HDPE 
high-density polyethylene 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HPV 
human papillomavirus 
HPV-ve 
HPV-negative 
HPV+ve 
HPV-positive 
IB 
investigator’s brochure 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IPF 
interstitial pulmonary fibrosis 
IEC 
Independent Ethics Committee 
IgG4 
immunoglobulin G4 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
IV 
Intravenous(ly) 

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Ki 
inhibition constant 
LD 
longest diameter 
LFC 
limit fold change 
lsmeans 
least-square means 
mAb 
monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDR2 
multidrug resistance protein 2 
MRI 
magnetic resonance imaging 
myCAF 
myofibroblastic CAF 
NADPH 
nicotinamide adenine dinucleotide phosphate oxidase 
NASH 
nonalcoholic steatohepatitis 
NOAEL 
no-observed-adverse-effect level 
NOX 
NADPH oxidase 
OAT3 
organic anion transporter 3 
OD 
once daily 
ORR 
overall response rate 
OS 
overall survival 
PBC 
primary biliary cholangitis 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics 
PD 
progressive disease 
PD-1 
programmed cell death 1 
PD-L 
PD-ligand 
PDGF 
platelet-derived growth factor 
PEG 
percutaneous endoscopic gastrostomy  
PET 
positron emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetics 
PO 
per os (orally) 

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PR 
partial response 
q3w 
every 3 weeks 
QoL 
quality of life 
QTL 
quality tolerance limit 
R/M 
recurrent and/or metastatic 
RBC 
red blood cell 
RECIST v1.1 
response evaluation criteria in solid tumours version 1.1 
ROS 
reactive oxygen species 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SCCHN 
squamous cell carcinoma of the head and neck 
SD 
stable disease 
SD 
standard deviation 
SEER 
Surveillance Epidemiology and End Results 
sh 
short hairpin 
si 
small interfering 
αSMA 
alpha smooth muscle action 
SmPC 
summary of product characteristics 
SOC 
system organ class 
STAM 
stelic animal model 
SUSAR 
suspected unexpected serious adverse reaction 
T4 
thyroxine 
TEAE 
treatment-emergent adverse event 
TGF-β 
tumour growth factor beta 
TIL 
tumour-infiltrating lymphocyte 
TLR 
toll-like receptor 
TSH 
thyroid-stimulating hormone 
UDCA 
ursodeoxycholic acid 
UDP 
uridine diphosphate 

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UGT 
UDP-glucuronosyltransferase 
ULN 
upper limit of normal 
US FDA 
United States Food and Drug Administration 
WBC 
white blood cell 

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1 INTRODUCTION AND RATIONALE 
1.1 
Background 
1.1.1 
Squamous Cell Carcinoma of the Head and Neck 
Head and neck cancer describes a range of tumours that arise in the head and neck region, 
which includes the oral cavity, pharynx, larynx, nasal cavity, paranasal sinuses, thyroid, 
and salivary glands. Cancer of the head and neck is the sixth most common type of 
malignancy, representing approximately 6% of all cases; worldwide, approximately 
830,000 patients develop head and neck cancer each year, and approximately 430,000 
will die from this disease (Bray et al 2018). Although the head and neck region contains a 
wide diversity of structures and cell types, the vast majority (>90%) of head and neck 
cancers arise from the mucosa of the upper aerodigestive tract and are squamous cell in 
origin (squamous cell carcinoma of the head and neck [SCCHN]). 
The median age of diagnosis of SCCHN is in the seventh decade, and there is an 
approximately two-fold higher incidence in men. Alcohol and tobacco use are thought to 
be important risk factors implicated in approximately 75% of cases of SCCHN; infection 
with cancer-causing types of human papillomavirus (HPV), especially HPV type 16, is 
also an important risk factor for oropharyngeal cancers that involve the tonsils or base of 
the tongue. 
Two-thirds of patients with SCCHN present with locally advanced, Stage III or IV 
disease, commonly involving regional lymph nodes. Distant metastasis at initial 
presentation is uncommon, arising in approximately 10% of patients. The 5-year survival 
for all stages combined on the basis of Surveillance Epidemiology and End Results 
(SEER) data is about 60%. 
The treatment of SCCHN at initial presentation usually comprises a combination of 
chemotherapy, radiotherapy and/or surgery, which is often considered “definitive”. 
Surgery is a standard treatment for SCCHN but may be limited by the anatomical extent 
of tumour and desire to achieve organ preservation; radiotherapy is similarly an integral 
part of primary or adjuvant treatment of SCCHN. Initial chemotherapy regimens are 
usually reserved for locally advanced disease and typically comprise a combination of 
platinum plus paclitaxel or fluorouracil. 
Treatment is associated with significant morbidity and a relatively static 5-year survival 
rate of approximately 50% to 60% in patients with HPV-negative (HPV-ve) disease 
(patients with HPV-positive [HPV+ve] tumours have significantly better survival) (Ward 
et al 2014, Ferlay et al 2015). At least 50% of patients with locally advanced SCCHN 
develop locoregional or distant relapses, which are usually detected within the first 2 
years of treatment (Argiris et al 2008, Chow 2020). A minority of patients present with 
locally recurrent, non-metastatic SCCHN that is amenable to salvage surgery and/or re-

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irradiation, where long-term survival is possible; however, for the majority of patients, 
treatment options are limited and historical survival rates have been poor. 
In the setting of recurrent and/or metastatic disease (R/M), first-line treatment with 
platinum combined with fluorouracil or a taxane has typically resulted in a 30% response 
rate and median progression-free survival (PFS) of 3 to 4 months, and median overall 
survival (OS) of 6 to 8 months (Gibson et al 2005, Colevas 2006). Addition of the 
epidermal growth factor receptor (EGFR)-target therapy cetuximab to a platinum-based 
chemotherapy with fluorouracil (platinum–fluorouracil) has been shown to significantly 
prolong median OS from 7.4 months (chemotherapy-alone) to 10.1 months 
(chemotherapy plus cetuximab) with an increase in PFS from 3.3 to 5.6 months 
(Vermorken et al 2008). 
1.1.2 
Setanaxib (Investigational Medicinal Product) 
Setanaxib is a first-in-class, selective inhibitor of the human protein nicotinamide adenine 
dinucleotide phosphate (NADPH) oxidase (NOX) isoforms 1 and 4. It is a low molecular 
weight member of the pyrazolopyridine dione chemical class. It selectively inhibits 
human isolated NOX4 (Ki 0.09 μM) and NOX1 (Ki 0.15 μM) but is less active at 
inhibiting isolated human NOX2 (Ki 2.13 μM), NOX3 (Ki 0.36 μM), and NOX5 (Ki 
0.33 μM). This selectivity against NOX2 means that setanaxib does not compromise 
phagocyte function. There is no evidence from literature evaluating the effect of gene 
deletion of NOX isoforms to indicate that chronic inhibition of NOX1 and NOX4 is 
likely to result in safety concerns. 
Setanaxib is being investigated in fibrotic and inflammatory disorders, with clinical 
studies completed or underway in primary biliary cholangitis (PBC), type 2 diabetes with 
albuminuria, type 1 diabetes with micro-albuminuria, and interstitial pulmonary fibrosis 
(IPF). 
In vitro studies have shown that setanaxib attenuates the induction of multiple fibrogenic 
pathways including tumour growth factor beta 1 (TGF-β1), platelet-derived growth factor 
(PDGF), toll-like receptor 4 (TLR4), Hedgehog, and angiotensin 2. Specifically, 
setanaxib markedly reduced the induction of markers of myofibroblast activation 
including alpha smooth muscle action (αSMA), fibronectin, and pro-collagen 1. In 
addition, setanaxib has shown potent anti-inflammatory effects including reduced 
expression of adhesion molecules, cytokines, and chemokines. These effects were 
observed in human podocytes, primary human hepatic stellate cells, macrophages, human 
aortic endothelial cells, and in rat retinal microglial and Müller cells. 
These direct anti-inflammatory and anti-fibrogenic effects translate into anti-
inflammatory and anti-fibrotic activity in multiple in vivo models of liver fibrosis. 
Specifically, setanaxib attenuated the development of liver fibrosis induced by 
experimental cholestasis (bile duct ligation and multidrug resistance protein 2 [MDR2]-/- 
mouse models). Setanaxib also prevented liver inflammation and fibrosis in models of 

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nonalcoholic steatohepatitis (NASH) (stelic animal model [STAM] and fast food diet 
models) and in toxic hepatitis (carbon tetrachloride [CCl4]-induced liver injury). Reduced 
in vivo fibrogenesis was associated with a marked reduction in markers of myofibroblast 
activation. In addition, setanaxib prevented the induction of adhesion molecules, 
cytokines, and chemokines. These effects on innate immunity resulted in a profound 
reduction of macrophage infiltration. 
In addition, setanaxib was shown to prevent lung fibrosis in the bleomycin model of IPF. 
In contrast to the spontaneously reversible fibrosis induced in young mice, bleomycin 
causes irreversible fibrosis in aged mice. Setanaxib was able to reduce lung fibrosis in 
both young and aged mice, and also improved survival in aged mice. In these aged mice, 
setanaxib again prevented the activation and persistence of lung myofibroblasts and 
facilitated their clearance through apoptosis. These data are consistent with results 
obtained in mice lacking NOX4, who showed protection in the bleomycin model. NOX4 
over-expression in lung tissue of IPF patients has been reported by several groups, 
suggesting that NOX1/4 inhibition with setanaxib may delay or reverse fibrotic lung 
remodelling in these patients. 
Separately, studies in murine models of diabetic kidney disease have demonstrated that 
setanaxib reduces podocyte loss, glomerular and interstitial fibrosis, as well as 
inflammation and macrophage infiltration. Reduced inflammation and fibrosis were 
associated with reduced albuminuria, a highly validated marker of disease progression in 
man. 
Altogether, the available preclinical evidence in multiple models indicates that setanaxib 
exerts its direct anti-fibrogenic effects through the down-regulation of multiple fibrogenic 
and inflammatory pathways. 
A total of 120 healthy adult male subjects have been exposed to single oral doses of 
setanaxib ranging from 10 mg up to 1800 mg in the 5 completed Phase 1 studies. In the 
multiple dose study, setanaxib was administered at doses up to 900 mg daily over 10 
successive days. A sixth Phase 1 study has recently also been performed, to evaluate 
higher multiple oral doses of setanaxib than previously assessed. A total of 46 healthy 
male and female subjects were enrolled and received single oral doses of setanaxib of up 
to 1600 mg (N=30) or multiple oral doses of setanaxib of up to 800 mg twice daily (BID) 
(total daily dose 1600 mg) for 10 days (N=32). In the Phase 1 program, setanaxib was 
well tolerated with low incidence of AEs. There were no deaths, no serious AEs (SAEs), 
and no AE of severe intensity. Most were treatment-emergent adverse events (TEAEs) 
and were mild and self-limiting and were considered by the investigator to be not related 
to treatment. 
A total of 4 Phase 2 clinical studies have been initiated with setanaxib in PBC (one 
study), diabetic kidney disease (2 studies), and IPF (one study). 

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In PBC, setanaxib has been evaluated in a total of 111 patients with inadequate response 
to ursodeoxycholic acid (UDCA); patients were randomised to receive setanaxib 400 mg 
once daily (OD), 400 mg BID or matching placebo for 24 weeks in addition to continued 
treatment with a stable dose of UDCA. The primary efficacy endpoint was the percent 
gamma-glutamyltransferase (GGT) reduction from Baseline to Week 24; secondary 
efficacy endpoints included alkaline phosphatase (ALP) changes, liver stiffness measured 
by transient elastography (Fibroscan®), and quality of life (QoL). Overall, setanaxib was 
safe and well tolerated at all doses; treatment with setanaxib attenuated markers of 
cholestatic injury (GGT, ALP), markedly reduced liver stiffness in patients with elevated 
liver stiffness, and improved QoL by reducing fatigue and the emotional and social QoL 
domains. In addition, setanaxib did not worsen pruritus. 
For further details, refer to the investigator’s brochure (IB). 
1.1.3 
Pembrolizumab 
Pembrolizumab is a potent and highly selective humanised monoclonal antibody (mAb) 
of the immunoglobulin G4 (IgG4)/kappa isotype designed to directly block the 
interaction between programmed cell death 1 (PD-1) and its ligands, PD-L1 and PD-L2. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumours to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. The ligands for PD-1 (PD-L1 and PD-L2) 
are constitutively expressed or can be induced in a variety of cell types, including non-
hematopoietic tissues as well as in various tumours. 
The safety and clinical activity of pembrolizumab was first evaluated in patients with 
recurrent or metastatic SCCHN in an open-label, multicentre, Phase 1b study 
(KEYNOTE-012) (Seiwert et al 2016). In this study, 60 patients with PD-L1-positive 
SCCHN were enrolled and treated. The proportion of patients with an overall response by 
central imaging review was 18% (8/45 patients); the proportion was higher in HPV+ve 
(5/20 [25%]) than HPV-ve patients (7/36 [19%]). Pembrolizumab was well tolerated, with 
10 (17%) of 60 patients having Grade 3 to 4 drug-related AEs, the most common of 
which were increases in alanine aminotransferase (ALT) and in aspartate 
aminotransferase (AST), and hyponatraemia, each occurring in two of 60 patients; one 
patient developed a Grade 3 drug-related rash. A total of 27 (45%) of 60 patients 
experienced an SAE. There were no drug-related deaths. 
In a second study (KEYNOTE-055) in 171 patients with recurrent or metastatic SCCHN 
who had experienced disease progression within 6 months of platinum and cetuximab 
treatment, an overall response rate (ORR) of 16% and a median duration of response 
(DoR) of 8 months was observed following treatment with pembrolizumab 200 mg every 
3 weeks (q3w) (Bauml et al 2017). Response rates were similar in all HPV and PD-L1 
subgroups; median PFS was 2.1 months, and median OS was 8 months. At the time of the 
analysis, 109 patients (64%) experienced a treatment-related AE, with 26 patients (15%) 

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experiencing a Grade ≥3 event. Seven patients (4%) discontinued treatment, and one died 
of treatment-related pneumonitis. 
Two Phase 3 studies have further evaluated the efficacy and safety of pembrolizumab in 
patients with recurrent or metastatic SCCHN. In KEYNOTE-040 (Cohen et al 2019), 
495 patients with SCCHN who had progressed during or after platinum-containing 
treatment for recurrent or metastatic disease (or both), or whose disease recurred or 
progressed within 3 to 6 months of previous multimodal therapy containing platinum for 
locally advanced disease, were randomly assigned to treatment with pembrolizumab 
200 mg q3w or investigator’s choice of standard doses of methotrexate, docetaxel or 
cetuximab (“standard-of-care”). In this study, the median OS was 8.4 months with 
pembrolizumab and 6.9 months with standard-of-care (p=0.0161). Fewer patients treated 
with pembrolizumab than with standard-of-care had Grade 3 or worse treatment-related 
AEs (33 [13%] of 246 pembrolizumab-treated patients versus 85 [36%] of 234 standard-
of-care-treated patients). The most common treatment-related AE was hypothyroidism in 
33 (13%) patients with pembrolizumab and fatigue in 43 (18%) patients treated with 
standard-of-care. Treatment-related death occurred in 4 patients treated with 
pembrolizumab (unspecified cause, large intestine perforation, malignant neoplasm 
progression, and Stevens-Johnson syndrome) and 2 patients treated with standard-of-care 
(malignant neoplasm progression and pneumonia). 
KEYNOTE-048 was a Phase 3, randomised, open-label study conducted in patients with 
recurrent or metastatic SCCHN that was not curable by local therapy (Burtness et 
al 2019). Patients were randomly allocated (1:1:1) to pembrolizumab alone, 
pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), 
or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy); 
randomisation was stratified by PD-L1 expression, p16 status, and performance status. A 
total of 882 patients were allocated to receive pembrolizumab alone (n=301), 
pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); 
of these, 754 (85%) patients had a PD-L1 combined positive score (CPS) of 1 or more 
and 381 (43%) had CPS of 20 or more. 
At the second interim analysis, pembrolizumab alone improved OS versus cetuximab 
with chemotherapy in the CPS of 20 or more population (median 14.9 versus 10.7 
months, p=0.0007) and CPS of 1 or more population (median 12.3 versus 10.3 months, 
p=0.0086) and was non-inferior in the total population. Pembrolizumab with 
chemotherapy improved OS versus cetuximab with chemotherapy in the total population 
(13.0 versus 10.7 months, p=0.0034) at the second interim analysis and in the CPS of 20 
or more population (14.7 versus 11.0 months, p=0.0004), and CPS of 1 or more 
population (13.6 versus 10.4 months, p<0.0001) at final analysis. 
At final analysis, Grade 3 or worse all-cause AEs occurred in 164 (55%) of 300 treated 
patients in the pembrolizumab-alone group, 235 (85%) of 276 in the pembrolizumab with 
chemotherapy group, and 239 (83%) of 287 in the cetuximab with chemotherapy group. 

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Adverse events led to death in 25 (8%) patients in the pembrolizumab-alone group, 
32 (12%) patients in the pembrolizumab with chemotherapy group, and 28 (10%) patients 
in the cetuximab with chemotherapy group. 
Based on the efficacy and safety outcomes of KEYNOTE-048, it was concluded that 
pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for 
recurrent or metastatic SCCHN and pembrolizumab monotherapy is an appropriate first-
line treatment for PD-L1-positive recurrent or metastatic SCCHN. 
1.2 
Study Rationale 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades (Disis 2010). Accumulating evidence shows 
a correlation between tumour-infiltrating lymphocytes (TILs) in cancer tissue and 
favourable prognosis in various malignancies (Dong et al 2002, Sharpe & Freeman 2002, 
Brown et al 2003, Thompson et al 2007, Francisco et al 2010). In particular, the presence 
of cluster of differentiation 8 (CD8+) T-cells and the ratio of CD8+ effector T-
cells/forkhead box P3+ (FoxP3+) regulatory T-cells seems to correlate with improved 
prognosis and long-term survival in many solid tumours. 
Studies treating recurrent or metastatic SCCHN patients with anti-PD-1/PD-L1 
checkpoint inhibitors have produced ORR of approximately 15% (Ferris et al 2016, 
Cohen et al 2019), and these drugs are now approved for subsets of patients with 
advanced disease. Anti-PD-1/PD-L1 efficacy is predicated upon boosting a pre-existing 
anti-tumour immune response; the morphological correlate of this in cancer tissues is the 
presence of TILs; in numerous cancer types, including SCCHN, high TIL levels correlate 
significantly with longer survival (Ward et al 2014, Chakravarthy et al 2016, Ottensmeier 
et al 2016, Wood et al 2016, Chakravarthy et al 2018), and many patients who respond to 
checkpoint inhibitors fall into this category. This perhaps explains the better survival in 
HPV+ve SCCHN patients, where the majority of tumours (~85%) contain significant TIL 
levels (Ward et al 2014). TILlow tumours are commonly categorised as ‘immune desert’ 
(absent T-cells) or ‘immune excluded’ (excluded T-cells). For the latter group, strategies 
for promoting T-cell infiltration into tumours could significantly improve response to 
anti-PD-1 therapy. 
Although now recognised as a heterogenous cell population (Sahai et al 2020), the term 
cancer-associated fibroblast (CAF) has been used mostly to refer to cells with an 
‘activated’ myofibroblastic phenotype (myCAF). These contractile, αSMA-positive cells 
are generated principally through TGF-β signalling/mechanotransduction (Calvo et 
al 2013), and secrete extracellular matrix analogous to myofibroblasts found in healing 
wounds and fibrotic disorders. MyCAFs are a prominent component of most solid 
tumours and are generally associated with poor prognosis (Hanley et al 2018); multiple 
studies have shown their positive influence on tumour progression, promoting metastasis, 
immune evasion, and therapy resistance (Gaggioli et al 2007, Kraman et al 2010, Arwert 
et al 2020, Orimo et al 2005). Recent analyses of clinical studies and murine tumour 

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models indicate that myCAFs promote resistance to anti-PD-1 checkpoint 
immunotherapy (Mariathasan et al 2018, Dominguez et al 2020, Ford et al 2020, Kieffer 
et al 2020), and specifically exclude CD8+ T-cells from tumours, thereby promoting 
resistance to therapeutic vaccination and anti-PD-1 (Ford et al 2020). Notably, some 50% 
of HPV-ve SCCHN are dominated by the presence of myCAFs, which are invariably 
present in metastasis (Marsh et al 2011). Notably, ‘immune hot tumours’ frequently 
harbour sub-clonal immune-resistance mutations (Chakravarthy et al 2018); the relative 
paucity of immune-resistance mutations in ‘immune cold’ myCAF-rich tumours 
(presumably due to the lack of immune selection pressure for them) suggests that 
immunotherapy could be particularly effective in these tumours if lymphocyte exclusion 
could be overcome. 
Previous attempts to target myCAFs clinically have been unsuccessful (Hofheinz et 
al 2003, Narra et al 2007, Catenacci et al 2015); therapeutic possibilities include myCAFs 
depletion or inhibiting myCAFs differentiation and/or function. Recent studies have 
shown that CAFs are a plastic population of cells that are not fixed in a state of terminal 
differentiation (Öhlund et al 2017, Hanley et al 2018); a further possibility, therefore, is 
to skew myCAFs to a normal or immune permissive fibroblast phenotype (Grauel at 
al 2020), which may suppress tumour progression (Chen & Song 2019). 
Recently it has been shown that the reactive oxygen species (ROS)-producing enzyme 
NOX4, is a critical regulator of fibroblast-to-myofibroblast transdifferentiation (acting 
downstream of TGF-β1), regulates myCAFs accumulation in multiple tumour types, and 
is relatively specific to myCAFs (Hanley et al 2018, Ford et al 2020). Genetic (small 
interfering [si] RNA/short hairpin [sh] RNA) or pharmacological (setanaxib) inhibition of 
NOX4 suppresses myCAFs differentiation and slows growth of myCAF-rich tumours 
(Hanley et al 2018). Notably, inhibiting NOX4 in myCAFs, cultured ex vivo, reverts cells 
to a quiescent, fibroblastic phenotype, abrogating their tumour-promoting functions 
(Hanley et al 2018, Ford et al 2020), and suggesting that NOX4 is required not only 
during myCAFs differentiation, but is also needed to maintain the differentiated 
phenotype. Studies have shown that myCAFs can be targeted in vivo using setanaxib. 
Setanaxib suppressed intratumoral myCAFs accumulation and tumour growth (Chen & 
Song 2019), overcoming CD8+ T-cells exclusion and promoting an influx of intratumoral 
CD8+ T-cells into the tumour (Ford et al 2020). Treatment of mice with setanaxib 
overcame myCAF-mediated resistance to both anti-cancer vaccination (TC-1; E7 DNA 
vaccine) and anti-PD-1 (MC38) immunotherapies (Ford et al 2020). 
In summary, CAF-rich tumours respond poorly to anti-PD-1/PD-L1 immunotherapy, and 
currently there are no pharmacological means of targeting this cell type specifically. 
Studies suggest that CAF-mediated immunotherapy resistance results from the exclusion 
of CD8+ T-cells from the tumour mass. In preclinical studies, this phenomenon can be 
successfully overcome by reversing the CAF phenotype through NOX4 inhibition using 
setanaxib, a drug with considerable data in both healthy volunteers and patients, and 
which has an acceptable safety profile. A significant proportion of solid cancers are CAF-

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rich, and preclinical data suggest that the combination of NOX4 inhibition and 
immunotherapy would improve clinical outcome in these tumours. 
This study is being conducted to determine the tumour response in recurrent or metastatic 
SCCHN patients treated with setanaxib and pembrolizumab versus patients treated with 
placebo and pembrolizumab. 
The results of this study may be used to aid further development of setanaxib and 
potentially be used for submission to regulatory authorities. 
1.3 
Benefit/Risk Assessment 
Setanaxib is a selective inhibitor of NOX1 and NOX4 isoforms of the NADPH oxidase 
family of enzymes and is the first drug in this class of NOX inhibitors to enter the clinic. 
The NOX1 and NOX4 isoforms have been shown to play a key role in a broad range of 
inflammatory and fibrotic disorders (Krause & Bedard, 2008; Paik et al 2014; Liang et 
al 2016; Teixeira et al 2017). Inhibition of NOX1 and NOX4 with setanaxib has resulted 
in marked anti-inflammatory and anti-fibrotic effects in multiple in vitro and in vivo 
models of inflammatory and fibrotic disorders. Therefore, setanaxib is being investigated 
in inflammatory and fibrotic disorders, with several clinical studies completed or 
underway. 
CAFs are important cells in the tumour stroma of many cancers, and their presence is 
often associated with a poor prognosis. CAFs are involved in the adaptive anti-tumour 
immune response and contribute to the exclusion of CD8+ T lymphocytes from the 
tumour microenvironment, and therefore, represent a brake on the action of 
immunotherapies that target these lymphocytes. CAFs also affect the biology of dendritic 
cells by inhibiting their migration, maturation, and their ability to present the antigen. 
CAFs can also participate in the development of a fibrous capsule around tumours and 
within tumours around the vessels. This barrier affects the recruitment and activity of 
cells of the immune system. The NOX enzymes participate in establishing conditions that 
are favourable to the growth and to the local or remote extension of malignant tumours. It 
has been shown that NOX4 is strongly induced in many human cancers and plays a role 
in activation of CAFs. Pre-clinically, setanaxib has been shown to inhibit the activation 
of CAFs and thereby allows CD8+ T lymphocytes to reach and infiltrate the tumour. 
Immune checkpoint inhibitors are now a widely used therapy in many cancer settings, 
including SCCHN. However, of the proportion of cancer patients who can be treated with 
these agents, only a minority generally respond positively to the treatment. Identifying 
and overcoming the mechanisms that prevent immune checkpoint inhibitors being 
effective is a key goal within the oncology arena. The ability of tumours to exclude 
immune system elements is known to be a main cause of resistance to immunotherapies, 
such as immune checkpoints inhibitors that target inhibitory receptors such as cytotoxic 
T-lymphocyte antigen 4 (CTLA4) or PD1 and its ligand PD-L1. 

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Potential Benefits 
Patients with recurrent or metastatic SCCHN have a poor prognosis with a median 
survival of approximately 1 year. Immune checkpoint inhibitors have shown that they can 
enhance clinical outcomes in this disease setting and are well tolerated, but only a 
minority of patients (~20%) show a response to treatment. Increasing response to 
immune checkpoint inhibitors represents a major challenge, and there is a high unmet 
medical need for safe and efficacious treatment options in this disease setting. The 
addition of setanaxib therapy to pembrolizumab may enhance the ability of CD8+ T 
lymphocytes to reach and infiltrate the tumour and thereby increase the degree of 
response to pembrolizumab, thus increasing the proportion of patients who respond to 
pembrolizumab therapy, and thereby delaying the onset of disease progression and 
increasing OS. 
Participation in this study provides the patient with a standard-of-care treatment option in 
the form of the approved agent pembrolizumab, and a potential opportunity to take 
setanaxib, which is being evaluated for efficacy in this clinical study. While NOX1/4 
inhibition represents an attractive therapeutic strategy, therapeutic benefits in patients 
with SCCHN have yet to be demonstrated. During this study patients will undergo the 
regular medical evaluations and assessments for their cancer, as part of the study 
procedures. 
Potential Risks 
As summarised in Section 1.1.2, setanaxib has been extensively investigated in 
nonclinical and clinical studies. 
In the completed Phase 1 and Phase 2 studies, the safety profile of setanaxib has been 
shown to be acceptable, with no clinical safety signal and no dose limiting toxicity 
identified. The safety signals identified in the toxicology studies (thyroid function, 
electrocardiogram [ECG] abnormalities, haematological changes) have been carefully 
monitored in all clinical studies completed to date. No treatment-related clinical or 
pathological findings have been observed, irrespective of dose, treatment duration or type 
of clinical study. 
The dose of setanaxib under investigation in this study has been evaluated in healthy 
subjects but is higher than that used in clinical study of PBC patients in the GSN000300 
study; the duration of dosing in this study will be longer than in the healthy volunteer 
studies, with an anticipated median duration of dosing of 3 to 6 months dependent on 
clinical response of patients. Due to the higher setanaxib dose being evaluated in the 
current study and the longer duration of treatment, there is a potential risk of new safety 
signals that have not been observed to date in the previous clinical studies. 
Safety and tolerability data will be regularly reviewed by an unblinded Independent Data 
Monitoring Committee (IDMC), with the first assessment after approximately 12 patients 

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(6 per treatment group) have had the opportunity to complete at least 1 cycle of 
pembrolizumab +/- setanaxib, followed by periodic assessments at a frequency defined in 
the IDMC Charter (see Section 9.4). 
More detailed information about the known and expected benefits, risks, and reasonably 
expected AEs of setanaxib can be found in the IB. 
The safety profiles, potential overlapping toxicities with the combinations, toxicity 
management and risk mitigation for the individual agents and combinations are discussed 
in detail in Table 2. 
Table 2 
Risk Assessment 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
Study intervention: setanaxib 
Important Identified Risk  
None identified  
Across the setanaxib clinical 
program, the occurrence rates of 
adverse events have been low 
and similar between setanaxib 
and placebo. No treatment or 
dose-related adverse reactions 
have been observed to date. 
There have been no serious 
adverse drug reactions reported 
in the setanaxib development 
program to date. 
Not applicable. 
Important Potential Risk 
None identified 
Not applicable. 

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Potential Risk: 
Drug-drug interaction 
Cytochrome P450 (CYP) 3A4 
and uridine diphosphate (UDP)-
glucuronosyltransferase 1A9 
(UGT1A9) are the major 
metabolic pathways for 
setanaxib. Potent CYP3A4 and 
UGT1A9 inhibitors and inducers 
should be avoided. 
When administered at a dose of 
300 mg BID for 10 days or 800 
mg BID for 6 days, setanaxib 
increased the plasma area under 
the concentration-time curve 
(AUC) of the sensitive CYP3A4 
substrate midazolam by 34% and 
24%, respectively, and thus 
setanaxib is not considered to be 
an inhibitor of CYP3A4 in vivo 
at the 800 mg BID dose level. 
When administered at a dose of 
800 mg BID setanaxib increased 
the plasma AUC of the sensitive 
substrates of CYP2C9 (losartan) 
and CYP2C19 (omeprazole) by 
45% and 60%, respectively. 
Setanaxib is considered a weak 
inhibitor of these enzymes at the 
800 mg BID dose level. 
Setanaxib also has potential 
induction effects on CYP2B6. 
Thus, sensitive substrates of 
CYP2C9, CYP2C19 and 
CYP2B6 should be used with 
caution. 
Since setanaxib has been shown 
to inhibit organic anion 
transporter (OAT) 1 and OAT3 
in vitro, the effect of setanaxib 
800 mg BID has been assessed 
on substrates of OAT1 
(adefovir) and OAT3 
(sitagliptin) in healthy subjects. 
The AUC of adefovir and 
sitagliptin was increased by 18% 
and 33%, respectively, and thus 
setanaxib is considered a weak 
inhibitor of OAT3 and not to be 
an inhibitor of OAT1. It is 
recommended that medications 
that are primarily eliminated 
through OAT3 should be used 
with caution.. 
1. Setanaxib should not be 
administered concomitantly 
with potent CYP3A4 
inhibitors and inducers, nor 
with potent UGT1A9 
inhibitors and inducers. The 
medications being taken by a 
patient will be carefully 
evaluated by the investigator 
before the patient is enrolled 
into the study, and 
concomitant medications will 
be recorded throughout the 
study. 
2. Setanaxib should be used 
with caution when co-
administered with drugs that 
are sensitive substrates of 
CYP2C9, CYP2C19, 
CYP2B6, OAT3, BCRP or P-
gp. 
3. Appendix III and Section 6.8 
contain a list of common 
medications that should be 
avoided or used with caution. 

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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
In addition, setanaxib inhibited 
BCRP and MDR1 (P-
glycoprotein [P-gp]) in vitro. 
This may result in increased 
exposures of applicable 
concomitant medications, hence 
caution should be exercised with 
use of sensitive BCRP and P-gp 
substrates. 
 
Potential Risks based on 
preclinical studies: 
Abnormal thyroid function 
In canine toxicology studies, 
chronic administration of high-
dose setanaxib was occasionally 
associated with increases in 
plasma thyroid-stimulating 
hormone (TSH) levels, reduced 
plasma free thyroxine (T4) 
levels, and with thyroid cell 
follicular hypertrophy. 
Hypothyroidism is an identified 
risk for the concomitant study 
drug, pembrolizumab. The 
combined regimen could 
theoretically lead to an increased 
risk of hypothyroidism due to 
setanaxib use. 
1.  Patients with TSH levels > 
upper limit of normal (ULN) 
at Screening will be 
excluded. 
2. Patients included in the study 
will have regular laboratory 
blood tests that include 
thyroid function tests. 
3. In the case of TSH ≥10 
mIU/L, IMP administration 
will be interrupted while the 
patient undergoes evaluation 
for hypothyroidism.  
Electrocardiogram (ECG) 
abnormalities 
In canine studies, chronic 
administration of high doses of 
setanaxib was associated with 
reversible QT prolongation and 
atrioventricular block events. 
Significant, but limited, 
increases in QT interval were 
observed at 3-4 hours post-dose 
in dogs receiving doses of 100 
mg/kg or above. Setanaxib and 
its main active metabolite have 
no effect on the human ether-a-
go-go related gene (hERG) 
channel, with a half maximal 
inhibitory concentration (IC50) > 
300 µM. 
In clinical studies, there has been 
no evidence of clinically 
relevant changes in ECGs 
associated with setanaxib, 
including QT prolongations. 
1. Setanaxib will not be 
administered to patients 
taking concomitant drugs that 
prolong the QT interval. 
2. Patients included in the study 
will undergo regular 
monitoring for evidence of 
cardiac disorders by 12-lead 
ECGs. 
3. Appendix III contains a list of 
common medications that 
should be avoided. 

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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
Haematological changes 
In canine toxicology studies, 
administration of high-dose 
setanaxib was associated with a 
reduction in bone marrow 
erythroid precursors, reduced 
reticulocyte and red blood cell 
counts in peripheral blood, 
leading to severe aplastic 
anaemia in a dog. 
In clinical studies, there has been 
no evidence of bone marrow 
toxicity related to setanaxib 
exposure.  
1. Setanaxib should not be 
administered concomitantly 
with drugs that have known 
bone marrow toxicities. 
2. Patients included in the study 
will have regular laboratory 
blood tests that include 
haematology (including 
haemoglobin and 
reticulocytes count). 
3. Patients with a history of 
bone marrow disorder, 
including aplastic anaemia, or 
any current marked anaemia 
defined as haemoglobin <9.0 
g/dL will be excluded from 
the study. 
4. In the case of significant 
anaemia (Grade ≥3) not 
attributable to other causes, 
setanaxib administration will 
be interrupted while the 
patient undergoes further 
evaluation. 
Study intervention: setanaxib in combination with pembrolizumab  
Pembrolizumab is an approved 
established standard-of-care for 
the indication under study, and a 
key risk of treatment is immune-
related adverse reactions 
(including immune-related 
pneumonitis, colitis, hepatitis, 
nephritis and endocrinopathies); 
severe and fatal cases have 
occurred in patients receiving 
pembrolizumab. Severe 
infusion-related reactions, 
including hypersensitivity and 
anaphylaxis have occurred. 
 
Potential overlapping toxicities 
for the combination are: Thyroid 
disorders. 
Risks identified based on clinical 
data from the pembrolizumab 
summary of product 
characteristics (SmPC). 
 
Thyroid disorders, including 
hypothyroidism, 
hyperthyroidism and thyroiditis, 
have been reported in patients 
receiving pembrolizumab and 
can occur at any time during 
treatment. Hypothyroidism is 
more frequently reported in 
patients with SCCHN with prior 
radiation therapy. 
Risk minimisation activities are 
reflected in the study protocol 
specific inclusion and exclusion 
criteria, alongside the safety 
monitoring strategy and toxicity 
management guidelines (Section 
5.3.2.2). 
1. Patients with TSH levels 
>ULN at Screening will be 
excluded. 
2. Patients included in the study 
will have regular laboratory 
blood tests that include 
thyroid function tests. 
3. In the case of TSH ≥10 
mIU/L, IMP administration 
will be interrupted while the 
patient undergoes evaluation 
for hypothyroidism 
 
Pembrolizumab-induced adverse 
drug reactions will be managed 
in line with the respective 
product labelling. 
Further details can be found in 
the setanaxib investigator’s 

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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
brochure and the pembrolizumab 
SmPC. 
Study intervention: study procedures - tumour biopsy 
Injury from requirement for up 
to 2 tumour biopsies to be 
performed during the study. 
An inclusion criterion is that 
patients have high or moderately 
elevated tumour CAFs level and 
secondary objectives of the 
study include analysis of 
tumour-related biomarkers 
before and after treatment. These 
require patients to have up to 2 
biopsies of the tumour during the 
study. 
The risks of biopsy are 
primarily: 
• 
Bleeding 
• 
Infection 
• 
Accidental injury to 
adjacent structures  
Biopsies are routinely performed 
in patients with SCCHN for 
diagnostic purposes and will be 
performed by clinicians skilled 
in performing biopsies. Patients 
with tumour location or other 
factors that make it challenging 
to safely perform a biopsy will 
not enter the study. Archival 
tumour material can be used 
where available to check that 
patients are eligible for the study 
and thus minimise the number of 
patients who have a biopsy but 
are found to be ineligible.  
It is the sponsor’s position that setanaxib does not have immunosuppressive properties. In 
addition, the available literature and expert assessment concludes that patients taking 
pembrolizumab and other immune checkpoint inhibitors should be considered for Covid-
19 vaccination. Many cancer patients are extremely vulnerable and, therefore, the overall 
consensus is that the benefits of the Covid-19 vaccine will potentially outweigh the risks. 
All approved Covid-19 vaccines are allowed in setanaxib studies. It is important that the 
cancer treatments and Covid-19 vaccinations are not delayed. 
There is no foreseeable risk in the use of a placebo group in the study design because all 
of the patients will be treated with pembrolizumab. 
There are currently no important identified or potential risks for setanaxib. The identified 
and potential risks for pembrolizumab and tumour biopsy are established. Important risk 
mitigation is included in pembrolizumab product labelling. Risks due to tumour biopsies 
are minimised by limiting these procedures to experienced, qualified physicians. Risk 
minimisation activities are reflected in the study protocol specific inclusion and exclusion 
criteria, restrictions on concomitant medications alongside the safety monitoring strategy 
and toxicity management guidelines (Section 5.3.2.1 and Section 5.3.2.2). These risks are 
monitored via routine pharmacovigilance and managed via routine risk minimisation 
activities and standard treatment practices. 
Overall Benefit/Risk Conclusion 
Despite advances in treatments, outcomes for patients with SCCHN have remained 
mostly unchanged for the past few decades, especially for HPV-ve SCCHN, and short-
term and long-term treatment-associated morbidities are still substantial. Most patients 

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still present with advanced-stage disease and are treated with platinum-based 
chemotherapy regimens. In the randomised Phase 3 KEYNOTE-048 study of patients 
with untreated locally incurable recurrent or metastatic SCCHN, pembrolizumab 
monotherapy improved OS in patients with a PD-L1 CPS of 1 or more and had non-
inferior OS in the total study population compared with standard-of-care therapy with 
cetuximab, a platinum, and 5-flurouracil. Compared with standard therapy, the incidence 
of AEs of any grade and of Grade 3 or worse was lower with pembrolizumab 
monotherapy. In the CPS of 1 or more population, median OS with pembrolizumab alone 
was 12.3 months versus 10.3 months for cetuximab with chemotherapy (hazard ratio 
0.78; 95% confidence interval 0.64 to 0.96, p=0.0086). Nevertheless, there remains a 
considerable unmet medical need for new therapies and/or combinations to further 
improve treatment outcome in this poor prognosis group of patients with recurrent or 
metastatic SCCHN. 
Considering the measures taken to minimise risk to the patients participating in this 
study, the potential risks identified in association with setanaxib are justified by the 
anticipated benefits that may be afforded to patients with SCCHN. All patients will 
receive a standard-of-care agent in the form of the approved treatment, pembrolizumab. 
The nonclinical profile and emerging clinical safety profile from the early clinical studies 
with setanaxib have not identified risks that would preclude investigation in this setting. 
Moreover, the study design aims to minimise potential risks in several ways. Adverse 
drug reactions to setanaxib will be managed as per the toxicity management guidelines. 
Adverse drug reactions to pembrolizumab will be managed as per the local product labels 
or clinical practice guidelines at the discretion of the investigator. Furthermore, a dose 
modification strategy for the management of setanaxib and pembrolizumab related 
toxicities is in place for those risks deemed to be most likely or serious (Section 5.3.2.1, 
and Section 5.3.2.2). Appropriate inclusion and exclusion criteria in the study protocol 
ensure patient safety. For example, to be enrolled, patients must be eligible for 
pembrolizumab treatment (as per local investigator assessment), which is administered in 
both groups of the study. Second, the protocol includes safety monitoring in excess of 
standard-of-care monitoring, with the intent of protecting patients involved in the study. 
Taking into account the measures to minimise risk to the patients participating in this 
study, the potential risks identified in association with setanaxib and pembrolizumab are 
justified by the anticipated benefits that may be afforded to patients with SCCHN. 

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2 STUDY OBJECTIVES AND ENPOINTS 
2.1 
Primary Objective and Endpoint 
Primary Objective 
Primary Endpoint 
• To compare the change in tumour 
size per Response Evaluation Criteria 
in Solid Tumours Version 1.1 
(RECIST v1.1) in recurrent or 
metastatic SCCHN patients treated 
with setanaxib and pembrolizumab 
versus patients treated with placebo 
and pembrolizumab 
• Best percentage change in tumour 
size, defined as the best percentage 
change from Baseline in the sum of 
diameters of target lesions, as 
assessed by RECIST v1.1  
2.2 
Secondary Objectives and Endpoints 
Key Secondary Objectives 
Key Secondary Endpoints 
• To compare the PFS per RECIST 
v1.1 in recurrent or metastatic 
SCCHN patients treated with 
setanaxib and pembrolizumab versus 
patients treated with placebo and 
pembrolizumab 
• PFS, defined as time from 
randomisation to the first documented 
disease progression per RECIST v1.1 
or death due to any cause, whichever 
occurs first. PFS at 3, 6, and 12 
months and median PFS will be 
summarised 
• To compare the change from 
Baseline in CAFs level in tumour 
tissue from recurrent or metastatic 
SCCHN patients treated with 
setanaxib and pembrolizumab versus 
patients treated with placebo and 
pembrolizumab 
• Change from Baseline in CAFs level 
in tumour tissue 
• To compare the change from 
Baseline in the number of CD8+ TILs 
and regulatory T-cells in tumour 
tissue from recurrent or metastatic 
SCCHN patients treated with 
setanaxib and pembrolizumab versus 
patients treated with placebo and 
pembrolizumab 
• Change from Baseline in the number 
of CD8+ TILs and regulatory T-cells 
in tumour tissue 
Other Secondary Objectives 
Other Secondary Endpoints 
• To assess the ORR, the DoR and 
disease control rate (DCR) per 
RECIST v1.1 in recurrent or 
metastatic SCCHN patients treated 
• Proportion of the patients who have a 
complete response (CR) or partial 
response (PR) per RECIST v1.1 will 
be used to assess ORR 

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with setanaxib and pembrolizumab 
versus patients treated with placebo 
and pembrolizumab 
• The minimum time when CR or PR is 
first observered to the time of 
progression of disease (PD) or death 
will be used to assess DoR 
• Proportion of the patients in whom 
the best overall response is 
determined as CR, PR, or stable 
disease (SD) per RECIST v1.1 will be 
used to assess DCR 
• To assess the OS in recurrent or 
metastatic SCCHN patients treated 
with setanaxib and pembrolizumab 
versus patients treated with placebo 
and pembrolizumab 
• OS, defined as the time from 
Randomisation to death due to any 
cause. Patients without documented 
death at the time of the final analysis 
will be censored at the date of the last 
follow-up 
• To evaluate the safety and tolerability 
profile of setanaxib and 
pembrolizumab, versus placebo and 
pembrolizumab, in recurrent or 
metastatic SCCHN patients 
• AEs: monitoring for AEs at all visits 
• AESIs: 
o Anaemia 
o Hypothyroidism 
• Vital signs: pulse rate, systolic blood 
pressure (SBP), and diastolic blood 
pressure (DBP) 
• 12-lead electrocardiogram (ECG): 
clinically significant abnormalities 
• Physical examination: abnormal 
findings 
• Laboratory tests: 
o Haematology 
o Biochemistry 
o Urinalysis 
o Thyroid function test 
• To compare the change from 
Baseline in PD-L1 expression in 
tumour tissue from recurrent or 
metastatic SCCHN patients treated 
with setanaxib and pembrolizumab 
versus patients treated with placebo 
and pembrolizumab 
• Levels of PD-L1 expression in 
tumour tissue 
• To compare the change from 
Baseline in patterns of gene 
expression and differential gene 
expression in tumour tissue from 
recurrent or metastatic SCCHN 
• Gene expression quantification and 
analysis of patterns of gene activation 
for CAFs, CD8+ TILs, and regulatory 
T-cells 

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patients treated with setanaxib and 
pembrolizumab versus patients 
treated with placebo and 
pembrolizumab, using RNA 
sequencing 
• To assess the plasma exposure of 
setanaxib and its metabolite 
GKT138184 
• Pre-dose and post-dose plasma 
concentrations of setanaxib and 
GKT138184: 
o Area under the concentration-
time curve over the last 24-h 
dosing interval at steady state 
(AUC[0-24]-ss) 
o Minimum plasma concentration 
at steady state (Cmin-ss) 
o Maximum plasma concentration 
at steady state (Cmax-ss) 
2.3 
Exploratory Objectives and Endpoints 
Exploratory Objectives 
Exploratory Endpoints 
• To assess the relationship between 
setanaxib and GKT138184 plasma 
exposure and response, if data 
permits 
• Where data permit, the 
pharmacokinetics (PK) (setanaxib and 
GKT138184 plasma 
exposure)/pharmacodynamics (PD) 
(eg, changes in biomarkers, efficacy, 
and safety parameters) relationship 
may be explored graphically and/or 
using appropriate PK/PD modelling 
techniques 
• To compare the change from 
Baseline in patterns of gene 
expression and differential gene 
expression in tumour tissue from 
recurrent or metastatic SCCHN 
patients treated with setanaxib and 
pembrolizumab versus patients 
treated with placebo and 
pembrolizumab, using RNA 
sequencing 
• Gene expression quantification and 
analysis of patterns of gene activation 
for relevant immuno-oncology, 
inflammatory, and other relevant gene 
signatures 
• To compare changes in circulating 
biomarkers detectable in peripheral 
blood in recurrent or metastatic 
SCCHN patients treated with 
setanaxib and pembrolizumab versus 
• Evaluations of pre-, on-treatment, and 
progression peripheral blood samples 
for circulating biomarkers which may 
include but will not be limited to 
panels of cytokines, chemokines and 

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patients treated with placebo and 
pembrolizumab 
 
other soluble biomarkers; T-cell 
receptor repertoire analysis; and 
analysis of gene expression 
biomarkers associated with 
immunomodulatory effects 

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3 STUDY PLAN 
3.1 
Overall Study Design and Plan 
This is a randomised, double-blind, placebo-controlled, proof-of-concept, Phase 2 study 
assessing setanaxib co-administered with pembrolizumab in patients with recurrent or 
metastatic SCCHN. The safety and efficacy of setanaxib 800 mg BID will be assessed 
against matching placebo over up to 105 weeks of treatment. It is planned to randomise 
approximately 50 patients at up to approximately 35 investigational centres in North 
America and Europe. However, depending on the number of patients providing evaluable 
Week 9 biopsy and imaging data, an additional up to 20 patients (making a maximum of 
70 patients) may be randomised to ensure an adequate amount of data is available for the 
efficacy and biomarker analyses. 
The study design is outlined in Figure 1 (Study Schematic), and the visit schedule and 
planned assessments at each visit are detailed in Table 1. 
The study will consist of an up to 35-day Screening Period, an up to 24-month Treatment 
Period (Day 1 to Week 105), and a 28-day Safety Follow-up Period. The total duration of 
the study for patients remaining in the study until their final follow-up assessment will be 
up to approximately 114 weeks (approximately 2 years and 2 months). 
The investigator will obtain signed informed consent from the patient before any study 
procedures are performed. For further details regarding the informed consent process, see 
Section 9.3. Patients will be assessed for eligibility during the Screening Period. Patients 
will attend the Screening Visit within 35 days of Day 1, such that all of the results of the 
screening tests will be available at the time that patient eligibility is reconfirmed prior to 
dosing. If serum pregnancy (see Footnote ‘d’ of Table 1) retest is required, it should be 
repeated within 7 days prior to randomisation. 
As part of eligibility criteria, tumour tissue CAFs level must be assessed by a central 
laboratory and an elevated tumour CAFs level demonstrated. For Baseline biomarker 
determination and determination of eligibility, a fresh tumour biopsy will be required 
from all patients before dosing in the study (unless there is a tumour material available 
from a biopsy taken within 30 days prior to the Screening Visit, which can be used for the 
Baseline biomarker analysis). 
In addition, for patients with a suitable archival tumour biopsy sample available, the 
archival sample may be used to assess CAFs level and determine eligibility (Note: this 
can only be performed after the patient has provided signed informed consent). This will 
not dispense from the need for a recent pre-study tumour biopsy, collected during or 
within 30 days prior to the Screening Period, for patients eligible for the study. 
To be considered suitable for determination of CAF levels, archival biopsy must have 
been collected within 6 months prior to the Screening Visit (Visit 1), and the patient must 

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have received no further anti-cancer therapy since then (see Section 5.2.2 for more details 
on suitability). Elevated CAF levels in suitable archival tumour tissue will meet the 
eligibility requirement based on CAF levels, but an additional pre-study biopsy (during or 
within 30 days of the Screening Period) is needed for reliable Baseline biomarker 
analysis. 
Eligible patients will be randomised to the investigational medicinal product (IMP) 
setanaxib 800 mg BID, or placebo, according to a 1:1 randomisation ratio, stratified by 
HPV status. See Section 6.3 for further details on the method of assigning patients to the 
treatment groups, and see Section 6.4 for further details on the dose and administration of 
setanaxib and placebo. Treatment with pembrolizumab will be initiated on the same day 
(Day 1) as the first dose of IMP, and will be administered according to current clinical 
guidelines and labelling, ie, 200-mg intravenous (IV) infusion q3w. See Section 6.7 for 
further details on the dose and administration of pembrolizumab. 
Treatment with pembrolizumab will continue until: RECIST v1.1-defined disease 
progression as determined by the investigator (Eisenhauer et al 2009), unacceptable 
toxicity, or a maximum of 24 months. If progression is suspected, but not confirmed, 
study treatment may continue until confirmation of radiological progression. 
Treatment with setanaxib or placebo will continue throughout the period of 
pembrolizumab therapy. When pembrolizumab is discontinued, blinded study treatment 
will be discontinued at the same time. 
Baseline assessments will be performed on Day 1 (Visit 2). Post-Baseline assessments 
will be performed every 3 weeks up to pembrolizumab discontinuation. Following 
permanent IMP discontinuation at any time during the study, patients will undergo an 
End-of-Treatment (EoT) Visit as soon as possible and a Safety Follow-up Visit at 28 days 
after the last dose. Tumour assessments will be conducted from the date of randomisation 
and continue until RECIST v1.1-defined disease progression, irrespective of treatment 
discontinuation. Efficacy Follow-up for PFS and survival will continue until at least 38 
progression events have occurred. AEs will be recorded up to 28 days after study 
treatment discontinuation, while any further anti-cancer medication will be recorded until 
disease progression. 
Throughout the study, particular attention will be given to the detection and management 
of potential cases of anaemia (see Section 5.3.2.1), and potential cases of hypothyroidism 
(see Section 5.3.2.2). 
Safety and tolerability data will be regularly reviewed by an unblinded IDMC, with the 
first assessment after approximately 12 patients (6 per treatment group) have had the 
opportunity to complete at least 1 cycle of pembrolizumab +/- setanaxib, followed by 
periodic assessments at a frequency defined in the IDMC Charter (see Section 9.4). The 
IDMC may recommend change(s) to the setanaxib dose regimen or study conduct based 

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on the safety data reviews, as defined in the IDMC Charter. The role and responsibilities 
of the IDMC will be outlined in the IDMC Charter. 
After approximately 12 patients (6 per treatment group) have completed their Baseline 
and post-treatment biopsy, initial gene expression and biomarker data in tumour tissue 
may be reviewed by the sponsor, who will remain masked to randomised treatment 
assignment. A second review may be performed, if required. 
The investigator, site personnel, the sponsor and their representatives involved in 
monitoring and conducting the study, and the patients will be blinded to the IMP 
administered. See Section 6.2 for details on access to the treatment codes in the event of 
emergency unblinding. 
3.2 
Discussion of Study Design 
This study will be randomised, double-blind, and placebo-controlled. Study 
randomisation will prevent bias in treatment allocation. In addition, stratification by HPV 
status will help to ensure that the treatment groups are balanced in terms of population 
characteristics, thereby minimising factors that could confound the interpretation of study 
results. The double-blinding of the study with regard to setanaxib and placebo treatment 
assignments will minimise bias in the assessment of treatment effect. 
The patients included in this study will have recurrent or metastatic SCCHN. All patients 
included in this study will receive pembrolizumab. Therefore, setanaxib or placebo will 
be given as add-on therapy to a recognised and approved standard-of-care agent. 
The primary endpoint is best percentage change in tumour size. A population with 
measurable disease will be selected to generate the maximum tumour response data. The 
use of best percentage change in tumour size has been proposed as an endpoint to 
compare treatments and make decisions in early drug development (Claret et al 2009) as 
it has been shown to be a predictor of overall survival (Claret et al 2009; Wang et al 
2019) and offers greater statistical power that the traditional categorical response of ORR 
for comparison of treatment groups. Waterfall plots of best percentage change in tumour 
size clearly display both the magnitude and the variability of the response. Traditional 
efficacy endpoints of PFS, ORR, DoR, and DCR are retained as secondary endpoints. 
The secondary endpoints related to numbers of CAFs, CD8+ TILs, and regulatory T-cells 
in tumour tissue, and gene expression analysis in tumour tissue will be used to 
demonstrate the underlying mechanisms of action of setanaxib and support the primary 
objective. 
Setanaxib Dose Rationale and Justification of Safety Margins 
The tolerability, safety, and pharmacokinetics (PK) of setanaxib have been evaluated in 5 
completed Phase 1 studies. A total of 120 healthy adult males have been exposed to 

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single oral doses of setanaxib of up to 1800 mg and multiple oral doses of setanaxib of up 
to 900 mg daily for 10 days. A sixth Phase 1 study has recently also been performed, to 
evaluate higher multiple oral doses of setanaxib than previously assessed. A total of 46 
healthy male and female subjects were enrolled and received single oral doses of 
setanaxib of up to 1600 mg (N=30) or multiple oral doses of setanaxib of up to 800 mg 
BID (total daily dose 1600 mg) for 10 days (N=32). 
In the Phase 1 program, setanaxib has been generally well tolerated, with a low incidence 
of AEs. There have been no deaths, no SAEs, and no AE of severe intensity. Most were 
TEAEs and were mild and self-limiting and were considered not related to treatment by 
the investigator. 
In a clinical study in patients with PBC (GSN000300), a total of 111 patients with PBC 
and inadequate response to UDCA were randomised in equal proportions to receive 
placebo, setanaxib 400 mg OD, or setanaxib 400 mg BID for 24 weeks. This dosing 
regimen was considered safe and well tolerated, and the treatment was pharmacologically 
active (based on observed dose-related improvements in liver enzymes); however, the 
observed clinical efficacy in the target patient population was considered insufficient, and 
a Phase 2b/3 clinical study in patients with PBC is planned in which doses of up to 
800 mg BID for 52 weeks will be evaluated (GSN000350). 
In this study in SCCHN, setanaxib 800 mg BID will be evaluated. This is the same as the 
proposed highest dose in the planned Phase 2b/3 study in PBC (GSN000350) and 
represents a two-fold increase compared to the highest dose evaluated in the previous 
study in patients with PBC (GSN000300), where there were no safety signals of concern. 
At this dose, the expected exposures will be around the defined no-observed-adverse-
effect level (NOAEL) for both the parent (setanaxib) and metabolite (GKT138184); 
however, the NOAEL defining toxicology signals can be monitored in the clinical setting, 
and were not observed in either healthy volunteers at 800 mg BID for 10 days or patients 
at 400 mg BID for 24 weeks. 
In this study in SCCHN, setanaxib (or placebo) will be co-administered with 
pembrolizumab until pembrolizumab is discontinued. It is anticipated that approximately 
20 patients (80% of the 25 patients randomised to setanaxib) will receive treatment with 
setanaxib for ≥3 months, 12 patients (approximately 50%) for ≥6 months, and 8 patients 
(approximately 30%) for ≥12 months. The maximum duration of pembrolizumab 
treatment (and, hence, corresponding setanaxib/placebo treatment) is 24 months. 
 
For the proposed dose (setanaxib 800 mg BID [total daily dose 1600 mg]), toxicology 
studies in the dog, the most sensitive species, provide a safety margin of ≥1, when the 
combined concentration of setanaxib and its main active metabolite (GKT138184) is 
considered. The safety margin of setanaxib alone is also ≥1. However, for the main active 
metabolite GKT138184, the safety margin is calculated to be 0.7. Please see Table 3 for 
the calculation of safety margins based on the 39-week repeat dose study in the dog. 

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Table 3 
Calculation of Safety Margins Based on 39-Week Repeat Dose Study 
in Dogs 
Timepoint 
PK Parameter 
Exposure at NOAELa 
in 39-Week Dog 
Human Exposure 
at 800 mg BIDb 
Exposure 
Margins 
Week 1 
Setanaxib 
Cmax 
(µg/mL) 
77.3 
27.3 
2.8 
AUC 
(µg•h/mL) 
453.6 
193 
2.4 
GKT138184 
Cmax 
(µg/mL) 
8.2 
3.9 
2.1 
AUC 
(µg•h/mL) 
69.6 
38.2 
1.8 
Combined 
Cmax 
(µg/mL) 
85.5 
31.2 
2.7 
AUC 
(µg•h/mL) 
523.2 
231.2 
2.3 
Week 13 
Setanaxib 
Cmax 
(µg/mL) 
57.4 
27.3 
2.1 
AUC 
(µg•h/mL) 
286.8 
193 
1.5 
GKT138184 
Cmax 
(µg/mL) 
6.2 
3.9 
1.6 
AUC 
(µg•h/mL) 
47.9 
38.2 
1.3 
Combined 
Cmax 
(µg/mL) 
63.6 
31.2 
2.0 
AUC 
(µg•h/mL) 
334.7 
231.2 
1.4 
Week 39 
Setanaxib 
Cmax 
(µg/mL) 
50.6 
27.3 
1.9 
AUC 
(µg•h/mL) 
195.5 
193 
1.0 
GKT138184 
Cmax 
(µg/mL) 
4.6 
3.9 
1.2 
AUC 
(µg•h/mL) 
27.0 
38.2 
0.7 
Combined 
Cmax 
(µg/mL) 
55.2 
31.2 
1.8 
AUC 
(µg•h/mL) 
222.5 
231.2 
1.0 
AUC=area under the concentration-time curve; BID=twice daily; Cmax=maximum concentration; 
NOAEL=no-observed-adverse-effect level; PK=pharmacokinetics 
a 300 mg/kg/day. 
b Data derived from Day 8 data from GSN000310. 

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3.3 
End of Study 
A patient is considered to have completed the study if he/she has discontinued study 
treatment, completed all tumour assessments until RECIST v1.1-defined disease 
progression, and performed the EoT and Safety/Efficacy Follow-up Visits. The end of the 
study is defined as the date of the last visit or last procedure of the last patient in the 
study. 
3.4 
Stopping Rules 
At any time point during the study, recruitment will pause if at least one of the following 
events occurs: 
• 
Fatal event deemed related to study therapy by the Sponsor and, in discussion with 
the IDMC, probable or certain causality after full etiological work up. This will also 
result in a comprehensive review of safety. 
• 
Unexpected and life-threatening events deemed related to study therapy by the 
Sponsor and in discussion with the IDMC. 
Recruitment may restart following detailed review of the available data only upon the 
recommendation of the IDMC and a substantial protocol amendment. 

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4 STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
4.1 
Inclusion Criteria 
The following inclusion criteria must be met for a patient to be eligible for inclusion in 
the study: 
1. Male or female patients aged ≥18 years, inclusive, at the time of informed consent. 
2. Willing and able to give informed consent and to comply with the requirements of the 
study. 
3. Histologically- or cytologically-confirmed diagnosis of SCCHN (ie, primary tumour 
arising from the oral cavity [including tongue], nasal cavity, paranasal sinuses, 
oropharynx, hypopharynx, or larynx) that is recurrent or metastatic (including both 
HPV+ve and HPV-ve SCCHN), with or without nodal involvement, and with or without 
metastatic spread, and is not eligible for surgical resection. 
4. Candidates for first-line treatment for pembrolizumab for recurrent or metastatic 
SCCHN, at the discretion of the investigator. 
5. A positive CAFs level (defined as CAFs level in tumours ≥5%), performed at a 
central laboratory, with fresh tumour biopsy taken during or within 30 days prior to 
the Screening Period. If available, suitable archival tissue (taken within 6 months 
prior to the Screening Visit and where the patient has received no further anti-cancer 
therapy during this 6-month period)can be used to assess tumour CAFs level and 
determine patient eligibility (Note: patients found to have low CAF levels in archival 
tissue material should not proceed to have further biopsies or screening activities). 
6. Measurable disease, in accordance with RECIST v1.1, and with tumour accessible 
and of sufficient volume for pre-treatment and on-treatment biopsy. 
7. CPS ≥1, as determined on the archival or fresh tumour biopsy taken during or within 
30 days prior to the Screening Period. 
8. HPV status known at randomisation. 
9. Life expectancy of at least 6 months in the judgment of the investigator. 
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 

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11. Adequate organ and bone marrow function within 35 days of starting study treatment. 
Criteria “a” to “c” cannot be met in patients with ongoing or recent (within 14 days of 
screening test) transfusions or who require ongoing growth factor support: 
a. Absolute neutrophil count ≥1,000/mm3 (≥ 1.0×109/L). 
b. Platelet count ≥100,000/mm3 (≥ 100×109/L). 
c. Haemoglobin ≥9 g/dL, in the absence of transfusions for at least 2 weeks. Patients 
requiring ongoing transfusions or growth factor support to maintain haemoglobin 
≥ 9g/dL are not eligible. 
d. Total bilirubin ≤1.5×upper limit of normal (ULN) (if associated with liver 
metastases or Gilbert's disease, ≤3×ULN). 
e. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3×ULN. 
f. Serum creatinine ≤2.0 mg/dL or creatinine clearance ≥40 mL/min (measured or 
calculated according to the method of Cockcroft and Gault). 
12. Female patients of childbearing potential must use a highly effective method of 
contraception to prevent pregnancy for ≥4 weeks before randomisation and must 
agree to continue strict contraception up to 120 days after the last dose of IMP or 
pembrolizumab, whichever is the later. 
a. For the purposes of this study, women of childbearing potential are defined as 
“fertile, following menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilisation methods include hysterectomy, 
bilateral salpingectomy and bilateral oophorectomy.” 
b. Postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. In female patients who are not using hormonal 
contraception or hormonal replacement therapy but with suspected menopause 
and less than 12 months of amenorrhea, a high follicle stimulating hormone 
(FSH) level in the postmenopausal range will be required at Screening to confirm 
a postmenopausal state. Confirmation with more than one FSH measurement is 
required. 
c. Highly effective contraception is defined as methods that can achieve a failure rate 
of less than 1% per year when used consistently and correctly. These methods are: 
(1) Combined (oestrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal) 

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(2) Progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, or implantable) 
(3) Intrauterine device 
(4) Intrauterine hormone-releasing system 
(5) Bilateral tubal occlusion 
(6) Vasectomised partner 
(7) Sexual abstinence (refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments). The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the 
clinical study and the preferred and usual lifestyle of the patient.  
Periodic abstinence (calendar, symptothermal, post-ovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhoea method are not acceptable methods of contraception). 
13. Female patients of childbearing potential must have a negative serum pregnancy test 
at Screening and a negative urine pregnancy test at Baseline/Randomisation before 
dosing. 
14. Male patients with female partners of childbearing potential must be willing to use a 
condom and require their partner to use a highly effective contraceptive method (as 
defined in the list in item 12c). Female condom and male condom should not be used 
together. This requirement begins at the time of informed consent and ends 120 days 
after receiving the last dose of IMP or pembrolizumab, whichever is the later. 
15. Male patients must refrain from donating sperm, and female patients must refrain 
from donating eggs, from Baseline until 120 days after the last dose of IMP or 
pembrolizumab, whichever is the later. 
4.2 
Exclusion Criteria 
A patient who meets any of the following exclusion criteria will not be eligible for 
inclusion in the study: 
1. Diagnosis of immunosuppression or receiving systemic steroid therapy or any other 
form of immunosuppressive therapy within 7 days prior to the first dose of study 
treatment, with the exception of intranasal and inhaled corticosteroids or systemic 
corticosteroids at doses not to exceed 10 mg/day of prednisone or equivalent. Steroids 
as premedication for hypersensitivity reactions due to radiographic contrast agents are 
allowed. 

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2. Anti-cancer mAb treatment within 4 weeks prior to study Day 1. 
3. Chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks 
prior to study Day 1 (radiation therapy can be allowed for palliative therapy of bone 
metastasis only). 
4. Not recovered from AEs Grade 2 or greater (except for alopecia) due to previously 
administered agents. 
5. Treatment with any investigational agent within 12 weeks of Screening Visit or 
5 half-lives of the IMP (if known), whichever is longer, or current enrolment in an 
interventional clinical study. 
6. Prior treatment with setanaxib or participation in a previous setanaxib clinical study. 
7. Prior treatment with pembrolizumab. 
8. Known additional malignancy that is progressing or requires active treatment 
excepting basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in 
situ cervical cancer that has undergone potentially curative therapy, or malignancy 
treated with curative intent and with no known active disease ≥2 years before the first 
dose of IMP and of low potential risk for recurrence. 
9. Known active central nervous system metastases and/or carcinomatous meningitis. 
10. Active autoimmune disease requiring systemic treatment within the past 3 months or 
documented history of clinically severe autoimmune disease, or syndrome that 
requires systemic steroids or immunosuppressive agents. The following are 
exceptions to this criterion: 
a. Patients with vitiligo or alopecia. 
b. Any chronic skin condition that does not require systemic therapy. 
c. Patients with coeliac disease controlled by diet alone. 
11. Any evidence of current interstitial lung disease or pneumonitis, or a prior history of 
interstitial lung disease or non-infectious pneumonitis requiring high-dose 
glucocorticoids. 
12. Active infection requiring systemic therapy. 
13. Known human immunodeficiency virus (HIV) infection or acute or chronic hepatitis B 
or C infection. Patients with a past or resolved hepatitis B virus infection (defined as 
the presence of hepatitis B core antibody [HBcAb] and absence of hepatitis B surface 
antigen [HBsAg]) are eligible provided the hepatitis virus DNA test is negative. 

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Patients positive for hepatitis C antibody are eligible only if polymerase chain reaction 
(PCR) is negative for hepatitis C virus RNA. Patients with ongoing anti-viral therapy 
with potent inhibitors of CYP3A4 are not eligible. Testing for HIV is only required if 
clinically indicated and is not mandatory for this study. 
14. Serious chronic gastrointestinal conditions associated with diarrhoea. 
15. History of significant haematological problems, such as blood dyscrasias requiring 
treatment, aplastic anaemia, myelodysplastic syndrome, or leukaemia. 
16. Surgery (eg, stomach bypass) or medical condition that might significantly affect 
absorption of medicines (as judged by the investigator). 
17. A positive pregnancy test or breastfeeding for female patients. 
18. Evidence of any of the following cardiac conduction abnormalities: a QTc Fredericia 
interval >450 milliseconds for male patients or >470 milliseconds for female patients. 
Patients with a second- or third-degree atrioventricular block are to be excluded. 
19. TSH >ULN at Screening. 
20. Unstable cardiovascular disease as defined by any of the following: 
a. Unstable angina within 6 months prior to Screening 
b. Myocardial infarction, coronary artery bypass graft surgery, or coronary 
angioplasty within 6 months prior to Screening 
c. Cerebrovascular accident within 6 months prior to Screening 
d. New York Heart Association Class III or IV heart failure 
21. Presence of any laboratory abnormality or condition that, in the opinion of the 
investigator, could interfere with or compromise a patient’s treatment, assessment, 
or compliance with the protocol and/or study procedures. 
22. Any other condition that, in the opinion of the investigator, constitutes a risk or 
contraindication for the participation of the patient in the study, or that could interfere 
with the study objectives, conduct, or evaluation. 
23. Use of medications known to be potent CYP3A4 inhibitors or inducers, or potent 
uridine diphosphate (UDP)-glucuronosyltransferase 1A9 (UGT1A9) inhibitors or 
inducers, within 21 days prior to IMP administration. 
24. Legal incapacity or limited legal capacity. 

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25. Psychiatric illness/social situations that would limit compliance with study 
requirement, substantially increase risk of incurring AEs or compromise the ability of 
the patient to give written informed consent. 
26. Patients who are unable to provide informed consent, are incarcerated or unable to 
follow protocol requirements`` 
27. Previous randomisation in this study. 
4.3 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but 
who do not meet one or more criterion required for participation and are not subsequently 
entered in the study. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure patients, to meet the Consolidated Standards of 
Reporting Trials publishing requirements, and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any SAE. 
Patients who are screen failures may undergo full rescreening once at the discretion of 
the investigator and medical monitor if there is a reasonable expectation that the patient is 
potentially eligible for the study. In these cases, the rescreened patient should be assigned 
a new unique screening number. 
Of note, during the Screening Period, some assessments (eg, laboratory tests, ECGs, vital 
signs) can be repeated if abnormal without being considered as screen failure. In these 
cases, a whole new rescreening is not required. 
4.3.1 
Premature Discontinuation of Investigational Medicinal Product 
Patients should discontinue the IMP if any of the following occurs: 
1. The patient withdraws his/her consent to participate in the study. 
2. The patient develops an illness that would interfere with his/her continued 
participation in the study, at the investigator’s discretion. 
3. The patient is noncompliant with study procedures or medication, that in the opinion 
of the investigator, impacts patient safety and/or the integrity of the study results. 
4. The patient takes a prohibited medication that warrants the IMP discontinuation at the 
discretion of the investigator (see Section 6.7). 
5. The patient is confirmed to be pregnant. 
6. The sponsor or regulatory agency requests withdrawal of the patient. 

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7. The patient is withdrawn for safety reason per the investigator’s judgment. 
8. IMP rechallenge results in anaemia or hypothyroidism IMP interruption criteria being 
met again (see Section 6.4.2). 
At the time of premature IMP discontinuation, the patient should complete the 
assessments indicated at the EoT Visit (see Table 1). The patient will also be required to 
attend a Safety Follow-up Visit at 28 days after the last IMP dose. In addition, patients 
who discontinue study treatment prior to radiological progression will continue to be 
followed for tumour assessments until RECIST v1.1-defined disease progression, and for 
survival. 
Patients who withdraw consent should be asked whether they would still allow contact 
for determination of survival follow-up. If patients consent to survival follow-up, they 
will be withdrawn from study treatment and other study procedures but are not 
considered to have withdrawn from the study. 
Patients who discontinue IMP prematurely will not be replaced. 
For details of permitted IMP dechallenge and rechallenge, see Section 6.4.2. 
Patients who fail to meet the eligibility criteria should not under any circumstances be 
enrolled or receive study medication. There can be no exceptions to this rule. Where a 
patient does not meet all the eligibility criteria but is incorrectly started on-treatment, the 
investigator should inform the medical monitor and the Calliditas Study Physician 
immediately, and a discussion should occur between the medical monitor, the Calliditas 
Study Physician, and the investigator regarding whether to continue or discontinue the 
patient from treatment. The Calliditas Study Physician must ensure all decisions are 
appropriately documented. 
4.3.2 
Premature Discontinuation from the Study 
Participation in the study is strictly voluntary. A patient has the right to withdraw from 
the study at any time for any reason, without any reprisal. 
The investigator has the right to terminate participation of a patient for any of the 
following reasons: 
• 
Violation of the protocol jeopardising patient safety and/or integrity of study results 
• 
Any other reason relating to the patient's safety 
• 
Any other reason relating to the integrity of the study data 

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Investigators should make every effort to discuss with the study monitor/sponsor before 
discontinuing a patient from the study. 
If a patient is withdrawn from the study, the study monitor/sponsor will be informed 
immediately. If there is a medical reason for withdrawal, the patient will remain under the 
supervision of the investigator until satisfactory health has returned. 
If the patient withdraws consent for disclosure of further information, the sponsor may 
retain and continue to use any collected data before such a withdrawal of consent. If a 
patient withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
Although a patient is not obliged to give his/her reason(s) for withdrawing prematurely 
from a study, the investigator should make a reasonable effort to ascertain the reason(s), 
while fully respecting the patient's rights. 
At the time of premature study discontinuation, the investigator should make every effort 
to ensure the patient completes the assessments indicated at the EoT Visit (see Table 1). 
Patients who prematurely discontinue from the study cannot subsequently re-join the 
study. 
For details on the discontinuation of study sites or the study as a whole, see Section 14. 
4.3.3 
Lost to Follow-up 
A patient will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a patient fails to return to the clinic for a required 
study visit: 
• 
The site must attempt to contact the patient and reschedule the missed visit as soon 
as possible, counsel the patient on the importance of maintaining the assigned visit 
schedule, and ascertain whether or not the patient wishes to and/or should continue in 
the study. 
• 
Before a patient is deemed lost to follow-up, the investigator (or designee) must 
make every effort to regain contact with the patient (where possible, 2 telephone 
calls and, if necessary, a certified letter to the patient’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the 
patient’s medical notes. 
• 
Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 

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5 DESCRIPTION OF STUDY ASSESSMENTS 
Refer to Table 1 for the schedule of assessments. 
Patients will be reminded to bring the IMP with them to each study visit. On visit days, 
patients will take their morning doses of IMP with food (or up to 30 minutes after a meal) 
after the study procedures have been completed. In general, study assessments may be 
performed on any days within the allowed visit windows around nominal visit dates, in 
particular tumour assessment (biopsy and imaging) may be carried out on a different day 
to the main study visit, refer to Section 5.2 for details of efficacy assessments.  
In general, the assessments will be conducted in the following order: 
• 
AEs/concomitant medications recording 
• 
Physical examinations/vital signs/ECGs 
• 
Laboratory assessments/Tumour assessment (tumour assessment must be performed 
before tumour biopsy when applicable) 
• 
Dispense IMP 
• 
Patient takes morning dose of IMP with food (or up to 30 minutes after a meal) 
(see Section 6.4) 
5.1 
Demographics and Other Screening Assessments 
Patients will attend the Screening Visit within 35 days of Day 1. If serum pregnancy (see 
Footnote ‘d’ of Table 1) retest is required, it should be repeated within 7 days prior to 
randomisation. Screening Period extensions of up to 7 days may be considered on a 
case-by-case basis, if agreed by the investigator and medical monitor. 
Demographics, ECOG performance status, and relevant medical history will be collected 
as described in Sections 5.1.1 and 5.1.1, respectively. 
Safety assessments, including laboratory assessments, that are also part of the screening 
assessments are described in Section 5.3. 
The screening assessment of tumour response will be assessed as described in 
Section 5.2.1.1. 
A fresh tumour biopsy will be taken during the Screening Period for assessment of 
tumour biomarkers (CAFs, CD8+ TILs, regulatory T-cells, and PD1-L1) and gene 
expression analysis, as described in Section 5.2.2. 

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Prior medications will be assessed at Screening, as described in Section 6.6. 
5.1.1 
Demographics 
Demographic data, including year of birth/age, sex, and race, will be recorded in the 
electronic case report form (eCRF). 
5.1.2 
Eastern Cooperative Oncology Group Performance Status 
ECOG performance status will be assessed as described in Appendix II and recorded in 
the eCRF. 
5.1.3 
Medical History 
Medical history, including any ongoing illnesses up to the time the patient has provided 
informed consent, will be recorded in the eCRF, with the start date and stop date (if 
applicable) of the illness/condition. 
Any pre-study procedures will be recorded in the eCRF as part of the medical history 
assessment. 
5.2 
Efficacy Assessments 
5.2.1 
Tumour Imaging and Assessment of Disease 
Tumour assessments will include all known or suspected disease sites. For all patients, 
study imaging assessments will include computed tomography (CT) or magnetic 
resonance imaging (MRI) scans. Other imaging assessments, eg, positron emission 
tomography (PET) CT and bone scans, may be performed if needed to further investigate 
or delineate abnormalities seen on CT/MRI. 
The same imaging technique regarding modality, ideally the same scanner, and the use of 
contrast should be used in a patient throughout the study to optimise the reproducibility 
of the assessment of existing and new tumour burden and improve the accuracy of the 
assessment of response or progression based on imaging. During follow-up, lesions 
should be recorded on the eCRF page in the same order as they were recorded at 
screening. Note: for the purposes of assessing tumour imaging, the term “investigator” 
refers to the local investigator at the site and/or the radiological reviewer located at the 
site or at an offsite facility. Expedited confirmation of measurable disease based on 
RECIST v1.1 will be used to determine patient eligibility. 
The RECIST guidelines v1.1 for measurable (target) and non-measurable (non-target) 
lesions, and the objective tumour response criteria (CR, PR, SD, or PD) are presented in 
Appendix IV. The RECIST criteria will be used to programmatically determine ORR, 
DoR, and DCR. 

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5.2.1.1 
Initial Tumour Imaging 
Initial tumour imaging at Screening must be performed within 35 days prior to the date of 
treatment. The site study team must review screening images to confirm the patient has 
measurable disease per RECIST v1.1. This scan will also be used as the Baseline scan for 
the tumour assessments in this study. 
All measurable lesions confirmed and assessed by radiological methods (CT or MRI 
scans) up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all 
involved organs, should be identified as target lesions, recorded and measured at 
Baseline, and at the time points specified in the protocol. 
5.2.1.2 
Tumour Imaging During the Study 
The first on study imaging assessment should be performed at Visit 5 (Week 9 ±1 week), 
and then every 6 weeks (±1 week) through the first year, and every 9 weeks (±1 week) 
thereafter for up to 24 months. Tumour assessments will be conducted from the date of 
randomisation and continue until RECIST v1.1-defined disease progression, irrespective 
of treatment discontinuation. Any further anti-cancer medication will be recorded until 
progression. 
Imaging timing should follow the planned schedule relative to randomisation and should 
not be adjusted for delays in cycle starts. Imaging should continue to be performed until 
radiological progressive disease is confirmed by the investigator, withdrawal of consent, 
death, or notification by the sponsor, whichever occurs first. 
A patient will be determined to have progressed if they have progression of target lesions, 
unequivocal progression of existing non-target lesions, or the appearance of one or more 
new lesions during follow-up. Death will be regarded as a progression event in those 
patients who die before disease progression. Unequivocal malignant disease not 
identified prior to starting study treatment on additional anatomical imaging (eg, CT, 
MRI or bone scan confirmed by X-ray) prompted by symptoms, is considered disease 
progression and should be recorded as new lesions. If progression is uncertain, patients 
may continue on-treatment until the next scheduled assessment. If an unscheduled 
assessment is performed, it is important to return to the correct scanning schedule for 
subsequent scans relative to randomisation, so that the 2 treatment groups are 
comparable. If the investigator is in doubt as to whether progression has occurred, it is 
advisable to continue treatment and reassess at the next scheduled assessment, or sooner, 
if clinically indicated. 
To achieve ‘unequivocal progression’ on the basis of non-measurable disease, there must 
be an overall level of substantial worsening in non-target disease such that, even in the 
presence of SD or PR in target disease, the overall tumour burden has increased 
sufficiently to merit discontinuation of treatment. A modest increase in the size of one or 

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more non-target lesions is usually not sufficient to qualify for unequivocal disease 
progression status. 
Response will be calculated in comparison to the baseline tumour measurements obtained 
before starting treatment. Progression will be calculated in comparison to when the 
tumour burden was at a minimum (nadir). Overall visit response will be recorded on the 
eCRF. A copy of the CT/MRI scans and radiologist report performed for tumour 
assessment may be collected by a Calliditas appointed representative and analysed 
centrally for further scientific determination of changes in tumour size by volumetric 
assessment. 
Refer to Appendix IV for further details on RECIST v1.1 methodology. 
5.2.2 
Tumour Biopsy 
Up to 2 mandatory fresh tumour biopsies will be collected for assessment of tumour 
biomarkers (CAFs, CD8+ TILs, regulatory T-cells, and PD1-L1) and gene expression 
analysis. 
Tumour biopsies can be taken from primary tumour site, involved lymph node or 
metastasis site. Any decision to perform the on-treatment biopsy must consider the 
patient’s condition at that time point, and not be done if the risk to the patient appears 
unacceptable. Investigators must ensure appropriate clinical judgment is applied when 
considering whether to perform tumour biopsies as this is a surgical procedure that may 
not intrinsically benefit individual patients but may benefit medical research. 
The first biopsy will be collected during or within 30 days prior to the Screening Period 
and will be used to determine the CPS score and CAFs level in tumour tissue as part of 
eligibility criteria, in case no archival tissue was available. Other assessments will 
include: 
• 
Levels of PD-L1 expression in tumour tissue using the PD-L1 IHC 22C3 pharmDx 
assay (Agilent), a qualitative immunohistochemical assay using monoclonal mouse 
anti-PD-L1 clone 22C3 intended for use in the detection of PD-L1 protein in 
formalin-fixed, paraffin-embedded non-small cell lung cancer, gastric or 
gastroesophageal junction adenocarcinoma, oesophageal squamous cell carcinoma, 
cervical cancer, urothelial carcinoma, SCCHN, and triple-negative breast cancer 
tissues, using EnVision FLEX visualisation system on Autostainer Link 48 
• 
Number of CD8+ TILs and regulatory T-cells in tumour tissue 
• 
RNA sequence analysis 
To be considered suitable for initial determination of CAF levels, archival tissue biopsy 
material must have been collected within 6 months prior to the Screening Visit, and the 

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patient must have received no further anti-cancer therapy since then. To be considered 
suitable for full Baseline (pre-treatment) biomarker assessment, tumour biopsy specimens 
must have been collected within 30 days prior to Screening. Samples may be from the 
primary SCCHN site, regional lymph node, or metastatic site. 
Tumour sample may be from either a surgical resection or core needle biopsy or collected 
as an excisional or incisional tumour biopsy from either the primary or metastatic site 
during surgery or interventional procedure. Fine needle aspirates are not acceptable. 
Formalin-fixed paraffin-embedded needle core biopsies may have been obtained via 
direct visualisation of tumour, or with CT, fluoroscopy, or ultrasound image guided 
needle biopsy procedures. The tissue cores should have been obtained by the use of an 18 
gauge (or larger core diameter) biopsy needle. If smaller needle is used, then additional 
biopsy cores are to be provided in the block. 10% Neutral buffered formalin is 
recommended as the tissue fixative. 
Samples meeting any of the criteria below are not acceptable: 
• 
Archived tissue with limited tumour content: preferably at least 30% of viable 
tumour cells 
• 
Cytology samples and fine needle aspirates 
• 
Tissues fixed with other unacceptable fixatives, including 95% alcohol, alcohol 
formalin acetic acid, and PREFER™ 
• 
Specimens from bone lesions are generally not acceptable unless there is significant 
soft tissue component or there is no bone tissue in the biopsy 
The second biopsy (mandatory for all patients) will be performed 9 weeks (±1 week) 
after the start of study treatment or earlier if progression occurs before 9 weeks. 
A third optional tumour biopsy can be performed at disease progression (only for patients 
who had their second biopsy at 9 weeks, who consented to having a third sample). 
CAFs will identified in formalin-fixed, paraffin-embedded tissue sections using 
immunohistochemistry for αSMA. CAFs are positive for α-SMA, and tumour stroma will 
be assessed for CAFs as previously described (Marsh et al 2011). SMA staining and 
evaluation of CAF scores will be performed by a single pathologist (or a suitably 
qualified and trained deputising pathologist) at a central laboratory. The semi-quantitative 
scoring system separates tumours into 3 groups: low (<5% stroma positive), moderate (5 
to 50% stroma positive) and high (>50% stroma positive). Patients with tumours 
containing moderate or high levels of CAFs will be eligible for the study. 

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The tumour samples will be used for analyses of biomarkers related to SCCHN. The 
biomarker analyses results will be used to explore the potential relationship with 
setanaxib response and/or disease progression data obtained in this study. 
The samples may be analysed as part of a multistudy assessment of genetic factors 
involved in the response to setanaxib or IMPs of this class to understand study disease or 
related conditions. 
The tumour sample will be collected, processed, stored, sent for central review, and 
analysed as defined in the central laboratory manual. Refer to the central laboratory 
manual for further details. 
5.2.3 
Peripheral Blood for Circulating Biomarkers Analysis 
Blood samples (20 mL whole blood) will be collected for analysis of exploratory 
circulating biomarkers, before commencing study treatment, during treatment and at 
progression, as outlined in Table 1. The blood samples will be used for analyses of 
circulating biomarkers related to SCCHN. The results of biomarker analyses will be used 
to explore the potential relationship with setanaxib response and/or disease progression 
data obtained in this study. Samples collected before treatment will be analysed for 
predictive biomarkers of response to treatment and may be used to develop future in vitro 
diagnostic tests. Samples collected during treatment and at progression will be used for 
additional exploratory research which may include but is not limited to interrogation of 
changes in genetic expression and potential mechanisms of resistance to treatment. A 
range of oncology and immunological biomarkers that may corelate with drug response 
will be examined; these may include but are not limited to panels of cytokines, 
chemokines and other soluble biomarkers; T-cell receptor repertoire analysis; and 
analysis of gene expression biomarkers associated with immunomodulatory effects. 
The samples may be analysed as part of a multistudy assessment of genetic factors 
involved in the response to setanaxib or IMPs of this class to understand study disease or 
related conditions. 
The blood samples will be collected, processed, stored, sent for central review, and 
analysed as defined in the central laboratory manual. Refer to the central laboratory 
manual for further details. 
5.3 
Safety Assessments 
5.3.1 
Adverse Events 
AEs will be followed, recorded, and reported in line with the procedures described in 
Section 7. AESIs are defined in Section 7.1.5. 

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Particular attention will be given to the detection and management of potential cases of 
anaemia (Section 5.3.2.1), or potential cases of hypothyroidism (see Section 5.3.2.2). 
5.3.2 
Clinical Laboratory Evaluations 
Laboratory assessments will be performed by a central laboratory, unless otherwise 
specified. The central laboratory will analyse the samples or send them to reference 
laboratory(ies) for analysis, as indicated in the central laboratory manual. Laboratory 
assessments of PK are described in Section 5.4. 
Blood and urine samples will be collected pre-dose at the times indicated in Table 1. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. The blood volumes to be collected per patient during the study will be 
provided in the informed consent form (ICF) and/or in the central laboratory manual. For 
further details, refer to the central laboratory manual. 
Sampling for the analysis of clinical laboratory parameters will be performed before the 
administration of IMP. 
The following parameters will be assessed: 
Haematology: haematocrit, haemoglobin, absolute and relative reticulocyte counts, red 
blood cell (RBC) count, white blood cell (WBC) count, differential WBC count, platelet 
count, absolute neutrophil count, mean cell volume, and international normalised ratio 
(INR only at Screening) 
Biochemistry: ALP, ALT, AST, amylase, total and conjugated bilirubin, GGT, glucose, 
total protein, albumin, creatinine, urea, total cholesterol, triglycerides, sodium, potassium, 
and chloride 
Thyroid function test: TSH and free T4 
Pregnancy test (serum): See Section 5.3.3. 
Urinalysis: qualitative tests will be performed using urine dipsticks (refer to the central 
laboratory manual for more details) 
Pregnancy test (urine): See Section 5.3.3. 
In case the HPV status is not known or not documented in the medical records, HPV 
status will need to be determined before randomisation as per site standard operating 
procedures (eg, p16 immunohistochemistry or HPV DNA detection [PCR or in situ 
hybridisation]). The methodology used for HPV testing will be recorded in the eCRF. 
Refer to the central laboratory manual for details regarding the collection, processing, and 
shipping of the blood and urine samples. 

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The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those that are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the 
patient’s condition. 
All laboratory tests with values considered clinically significantly abnormal during the 
patient’s participation in the study or within 28 days after the last dose of IMP, whichever 
is later, should be repeated until the values return to normal, to Baseline levels, or have 
stabilised and are no longer considered clinically significant by the investigator or 
medical monitor. 
If such values do not return to normal/Baseline within a period of time judged reasonable 
by the investigator, then the aetiology should be identified, and the sponsor (or designee) 
notified. 
If required due to Covid-19-related restrictions, laboratory samples to follow up an 
AE, including the retests for haemoglobin (see Section 5.3.2.1), or TSH and free T4 (see 
Section 5.3.2.2), may be collected by a qualified healthcare professional at a location 
other than the study site. For other circumstances pertaining to patient safety during 
Covid-19-related restrictions, follow-up with the sponsor (or designee). 
Laboratory samples taken to follow up an AE, including the retests for absolute 
haemoglobin, or TSH and free T4 noted above, may be tested locally so that the results 
are communicated to the investigator’s site promptly. If required due to Covid-19-related 
restrictions, the results of local safety laboratory tests may be provided to the investigator 
by telephone. Local laboratory results will not be entered into the eCRF. However, where 
unscheduled central laboratory confirmation is not possible for protocol-specified retests 
for evaluation of potential anaemia or hypothyroidism, the retest results may be 
requested. 
5.3.2.1 
Detection and Management of Anaemia 
Particular attention will be given to the detection and management of potential cases of 
anaemia. In case of Grade ≥3 severity anaemia, the investigator will instruct the patient to 
interrupt IMP administration and to return to the study centre within 7 days so that 
haemoglobin can be retested. If the severity of anaemia is still Grade ≥3, and if an 
alternative cause for the anaemia cannot be documented (alternative cause may include 
the underlying cancer), IMP will not be resumed and will be permanently discontinued. 
IMP administration will be resumed only if the retest value for haemoglobin is ≥9 g/dL 
and an alternative cause for the anaemia can be documented. The patient will continue to 
be closely monitored (at least weekly) until normalisation of haemoglobin, ie, return to 
Baseline values. 

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Anaemia will be reported to the sponsor (or designee) as an AESI, as defined in 
Section 7.1.5, following the same procedure as for SAEs (Section 7.4). 
5.3.2.2 
Detection and Management of Hypothyroidism 
Particular attention will be given to the detection and management of potential cases of 
hypothyroidism. In case of TSH ≥10 mIU/L, the investigator will instruct the patient to 
interrupt IMP administration and to return to the study centre within 5 days so that TSH 
and free T4 values can be retested. If the retest value is ≥10 mIU/L and the patient 
presents with signs and symptoms consistent with hypothyroidism or if overt biological 
hypothyroidism is confirmed (ie, TSH ≥10 mIU/L and reduced free T4), IMP will not be 
resumed. If drug-induced hypothyroidism is not confirmed, IMP administration will be 
resumed as per protocol. The patient will continue to be closely monitored by at least 
their clinical status and TSH/free T4 levels (at least weekly) until normalisation of the 
TSH and free T4 values, ie, return to Baseline values. 
Hypothyroidism will be reported to the sponsor (or designee) as an AESI, as defined in 
Section 7.1.5, following the same procedure as for SAEs (Section 7.4). 
5.3.3 
Pregnancy 
All patients are required to meet the requirements relating to pregnancy and use of 
contraception described in the inclusion and exclusion criteria (see Section 4.1 and 
Section 4.2, respectively). Male and female patients of childbearing potential must 
receive pregnancy prevention counselling and be advised of the risk to the foetus if they 
become pregnant or father a child during treatment and for 6 months after the last dose of 
IMP or pembrolizumab, whichever is the later. Additional medications given during the 
study may alter the contraceptive requirements. These additional medications may 
require female patients to use highly effective methods of contraception and/or for an 
increased length of time. In addition, male patients are also required to use contraception. 
The investigator must discuss these contraceptive changes with the patient. 
For female patients who are considered postmenopausal but have less than 12 months of 
amenorrhea and who are not on concomitant oestrogen replacement therapy, a high FSH 
level in the postmenopausal range will be required at Screening. Confirmation with more 
than one FSH measurement is required. 
Serum (beta human chorionic gonadotrophin) or urine pregnancy tests will be performed 
for female patients of childbearing potential at the time points indicated in Table 1. 
Female patients of childbearing potential must have a serum pregnancy test at the 
Screening Visit. The blood sample for the serum pregnancy test must be taken within 
7 days of Day 1. Therefore, if Screening Visit is performed more than 7 days prior to 
Day 1, the serum pregnancy test must be repeated within 7 days of Day 1. The result 
must be negative for the patient to be eligible for the study. If the test result is positive, 

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the patient must be excluded from the study. The serum pregnancy tests will be analysed 
by the central laboratory. A negative urine pregnancy test result is required at 
Baseline/Randomisation and at each visit before dosing. Urine pregnancy tests will be 
analysed locally. 
Any pregnancies in female patients and the partners of male patients will be recorded 
from the patient’s inclusion in the study until 6 months after the last dose of IMP or 
pembrolizumab, whichever is the later. Male patients will be required to inform the 
investigator if their partner becomes pregnant during the study and for 6 months after the 
last dose of IMP or pembrolizumab, whichever is the later. The investigator should 
inform the sponsor (or designee) within 24 hours of learning of the pregnancy or partner 
pregnancy by completing and submitting a Pregnancy Report Form to the sponsor 
(or designee) using the contact details provided. (Note: Sites are not required to provide 
any information on the pregnancy notification form that violates the country or regions 
local privacy laws). 
If a patient becomes pregnant, she will permanently discontinue IMP and attend an EoT 
Visit as soon as possible and a Safety Follow-up Visit at 28 days after the last dose of 
IMP, after which the patient will be encouraged to continue study assessments until 
disease progression. 
After obtaining the female patient’s signed authorisation for release of pregnancy and 
infant health information, the investigator will collect pregnancy and infant health 
information and complete the pregnancy questionnaire for any female patient who 
becomes pregnant while taking IMP or pembrolizumab through 6 months following the 
last dose of IMP or pembrolizumab, whichever is the later. This information will be 
forwarded to sponsor (or designee). Generally, infant follow-up will be conducted up to 
12 months after the birth of the child (if applicable). 
Any termination of pregnancy will be reported to sponsor (or designee), regardless of 
foetal status (presence or absence of anomalies) or indication for procedure. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE. Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal death, 
stillbirth, congenital abnormalities, ectopic pregnancy) will be considered SAEs. 
Any SAE occurring as a result of a post-study pregnancy which is considered reasonably 
related to the study treatment by the investigator, will be reported to sponsor (or 
designee). While the investigator is not obligated to actively seek this information in 
former study patients, he or she may learn of a SAE through spontaneous reporting. 
For any male study patient’s partner who becomes pregnant, the investigator will attempt 
to collect pregnancy information on the male patient’s partner while the male patient is in 
this study until 6 months after the last dose of IMP or pembrolizumab, whichever is the 

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later. The investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor (or designee) within 24 hours of learning of the partner’s 
pregnancy. The investigator will obtain informed consent from the female partner to 
collect information about the pregnancy and its outcome. Information on the status of the 
mother and child will be forwarded to the sponsor (or designee). Generally, infant follow-
up will be conducted up to 12 months after the birth of the child (if applicable). Any 
termination of the pregnancy will be reported regardless of foetal status (presence or 
absence of anomalies) or indication for the procedure. Abnormal pregnancy outcomes 
(eg, spontaneous abortion, foetal death, stillbirth, congenital abnormalities, ectopic 
pregnancy) will be considered SAEs. 
5.3.4 
Breastfeeding 
Breastfeeding women will be excluded from the study. 
5.3.5 
12-lead Electrocardiogram 
12-lead ECG will be obtained as outlined in Table 1. 
At Visit 2 (Study Day 1) and Visit 3, 12-lead ECG will be recorded pre-dose and 2 hours 
(± 30 minutes) post setanaxib/placebo dosing. From Visit 4 onwards, 12-lead ECG are 
only required before setanaxib/placebo dosing; additional ECGs may be recorded as 
clinically indicated. 
The ECGs will be conducted in the supine position after 5 minutes’ rest. 
The ECG tracing printout should be signed and dated by the person who made the 
interpretation locally (for purposes of patient safety management); the tracing printout 
will be archived at the study site. The machines will provide heart rate, PR, QRS, QT, 
and QTc intervals. If the ECG tracing printouts are in a non-archivable quality, including 
fading ink, a certified copy should be printed, signed and dated by the person who made 
the copy and labelled “certified copy”. Electronically archived ECG tracings are 
acceptable as source data provided the electronic archival system is validated. 
If there is any evidence of the cardiac conditions or abnormalities noted in Section 4.3.1, 
IMP is to be permanently discontinued. 
Further details regarding the ECG assessments are provided in the site operations manual 
or manual provided by the vendor. 
5.3.6 
Vital Signs 
Vital signs will be measured as outlined in Table 1 with the patient in a sitting position 
after 5 minutes’ rest and will include pulse rate, SBP, and DBP. Body temperature will be 
measured at Screening Visit 1 according to local standard-of-care. 

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5.3.7 
Physical Examination, Including Height and Body Weight 
Patients will undergo complete physical examination or symptoms-directed physical 
examinations as outlined in Table 1. 
The complete physical examination will include assessments of the standard physical 
examination items, including general appearance, skin, eyes, ears, nose, throat, head and 
neck, heart, chest and lungs, abdomen, extremities, lymph nodes, musculoskeletal, 
neurological, and other body systems, if applicable, for describing the status of the 
patient’s health. 
Body weight and height (height at Screening Visit only) will also be measured and 
recorded. The patient should be dressed in light clothing, without shoes. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. Any new abnormalities or worsening of existing abnormalities that are 
associated with signs and/or symptoms (except for SCCHN related -pre-
existing- conditions, including disease progression) should be reported as AEs or SAEs, 
as appropriate (see Section 7). 
5.4 
Pharmacokinetics 
Blood samples will be collected for measurement of plasma concentrations of setanaxib 
and its metabolite GKT138184 for all patients during the study at the visits specified in 
Table 1. The PK blood volumes to be collected during the study will be provided in the 
ICF and/or in the central laboratory manual. 
PK samples will be collected just before the start of pembrolizumab infusion and before 
the IMP morning dose at Day 1, Week 3, Week 24, Week 51, and Week 105, and 
anytime for the PK samples taken on the day of the second biopsy and at EoT Visit. 
Instructions for the collection and handling of biological samples will be provided by the 
sponsor (or designee) and will be included in the central laboratory manual. The actual 
date and time that each sample is collected will be recorded. 
The measurement of plasma setanaxib and GKT138184 concentrations will be performed 
by a central laboratory. 
 

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6 TREATMENTS 
6.1 
Investigational Medicinal Product 
6.1.1 
Description of Investigational Medicinal Product 
 
Test Product 
 
IMP/non-IMP: 
IMP  
Name: 
Setanaxib 
Dose:  
800 mg BID (2 tablets in the morning and 2 tablets in the 
evening) 
Setanaxib tablets will contain 400 mg setanaxib powder 
formulated with excipients. 
Mode of administration: 
Orally (or via either a feeding tube or a percutaneous 
endoscopic gastrostomy device in case patients are unable 
to swallow tablets) 
 
Manufacturer: 
Aptuit 
Via Alessandro Fleming, 4 
37135 Verona VR 
Italy 
 
Placebo 
 
Substance: 
Matching placebo tablets, containing only excipients, will 
be provided. The placebo tablets will be visually identical 
to setanaxib tablets to maintain the blind. 
Dose:  
Not applicable 
Mode of administration: 
Orally (or via either a feeding tube or a percutaneous 
endoscopic gastrostomy device in case patients are unable 
to swallow tablets) 
Manufacturer: 
Aptuit 
Via Alessandro Fleming, 4 
37135 Verona VR 
Italy 
6.1.2 
Preparation, Handling, and Storage 
Refer to the pharmacy manual for full details regarding the preparation of setanaxib and 
placebo tablets. 
The investigator (or designee) is responsible for the safe and proper storage of IMP at the 
site. The bottles containing setanaxib and placebo tablets will be stored under controlled 
conditions according to the storage requirements described on the label. The IMP is to be 

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stored at room temperature (15-25°C). The tablets must not be frozen or stored above 
25ºC or 77ºF. The investigator (or designee) will instruct the patients to store the IMP in 
accordance to the instructions on the label. 
6.1.3 
Labelling and Shipment 
Setanaxib and placebo bottles will be labelled in accordance with all applicable 
regulatory requirements and Good Manufacturing Practice guidelines. 
Setanaxib and placebo will be provided in high-density polyethylene (HDPE) bottles 
containing: 
• 
Setanaxib 400 mg tablets 
• 
Matching placebo tablets 
Each bottle will contain 70 tablets. 
The labelling of the placebo will be the same as the test product to maintain the blind. 
Setanaxib and placebo will be shipped and stored under controlled conditions according 
to the storage requirements. The IMP is to be stored and shipped at room temperature 
(15-25ºC). 
Refer to the pharmacy manual for full details for labelling and shipment of the IMP. 
An authorised service provider will label the IMP bottles and will supply the IMP to local 
depots/study sites on behalf of the sponsor (or designee). 
6.2 
Blinding 
The study is double-blinded. The investigator, the site personnel, the sponsor and their 
representatives involved in monitoring and conducting the study, and the patients will be 
blinded to treatment assignments. 
Randomisation data will be kept strictly confidential, accessible only to authorised staff 
and the IDMC until the time of unblinding. Authorised staff may include the 
randomisation statistician, who will store the master randomisation list in a secure 
system, an unblinded statistician, and unblinded programmers, who will provide the 
IDMC with unblinded safety data for review, and as and when required, in accordance 
with the procedures described in the IDMC Charter. All authorised unblinded staff must 
be documented. 
The setanaxib and placebo tablets are visually identical to maintain the blind. Setanaxib 
and placebo bottles will be coded and labelled in a manner that protects blinding. The 

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coding system will permit rapid identification of the product (in case of medical 
emergencies), that does not permit undetectable breaking of the blind. 
Breaking of the blind is only allowed in the case of an emergency, when knowledge of 
the IMP is essential for the clinical management of the patient. In such emergency 
situations, the responsibility to break the treatment code resides solely with the 
investigator. The investigator will have immediate access to break the blind through the 
interactive response technology (IRT). The investigator must contact the sponsor within 
1 working day after the event, without revealing to the sponsor (or contract research 
organisation [CRO]) the results of the code break, except to the designated global patient 
safety representative. The investigator must document the date of unblinding and the 
reason. 
Emergency unblinding will be organised through IRT. The investigator must record the 
date of unblinding and the reason. All breaks of the blind must be adequately 
documented. 
If an SAE is reported, the designated global patient safety representative may unblind the 
treatment assignment for the individual patient through IRT to meet regulatory reporting 
requirements. 
6.3 
Method of Assigning Treatment 
Each patient will have a unique patient screening number obtained from the IRT. This 
will be assigned at the Screening Visit. If a patient is rescreened (see Section 4.3), the 
rescreened patient should be assigned a new unique screening number. The investigator 
will keep a record (the patient screening log) of patients who entered Screening. 
Once the patient has been successfully screened and the investigator has determined that 
the patient is eligible, the patient will be confirmed as enrolled within the IRT. 
Randomisation will be performed via a centralised IRT. On Day 1, eligible patients will 
be assigned to setanaxib or placebo in a 1:1 ratio, stratified by HPV status. Each patient 
will receive a unique randomisation number when he/she is assigned treatment. Patients 
will be allocated to treatment according to the randomisation code. 
The randomisation codes will be prepared by the randomisation statistician. The 
randomisation statistician will store the master randomisation list in a secure system. 
If a patient withdraws from study participation, his/her unique identification number(s) 
cannot be re-used for another patient. 

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6.4 
Dose and Administration 
At each dispensing visit, patients will receive setanaxib or placebo bottles. Each bottle 
contains 70 tablets. Patients will be dispensed 1 to 3 IMP bottles at each dispensing visit, 
as described in the site operations manual, to ensure that the patient has sufficient IMP to 
last until the next scheduled visit. 
Patients will take 4 tablets per day. Two tablets will be taken in the morning and 2 tablets 
will be taken in the evening. 
• 
Patients allocated to setanaxib 800 mg BID will self-administer 2 tablets of setanaxib 
400 mg in the morning and 2 tablets of setanaxib 400 mg in the evening. 
• 
Patients allocated to placebo will self-administer 2 placebo tablets in the morning 
and 2 placebo tablets in the evening. 
Patients will be instructed not to take their morning IMP dose on PK visit days until after 
the study assessments have been completed, except the PK visit days where tumour 
biopsy is collected and the EoT Visit. 
Patients should take the first dose at the clinic under supervision of site staff to ensure the 
first dose is taken and that patients can swallow the tablets. The first dose taken should be 
documented in medical records. 
For patients that can swallow setanaxib/placebo tablets, the tablets should be taken orally 
with food or up to 30 minutes after a meal. Each tablet should be taken separately and 
swallowed with water. The patients will be instructed to distribute their morning and 
evening doses as evenly as possible. 
Patients who cannot swallow tablets and have either a feeding tube or a percutaneous 
endoscopic gastrostomy (PEG) device inserted are allowed to disperse setanaxib tablets 
in water using a compatible syringe and administer the dispersed tablets through the 
feeding device. See further details in the pharmacy manual. A separate patient 
information leaflet should be provided to the patient and verbal instructions given by the 
investigator or other appropriately trained staff at the clinic on how to disperse and 
administer the IMP. 
Patients will be provided with a patient IMP dosing card. Patients will be instructed to 
record the date and time of each dose that they take, as well as the route of administration 
(oral, feeding tube, or PEG device), on the dosing card straight after they have taken the 
tablet. 
Patients will be reminded to bring the IMP (including any empty bottles) and the patient 
IMP dosing card with them to each study visit. 

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The IMP dosing card will be considered as a source document. Site personnel will record 
the date and time of the IMP dose as well as the route of administration (oral, feeding 
tube, or PEG device) prior to PK Visits (ie, prior to the PK sample) in the eCRF. 
6.4.1 
Dose Modification 
Dose interruptions are required in case of anaemia and hypothyroidism, when the events 
meet the criteria as defined in Section 5.3.2.1, and Section 5.3.2.2, respectively. Events 
that require permanent discontinuation of IMP are listed in Section 4.3.1. 
Dose reduction of setanaxib to 400 mg BID to manage anaemia, hypothyroidism, or any 
Grade 3 or otherwise intolerable toxicity, which is considered related to setanaxib may be 
instituted at the investigator’s discretion after discussion with the medical monitor. 
6.4.2 
Dechallenge and Rechallenge 
Investigational medicinal product should be interrupted in cases of anaemia (as described 
in Section 5.3.2.1) or hypothyroidism (as described in Section 5.3.2.2). If the criteria 
specified in those sections are met, IMP may be resumed. If the rechallenge results in the 
IMP interruption criteria being met again, the IMP must be permanently discontinued 
(see Section 4.3.1). 
6.4.3 
Intervention After the End of the Study 
Continued access to IMP is not planned beyond the completion of the study. 
6.5 
Precautions and/or Lifestyle Considerations 
There are no other lifestyle considerations (such as dietary or physical activity 
restrictions) for this study further to those listed in the inclusion/exclusion criteria 
(Section 4). 
6.6 
Prior Medication 
See Section 4 for details of the prior medication that is permitted or prohibited according 
to the inclusion and exclusion criteria. 
The following medications are prohibited: 
• 
Anti-cancer mAb treatment within 4 weeks prior to study Day 1 
• 
Chemotherapy, targeted small molecule therapy or radiation therapy within 2 weeks 
prior to study Day 1 (radiation therapy can be allowed for palliative therapy of bone 
metastasis only) 

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• 
Treatment with any investigational agent within 12 weeks of Screening Visit 1 or 
5 half-lives of the IMP (if known), whichever is longer 
• 
Current enrolment in another interventional clinical study 
• 
Medications known to be potent CYP3A4 inhibitors or inducers, as well as potent 
UGT1A9 inhibitors or inducers, within 21 days prior to IMP administration 
Live-attenuated vaccines should be avoided where possible within 30 days before study 
treatment but may be used where other alternatives are not available, considered inferior, 
or otherwise unsuitable. 
6.7 
Background Treatment 
Setanaxib or matching placebo will be administered in combination with pembrolizumab. 
Pembrolizumab (KEYTRUDA, Merck) is a PD-1-blocking antibody indicated for the 
first-line treatment of patients with metastatic or unresectable recurrent SCCHN. 
Pembrolizumab is administered as 200-mg IV infusion q3w. Treatment will be initiated 
on Day 1, ie, at the same time as the first dose of IMP. 
Pembrolizumab is considered as a non-investigational product and will be administered 
according to current clinical guidelines and labelling. 
Refer to the pharmacy manual for full details for labelling and shipment of 
pembrolizumab. 
6.8 
Concomitant Medication 
See Section 4 for details of the prior medication that is permitted or prohibited according 
to the inclusion and exclusion criteria. The prohibited (prior) medications and devices 
listed in Section 6.6 are also prohibited during the study. The following medications are 
prohibited during the study: 

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• Drugs that have known bone marrow toxicities 
• Potent CYP3A4 inhibitors (boceprevir, clarithromycin, conivaptan, 
elvitegravir/ritonavir, fluconazole, indinavir, itraconazole, ketoconazole, 
lopinavir/RIT, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, 
telaprevir, telithromycin, tipranavir/ritonavir, troleandomycin, voriconazole) 
• Potent CYP3A4 inducers (avasimibe, carbamazepine, enzalutamide, mitotane, 
nevirapine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St John’s wort) 
• Potent UGT1A9 inhibitors/inducers (UGT1A9 inhibitors/inducers include 
belumosudil, cannabidiol, cannabinol, deferasirox, diflunisal, eltrombopag, 
fosphenytoin/phenytoin, isavuconazole, medical cannabis, mefenamic acid, 
methylene blue, morniflumate, niflumic acid, perampanel, regorafenib, rifampicin, 
sorafenib, umifenovir) 
Setanaxib is considered to be a weak inhibitor of CYP2C9, CYP2C19, and OAT3. 
Sensitive CYP2C9, CYP2C19 and OAT3 substrates, such as warfarin and phenytoin 
(CYP2C9), S-mephenytoin (CYP2C19), and acyclovir, cefaclor, ceftizoxime, famotidine, 
furosemide, methotrexate, oseltamivir carboxylate, and penicillin G (OAT3), should be 
used with caution when co-administered with setanaxib due to risk of increased drug 
concentrations. Setanaxib has potential induction effects on CYP2B6. Sensitive 
substrates of CYP2B6, such as tamoxifen, valproic acid, and cyclophosphamide should 
be used with caution due to risk of decreased drug concentration and reduced efficacy. 
In addition, setanaxib inhibited BCRP and MDR1 (P-gp) in vitro. This may result in 
increased exposures of applicable concomitant medications, and hence caution should be 
exercised with use of sensitive BCRP and P-gp substrates, such as digoxin. 
Appendix III contains a list of common medications that should be avoided or used with 
caution. 
Regarding Covid-19 vaccination, as setanaxib does not have immunosuppressive 
properties based on nonclinical and clinical safety data, and as the available literature and 
expert assessment concludes that patients taking pembrolizumab and other immune 
checkpoint inhibitors should be considered for Covid-19 vaccination, the sponsor 
considers that study patients may undergo Covid-19 vaccination during the study. All 
approved Covid-19 vaccines are allowed in setanaxib studies and are to be recorded as a 
concomitant medication. It is important that the Covid-19 vaccinations are not delayed. 
If patients receive a prohibited medication, investigators should consider whether IMP 
administration should be temporarily interrupted or permanently discontinued. 
Additionally, if a patient has taken a prohibited medication (eg, short-term antifungal 
therapy) and the investigator learns about it later, this might not lead to the permanent 
discontinuation of IMP. 

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All medication (including vaccines, over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) taken from 3 months (90 days) before Screening Visit until 
the end of the Safety/Efficacy Follow-up Period will be recorded in the appropriate 
section of the eCRF. 
The following details must be recorded in the eCRF: 
• 
Medication name, ideally the generic and/or brand names 
• 
Reason for use 
• 
Start and end date of administration 
• 
The dose, route and frequency of administration 
The medical monitor should be contacted if there are any questions regarding prior or 
concomitant medication or procedures. 
For patients who discontinued study treatment but remain followed for tumour 
assessment until RECIST v1.1-defined disease progression, any further anti-cancer 
medication will be recorded until progression. 
6.9 
Overdose 
For this study, a single intake of 5 or more setanaxib tablets and/or a total daily dose of 
7 or more tablets will be considered an overdose. 
The sponsor does not recommend specific treatment for an overdose with setanaxib. 
Decisions regarding dose interruptions will be made by the investigator based on the 
clinical evaluation of the patient. 
In the event of an overdose, patients should be closely observed/hospitalised for close 
observation and appropriate symptomatic/supportive medical care and be followed until 
resolution/stabilisation of any clinical issues. 
Any instance of overdose (suspected or confirmed and irrespective of whether or not it 
involved setanaxib) must be communicated to the sponsor (or a specified designee) using 
the overdose report form within 24 hours of becoming aware of its occurrence, using the 
contact details provided. 
Any overdose associated with clinical symptoms will be recorded as an AE or SAE, as 
appropriate. Note that an overdose without clinical symptoms will not be recorded as an 
AE or SAE, even if the patient was hospitalised for observation. Details of any signs or 
symptoms and their management should be recorded, including details of any treatments 

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administered for the overdose. All overdoses with clinical symptoms meeting the SAE 
criteria must be reported as described in Section 7.4. 
6.10 
Compliance 
The investigator (or designee) will explain the correct use of the IMP to each patient and 
will check that each patient is following the instructions properly. Patients will document 
the IMP doses that they take on a patient IMP dosing card. 
Compliance will be assessed by counting the returned tablets and will be documented in 
the source documents and eCRF. Any deviation from the correct use of the IMP will be 
recorded in the eCRF. 
A record of the number of IMP tablets dispensed to and taken by each patient will be 
maintained and reconciled with IMP and compliance records. The IMP start and stop 
dates, including dates for IMP interruptions, will also be recorded in the eCRF. 
6.11 
Accountability 
The IMP must not be used for any purpose other than that defined in this protocol. All 
supplies of IMP will be accounted for in accordance with Good Clinical Practice (GCP). 
The pharmacist or (designee) should maintain accurate records of all IMP supplies 
received during the study. These records should include the dates and amounts of IMP 
that were received at the site, dispensed, and destroyed or returned to the sponsor (or 
designee). The records should include dates, quantities, batch/serial numbers, expiration 
dates (if applicable), and the unique code numbers assigned to the IMP and study 
patients. If errors or damage in the IMP shipments occur, the investigator should contact 
the sponsor (or its designee) immediately. Copies of the IMP accountability records will 
be provided by each investigator for inclusion in the trial master file. The study monitor 
will periodically check the supplies of IMP held by the investigator or pharmacist to 
verify accountability of the IMP used. 
The investigator (or designee) will dispense the IMP only to the identified and 
randomised patients in this study, according to the procedures described in this study 
protocol. Details of IMP dispensed to patients will be recorded in the eCRF. Investigators 
should maintain records that document adequately that the patients were provided the 
doses specified by the protocol and reconcile all IMP received from the sponsor (or 
designee). Patients will be reminded to bring the IMP with them to each study visit. 
Details of returned IMP will be recorded in the eCRF and accountability records. 
After the end of the study, all unused IMP and all medication containers should be 
destroyed at the study centre or returned to the drug depot for destruction, as instructed in 
the pharmacy manual. In either instance, complete documentation will be returned to the 
sponsor (or designee). The IMP resupply will be managed by the IRT. 

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7 ADVERSE EVENTS 
7.1 
Definitions 
7.1.1 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical study patient 
administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment. An AE can, therefore, be any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
AEs that occur, having been absent before the date and time of the first dose of the IMP, 
or having worsened in severity or seriousness after initiating the IMP until 28 days after 
the date and time of last dose of IMP, will be classified as TEAEs. 
An event solely attributed to tumour progression should not be reported as an AE, unless 
the signs and symptoms of the event are more severe than expected for the patient`s 
condition. If the criteria for an AE is not met, disease progression will be recorded as 
efficacy data. Any event that meets one or more of the seriousness criteria will be 
reported as an SAE per the procedures outlined in Section 7.4. 
7.1.2 
Serious Adverse Events 
An SAE is any event that meets any of the following criteria: 
• 
Results in death (investigators should identify 1 SAE that is the leading cause of 
death). 
• 
Is life-threatening. 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation. 
• 
Results in persistent or significant disability/incapacity. 
• 
Is a congenital anomaly/birth defect. 
• 
Is an important medical event that may not result in death, be life-threatening, or 
require hospitalisation. The event will be considered an SAE when, based upon 
appropriate medical and scientific judgment, the event may jeopardise the patient and 
may require medical or surgical intervention to prevent one of the outcomes listed 
above. Examples of such events include: intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not 

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result in inpatient hospitalisation, or the development of drug dependency or drug 
abuse. 
Definition of Terms 
Life-threatening: an AE is life-threatening if the patient was at immediate risk of death 
from the event as it occurred; ie, it does not include a reaction that, if it had occurred in a 
more severe form, might have caused death. For example, drug-induced hepatitis that 
resolved without evidence of hepatic failure would not be considered life-threatening 
even though drug-induced hepatitis can be fatal. It does not include an AE or suspected 
adverse reaction that, had it occurred in a more severe form, might have caused death. 
Hospitalisation: AEs requiring hospitalisation should be considered SAEs. 
Hospitalisation for elective surgery, or for procedures planned prior to the patient 
providing informed consent, or routine clinical procedures that are not the result of an AE 
(eg, elective surgery for a pre-existing condition that has not worsened) need not be 
considered AEs or SAEs. If anything untoward is reported during the procedure, that 
occurrence must be reported as an AE, either 'serious' or 'nonserious' according to the 
usual criteria. 
In general, hospitalisation signifies that the patient has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician's office or outpatient 
setting. When in doubt as to whether hospitalisation occurred or was necessary, the AE 
should be considered serious. 
Disability/incapacity: an AE is incapacitating or disabling if the experience results in a 
substantial and/or permanent disruption of the patient’s ability to carry out normal life 
functions. 
7.1.3 
Suspected Unexpected Serious Adverse Reactions 
A suspected unexpected serious adverse reaction (SUSAR) is defined as an untoward and 
unintended response to a study drug, which is not listed is the applicable product 
information (eg, IB for an unapproved IMP or the SmPC for an authorised medicinal 
product), and meets one of the following serious criteria: results in death, is 
life-threatening, requires hospitalisation or prolongation of an existing hospitalisation, 
results in persistent or significant disability or incapacity, or is a congenital anomaly or 
birth defect, or is an important medical event that may not result in death, be life-
threatening, or require hospitalisation; and is assessed as causally related to the IMP. For 
SUSARs, the blind will be broken for safety reporting purposes. 

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7.1.4 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
Laboratory abnormalities without clinical significance should not be recorded as AEs or 
SAEs. However, laboratory abnormalities as per the investigator’s assessment (eg, 
clinical chemistry, haematology, and urinalysis abnormalities) that require medical or 
surgical intervention or lead to IMP interruption, modification, or discontinuation must 
be recorded as an AE or SAE, as applicable. In addition, laboratory or other abnormal 
assessments (eg, in ECGs, X-rays, or vital signs) that are associated with signs and/or 
symptoms must be recorded as an AE or SAE if they meet the definition of an AE or 
SAE as described in Sections 7.1 and 7.1.2. Any worsening of existing abnormalities that 
are associated with signs and/or symptoms (except for SCCHN-related pre-existing 
conditions, including disease progression [see Section 7.3]) should be reported as AEs or 
SAEs, as appropriate. If the laboratory abnormality is part of a syndrome, record the 
syndrome or diagnosis (eg, anaemia), not the laboratory result (ie, decreased 
haemoglobin). 
For specific information on handling of clinical laboratory abnormalities, see 
Section 5.3.2. 
7.1.5 
Adverse Events of Special Interest 
The AESIs for this study are anaemia and hypothyroidism. 
AESIs of anaemia will be defined as CTCAE Grade ≥3 anaemia. Please refer to 
Section 5.3.2.1 for details regarding the detection and management of potential cases of 
anaemia. 
AESIs of hypothyroidism will be defined as TSH levels of ≥10 mIU/L. AESI will be 
unconfirmed with only one test. Please refer to Section 5.3.2.2 for details regarding the 
detection and management of hypothyroidism. 
The AESI should be reported by the investigative site to the ICON Drug Safety Centre 
within 24 hours of learning about the event by completing the paper safety report form 
and sending it via email or fax. The documentation and processing of AESIs is further 
detailed in the investigator site file. 
Investigators will indicate on the relevant Adverse Event eCRF page if the event meets 
the criteria for an AESI. 
7.2 
Assessment of Adverse Events 
7.2.1 
Severity 
The terms serious and severe are not synonymous. The general term “severe” is often 
used to describe the intensity (severity) of a specific event; the event itself, however, may 

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be of relatively minor medical significance (such as a Grade 3 headache). This is NOT 
the same as serious, which is usually associated with events that pose a threat to a 
patient’s life or ability to function (see Section 7.1.2). A severe AE (classified as 
Grade 3) does not necessarily need to be considered serious. For example, a WBC count 
of 1000/mm3 to less than 2000/mm3 is considered Grade 3 (severe) but may not be 
considered serious. Seriousness (not intensity) serves as a guide for defining regulatory 
reporting obligations. 
Investigators will grade all AEs by severity using CTCAE (Version 5.0). 
If an AE is not listed in the CTCAE criteria, a corresponding grading is to be performed 
by the investigator based on his/her best medical judgment as follows: 
• 
Mild (Grade 1): asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
• 
Moderate (Grade 2): minimal, local, or noninvasive intervention indicated; limited 
age-appropriate instrumental activities of daily living (ADL) 
• 
Severe (Grade 3): medically significant but not immediately life-threatening; 
hospitalisation or prolongation of hospitalisation indicated; disabling; or limiting 
self-care ADL 
• 
Life-threatening (Grade 4): life-threatening consequences; urgent intervention 
indicated 
• 
Death (Grade 5): death related to an AE 
7.2.2 
Causality 
Investigators are required to systematically assess the causal relationship between the 
AEs and SAEs and the exposure to the IMP using the following definitions: 
Related: 
• 
The AE has a reasonable possibility of an association with the IMP because: 
o 
The AE follows a reasonable temporal sequence to IMP administration, and 
cannot be reasonably explained by the patient’s clinical state or other risk 
factors (eg, disease under study, concurrent diseases, or concomitant 
medications). 
o 
The AE follows a reasonable temporal sequence to IMP administration, and it 
is a known reaction to the drug under study or a related chemical group or is 
predicted by known pharmacology or nonclinical safety. 

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Not Related: 
• 
The AE does not follow a reasonable sequence from IMP administration, or it can be 
reasonably explained by the patient’s clinical state or other risk factors (eg, disease 
under study, concurrent diseases, and concomitant medications). 
7.3 
Documenting and Reporting Adverse Events 
Reporting of AEs will begin when the patient has provided informed consent and will 
continue up to the 28 days after the last IMP administration. 
Occurrence of AEs may be volunteered spontaneously by the patient; discovered as a 
result of general, nonleading verbal questioning by the study staff; or determined by 
physical examination or other safety assessments. All AEs will be monitored and 
recorded in the eCRF throughout the entire study. Note that worsening of SCCHN-related 
pre-existing conditions, including disease progression, will not be reported as AEs. An 
event solely attributed to tumour progression should not be reported as an AE, unless the 
signs and symptoms of the event are more severe than expected for the patient`s 
condition. If the criteria for an AE is not met, disease progression will be recorded as 
efficacy data. Worsening of other existing abnormalities that are associated with signs 
and/or symptoms should be reported as AEs (or SAEs), as appropriate. Any event that 
meets one or more of the seriousness criteria will be reported as an SAE per the 
procedures outlined in Section 7.4. 
For all AEs, the investigator must pursue and obtain adequate information (a description 
of the event, severity, time of occurrence, including whether the AE onset was before, 
during, or after the IMP administration if the AE started on a dosing day, duration, and 
any action, eg, treatment/follow-up tests). The outcome of the event should be provided 
along with the investigator’s assessment of the relationship to the IMP. The investigator 
must also assess whether the event meets the criteria for classification as an SAE. 
It is the investigator’s responsibility to review all documentation (eg, hospital notes, 
laboratory reports, and diagnostic reports) related to an AE. Wherever possible, the 
investigator’s diagnosis, not the individual signs and symptoms, will be documented as 
the AE. 
Investigators are not obligated to actively seek AEs or unrelated SAEs after the patient’s 
conclusion of study participation. However, if the investigator learns of any SAE, 
including death, at any time after a patient has been discharged from the study, and 
he/she considers the event to be reasonably related to the IMP or study participation, the 
investigator must promptly notify the sponsor. The investigator is expected to follow a 
potentially related SAE until it has resolved, it has resolved with sequelae, or the patient 
is lost to follow-up. 

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7.4 
Reporting of Serious Adverse Events 
For SAEs with an onset inside the reporting period (ie, onset after provision of informed 
consent and up to the EoT Visit) and SAEs considered related to IMP that occur after this 
reporting period (ie, after the EoT until the Safety/Efficacy Follow-up Visits), the 
investigator must immediately (no later than 24 hours after becoming aware of the event) 
inform the sponsor (or designee) of the SAE utilising the safety report form (refer to the 
SAE contact information at the beginning of this protocol). 
The investigator is obliged to respond to any request for follow-up information (eg, 
additional information, event outcome, final evaluation, or other records where needed) 
or to any question the sponsor (or designee) may have concerning the SAE within the 
same timelines as those noted above for initial reports. This is necessary to ensure prompt 
assessment of the event by the sponsor (or designee) and, as applicable, to allow the 
sponsor to meet strict regulatory timelines associated with expedited reporting obligations 
for events of this nature. 
7.5 
Adverse Event and Serious Adverse Event Follow-up 
During the study (and after the patient’s participation in the study has ended), all AEs and 
SAEs should be followed proactively by the investigator until the event resolves or the 
condition stabilises to a level acceptable to the investigator, until the event is otherwise 
explained, or until the patient is lost to follow-up. At the time the patient’s study 
participation ends, all ongoing AEs and SAEs should be evaluated for resolution. New or 
updated information will be recorded in the originally completed eCRF, and the 
investigator will submit any updated SAE information to the sponsor (or designee) within 
24 hours of receipt of the information. 
7.6 
Safety Reporting Oversight 
In accordance with ICH guidelines GCP, the sponsor (or designee) will inform 
investigators of “findings that could affect adversely the safety of patients, impact the 
conduct of the study, or alter the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC)’s approval/favourable opinion to continue the study.” 
The sponsor (or designee) has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of an IMP under clinical 
investigation. The sponsor (or designee) will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, IRB/IEC, and 
investigators. To support compliance with these requirements, the investigator must 
provide requested information in a timely manner. 
An investigator who receives an investigator safety report describing SAEs or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor (or 

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designee) will file it along with the IB and will notify the IRB/IEC, if appropriate, 
according to local requirements. 

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8 STATISTICS 
8.1 
General Procedures 
The statistical analysis will be performed by ICON under the direction of Calliditas. 
With the exception of the unblinded statistician and programmers supporting the IDMC, 
all personnel involved with the analysis of the study will remain blinded until database 
lock and identification of protocol deviations. Analyses will be performed using SAS® 
(SAS Institute, Cary, NC, US) by the sponsor or its representatives. 
A detailed description of all statistical analyses to be performed for this study and any 
deviations from the analysis detailed in the protocol will be outlined in the statistical 
analysis plan (SAP). A first version of the SAP will be prepared prior to the inclusion of 
the first study patient, and the SAP will be approved prior to database lock and 
unblinding of the study data. 
All data will be presented by treatment group. For qualitative variables, the population 
size (N for sample size and n for available data) and the percentage (of available data) for 
each class of the variable will be presented. Quantitative variables will be summarised 
using descriptive statistics, including n, mean, standard deviation (SD), median, 
minimum, and maximum values. Graphical presentations of the data will be produced to 
aid interpretation. 
Baseline is defined as the last nonmissing measurement before or on the date of first 
administration of IMP, unless otherwise stated in the SAP. 
A strategy for dealing with data affected by protocol deviations will be agreed by the 
study sponsor physician, pharmacokineticist and statistician prior to database lock. Data 
from patients who discontinue from the study, or who have missing values for other 
reasons, will be included in the analysis in such a way as to minimise any possible bias. 
An initial data cut-off will occur approximately 9 weeks after completion of enrolment, 
when all patients are expected to have had at least 3 cycles of pembrolizumab, at least 
one post-treatment scan, and the opportunity for a post-treatment tumour biopsy. At this 
point, the primary endpoint of best percentage change in tumour size and some secondary 
endpoints will be analysed. An updated analysis may be performed after 38 progression 
events have been reported. During ongoing review of the overall progression event count, 
if the predicted timing of the initial and updated analyses are expected to be close in 
proximity, one analysis may be performed. 
Investigators and patients will continue to be blinded to randomised study treatment after 
initial unblinding of data for the primary analysis until the final database lock. 

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Safety and tolerability data will be regularly reviewed by an unblinded IDMC, with the 
first assessment after approximately 12 patients (6 per treatment group) have had the 
opportunity to complete at least 1 cycle of pembrolizumab +/- setanaxib. Safety data 
analyses will be descriptive only and will be described in the SAP and IDMC charter. 
After approximately 12 patients (6 per treatment group) have completed their Baseline 
and post-treatment biopsy, initial gene expression and biomarker data in tumour tissue 
may be reviewed by the sponsor, who will remain masked to randomised treatment 
assignment. A second review may be performed, if required. Analyses will be descriptive 
only. Further details will be provided in the SAP. 
8.2 
Analysis Populations 
The Full Analysis Set (FAS) will include all randomised patients who receive at least 
1 full dose of IMP or placebo. Patients will be analysed according to randomised 
treatment regardless of the treatment they actually received. This analysis set will be the 
primary set used for all efficacy analyses, along with the summary of disposition, 
demographics, and Baseline characteristics. 
The Safety Analysis Set will include all randomised patients who receive at least 1 tablet 
of IMP or placebo. Patients will be analysed according to treatment they actually 
received. This analysis set will be used for summaries of safety data. 
The Per-Protocol Analysis Set will include all patients in the FAS who complied 
sufficiently with the protocol with respect to exposure to IMP, availability of tumour 
assessments, and absence of important protocol deviations likely to impact efficacy 
outcome. Important protocol deviations will be defined in the SAP and this analysis set 
will be finalised in a blinded manner prior to database lock. 
The PK Analysis Set will include all patients who receive at least 1 dose of setanaxib and 
have at least 1 measured concentration at a scheduled PK time point post-dose. 
The Biomarker Analysis Set will include all patients who received at least one tablet of 
IMP or placebo and have evaluable biomarker data. 
8.3 
Sample Size 
An overall sample size of approximately 50 patients (25 per treatment group) is 
considered sufficient to assess the primary endpoint of the best percentage change in 
tumour size following treatment with setanaxib when administered with pembrolizumab, 
versus placebo when administered with pembrolizumab, in patients with recurrent or 
metastatic SCCHN. With 25 patients per treatment group, using a 2-sided t-test, there will 
be 85% power to detect a 20% mean difference between the treatment groups in best 
percentage change in tumour size, with an estimated SD of 30% and a 2-sided alpha of 
20%. To mitigate risks from a higher than expected number of patients discontinuing the 

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study early or declining to have imaging or biopsies at Week 9, an additional up to 20 
patients (making a maximum of 70 patients) may be randomised. 
The key secondary endpoints of numbers of CAFs, CD8+ TILs, and regulatory T-cells in 
tumour tissue, and gene expression analysis in tumour tissue will be used to determine 
proof-of-concept. With 25 patients per treatment group, there will be 90% power to 
detect a limit fold change (LFC) of more than 1.5 in gene sequencing endpoints measured 
in tumour tissue, assuming at least 20 patients have an evaluable Baseline and post-
Baseline tissue sample. 
For the key secondary endpoint of PFS, if the true hazard ratio for PFS is 0.5, at least 38 
progression events as defined by RECIST v1.1 will be required to have >80% power to 
demonstrate a statistically significant difference in PFS with 2-sided p<0.2. 
8.4 
Statistical Methods 
8.4.1 
Statistical Hypothesis 
The statistical hypothesis to be tested for the primary analysis with change in tumour size 
as the primary endpoint is as follows: 
• 
H0: the average change in the tumour size between the treatment groups are the same 
• 
HA: the average change in the tumour size between the treatment groups are 
different 
The simple null hypotheses (H0) for the primary analysis using the t-test assumes that the 
observation for the difference in the best percentage change in tumour size for patients 
between the 2 treatment groups will follow a normal distribution with mean zero and a 
constant unknown variance. The composite alternative hypothesis (HA) assumes that the 
observation for the difference in the best percentage change in tumour size for patients 
between the 2 treatment groups will follow a normal distribution with an unknown mean 
and the same constant unknown variance which will be estimated from the data. This 
unknown mean under the distribution of the observations under the composite alternative 
hypothesis is the non-centrality parameter which determines the power of the statistical 
test on which the primary analysis is based. For the sample size calculation this non-
centrality parameter was assumed to be 20%. 
8.4.2 
Primary Endpoint 
The primary endpoint is the best percentage change in tumour size, defined as the 
percentage change from Baseline in the sum of diameters of target lesions, as assessed by 
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For the primary endpoint of best percentage change in tumour size, the absolute values at 
Baseline and Week 9 and best percentage change in target lesion tumour size will be 
summarised using descriptive statistics and presented by treatment group in summary 
tables and waterfall plots. The primary endpoint will be used to assess the effect of the 
setanaxib + pembrolizumab versus placebo + pembrolizumab. The primary efficacy 
analysis will be based on the FAS and will evaluate the effect of setanaxib on best 
percentage change in tumour size from an analysis of covariance (ANCOVA) model 
including a term for the best percentage change in tumour size, a covariate for Baseline 
tumour size and a term for treatment. The number of patients, unadjusted mean, and 
adjusted least-square means (lsmeans) for each treatment group will be presented, 
together with the difference in adjusted lsmeans, 80% confidence interval, and 
corresponding p-value from the fitted ANCOVA model. 
The primary estimand considered here is to compare the best percentage change in 
tumour size per RECIST v1.1 in recurrent or metastatic SCCHN adult patients treated 
with setanaxib and pembrolizumab versus patients treated with placebo and 
pembrolizumab. 
The attributes of the primary estimand considered are listed as follows: 
• 
Population: patients aged ≥18 years with recurrent or metastatic SCCHN who are 
eligible for treatment with pembrolizumab monotherapy 
• 
Treatment: setanaxib + pembrolizumab versus placebo + pembrolizumab 
• 
Variable: best percentage change in tumour size defined as the percentage change 
from Baseline in the sum of diameters of target lesions, as assessed by RECIST v1.1 
• 
Population level summary: to evaluate the percentage mean difference in the tumour 
size between the competing treatment groups. The main results to ascertain the 
difference will be the p-value of treatment comparison obtained from the coefficient 
from the fitted ANCOVA model and the value of the coefficient as an estimate of the 
treatment effect of the percentage change between the competing treatment groups 
with its 80% confidence intervals 
• 
Intercurrent events: premature study discontinuation, study drug 
interruption/premature discontinuation, use of certain alternative or additional 
therapy including a new anti-cancer therapy 
The PFS follow-up will continue to objective progression regardless of the stated 
intercurrent events. Patients who withdraw completely from the study will be right-
censored. For the patients who are right-censored, the time until which they were in the 
study from the randomisation would be recorded as the right-censored time. The 
treatment policy strategy used addresses the intercurrent events listed above. The 
occurrence of the intercurrent event in this case is considered irrelevant in defining the 

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treatment effect of interest: the value for the variable of interest is used regardless of 
whether or not the intercurrent events occur. For example, when specifying how to 
address use of additional anti-cancer therapy prior to disease progression as an 
intercurrent event, the values of the variable of interest will be used whether or not the 
patient takes the additional anti-cancer therapy. In the case of premature study 
discontinuation, and whether or not a patient experiences changes in other treatments (eg, 
background or concomitant treatments), the intercurrent event will be considered to be 
part of the treatments being compared. In that case, this reflects the comparison under the 
usual intent-to-treat principle as the effect of a treatment policy. 
8.4.3 
Secondary Endpoints 
The secondary endpoints are listed in Section 2.2. 
An initial data cut-off will occur approximately 9 weeks after completion of enrolment, 
when all patients are expected to have had at least 3 cycles of pembrolizumab, at least 
one post-treatment scan, and the opportunity for a post-treatment tumour biopsy. At this 
point, the secondary endpoints (with the exception of PFS and OS) will be analysed. An 
updated analysis may be performed after 38 progression events have been reported. At 
the updated analysis, ORR, PFS, DoR, DCR, and OS will be summarised and safety data 
summaries will be updated as appropriate. 
The key secondary endpoint of PFS will be summarised by Kaplan-Meier plots presented 
by treatment groups. Median PFS and the proportion of patients who are progression-free 
at 3, 6, and 12 months will be summarised along with 80% confidence intervals presented 
for each treatment group. Patients who have not progressed by the time of the data cut-off 
for the updated analysis will be censored. The comparison between the treatment groups 
of PFS will be performed by fitting a Cox proportional hazard model (Cox 1975) with 
treatment group as the only covariate. The hazard ratio for PFS, based on the profile 
partial likelihood from the fitted using Cox proportional hazards model, will be 
calculated as a measure of the treatment effect along with the respective 95% Wald 
confidence interval and the asymptotic p-value from the Wald test for the difference in 
the log hazards in the fitted model. 
The secondary endpoint of OS will not be formally compared between the treatment 
groups but will be summarised in a Kaplan-Meier plot together with descriptive statistics, 
as described for PFS. 
The secondary endpoints of ORR, DoR, and DCR will be summarised using descriptive 
statistics for each treatment group and associated 90% Agresti-Coull confidence interval. 
For the key secondary endpoints of numbers of CAFs, CD8+ TILs, and regulatory T-cells, 
and the secondary endpoint of PD-L1 expression analysis in tumour tissue, it is 
hypothesised based on the mode of action of setanaxib that there will be a reduction in 
CAFs level and an increase in the number of CD8+ TILs. Data will be summarised 

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descriptively and will be graphically presented by boxplots displayed for each treatment 
group and individual patient profiles displaying pre- and post-doses counts. Changes 
within treatment groups (ie, across paired tissue samples) and between treatment groups 
will be summarised. An ANCOVA model will be used to assess for significant 
differences after adjustment for Baseline differences. The treatment effect from the fitted 
ANCOVA model will estimate the treatment difference based on mean score. A 
logarithmic transformation will be applied prior to analysis, if appropriate. 
For the secondary endpoint of changes in patterns of gene expression and differential 
gene expression in tumour tissue, data will be displayed graphically and will be assessed 
by principal components analysis to identify distinction between clusters of genes. 
Detailed analysis methodology will be described in the SAP. 
Changes in tumour biomarkers will be correlated with change in tumour size and other 
efficacy parameters. 
8.4.4 
Sensitivity Analysis 
The proportionality of hazard will be examined in the sensitivity analysis for the fitted 
Cox proportional hazard model for PFS using the cumulative sums of martingale 
residuals for each treatment groups. The ASSESS statement with ODS Graphics in 
PROC PHREG step in SAS will perform this using both graphical and numerical 
methods of Lin, Wei, and Ying 1993 (Lin et al 1993). A violation of the proportional 
hazard assumption will indicate that the results obtained from the fitted Cox proportional 
hazard model will be invalid. In such circumstances, a modified max combo 
(Roychoudhury et al 2021) using the Fleming and Harrington 1981 weights (Fleming & 
Harrigton 1981) such as FH(0,0), FH(0.5,0.5), FH(0,0.5), FH(0.5,0) will be implemented 
for estimating the performance of the competing treatment groups for PFS. The p-value 
obtained from each of the modified max combo tests will be reported. 
For each of the fitted ANCOVA models in the primary efficacy analysis and the 
secondary efficacy analyses, a plot of the residuals against the fitted values from the 
ANCOVA model will be produced to check for randomness in the plot. This is to check 
for the assumption of constant variance of the fitted model. Any systematic effect in this 
residual plot will indicate that a suitable transformation should be applied on the response 
of the model as appropriate to stabilise the variability of the error. A normal probability 
plot will also be plotted of the residuals of each of the fitted ANCOVA model to check if 
this fairly fits a straight line. Significant deviation from a straight line in this residual plot 
will indicate the violation of the ANCOVA model assumptions of the errors being 
normally distributed. In such cases, logarithmic transformations on the response will be 
applied, as appropriate, to normalise the data. The ANCOVA in such scenario will be 
fitted again on the log-normal response with log baseline values as the covariate, and the 
validity of the assumption of the fitted transformed model will be checked similarly. The 
response here for the fitted ANCOVA is the post-dose baseline ratio. If the assumptions 

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are not satisfied for the fitted transformed model, appropriate non-parametric method will 
be applied. Further details will be provided in the SAP. 
The analysis of the primary endpoint will be repeated on the Per-Protocol Analysis Set to 
understand the effect of major protocol deviations on the treatment effect. 
8.4.5 
Supportive Analysis 
Another method of handling the PFS data will be to consider death due to any other cause 
as a competing event. In such cases, patients who have not faced disease progression or 
not died until the end of the study or have dropped out prior to the event will be right-
censored. A competing risk approach will therefore be implemented by fitting the Fine 
and Gray (1999) model (Fine & Gray 1999). A treatment effect in such cases will be 
estimated using the cumulative incidence function for a given cause. This is defined as 
the probability of a patient facing an event due to a given cause before a pre-specified 
time in the clinical study. The Fine and Gray (1999) model will be fitted considering time 
to disease progression as the main cause of interest and death due to any cause as the 
competing cause with treatment as the only explanatory variable. Similar to the Cox 
proportional hazard model, the placebo + pembrolizumab treatment group will be 
considered as the comparator group in the fitted model with the regression coefficient in 
the Fine and Gray (1999) model comparing the difference in the log-sub-distribution 
hazards between the competing treatment groups. The estimated ratio of the sub-
distribution hazard for disease progression will be an estimator of the treatment effect and 
will be obtained by exponentiating the regression coefficient from the fitted Fine and 
Gray (1999) model. This estimate will be reported along with the 95% profile partial 
likelihood based Wald confidence interval for the estimated ratio of the sub-distribution 
hazard for disease progression. 
A plot of the Cumulative Incidence Functions for facing disease obtained from the fitted 
Fine and Gray (1999) model at various time during the study will also be depicted, and 
the estimated quartiles along with its 95% confidence intervals will be presented to 
compare the treatment effects in regards to the cumulative incidence for disease 
progression after accounting for deaths as a competing event in the study. 
8.4.6 
Analysis of Safety 
The safety endpoints are listed in Section 2.2. 
The Safety Analysis Set will be used for the analysis of safety data (AEs, including 
AESIs, clinical laboratory tests, vital signs, 12-lead ECGs, and physical examination). 
The safety data will be presented descriptively and not formally analysed. 
AEs that occur, having been absent before the date and time of the first dose of the IMP, 
or have worsened in severity or seriousness after initiating the IMP until 28 days after the 
date and time of last dose of IMP will be classified as TEAEs. The number of TEAEs and 

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number and percentage of patients experiencing TEAEs will be summarised by treatment 
group, severity, and relation to IMP. TEAEs will be summarised by Medical Dictionary 
for Regulatory Activities (MedDRA) system organ class (SOC) and preferred term. All 
AEs will be listed by patient and treatment group. Any AE occurring before treatment or 
more than 28 days after discontinuation of treatment will be flagged in the data listings 
but will not be included in the summary tables of AEs. Any AE occurring after a patient 
has received another anti-cancer therapy (after discontinuation of study treatment) will 
also be flagged in the listings. 
SAEs will be listed by patients and summarised by treatment group, MedDRA SOC, and 
preferred term. Summaries will also be presented by severity and relationship to IMP. 
Laboratory data (haematology, serum chemistry, thyroid function tests, and urinalysis) 
will be converted to Système International units for reporting and processing purposes. 
Absolute values and changes from Baseline will be presented descriptively. Laboratory 
data outside study-specific reference ranges will be listed. 
Abnormal laboratory values will be listed by patient and summaries of the incidence and 
frequency by treatment group, scheduled visit, severity, and relationship to IMP will be 
presented. Shift tables of CTCAE grades from baseline to worst CTC grade post-baseline 
will be presented. Summary of clinically significant abnormalities and modified World 
Health Organisation ratings will also be presented. WBC and reticulocyte counts will be 
expressed in absolute values. Differential count will be expressed as both absolute count 
and percentage of WBCs. 
Vital signs and ECG parameters will be presented descriptively. Vital signs including 
pulse rate, SBP, and DBP, and 12-lead ECG data will be summarised by treatment group 
and listed by patient. 
A summary of abnormal physical examination findings by treatment group and scheduled 
visit will be presented. Demographic and Baseline Characteristics 
Demographic characteristics (including age, sex, ethnicity, and race) and Baseline 
characteristics (including height, weight, and disease characteristics) will be presented 
descriptively. 
Discrepancies between randomisation stratification information (obtained from IRT) and 
strata formed based on Screening factor collected on eCRFs (HPV status) will be 
summarised and listed. 
8.4.7 
Pharmacokinetic Endpoints 
The PK Analysis Set will be used for PK analyses. 

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Plasma concentrations of setanaxib and GKT138184, along with blood sampling dates 
and actual blood sampling time relative to dosing time, will be listed by dose group, 
patient, and nominal sampling time. Pre-dose and post-dose plasma concentrations of 
setanaxib and GKT138184 will be summarised as appropriate. AUC(0-24)-ss, Cmin-ss 
and Cmax-ss will be estimated for each individual patient using non-linear mixed effect 
methodology and prior PK knowledge of the compound, and summarised as appropriate. 
More details regarding the PK analysis and exploratory PK/PD analyses will be provided 
in a separate pharmacokinetic analysis plan. 
An interim pharmacokinetic analysis will be performed at the initial data cut-off 
approximately 9 weeks after completion of enrolment, when all patients are expected to 
have had at least 3 cycles of pembrolizumab, at least one post-treatment scan, and the 
opportunity for a post-treatment tumour biopsy. This analysis will result in an interim 
report. 
The final pharmacokinetic analysis will be performed at the end of the study after 
database lock. If the predicted timing of the initial and final analyses are expected to be 
close in proximity, only one analysis may be performed. Only the final analysis will be 
reported formally and summarised for the CSR. 
8.4.8 
Handling of Missing Values 
Rules for imputation of missing data will be detailed in the SAP. 

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9 ETHICS AND RESPONSIBILITIES 
9.1 
Good Clinical Practice 
This study will be conducted in accordance with the Note for Guidance on ICH 
guidelines on GCP Harmonised Tripartite Guideline E6 (R1)/Integrated Addendum E6 
(R2); United States Food and Drug Administration (US FDA) Code of Federal 
Regulations (Title 21 Parts 50, 56, 312), requirements for the conduct of clinical studies 
as provided in the European Directive 2001/20/EC; the general guidelines indicated in the 
Declaration of Helsinki; and all applicable regulatory requirements. 
9.2 
Institutional Review Board/Independent Ethics Committee 
Before initiating a study, the investigator/institution must have written and dated 
approval/favourable opinion from the IRBs/IECs for the study protocol/amendment(s), 
written ICF, any ICF updates, patient recruitment procedures (eg, advertisements), and 
any written information to be provided to patients and a statement from the IRBs/IECs 
that these comply with GCP requirements (if applicable). A current copy of the IB should 
be included as part of the written application to the IRB/IEC. 
The IRB/IEC approval(s) must identify the protocol version as well as the documents 
reviewed. Any amendments to the protocol will require IRB/IEC approval before the 
implementation of the changes made to the study, except for changes necessary to 
eliminate an immediate hazard to the study patients. 
The investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
• 
Notifying the IRB/IEC of SAEs or other significant safety findings, including 
adverse drug reactions that are both serious and unexpected, as required by IRB/IEC 
procedures 
• 
Providing oversight of the conduct of the study at the site and adherence to the 
requirements of all applicable regulations 
• 
Promptly reporting deviations from, or changes to, the protocol to eliminate 
immediate hazards to the study patients 
9.3 
Informed Consent 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s) and should adhere to GCP and to the ethical 

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principles that have their origin in the Declaration of Helsinki. Prior to the beginning of 
the study, the investigator should have the IRB/IEC's written approval/favourable opinion 
of the written ICF and any other written information to be provided to study patients. 
• 
The investigator or his/her representative will explain the purpose and nature of the 
study as well as possible AEs to the patient or his/her legally acceptable 
representative and answer all questions regarding the study. 
• 
Patients must be informed that their participation is voluntary, and consent can be 
withdrawn at any point. 
• 
Patients or their legally acceptable representative will be required to sign a statement 
of informed consent that meets the requirements of local regulations, ICH guidelines, 
and the IRB/IEC or study site. 
• 
Prior to a patient’s participation in the study, the written ICF should be signed and 
personally dated by the patient or by the patient's legally acceptable representative, 
and by the person who conducted the informed consent discussion. 
• 
The medical record must include a study identifier and a statement that written 
informed consent was obtained before the patient was enrolled in the study and the 
date the written consent was obtained. 
• 
The original copy of the signed ICF will be retained at the study site. 
• 
A copy of the ICF and any other written information must be provided to the patient 
or the patient’s legally acceptable representative. 
• 
If the ICF is revised, the revised ICF must have received the IRB/IEC's 
approval/favourable opinion in advance of its use. Patients must be informed of the 
changes to the ICF and must re-consent to the most current version during their 
participation in the study. The patient or the patient’s legally acceptable 
representative 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. 
A patient who is rescreened is not required to sign another ICF if the rescreening occurs 
within 35 days of the previous ICF signature date. 
The ICF will contain a separate section that addresses the collection of a third optional 
tumour biopsy for an additional assessment of tumour biomarkers and gene expression 
analysis. The investigator (or authorised designee) will explain to each patient the 
objectives of this research. Patients will be told that they are free to refuse to participate 
and may withdraw their consent at any time and for any reason. 

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If a patient is unable to read or if a legally acceptable representative is unable to read, an 
impartial witness should be present during the entire informed consent discussion. The 
witness should sign and personally date the ICF after: 
• 
The written ICF and any other written information to be provided to patients is read 
and explained to the patient or the patient’s legally acceptable representative 
• 
The patient or the patient’s legally acceptable representative has orally consented to 
the patient’s participation in the study 
• 
The patient or the patient’s legally acceptable representative has signed and 
personally dated the ICF, if they are capable of doing so 
By signing the ICF, the witness attests that the information in the ICF and any other 
written information was accurately explained to, and apparently understood by, the 
patient or the patient's legally acceptable representative, and that informed consent was 
freely given by the patient or the patient’s legally acceptable representative. 
9.4 
Independent Data Monitoring Committee 
The IDMC will oversee the safety of participating patients. 
Treatment safety and tolerability will be regularly reviewed, with the first assessment 
after approximately 12 patients (6 per treatment group) have had the opportunity to 
complete at least 1 cycle of pembrolizumab +/- setanaxib, followed by periodic 
assessments at a frequency defined in the IDMC Charter. 
The IDMC may recommend change(s) to the setanaxib dose regimen or study conduct 
based on the safety data reviews, as defined in the IDMC Charter. The IDMC will 
include an unblinded statistician and 2 physicians (one of whom shall have expertise in 
head and neck cancer), and will be supported by an IDMC Specialist and programmers, 
as well as any other functions detailed in the IDMC Charter. 
The role and responsibilities of the IDMC will be outlined in the IDMC Charter. 
9.5 
Financing and Insurance 
9.5.1 
Contractual and Financial Details 
The investigator (and/or, as appropriate, the hospital administrative representative) and 
the CRO and/or sponsor (or designee) will sign a clinical trial agreement prior to the start 
of the study, outlining overall sponsor and investigator responsibilities in relation to the 
study. The contract should describe whether costs for pharmacy, laboratory, and other 
protocol-required services are being paid directly or indirectly. 

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9.5.2 
Insurance, Indemnity, and Compensation 
The sponsor will maintain an appropriate clinical study insurance policy. 
9.5.3 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 

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10 RECORDS MANAGEMENT 
All clinical study information should be recorded, handled, and stored in a way that 
allows its accurate reporting, interpretation, and verification. This principle applies to all 
records referenced in this protocol, irrespective of the type of media used. 
An eCRF will be used to store and transmit patient information. Information from the 
medical records (progress notes) and other source documents is to be promptly entered 
into the appropriate section of the eCRF. The eCRF must be reviewed and electronically 
signed and dated by the investigator on an ongoing basis. The investigator is responsible 
for verifying that the data entries are accurate and correct by signing the eCRF. 
Access to the eCRF will be strictly password protected and limited to personnel directly 
participating in the study. Data should be entered into the eCRF completely by authorised 
site personnel (eg, investigators and the study coordinator). The eCRF must be completed 
as soon as possible after any patient evaluation or communication. If data are to be 
changed due to erroneous input or other reason, an electronic audit trail will track these 
changes. The eCRFs and computers that store them must be accessible to study monitors 
and other regulatory auditors. 
During each study visit, a physician participating in the study will maintain progress 
notes in the patient’s medical records to document all significant observations. At a 
minimum, these notes are to contain: 
• 
The date of the visit and the corresponding day or visit in the study schedule 
• 
General condition and status remarks by the patient, including any significant 
medical findings. The severity, frequency, duration, and resolution of any reported 
AE, and the investigator's assessment as to whether or not the reported AE is related 
to IMP 
• 
Changes (including dosages) in concomitant medications/therapies (including 
medical foods) or procedures 
• 
A general reference to the procedures completed 
• 
Protocol deviations identified that could potentially affect safety and/or study results 
• 
The signature or initials of all physicians making an entry in the medical record 
(progress notes) 
In addition, any contact with the patient via telephone or other means that provides 
significant clinical information is to also be documented in the medical record (progress 
notes), as described above. 

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Changes to information in the medical record (progress notes) and other source 
documents are to be initialled and dated on the day the change is made by the investigator 
(or designee). If the reason for the change is not apparent, a brief explanation for the 
change is to be written adjacent to the change. Changes to the eCRF will be electronically 
tracked. 
A data management plan will be written and finalised prior to performing any data 
validation. 
10.1 
Source Documentation 
Source documents contain the results of original observations and activities of a clinical 
investigation. They are the original records in which raw data are first recorded. Source 
documents include, but are not limited to, medical records (progress notes), ECG and 
computer printouts, screening logs, completed scales, QoL questionnaires, and recorded 
data from automated instruments. 
The investigator/site personnel should maintain adequate and accurate source documents 
and study records that include all pertinent observations on each of the site’s study 
patients. Source data should be attributable, legible, contemporaneous, original, accurate, 
and complete. Changes to source data should be traceable, should not obscure the original 
entry, and should be explained if necessary (eg, via an audit trail). 
All source documents from this study are to be maintained by the investigator and made 
available for inspection by authorised persons. The investigator will provide direct access 
to source documents/data for study-related monitoring, audits, IRB/IEC review, and 
regulatory inspections. The sponsor should verify that each patient has consented, in 
writing, to direct access to his/her original medical records for study-related monitoring, 
audit, IRB/IEC review, and regulatory inspection. 
10.2 
Electronic Case Report Form Completion and Data Management 
An eCRF will be used to store and transmit patient information. The file structure and 
format for the eCRF will be provided by the sponsor or its representative and should be 
handled in accordance with the instructions provided. 
The eCRF must be reviewed and electronically signed and dated by the investigator. 
Access to the eCRF will be strictly password protected and limited to personnel directly 
participating in the study. Data should be entered into the eCRF completely by authorised 
site personnel (eg, investigators and the study coordinator). The eCRF must be completed 
as soon as possible after any patient evaluation or communication. If data are to be 
changed due to erroneous input or other reason, an electronic audit trail will track the 
changes. The eCRFs and computers that store them must be accessible to study monitors 
and other regulatory auditors. Changes to the eCRF will be electronically tracked. 

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Data will be entered/loaded into a validated electronic database using a clinical data 
management system. Computerised data cleaning checks will be used in addition to 
manual review to check for discrepancies and to ensure consistency of the data. 
10.3 
Study Files and Record Retention 
All data derived from the study will remain the property of the sponsor. The sponsor 
assumes accountability for actions delegated to other individuals, eg, the CRO. 
Records must be retained in accordance with the current ICH guidelines on GCP. All 
essential study documents, including records of patients, source documents, eCRFs, and 
the IMP inventory, must be kept on file. 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region, or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of setanaxib. However, essential 
documents may be retained for a longer period if required by the applicable regulatory 
requirements or by agreement with the sponsor. The sponsor is responsible for informing 
the investigator when these documents need no longer be retained. 
The investigator is not to dispose of any records relevant to this study without written 
permission from the sponsor and is to provide the sponsor the opportunity to collect such 
records. The investigator shall take responsibility for maintaining adequate and accurate 
hard copy source documents of all observations and data generated during this study. 
Such documentation is subject to inspection by the sponsor, its representatives, and 
regulatory authorities. 
If an investigator moves, withdraws from a study, or retires, the responsibility for 
maintaining the records may be transferred to another person who will accept 
responsibility. Notice of transfer must be made to and agreed by the sponsor. 

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11 AUDITING AND MONITORING 
Sponsor-assigned monitors will conduct regular site visits to the investigational facilities 
for the purpose of monitoring various aspects of the study, such as verifying that the ICFs 
were signed and dated before any study-specific procedure was performed, assessing 
patient enrolment, compliance with protocol procedures, completeness and accuracy of 
data entered into the eCRFs, verification of eCRF data against original source documents, 
and occurrence of AEs. The investigator must agree to sponsor-authorised personnel 
having direct access to the clinical (or associated) files and clinical study supplies 
(dispensing and storage areas) to ensure compliance with applicable regulations, and the 
investigator will assist with the sponsor’s monitoring activities. 
Quality control will occur at each stage of data handling to ensure that all data are reliable 
and have been processed correctly. The sponsor should ensure oversight of any 
study-related duties and functions carried out on its behalf, including study-related duties 
and functions that are subcontracted to another party by the sponsor’s contracted CRO(s). 
The eCRFs should be completed in a timely manner and on an ongoing basis to allow 
regular review by the study monitor. 
Details describing the strategy, responsibilities, and requirements of study monitoring are 
provided in the study Monitoring Plan. 
The purpose of an audit is to assess whether ethics, regulatory, and quality requirements 
are being fulfilled. The sponsor or its representative may conduct audits at the 
investigative sites including, but not limited to, drug supply, presence of required 
documents, the informed consent process, and comparison of eCRFs with source 
documents. Government regulatory authorities may also inspect the investigator during or 
after the study. The investigator (or designee) should contact the sponsor/CRO 
immediately if this occurs. All medical records (progress notes) must be available for 
audit. The investigator must agree to participate with audits conducted at a convenient 
time in a reasonable manner. 
11.1 
Risk and Quality Tolerance Limits 
Perceived risks and quality tolerance limits (QTLs) will be identified and documented in 
the Protocol Risk Evaluation Plan before the start of the study. 
The sponsor will review risk control measures periodically to ascertain whether the 
implemented quality management activities remain effective and relevant. The quality 
management approach and any important deviations from the predefined QTLs (and 
remedial actions adopted) will be described in the clinical study report (CSR). 

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11.2 
Protocol Adherence and Deviations 
The investigator and site personnel should conduct the study in compliance with the 
protocol and should use continuous vigilance to identify and report protocol deviations. 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the protocol that may be on the part of the investigator, site 
personnel, or the patient. 
Important protocol deviations are a subset of protocol deviations that may significantly 
impact the completeness, accuracy, and/or reliability of the study data or that may 
significantly affect a patient's rights, safety, or well-being. For example, important 
protocol deviations may include enrolling patients in violation of key eligibility criteria 
designed to ensure a specific patient population or failing to collect data necessary to 
interpret primary endpoints, as this may compromise the scientific value of the study. 
The investigator should not implement any deviation from the protocol without 
agreement from the sponsor and prior review and approval from the IRB/IEC of an 
amendment, except where necessary to eliminate an immediate hazard to a study patient, 
or when the change involves only logistical or administrative aspects of the study, such as 
a change in a monitor or telephone number. 
In the event of an important protocol deviation, the investigator will discuss the deviation 
with the sponsor’s medical monitor and will come to an agreement as to whether the 
patient should be withdrawn from the study due to the important protocol deviation. 

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12 AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study patients, 
may be made only by the sponsor. A protocol change intended to eliminate an apparent 
immediate hazard to patients should be implemented immediately. 
Any permanent change to the protocol must be handled as a protocol amendment. The 
written amendment must be submitted to the IRB/IEC, and the investigator must await 
approval before implementing the changes. The sponsor will submit protocol 
amendments to the appropriate regulatory authorities for approval. 
The current version of the ICF will require similar modification if the IRB/IEC, 
investigator, and/or sponsor, judge the amendment to the protocol to substantially change 
the study design and/or increase the potential risk to the patient and/or impact the 
patient's involvement as a study patient. In such cases, the ICF will be renewed for 
enrolled patients before their continued participation in the study. 

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13 STUDY REPORT AND PUBLICATIONS 
This study will be registered on ClinicalTrials.gov in accordance with applicable laws or 
publication policy and may also be registered on other publicly accessible websites, 
such as EudraCT (EU Drug Regulating Authorities Clinical Trials), as necessary. 
The sponsor is responsible for preparing and providing the appropriate regulatory 
authorities with the CSR according to the applicable regulatory requirements. The 
sponsor should ensure that the CSR meets the standards of the ICH Guideline for 
Structure and Content of Clinical Study Reports (ICH E3). 

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14 STUDY START AND TERMINATION 
The study start date is the date on which the first patient provides informed consent. 
The end of the study is defined as the last patient’s last assessment. 
Both the sponsor and the investigator reserve the right to terminate the study or the 
participation in the study at an investigator’s site at any time. In terminating the study, the 
sponsor and the investigator will assure that adequate consideration is given to the 
protection of the patients’ interests. 
If the study is prematurely terminated or suspended for any reason, the 
sponsor/investigator/site personnel should promptly inform the study patients and should 
assure appropriate therapy and follow-up for the patients. Where required by the 
applicable regulatory requirements, the IRB/IEC should be informed promptly and be 
provided with a detailed written explanation of the termination or suspension. 
If the investigator terminates or suspends a study without prior agreement of the sponsor, 
the investigator should inform the site personnel. The investigator/site personnel should 
promptly inform the sponsor and the IRB/IEC. The investigator/site personnel should 
also provide the sponsor and the IRB/IEC a detailed written explanation of the 
termination or suspension. 

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15 CONFIDENTIALITY 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written 
consent is gained from the sponsor. However, authorised regulatory officials, IRB/IEC 
personnel, the sponsor and its authorised representatives are allowed full access to the 
records. 
All study patients must be informed that their personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the patient, who will be required to give consent for their data to be 
used as described in the ICF. The patients must be informed that their medical records 
may be examined by auditors or other authorised personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. In case of 
any data security breach, this will be reported to authorities in line with local 
requirements. 
Identification of patients and eCRFs shall be by unique patient identification numbers 
(such as screening or randomisation number) only. All personal identifiers according to 
applicable regulations (eg, name, phone number) must be redacted permanently by the 
site personnel and replaced with the patient’s unique identification number in all records 
and data before transfer to the sponsor (or designee). 
All personal details will be treated as confidential by the investigator and staff at ICON. 

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17 APPENDICES 
17.1 
APPENDIX I – Study Administrative Structure 
Sponsor: 
Calliditas Therapeutics Suisse SA 
Chemin des Aulx 16 
1228 Plan-les-Ouates 
Switzerland 
Operationally 
responsible for study 
conduct, including 
certain sponsor 
obligations: 
The sponsor is a controlled subsidiary of Calliditas Therapeutics AB,  
a Swedish corporation with its registered office and mailing address at 
PO Box 70351, SE-107 24 Stockholm, Sweden and its principal office and 
address for courier delivery at Kungsbron 1 C8, SE11122 Stockholm, Sweden 
(“Calliditas” and, with its controlled affiliates, the “Calliditas Group”).  
As such, the sponsor applies standard operating procedures relating to clinical 
development, medical affairs, manufacturing, quality assurance, quality 
control, 
and 
pharmacovigilance 
of 
the 
Calliditas 
Group. 
Certain Calliditas Group managers, including the Calliditas Group Chief 
Medical Officer, have been delegated responsibility by sponsor for sponsor’s 
activities within their functional areas. 
Sponsor’s medical 
expert: 
 
Chief Medical Officer 
c/o Calliditas Therapeutics AB 
Mailing address: PO Box 70351, SE-107 24 Stockholm, Sweden 
Principal office and address for courier delivery: Kungsbron 1 C8, SE11122 
Stockholm, Sweden 
Telephone: +46 (0)8 411 3005 
Medical monitor: 
The names and contact details of the study Medical Monitor(s) will be 
provided in the Key Study Team Contact List. 
CRO: 
ICON Clinical Research Limited,  
South County Business Park,  
Leopardstown, Dublin 18,  
D18 X5R3, 
Ireland 
ICON is a corporate affiliate of PRA 
Central laboratory: 
ICON Laboratory Services (ILS)  
South County Business Park 
Leopardstown, Dublin 18 
D18 X5R3 
Ireland 
OR 
ICON Laboratory Services (ILS)  
123 Smith St. Farmingdale 
New York 11735 USA 
OR 
ICON Speciality Lab 
1341 SW Custer Dr. 
Portland 
Oregon, USA 97219 

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Pharmacokinetics 
laboratory: 
Unilabs York Bioanalytical Solutions 
Cedar House 
Northminister Business Park 
Upper Poppleton 
York 
Y026 6QR 
UK 
Central biomarker 
assessment (tumour 
biopsy): 
University of Southampton 
Experimental Pathology 
Cancer Research UK Centre 
Southampton  
SO16 6YD 
UK 
RNA sequencing central 
laboratory 
WISH Lab 
LF110 Southampton General Hospital 
Tremona Road, Southampton 
S016 6YD 
United Kingdom  
Setanaxib and placebo 
manufacturer: 
Aptuit 
Via Alessandro Fleming, 4 
37135 Verona VR 
Italy 
Setanaxib and placebo 
distributor of drug 
supplies: 
Almac Clinical Services 
9 Charlestown Road 
Seagoe Industrial Estate 
Craigavon 
BT63 5PW 
UK 
OR 
Almac Clinical Services  
4204 Technology Drive 
Durham, NC 27704 USA 
IRT: 
ICON PLC 
2100 Pennbrook Pkwy 
Lansdale, PA 19446 
eCRF: 
Medidata 
12 Hammersmith Grove, 9th Floor 
Hammersmith, London 
W6 7AP 
UK 
A log of the name and title of the investigators who are responsible for conducting the 
study, and the address and telephone numbers of the study sites will be maintained. 
The names and addresses of any other laboratories involved in the study (further to those 
stated above) will be provided in the laboratory manual. 
 
 

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17.2 
APPENDIX II – Eastern Cooperative Oncology Group Performance Status 
ECOG performance status will be assessed as outlined in Table 1 based on the following: 
 
Score 
Definition 
0 
Fully active, able to carry on pre-disease activities without 
restrictions. 
1 
Restricted in strenuous activity, but ambulatory and able to carry 
out light work or work of a sedentary nature (eg, light housework 
or office work). 
2 
Ambulatory and capable of 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; unable to carry out any self-care and totally 
confined to bed or chair. 
5 
Dead. 
 
 
 

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17.3 
APPENDIX III – Medications or Substances to Be Avoided or Used with 
Caution During Treatment with Setanaxib 
Based on regulatory guidelines for development of new investigational agents and/or 
results from nonclinical pharmacology studies with setanaxib, precautions will be 
adopted for use of specific types of concomitant medications or substances. The types of 
medications to be considered are listed in Table 4. Specific concomitant medications to 
be used with caution due to known risk of QT interval prolongation or increased risk of 
torsades de pointes are listed in Table 5. Medications to be avoided as being potent 
cytochrome P450 (CYP) 3A4 inhibitors or inducers, as well as uridine diphosphate 
(UDP)-glucuronosyltransferase 1A9 (UGT1A9) inhibitors or inducers are listed in 
Table 6. Sensitive CYP2C9, CYP2C19, OAT3, CYP2B6, BCRP and P-gp substrates to 
be co-administered with caution are listed in Table 7. 
Table 4 
Type of Concomitant Medications to Avoid or Use with Caution with 
Setanaxib 
Concomitant 
Medication Types  
Setanaxib 
Characteristics  
Potential Effects of Co-
Administration  
Approach  
Prolongs QT  
Preclinical signal 
identified in vitro, and 
in vivo, but risk 
considered low; no 
clinical events or other 
evidence of QT 
prolongation identified 
in clinical studies 
conducted to date 
Possible increased risk 
of torsades de Pointes  
Caution  
Potent CYP3A4 
inhibitors 
Metabolised by 
CYP3A4  
Setanaxib levels may be 
increased if 
administered with 
CYP3A4 inhibitors 
Avoid 
Potent CYP3A4 
inducers 
Metabolised by 
CYP3A4  
Setanaxib levels may be 
decreased if 
administered with 
CYP3A4 inducers 
Avoid 
Potent UGT1A9 
inhibitors 
Metabolised by 
UGT1A9  
Setanaxib levels may be 
increased if 
administered with 
UGT1A9 inhibitors 
Avoid 
Potent UGT1A9 
inducers 
Metabolised by 
UGT1A9  
Setanaxib levels may be 
decreased if 
administered with 
UGT1A9 inducers 
Avoid 
Sensitive CYP2C9 and 
CYP2C19 substrates  
Weak inhibitor of 
CYP2C9 and CYP2C19 
May increase drug 
levels of concomitant 
medications  
Caution  
Sensitive CYP2B6 
substrates  
Potential induction 
effects on CYP2B6  
May decrease drug 
concentration of 
concomitant 
Caution 

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medications and reduce 
efficacy 
Sensitive OAT3 
substrates 
Weak inhibitor of OAT3 
May increase drug 
levels of concomitant 
medications  
Caution  
Sensitive BCRP or P-gp 
substrates 
Potential inhibitor of 
BCRP and P-gp 
May increase drug 
levels of concomitant 
medications  
Caution  

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Table 5 
Use with Caution – Concomitant Medications with Known Risk of QT 
Interval Prolongation or Increased Risk of Torsades de Pointes 
Aclarubicin (only on Non-US 
Market)  
Haloperidol  
Terfenadine (removed from US 
Market)  
Amiodarone  
Hydroquinidine 
(Dihydroquinidine) 
(Only on Non-US Market)  
Terlipressin (only on Non-US 
Market)  
Anagrelide  
Hydroxychloroquine  
Terodiline (only on Non-US Market)  
Arsenic trioxide  
Ibogaine (only on Non-US Market)  
Thioridazine  
Astemizole (removed from US 
Market)  
Ibutilide  
Vandetanib  
Azithromycin  
Levofloxacin  
  
Bepridil  
Levomepromazine 
(Methotrimeprazine) (only on Non-
US Market)  
  
Celsium Chloride  
Levomethadyl acetate (removed from 
US Market)  
  
Chloroquine  
Levosulpiride (only on Non-US 
Market)  
  
Chlorpromazine  
Meglumine antimoniate (only on Non-
US Market)  
  
Chlorprothixene (only on Non-US 
market)  
Mesoridazine (removed from US 
Market)  
  
Cilostazol  
Methadone  
  
Ciprofloxacin  
Moxifloxacin  
  
Cisapride (removed from US market)  Nifekalant (only on Non-US Market)    
Citalopram  
Ondansetron  
  
Clarithromycin  
Oxaliplatin  
  
Cocaine  
Papaverine HCl (Intracoronary)  
  
Disopyramide  
Pentamidine  
  
Dofetilide  
Pimozide  
  
Domperidone (only on Non-US 
Market)  
Probucol (Removed from US Market)    
Donepezil  
Procainamide  
  
Dronedarone  
Propofol  
  
Droperidol  
Quinidine  
  
Erythromycin  
Roxithromycin (only on Non-US 
Market)  
  
Escitalopram  
Sertindole (Only on Non-US Market)    
Flecainide  
Sevoflurane  
  
Fluconazole  
Sotalol  
  
Gatifloxacin (removed from US 
Market)  
Sparfloxacin (removed from US 
Market)  
  
Grepafloxacin (removed from US 
Market)  
Sulpiride (only on Non-US Market)  
  
Halofantrine (only on Non-US 
Market)  
Sultopride (only on Non-US Market)    
Source: CredibleMeds.org website, most recent update May 03, 2021 

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Table 6 
Avoid Usage – Guidance on Specific Concomitant Medications to Avoid 
with Setanaxib 
Drug Name 
Characteristic 
Potential DDI Effect 
Usage 
avasimibe 
Potent CYP3A4 inducer 
Decreased IMP 
exposure 
Avoid  
belumosudil 
UGT1A9 
inhibitor/inducer 
Increased IMP 
exposure 
Avoid 
boceprevir 
Potent CYP3A4 inhibitor  
Increased IMP 
exposure 
Avoid  
cannabidiol, cannabinol 
and medical cannabis 
UGT1A9 
inhibitor/inducer 
Increased IMP 
exposure 
Avoid 
carbamazepine 
Potent CYP3A4 inducer 
Decreased IMP 
exposure 
Avoid  
clarithromycin  
Potent CYP3A4 inhibitor  
Increased IMP 
exposure 
Avoid  
conivaptan  
Potent CYP3A4 inhibitor  
Increased IMP 
exposure 
Avoid  
deferasirox 
UGT1A9 
inhibitor/inducer 
Increased IMP 
exposure 
Avoid 
diflunisal 
UGT1A9 
inhibitor/inducer 
Increased IMP 
exposure 
Avoid 
eltrombopag 
UGT1A9 
inhibitor/inducer 
Increased IMP 
exposure 
Avoid 
elvitegravir 
Potent CYP3A4 inhibitor  
Increased IMP 
exposure 
Avoid  
enzalutamide 
Potent CYP3A4 inducer 
Decreased IMP 
exposure 
Avoid  
fluconazole 
Potent CYP3A4 inhibitor  
Increased IMP 
exposure 
Avoid  
fosphenytoin 
UGT1A9 
inhibitor/inducer  
Increased IMP 
exposure 
Avoid 
indinavir  
Potent CYP3A4 inhibitor  
Increased IMP 
exposure 
Avoid  
isavuconazole 
UGT1A9 
inhibitor/inducer 
Increased IMP 
exposure 
Avoid 
itonavir  
Potent CYP3A4 inhibitor  
Increased IMP 
exposure 
Avoid  
itraconazole  
Potent CYP3A4 inhibitor  
Increased IMP 
exposure 
Avoid  
ketoconazole  
Potent CYP3A4 inhibitor  
Increased IMP 
exposure 
Avoid  
lopinavir  
Potent CYP3A4 inhibitor  
Increased IMP 
exposure 
Avoid  
lopinavir/RIT 
Potent CYP3A4 inhibitor  
Increased IMP 
exposure 
Avoid  
mefenamic acid 
UGT1A9 
inhibitor/inducer 
Increased IMP 
exposure 
Avoid 
methylene blue 
UGT1A9 
inhibitor/inducer 
Increased IMP 
exposure 
Avoid 
mibefradil 
Potent CYP3A4 inhibitor  
Increased IMP 
exposure 
Avoid  

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Drug Name 
Characteristic 
Potential DDI Effect 
Usage 
mitotane 
Potent CYP3A4 inducer 
Decreased IMP 
exposure 
Avoid  
morniflumate 
UGT1A9 
inhibitor/inducer 
Increased IMP 
exposure 
Avoid 
nefazodone 
Potent CYP3A4 inhibitor  
Increased IMP 
exposure 
Avoid  
nelfinavir 
Potent CYP3A4 inhibitor 
Increased IMP 
exposure 
Avoid  
nevirapine 
Potent CYP3A4 inducer 
Decreased IMP 
exposure 
Avoid  
niflumic acid 
UGT1A9 
inhibitor/inducer 
Increased IMP 
exposure 
Avoid 
perampanel 
UGT1A9 
inhibitor/inducer 
Increased IMP 
exposure 
Avoid 
phenobarbital 
Potent CYP3A4 inducer  
Decreased IMP 
exposure 
Avoid  
phenytoin 
Potent CYP3A4 inducer; 
UGT1A9 
inhibitor/inducer  
Decreased IMP 
exposure 
Avoid  
posaconazole 
Potent CYP3A4 inhibitor  
Increased IMP 
exposure 
Avoid  
regorafenib 
UGT1A9 
inhibitor/inducer 
Increased IMP 
exposure 
Avoid 
rifabutin 
Potent CYP3A4 inducer 
Decreased IMP 
exposure 
Avoid  
rifampin 
Potent CYP3A4 
inducerUGT1A9 
inhibitor/inducer 
Decreased IMP 
exposure 
Avoid  
rifapentine 
Potent CYP3A4 inducer 
Decreased IMP 
exposure 
Avoid  
ritonavir 
Potent CYP3A4 inhibitor 
Increased IMP 
exposure 
Avoid  
saquinavir 
Potent CYP3A4 inhibitor  
Increased IMP 
exposure 
Avoid  
sorafenib 
UGT1A9 
inhibitor/inducer 
Increased IMP 
exposure 
Avoid 
St John’s wort 
CYP3A4 inducer 
Decreased IMP 
exposure 
Avoid  
telaprevir 
Potent CYP3A4 inhibitor  
Increased IMP 
exposure 
Avoid  
telithromycin 
Potent CYP3A4 inhibitor  
Increased IMP 
exposure 
Avoid  
tipranavir/ritonavir 
Potent CYP3A4 inhibitor 
Increased IMP 
exposure 
Avoid  
troleandomycin 
Potent CYP3A4 inhibitor  
Increased IMP 
exposure 
Avoid  
 umifenovir 
UGT1A9 
inhibitor/inducer 
Increased IMP 
exposure 
Avoid 
voriconazole 
Potent CYP3A4 inhibitor  
Increased IMP 
exposure 
Avoid  

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800 mg BID of setanaxib has been shown to increase the plasma concentration of 
sensitive CYP2C9, CYP2C19 and OAT3 transporter substrates less than two-fold. 
Caution should be exercised during concomitant use of such drugs with setanaxib due to 
risk of increased drug concentrations. Setanaxib has potential induction effects on 
CYP2B6. Sensitive substrates of CYP2B6 should be used with caution due to risk of 
decreased drug concentration and reduced efficacy. In addition, setanaxib inhibited 
BCRP and MDR1 (P-gp) in vitro. This may result in increased exposures of applicable 
concomitant medications, and hence caution should be exercised with use of sensitive 
BCRP and P-gp substrates. 
Some examples of sensitive CYP2C9, CYP2C19, CYP2B6, OAT3, BCRP, and P-gp 
substrates are included in Table 7, however the list is not comprehensive. 
Table 7 
Use with Caution – Sensitive CYP2C9, CYP2C19, CYP2B6, OAT3, 
BCRP, and P-gp Substrates 
Drug Name 
Characteristic 
Potential DDI Effect 
Usage 
acyclovir 
Sensitive OAT3 substrate  
May increase the drug 
level of concomitant 
medications 
Caution 
amitriptyline 
Sensitive CYP2B6 
substrate 
May decrease the drug 
level of concomitant 
medications and reduce 
efficacy 
Caution 
carbamazepine 
Sensitive CYP2B6 
substrate  
May decrease the drug 
level of concomitant 
medications and reduce 
efficacy 
Caution 
cefaclor 
Sensitive OAT3 substrate  
May increase the drug 
level of concomitant 
medications 
Caution 
ceftizoxime 
Sensitive OAT3 substrate  
May increase the drug 
level of concomitant 
medications 
Caution 
cyclophosphamide 
Sensitive CYP2B6 
substrate 
May decrease the drug 
level of concomitant 
medications and reduce 
efficacy 
Caution 
diazepam 
Sensitive CYP2C19 
substrate 
May increase the drug 
level of concomitant 
medications 
Caution 
digoxin 
Sensitive BCRP and P-gp 
substrate 
May increase the drug 
level of concomitant 
medications 
Caution 
dosulepin 
Sensitive CYP2B6 
substrate 
May decrease the drug 
level of concomitant 
medications and reduce 
efficacy 
Caution 
enasidenib 
Sensitive CYP2B6 
substrate 
May decrease the drug 
level of concomitant 
Caution 

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Drug Name 
Characteristic 
Potential DDI Effect 
Usage 
medications and reduce 
efficacy 
famotidine 
Sensitive OAT3 substrate  
May increase the drug 
level of concomitant 
medications 
Caution 
furosemide 
Sensitive OAT3 substrate  
May increase the drug 
level of concomitant 
medications 
Caution 
glimepiride 
Sensitive CYP2C9 
substrate 
May increase the drug 
level of concomitant 
medications 
Caution 
ifosfamide 
Sensitive CYP2B6 
substrate 
May decrease the drug 
level of concomitant 
medications and reduce 
efficacy 
Caution 
imipramine 
Sensitive CYP2B6 
substrate 
May decrease the drug 
level of concomitant 
medications and reduce 
efficacy 
Caution 
irinotecan 
Sensitive CYP2B6 
substrate 
May decrease the drug 
level of concomitant 
medications and reduce 
efficacy 
Caution 
ixazomib 
Sensitive CYP2B6 
substrate 
May decrease the drug 
level of concomitant 
medications and reduce 
efficacy 
Caution 
losartan 
Sensitive CYP2C9 
substrate 
May increase the drug 
level of concomitant 
medications 
Caution 
methotrexate 
Sensitive OAT3 substrate  
May increase the drug 
level of concomitant 
medications 
Caution 
omeprazole 
Sensitive CYP2C19 
substrate 
May increase the drug 
level of concomitant 
medications 
Caution 
oseltamivir carboxylate 
Sensitive OAT3 substrate  
May increase the drug 
level of concomitant 
medications 
Caution 
penicillin G 
Sensitive OAT3 substrate  
May increase the drug 
level of concomitant 
medications 
Caution 
phenytoin 
Moderate sensitive 
CYP2C9 substrate; 
sensitive CYP2B6 
substrate 
May increase the drug 
level of concomitant 
medications 
Caution 
romidepsin 
Sensitive CYP2B6 
substrate 
May decrease the drug 
level of concomitant 
medications and reduce 
efficacy 
Caution 
S-mephenytoin 
Sensitive CYP2C19 
May increase the drug 
Caution 

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Drug Name 
Characteristic 
Potential DDI Effect 
Usage 
substrate 
level of concomitant 
medications 
tamoxifen 
Sensitive CYP2B6 
substrate 
May decrease the drug 
level of concomitant 
medications and reduce 
efficacy 
Caution 
valproic acid 
Sensitive CYP2B6 
substrate 
May decrease the drug 
level of concomitant 
medications and reduce 
efficacy 
Caution 
voriconazole 
Sensitive CYP2C19 
substrate 
May increase the drug 
level of concomitant 
medications 
Caution 
warfarin 
Moderate sensitive 
CYP2C9 substrate 
May increase the drug 
level of concomitant 
medications 
Caution 
zanubrutinib 
Sensitive CYP2B6 
substrate 
May decrease the drug 
level of concomitant 
medications and reduce 
efficacy 
Caution 
Additionally, examples of potent CYP3A4 or UGT1A9 inhibitors and inducers, and 
sensitive CYP2C9, CYP2C19, CYP2B6, OAT3, BCRP and P-gp substrates may be found 
on the following websites; note that the published lists are not comprehensive. Refer to 
the specific product information for an intended concomitant drug. 
• FDA.gov: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Development
Resources/DrugInteractionsLabeling/ucm093664.htm (FDA 2016) 
• Pharmacytimes.com: http://www.pharmacytimes.com/publications/issue/2015/dec
ember2015/drug-interactions-with-cyp3a4-an-update (Horn and Hansen 2015) 
• DrugBank Online: https://go.drugbank.com/ 
• Drug Interaction Database (referred to as DIDB) from the University of 
Washington: https://www.druginteractionsolutions.org/ 
 
 

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17.4 
APPENDIX IV – RECIST v1.1 Methodology 
Response evaluation criteria in solid tumours: Revised RECIST criteria (Eisenhauer et al 
2009) are summarised below. 
Measurable/Non-Measurable Lesions. Each tumour lesion or site of disease identified 
at baseline is categorised as either a measurable lesion or a non-measurable lesion 
according to the following definitions. 
Lesion Type 
Qualifying Definition 
Measurable 
Tumour lesions: Must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of 10 
mm by CT or MRI scan (CT scan slice thickness no greater than 5 mm.). 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, 
a lymph node must be 15 mm in short axis when assessed by CT or MRI scan (CT 
scan slice thickness recommended to be no greater than 5 mm). At baseline and in 
follow-up, only the short axis will be measured and followed. 
Non-Measurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with 10 to <15 mm short axis) as well as truly non-measurable lesions. 
Lesions considered truly non-measurable include leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified 
by physical exam that is not measurable by reproducible imaging techniques. 
Special considerations regarding lesion measurability: 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment: 
Bone lesions: 
• Bone scan, PET scan, or plain films are not considered adequate imaging 
techniques to measure bone lesions. However, these techniques can be used to 
confirm the presence or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
• Blastic bone lesions are non-measurable. 
Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 

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However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
Lesions with prior local treatment: 
Tumour lesions situated in a previously irradiated area, or in an area subjected to other 
locoregional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. All measurements should be recorded in metric 
notation, using calipers if clinically assessed. All baseline evaluations should be 
performed as close as possible to the treatment start and never more than 35 days before 
the beginning of the treatment. 
Target Lesions. Target lesions are selected from measurable lesions at baseline on the 
basis of their size and suitability for accurate repeated measurements by imaging 
techniques or clinical judgment. The sum of the longest diameter (LD) for all target 
lesions provides a quantitative means of characterising objective tumour response to 
treatment as follows: 
Evaluation Criteria Used for Categorising Treatment Response of Target Lesions 
Response Category 
Definition 
Complete Response 
(CR) 
Disappearance of all target lesions 
Partial Response (PR) 
>30% decrease in the sum of the longest diameter (LD) of target lesions, taking 
as reference the baseline sum LD 
Progressive Disease 
(PD) 
>20% increase in the sum of the LD of target lesions, taking as reference the 
smallest sum LD recorded since the treatment started or the appearance of one 
or more new lesions 
Stable Disease 
(SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum LD since the treatment started 
Non-Target Lesions. Non-target lesions are other lesions (or sites of disease) not 
identified as target lesions at baseline. These include both non-measurable lesions as well 
as measurable lesions exceeding the maximum number allowed per organ or in total. The 
response of non-target lesions to treatment is evaluated on the basis of their presence or 
absence as follows: 
Evaluation Criteria Used for Categorising Treatment Response of Non-Target Lesions 
Response Category 
Definition 
Complete Response (CR) 
Disappearance of all non-target lesions and normalisation of tumour 
marker levels initially above upper limits of normal 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s) or/and maintenance of 
tumour marker level above the normal limits 
To achieve “unequivocal progression” on the basis of non-target lesions, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of 
SD or PR in target lesions, the overall tumour burden has increased sufficiently to merit 

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unequivocal progression by non-target lesions. A modest “increase” in the size of 1 or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status. The designation of overall progression solely on the basis of change in non-target 
disease in the face of SD or PD of target disease will therefore be exceptional. 
New Lesions. New lesions not present at baseline should be recorded at time of 
occurrence. 
Overall Response. The overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). For example, a 
patient who has SD at first assessment, PR at second assessment, and PD on last 
assessment has a best overall response of PR. In the case of SD, follow-up measurements 
must have met the SD criteria at least once with a minimum interval of at least 6 weeks 
from randomisation. 
 
Target Lesions 
 
Non-target Lesions 
 
New Lesions 
 
Overall Response 
 
CR 
 
CR 
 
No 
 
CR 
 
CR 
 
Non-CR/non-PD 
 
No 
 
PR 
 
CR 
 
Not evaluated 
 
No 
 
PR 
 
PR 
 
Non-PD 
or 
not 
all 
evaluated 
 
No 
 
PR 
 
SD 
 
Non-PD 
or 
not 
all 
evaluated 
 
No 
 
SD 
 
PD 
 
Any 
 
Yes or No 
 
PD 
 
Not all evaluated 
 
Non-PD 
 
No 
 
NE 
 
PD 
 
Any 
 
Yes or No 
 
PD 
 
Any 
 
PD 
 
Yes or No 
 
PD 
 
Any 
 
Any 
 
Yes 
 
PD 
CR=complete response; NE=not evaluable; PD=progressive disease; PR=partial response; SD=stable 
disease. 
Duration of Response. The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
Stable disease is measured from the start of the treatment until the criteria for progression 

Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000400 
Version and Date: Version 4.0 (25 April 2023) 
Page 137 of 137
 
 
 
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are met, taking as reference the smallest measurements recorded since the treatment 
started. 
Response review 
For studies where the response rate is the primary endpoint it is strongly recommended 
that all responses be reviewed by an expert(s) independent of the study at the study’s 
completion. Simultaneous review of the patients’ files and radiological images is the best 
approach. 
Reporting of results 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible. 
All of the patients who met the eligibility criteria should be included in the main analysis 
of the response rate. 
All conclusions should be based on all eligible patients. 
Sub-analyses may then be performed on the basis of a subset of patients, excluding those 
for whom major protocol deviations have been identified (eg, early death due to other 
reasons, early discontinuation of treatment, major protocol violations, etc). However, 
these sub-analyses may not serve as the basis for drawing conclusions concerning 
treatment efficacy, and the reasons for excluding patients from the analysis should be 
clearly reported.