A Study of Setanaxib Co-Administered With Pembrolizumab i... | NCT05323656

Label	Type	Description	Intervention Names
Setanaxib 1600 mg and Pembrolizumab 200 mg	Experimental	Participants will be administered setanaxib at a dose of 1600 mg/day for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks.	Drug: Setanaxib Biological: Pembrolizumab
Placebo and Pembrolizumab 200 mg	Active Comparator	Participants will be administered placebo for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks.	Biological: Pembrolizumab Drug: Placebo

Name	Type	Description	Arm Group Labels	Other Names
Setanaxib	Drug	Oral tablets, 400 mg per tablet	Setanaxib 1600 mg and Pembrolizumab 200 mg

Measure	Description	Time Frame
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.	Baseline to at least 15 weeks and up to 51 weeks

Measure	Description	Time Frame
Progression Free Survival (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.	Baseline up to approximately 21 months
Change From Baseline in Cancer-associated Fibroblasts (CAFs) Level in Tumour Tissue

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Male or female patients aged ≥18 years, inclusive, at the time of informed consent.
Willing and able to give informed consent and to comply with the requirements of the study.
Histologically- or cytologically-confirmed diagnosis of SCCHN that is recurrent or metastatic with or without nodal involvement, and with or without metastatic spread, and is not eligible for surgical resection.
Candidates for first-line treatment for pembrolizumab for recurrent or metastatic SCCHN, at the discretion of the investigator.
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.
Measurable disease, in accordance with RECIST v1.1, and with tumour accessible and of sufficient volume for pre-treatment and on-treatment biopsy.
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.
HPV status known at randomisation.
Life expectancy of at least 6 months in the judgment of the investigator.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
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:
1. Absolute neutrophil count ≥1,000/mm3 (≥ 1.0×109/L).
2. Platelet count ≥100,000/mm3 (≥ 100×109/L).
3. 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.
4. Total bilirubin ≤1.5×upper limit of normal (ULN) (if associated with liver metastases or Gilbert's disease, ≤3×ULN).
5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3×ULN.
6. Serum creatinine ≤2.0 mg/dL or creatinine clearance ≥40 mL/min (measured or calculated according to the method of Cockcroft and Gault).
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.
1. 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."
2. 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.
3. Highly effective contraception is defined as methods that can achieve a failure rate of less than 1% per year when used consistently and correctly.
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.
Male patients with female partners of childbearing potential must be willing to use a condom and require their partner to use an a highly effective contraceptive method.
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:

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.
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).
Not recovered from AEs Grade 2 or greater (except for alopecia) due to previously administered agents.
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.
Prior treatment with setanaxib or participation in a previous setanaxib clinical study.
Prior treatment with pembrolizumab.
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.
Known active central nervous system metastases and/or carcinomatous meningitis.
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:
1. Patients with vitiligo or alopecia.
2. Any chronic skin condition that does not require systemic therapy.
3. Patients with coeliac disease controlled by diet alone.
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.
Active infection requiring systemic therapy.
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. 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.
Serious chronic gastrointestinal conditions associated with diarrhoea.
History of significant haematological problems, such as blood dyscrasias requiring treatment, aplastic anaemia, myelodysplastic syndrome, or leukaemia.
Surgery (eg, stomach bypass) or medical condition that might significantly affect absorption of medicines (as judged by the investigator).
A positive pregnancy test or breastfeeding for female patients.
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.
TSH >ULN at Screening.
Unstable cardiovascular disease as defined by any of the following:
1. Unstable angina within 6 months prior to Screening
2. Myocardial infarction, coronary artery bypass graft surgery, or coronary angioplasty within 6 months prior to Screening
3. Cerebrovascular accident within 6 months prior to Screening
4. New York Heart Association Class III or IV heart failure
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.
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.
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.
Legal incapacity or limited legal capacity.
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.
Patients who are unable to provide informed consent, are incarcerated or unable to follow protocol requirements.
Previous randomisation in this study.

Facility	Status	City	State	ZIP	Country	Contacts
Mount Sinai Comprehensive Cancer Center		Miami Beach	Florida	33140	United States
Siteman Cancer Center - St. Peters

ID	Title	Description
FG000	Setanaxib 1600 mg and Pembrolizumab 200 mg	Participants will be administered setanaxib at a dose of 1600 mg/day for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Setanaxib: Oral tablets, 400 mg per tablet Pembrolizumab: 200 mg IV infusion

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Apr 25, 2023	Jan 23, 2025

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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.

Full Analysis Set

Posted

Least Squares Mean

Standard Error

Percentage change from baseline

Baseline to at least 15 weeks and up to 51 weeks

ID	Title	Description
OG000	Setanaxib 1600 mg and Pembrolizumab 200 mg	Participants will be administered setanaxib at a dose of 1600 mg/day for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Setanaxib: Oral tablets, 400 mg per tablet Pembrolizumab: 200 mg IV infusion
OG001	Placebo and Pembrolizumab 200 mg	Participants will be administered placebo for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Placebo: Oral tablets Pembrolizumab: 200 mg IV infusion

Units	Counts
Participants	OG00026 OG00128

Title

Denominators

Categories

Title	Measurements
	OG000-7.88± 9.323 OG001-12.93± 8.977

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000	Null hypothesis: the mean best percentage change in the tumour size between the treatment groups are the same. 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%.	ANCOVA		0.7008		LS Mean Difference	5.05	Standard Error of the Mean	13.077	2-Sided	80	-11.98	22.0			The LS Mean difference is for the Setanaxib Group minus the Placebo Group		Superiority

Secondary

Progression Free Survival (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.

Full Analysis Set

Posted

Median

80% Confidence Interval

days

Baseline up to approximately 21 months

ID	Title	Description
OG000	Setanaxib 1600 mg and Pembrolizumab 200 mg	Participants will be administered setanaxib at a dose of 1600 mg/day for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Setanaxib: Oral tablets, 400 mg per tablet Pembrolizumab: 200 mg IV infusion
OG001	Placebo and Pembrolizumab 200 mg	Participants will be administered placebo for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Placebo: Oral tablets Pembrolizumab: 200 mg IV infusion

Units	Counts
Participants

Secondary

Change From Baseline in Cancer-associated Fibroblasts (CAFs) Level in Tumour Tissue

Changes within treatment groups (ie, across paired tissue samples) and between treatment groups summarized both descriptively and as adjusted mean difference between treatment groups.

Full Analysis Set

Posted

Mean

Standard Deviation

% positivity of tumour stromal component

Baseline up to approximately 9 weeks

ID	Title	Description
OG000	Setanaxib 1600 mg and Pembrolizumab 200 mg	Participants will be administered setanaxib at a dose of 1600 mg/day for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Setanaxib: Oral tablets, 400 mg per tablet Pembrolizumab: 200 mg IV infusion
OG001	Placebo and Pembrolizumab 200 mg	Participants will be administered placebo for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Placebo: Oral tablets Pembrolizumab: 200 mg IV infusion

Units	Counts
Participants

Secondary

Change From Baseline in the Number of Cluster of Differentiation 8 (CD8+) Tumour Infiltrating Lymphocytes (TILs) in Tumour Tissue

Changes within treatment groups (ie, across paired tissue samples) and between treatment groups summarized both descriptively and as adjusted mean difference between treatment groups.

Full Analysis Set)

Posted

Mean

Standard Deviation

cells/High Power Field (HPF)

Baseline up to approximately 9 weeks

ID	Title	Description
OG000	Setanaxib 1600 mg and Pembrolizumab 200 mg	Participants will be administered setanaxib at a dose of 1600 mg/day for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Setanaxib: Oral tablets, 400 mg per tablet Pembrolizumab: 200 mg IV infusion
OG001	Placebo and Pembrolizumab 200 mg	Participants will be administered placebo for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Placebo: Oral tablets Pembrolizumab: 200 mg IV infusion

Units	Counts
Participants

Secondary

Change From Baseline in the Number of Regulatory T-cells in Tumour Tissue

Changes within treatment groups (ie, across paired tissue samples) and between treatment groups summarized both descriptively and as adjusted mean difference between treatment groups.

Posted

Mean

Standard Deviation

cells/High Power Field (HPF)

Baseline up to approximately 9 weeks

ID	Title	Description
OG000	Setanaxib 1600 mg and Pembrolizumab 200 mg	Participants will be administered setanaxib at a dose of 1600 mg/day for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Setanaxib: Oral tablets, 400 mg per tablet Pembrolizumab: 200 mg IV infusion
OG001	Placebo and Pembrolizumab 200 mg	Participants will be administered placebo for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Placebo: Oral tablets Pembrolizumab: 200 mg IV infusion

Units	Counts
Participants

Secondary

Overall Response Rate (ORR)

Proportion of the patients who have a complete response (CR) or partial response (PR) per RECIST v1.1 will be used to access ORR.

Full Analysis Set

Posted

Count of Participants

Participants

Baseline up to approximately 12 months

ID	Title	Description
OG000	Setanaxib 1600 mg and Pembrolizumab 200 mg	Participants will be administered setanaxib at a dose of 1600 mg/day for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Setanaxib: Oral tablets, 400 mg per tablet Pembrolizumab: 200 mg IV infusion
OG001	Placebo and Pembrolizumab 200 mg	Participants will be administered placebo for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Placebo: Oral tablets Pembrolizumab: 200 mg IV infusion

Units	Counts
Participants

Secondary

Duration of Response (DoR)

The minimum time when CR or PR is first observed to the time of progression of disease (PD) or death will be used to access DoR.

Full Analysis Set

Posted

Number

80% Confidence Interval

days

Baseline up to approximately 12 months

ID	Title	Description
OG000	Setanaxib 1600 mg and Pembrolizumab 200 mg	Participants will be administered setanaxib at a dose of 1600 mg/day for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Setanaxib: Oral tablets, 400 mg per tablet Pembrolizumab: 200 mg IV infusion
OG001	Placebo and Pembrolizumab 200 mg	Participants will be administered placebo for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Placebo: Oral tablets Pembrolizumab: 200 mg IV infusion

Units	Counts
Participants

Secondary

Disease Control Rate (DCR)

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 access DCR.

Full Analysis Set

Posted

Number

90% Confidence Interval

percentage of participants

Baseline up to approximately 12 months

ID	Title	Description
OG000	Setanaxib 1600 mg and Pembrolizumab 200 mg	Participants will be administered setanaxib at a dose of 1600 mg/day for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Setanaxib: Oral tablets, 400 mg per tablet Pembrolizumab: 200 mg IV infusion
OG001	Placebo and Pembrolizumab 200 mg	Participants will be administered placebo for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Placebo: Oral tablets Pembrolizumab: 200 mg IV infusion

Units	Counts
Participants

Secondary

Overall Survival (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.

Full Analysis Set

Posted

Number

80% Confidence Interval

percentage of participants

Baseline up to 12 months

ID	Title	Description
OG000	Setanaxib 1600 mg and Pembrolizumab 200 mg	Participants will be administered setanaxib at a dose of 1600 mg/day for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Setanaxib: Oral tablets, 400 mg per tablet Pembrolizumab: 200 mg IV infusion
OG001	Placebo and Pembrolizumab 200 mg	Participants will be administered placebo for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Placebo: Oral tablets Pembrolizumab: 200 mg IV infusion

Units	Counts
Participants

Secondary

Number of Participants With Adverse Events (AEs)

Any clinically significant abnormalities in vital signs, physical examination, clinical laboratory tests (including biochemistry, hematology, urinalysis, and thyroid function), or 12- lead electrocardiogram (ECG) results will be recorded as Adverse Events (AEs).

Safety Analysis Set

Posted

Count of Participants

Participants

Baseline up to approximately 21 months

ID	Title	Description
OG000	Setanaxib 1600 mg and Pembrolizumab 200 mg	Participants will be administered setanaxib at a dose of 1600 mg/day for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Setanaxib: Oral tablets, 400 mg per tablet Pembrolizumab: 200 mg IV infusion
OG001	Placebo and Pembrolizumab 200 mg	Participants will be administered placebo for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Placebo: Oral tablets Pembrolizumab: 200 mg IV infusion

Units	Counts
Participants

Secondary

Number of Participants With Adverse Events of Special Interest (AESI)

AESI include Anaemia and Hypothyroidism.

Safety Analysis Set

Posted

Count of Participants

Participants

Baseline up to approximately 21 months

ID	Title	Description
OG000	Setanaxib 1600 mg and Pembrolizumab 200 mg	Participants will be administered setanaxib at a dose of 1600 mg/day for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Setanaxib: Oral tablets, 400 mg per tablet Pembrolizumab: 200 mg IV infusion
OG001	Placebo and Pembrolizumab 200 mg	Participants will be administered placebo for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Placebo: Oral tablets Pembrolizumab: 200 mg IV infusion

Units	Counts
Participants	OG000

Secondary

Levels of Programmed Death-ligand 1 (PD-L1) Expression in Tumour Tissue

Combined Positive Score (CPS) is a scoring method that predicts response to pembrolizumab in patients with cancer defined as the number of PD-L1-staining cells (tumor cells, lymphocytes, and macrophages) relative to the total number of viable tumor cells. A higher CPS score indicates an increased likelihood to respond to pembrolizumab treatment. It was hypothesized based on the mode of action of setanaxib that there would be an increased immunological response and therefore an increase in PD-L1 in tumor tissue.

Changes within treatment groups (ie, across paired tissue samples) and between treatment groups summarized both descriptively and as adjusted mean difference between treatment groups.

Full Analysis Set

Posted

Mean

Standard Deviation

ratio

Baseline up to approximately 9 weeks

ID	Title	Description
OG000	Setanaxib 1600 mg and Pembrolizumab 200 mg	Participants will be administered setanaxib at a dose of 1600 mg/day for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Setanaxib: Oral tablets, 400 mg per tablet Pembrolizumab: 200 mg IV infusion
OG001	Placebo and Pembrolizumab 200 mg	Participants will be administered placebo for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Placebo: Oral tablets Pembrolizumab: 200 mg IV infusion

Secondary

Change From Baseline in CAFs Cell Type Abundance Based on Gene Expression Profiles

Digital cytometry was carried out using CIBERSORTx. This estimates cell type abundance based on gene expression profiles in bulk RNA-Seq data. The abundance of myofibroblastic CAF were enumerated using a custom signature matrix based on gene expression profiles derived from annotated SCCHN scRNA-Seq data.

CIBERSORTx Absolute Abundance ratio is calculated by the median expression level of all genes in the signature matrix divided by the median expression level of all genes in the mixture (bulk RNA-Seq data for the sample). This produces a score that quantitatively measures the overall abundance of each cell type using gene expression profiles.

Full Analysis Set with paired observations

Posted

Mean

Standard Deviation

CIBERSORTx Absolute Abundance ratio

Baseline up to approximately 9 weeks

ID	Title	Description
OG000	Setanaxib 1600 mg and Pembrolizumab 200 mg	Participants will be administered setanaxib at a dose of 1600 mg/day for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Setanaxib: Oral tablets, 400 mg per tablet Pembrolizumab: 200 mg IV infusion
OG001	Placebo and Pembrolizumab 200 mg	Participants will be administered placebo for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Placebo: Oral tablets Pembrolizumab: 200 mg IV infusion

Secondary

Change From Baseline in CD8+ TILs Cell Type Abundance Based on Gene Expression Profiles

Digital cytometry was carried out using CIBERSORTx. This estimates cell type abundance based on gene expression profiles in bulk RNA-Seq data. The abundance of tumor-infiltrating lymphocytes (TILs) were enumerated using a custom signature matrix based on gene expression profiles derived from annotated SCCHN scRNA-Seq data.

Full Analysis Set with paired observations

Posted

Mean

Standard Deviation

CIBERSORTx Absolute Abundance ratio

Baseline up to approximately 9 weeks

ID	Title	Description
OG000	Setanaxib 1600 mg and Pembrolizumab 200 mg	Participants will be administered setanaxib at a dose of 1600 mg/day for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Setanaxib: Oral tablets, 400 mg per tablet Pembrolizumab: 200 mg IV infusion
OG001	Placebo and Pembrolizumab 200 mg	Participants will be administered placebo for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Placebo: Oral tablets Pembrolizumab: 200 mg IV infusion

Secondary

Change From Baseline in Regulatory T-cell Abundance Based on Gene Expression Profiles

Digital cytometry was carried out using CIBERSORTx. This estimates cell type abundance based on gene expression profiles in bulk RNA-Seq data. The abundance of regulatory T-cells were enumerated using a custom signature matrix based on gene expression profiles derived from annotated SCCHN scRNA-Seq data.

Full Analysis Set with paired observations

Posted

Mean

Standard Deviation

CIBERSORTx Absolute Abundance ratio

Baseline up to approximately 9 weeks

ID	Title	Description
OG000	Setanaxib 1600 mg and Pembrolizumab 200 mg	Participants will be administered setanaxib at a dose of 1600 mg/day for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Setanaxib: Oral tablets, 400 mg per tablet Pembrolizumab: 200 mg IV infusion
OG001	Placebo and Pembrolizumab 200 mg	Participants will be administered placebo for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Placebo: Oral tablets Pembrolizumab: 200 mg IV infusion

Secondary

Area Under The Concentration-time Curve Over a 24-hour Period at Steady State (AUC[0-24]-ss) of Setanaxib

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ug*h*mL-¹

Baseline, Week 3, week 9, week 24, week 51

ID	Title	Description
OG000	Setanaxib 1600 mg and Pembrolizumab 200 mg	Participants will be administered setanaxib at a dose of 1600 mg/day for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Setanaxib: Oral tablets, 400 mg per tablet Pembrolizumab: 200 mg IV infusion

Units	Counts
Participants	OG000

Secondary

Area Under The Concentration-time Curve Over a 24-hour Period at Steady State (AUC24-ss) of GKT138184

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ug*h*mL-¹

Baseline, Week 3, week 9, week 24, week 51

ID	Title	Description
OG000	Setanaxib 1600 mg and Pembrolizumab 200 mg	Participants will be administered setanaxib at a dose of 1600 mg/day for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Setanaxib: Oral tablets, 400 mg per tablet Pembrolizumab: 200 mg IV infusion

Units	Counts
Participants	OG000

Secondary

Minimum Plasma Concentration at Steady State (Cmax-ss) of Setanaxib

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ug*mL-¹

Baseline, Week 3, week 9, week 24, week 51

ID	Title	Description
OG000	Setanaxib 1600 mg and Pembrolizumab 200 mg	Participants will be administered setanaxib at a dose of 1600 mg/day for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Setanaxib: Oral tablets, 400 mg per tablet Pembrolizumab: 200 mg IV infusion

Units	Counts
Participants	OG00027

Secondary

Minimum Plasma Concentration at Steady State (Cmin-ss) of GKT138184

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ug*mL-¹

Baseline, Week 3, week 9, week 24, week 51

ID	Title	Description
OG000	Setanaxib 1600 mg and Pembrolizumab 200 mg	Participants will be administered setanaxib at a dose of 1600 mg/day for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Setanaxib: Oral tablets, 400 mg per tablet Pembrolizumab: 200 mg IV infusion

Units	Counts
Participants	OG00027

Secondary

Maximum Plasma Concentration at Steady State (Cmax-ss) of Setanaxib

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ug*mL-¹

Baseline, Week 3, week 9, week 24, week 51

ID	Title	Description
OG000	Setanaxib 1600 mg and Pembrolizumab 200 mg	Participants will be administered setanaxib at a dose of 1600 mg/day for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Setanaxib: Oral tablets, 400 mg per tablet Pembrolizumab: 200 mg IV infusion

Units	Counts
Participants	OG00027

Secondary

Maximum Plasma Concentration at Steady State (Cmax-ss) of GKT138184

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ug*mL-¹

Baseline up to approximately 26 months

ID	Title	Description
OG000	Setanaxib 1600 mg and Pembrolizumab 200 mg	Participants will be administered setanaxib at a dose of 1600 mg/day for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Setanaxib: Oral tablets, 400 mg per tablet Pembrolizumab: 200 mg IV infusion

Units	Counts
Participants	OG00027

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Asthenia	General disorders	MedDRA 25.0	Systematic Assessment	EG00015 events11 affected27 at risk EG00114 events9 affected28 at risk
Fatigue	General disorders	MedDRA 25.0	Systematic Assessment	EG0006 events5 affected27 at risk EG0012 events2 affected28 at risk
Oedema peripheral	General disorders	MedDRA 25.0	Systematic Assessment	EG0002 events2 affected27 at risk EG0012 events2 affected28 at risk
Pyrexia	General disorders	MedDRA 25.0	Systematic Assessment	EG0004 events4 affected27 at risk EG0011 events1 affected28 at risk
Implant site extravasation	General disorders	MedDRA 25.0	Systematic Assessment	EG0004 events2 affected27 at risk EG0010 events0 affected28 at risk
Mucosal inflammation	General disorders	MedDRA 25.0	Systematic Assessment	EG0000 events0 affected27 at risk EG0012 events2 affected28 at risk
Xerosis	General disorders	MedDRA 25.0	Systematic Assessment	EG0002 events2 affected27 at risk EG0010 events0 affected28 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 25.0	Systematic Assessment	EG00010 events7 affected27 at risk EG00113 events5 affected28 at risk
Nausea	Gastrointestinal disorders	MedDRA 25.0	Systematic Assessment	EG0009 events7 affected27 at risk EG0016 events5 affected28 at risk
Constipation	Gastrointestinal disorders	MedDRA 25.0	Systematic Assessment	EG0005 events4 affected27 at risk EG0018 events6 affected28 at risk
Vomiting	Gastrointestinal disorders	MedDRA 25.0	Systematic Assessment	EG0006 events4 affected27 at risk EG0013 events3 affected28 at risk
Dry mouth	Gastrointestinal disorders	MedDRA 25.0	Systematic Assessment	EG0003 events3 affected27 at risk EG0014 events4 affected28 at risk
Stomatitis	Gastrointestinal disorders	MedDRA 25.0	Systematic Assessment	EG0002 events2 affected27 at risk EG0013 events3 affected28 at risk
Dysphagia	Gastrointestinal disorders	MedDRA 25.0	Systematic Assessment	EG0003 events3 affected27 at risk EG0011 events1 affected28 at risk
Gastrooesophageal reflux disease	Gastrointestinal disorders	MedDRA 25.0	Systematic Assessment	EG0003 events3 affected27 at risk EG0010 events0 affected28 at risk
Pruritus	Skin and subcutaneous tissue disorders	MedDRA 25.0	Systematic Assessment	EG0009 events7 affected27 at risk EG0016 events5 affected28 at risk
Dry Skin	Skin and subcutaneous tissue disorders	MedDRA 25.0	Systematic Assessment	EG0003 events3 affected27 at risk EG0014 events3 affected28 at risk
Skin Lesion	Skin and subcutaneous tissue disorders	MedDRA 25.0	Systematic Assessment	EG0003 events3 affected27 at risk EG0011 events1 affected28 at risk
Eczema	Skin and subcutaneous tissue disorders	MedDRA 25.0	Systematic Assessment	EG0000 events0 affected27 at risk EG0015 events3 affected28 at risk
Rash	Skin and subcutaneous tissue disorders	MedDRA 25.0	Systematic Assessment	EG0002 events2 affected27 at risk EG0011 events1 affected28 at risk
Erythema	Skin and subcutaneous tissue disorders	MedDRA 25.0	Systematic Assessment	EG0000 events0 affected27 at risk EG0014 events2 affected28 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA 25.0	Systematic Assessment	EG0007 events7 affected27 at risk EG0018 events6 affected28 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 25.0	Systematic Assessment	EG0003 events3 affected27 at risk EG0013 events2 affected28 at risk
Dysphonia	Respiratory, thoracic and mediastinal disorders	MedDRA 25.0	Systematic Assessment	EG0001 events1 affected27 at risk EG0012 events2 affected28 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA 25.0	Systematic Assessment	EG0004 events4 affected27 at risk EG00111 events6 affected28 at risk
Hypokalaemia	Metabolism and nutrition disorders	MedDRA 25.0	Systematic Assessment	EG0006 events3 affected27 at risk EG0013 events3 affected28 at risk
Hypercalcaemia	Metabolism and nutrition disorders	MedDRA 25.0	Systematic Assessment	EG0001 events1 affected27 at risk EG0014 events3 affected28 at risk
Hypermagnesaemia	Metabolism and nutrition disorders	MedDRA 25.0	Systematic Assessment	EG0003 events3 affected27 at risk EG0010 events0 affected28 at risk
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA 25.0	Systematic Assessment	EG0000 events0 affected27 at risk EG0012 events2 affected28 at risk
Hyponatraemia	Metabolism and nutrition disorders	MedDRA 25.0	Systematic Assessment	EG0000 events0 affected27 at risk EG0012 events2 affected28 at risk
Hypophosphataemia	Metabolism and nutrition disorders	MedDRA 25.0	Systematic Assessment	EG0002 events2 affected27 at risk EG0010 events0 affected28 at risk
Blood creatinine increased	Investigations	MedDRA 25.0	Systematic Assessment	EG00013 events4 affected27 at risk EG0011 events1 affected28 at risk
Lymphocyte count decreased	Investigations	MedDRA 25.0	Systematic Assessment	EG0009 events5 affected27 at risk EG0017 events2 affected28 at risk
Weight decreased	Investigations	MedDRA 25.0	Systematic Assessment	EG0003 events3 affected27 at risk EG0012 events2 affected28 at risk
Blood alkaline phosphatase increased	Investigations	MedDRA 25.0	Systematic Assessment	EG0000 events0 affected27 at risk EG0012 events2 affected28 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 25.0	Systematic Assessment	EG0003 events3 affected27 at risk EG0019 events4 affected28 at risk
Neck pain	Musculoskeletal and connective tissue disorders	MedDRA 25.0	Systematic Assessment	EG0004 events4 affected27 at risk EG0014 events3 affected28 at risk
Arthritis	Musculoskeletal and connective tissue disorders	MedDRA 25.0	Systematic Assessment	EG0002 events2 affected27 at risk EG0010 events0 affected28 at risk
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA 25.0	Systematic Assessment	EG0002 events2 affected27 at risk EG0010 events0 affected28 at risk
Oral fungal infection	Infections and infestations	MedDRA 25.0	Systematic Assessment	EG0000 events0 affected27 at risk EG0013 events3 affected28 at risk
Pneumonia	Infections and infestations	MedDRA 25.0	Systematic Assessment	EG0004 events4 affected27 at risk EG0010 events0 affected28 at risk
Lower respiratory tract infection	Infections and infestations	MedDRA 25.0	Systematic Assessment	EG0004 events2 affected27 at risk EG0010 events0 affected28 at risk
Anaemia	Blood and lymphatic system disorders	MedDRA 25.0	Systematic Assessment	EG0005 events4 affected27 at risk EG0014 events3 affected28 at risk
Neutropenia	Blood and lymphatic system disorders	MedDRA 25.0	Systematic Assessment	EG0002 events2 affected27 at risk EG0010 events0 affected28 at risk
Hypothyroidism	Endocrine disorders	MedDRA 25.0	Systematic Assessment	EG00011 events9 affected27 at risk EG0016 events5 affected28 at risk
Hyperthyroidism	Endocrine disorders	MedDRA 25.0	Systematic Assessment	EG0003 events3 affected27 at risk EG0010 events0 affected28 at risk
Headache	Nervous system disorders	MedDRA 25.0	Systematic Assessment	EG0003 events2 affected27 at risk EG0012 events2 affected28 at risk
Dizziness	Nervous system disorders	MedDRA 25.0	Systematic Assessment	EG0000 events0 affected27 at risk EG0013 events3 affected28 at risk
Depression	Psychiatric disorders	MedDRA 25.0	Systematic Assessment	EG0000 events0 affected27 at risk EG0012 events2 affected28 at risk
Tumour haemorrhage	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 25.0	Systematic Assessment	EG0000 events0 affected27 at risk EG0012 events2 affected28 at risk
Productive cough	Respiratory, thoracic and mediastinal disorders	MedDRA 25.0	Systematic Assessment	EG0000 events0 affected27 at risk EG0012 events2 affected28 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 25.0	Systematic Assessment	EG0003 events2 affected27 at risk EG0011 events1 affected28 at risk
Insomnia	Psychiatric disorders	MedDRA 25.0	Systematic Assessment	EG0001 events1 affected27 at risk EG0012 events2 affected28 at risk
Anxiety	Psychiatric disorders	MedDRA 25.0	Systematic Assessment	EG0000 events0 affected27 at risk EG0012 events2 affected28 at risk

ID	Term
D002294	Carcinoma, Squamous Cell
D002277	Carcinoma
D009375	Neoplasms, Glandular and Epithelial
D009370	Neoplasms by Histologic Type
D009369	Neoplasms
D006258	Head and Neck Neoplasms
D009371	Neoplasms by Site

ID	Title	Description
BG000	Setanaxib 1600 mg and Pembrolizumab 200 mg	Participants will be administered setanaxib at a dose of 1600 mg/day for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Setanaxib: Oral tablets, 400 mg per tablet Pembrolizumab: 200 mg IV infusion
BG001	Placebo and Pembrolizumab 200 mg	Participants will be administered placebo for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Placebo: Oral tablets Pembrolizumab: 200 mg IV infusion
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Setanaxib 1600 mg and Pembrolizumab 200 mg	Participants will be administered setanaxib at a dose of 1600 mg/day for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Setanaxib: Oral tablets, 400 mg per tablet Pembrolizumab: 200 mg IV infusion	6	27	8	27	27	27
EG001	Placebo and Pembrolizumab 200 mg	Participants will be administered placebo for the up to 24-month double-blind treatment period. Participants will also be administered Pembrolizumab 200 mg intravenously every 3 weeks. Placebo: Oral tablets Pembrolizumab: 200 mg IV infusion	13	28	10	28	23	28

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Aspiration	Respiratory, thoracic and mediastinal disorders	MedDRA 25.0	Systematic Assessment	EG0000 affected27 at risk EG0012 events2 affected28 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA 25.0	Systematic Assessment	EG0000 affected27 at risk EG0011 events1 affected28 at risk
Haemoptysis	Respiratory, thoracic and mediastinal disorders	MedDRA 25.0	Systematic Assessment	EG0001 events1 affected27 at risk EG0010 affected28 at risk
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA 25.0	Systematic Assessment	EG0000 affected27 at risk EG0011 events1 affected28 at risk
Respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA 25.0	Systematic Assessment	EG0000 affected27 at risk EG0011 events1 affected28 at risk
Colitis	Gastrointestinal disorders	MedDRA 25.0	Systematic Assessment	EG0002 events2 affected27 at risk EG0010 affected28 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 25.0	Systematic Assessment	EG0001 events1 affected27 at risk EG0010 affected28 at risk
Dysphagia	Gastrointestinal disorders	MedDRA 25.0	Systematic Assessment	EG0000 affected27 at risk EG0011 events1 affected28 at risk
Immune-mediated enterocolitis	Gastrointestinal disorders	MedDRA 25.0	Systematic Assessment	EG0002 events1 affected27 at risk EG0011 events1 affected28 at risk
Anaemia	Blood and lymphatic system disorders	MedDRA 25.0	Systematic Assessment	EG0000 affected27 at risk EG0013 events3 affected28 at risk
Herpes simplex	Infections and infestations	MedDRA 25.0	Systematic Assessment	EG0001 events1 affected27 at risk EG0010 affected28 at risk
Pneumonia	Infections and infestations	MedDRA 25.0	Systematic Assessment	EG0001 events1 affected27 at risk EG0010 affected28 at risk
Septic shock	Infections and infestations	MedDRA 25.0	Systematic Assessment	EG0001 events1 affected27 at risk EG0010 events0 affected28 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA 25.0	Systematic Assessment	EG0000 affected27 at risk EG0011 events1 affected28 at risk
Blood creatinine increased	Investigations	MedDRA 25.0	Systematic Assessment	EG0002 events1 affected27 at risk EG0010 affected28 at risk
Lipase increased	Investigations	MedDRA 25.0	Systematic Assessment	EG0001 events1 affected27 at risk EG0010 affected28 at risk
Troponin I increased	Investigations	MedDRA 25.0	Systematic Assessment	EG0001 events1 affected27 at risk EG0010 affected28 at risk
Tumour haemorrhage	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 25.0	Systematic Assessment	EG0000 affected27 at risk EG0011 events1 affected28 at risk
Tumour pain	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 25.0	Systematic Assessment	EG0000 affected27 at risk EG0013 events1 affected28 at risk
Cardiogenic shock	Cardiac disorders	MedDRA 25.0	Systematic Assessment	EG0001 events1 affected27 at risk EG0010 affected28 at risk
Asthenia	Gastrointestinal disorders	MedDRA 25.0	Systematic Assessment	EG0000 affected27 at risk EG0011 events1 affected28 at risk
Autoimmune hepatitis	Hepatobiliary disorders	MedDRA 25.0	Systematic Assessment	EG0001 events1 affected27 at risk EG0010 affected28 at risk
Hypokalaemia	Metabolism and nutrition disorders	MedDRA 25.0	Systematic Assessment	EG0003 events2 affected27 at risk EG0010 affected28 at risk
Neck pain	Musculoskeletal and connective tissue disorders	MedDRA 25.0	Systematic Assessment	EG0000 affected27 at risk EG0011 events1 affected28 at risk
Rash	Skin and subcutaneous tissue disorders	MedDRA 25.0	Systematic Assessment	EG0001 events1 affected27 at risk EG0010 affected28 at risk
Hypotension	Vascular disorders	MedDRA 25.0	Systematic Assessment	EG0001 events1 affected27 at risk EG0010 affected28 at risk
Fall	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG0002 events1 affected27 at risk EG0010 events0 affected28 at risk
Atrial fibrillation	Cardiac disorders	MedDRA 25.0	Systematic Assessment	EG0001 events1 affected27 at risk EG0010 events0 affected28 at risk
COVID-19	Infections and infestations	MedDRA 25.0	Systematic Assessment	EG0001 events1 affected27 at risk EG0010 events0 affected28 at risk
Dizziness	Nervous system disorders	MedDRA 25.0	Systematic Assessment	EG0001 events1 affected27 at risk EG0010 events0 affected28 at risk