Squamous Cell Carcinoma of Head and Neck
Conditions
Keywords
Squamous Cell Carcinoma of Head and Neck, Setanaxib, Pembrolizumab, SCCHN, Keytruda
Brief summary
The primary objective of this study is 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.
Interventions
DRUGSetanaxib
Oral tablets, 400 mg per tablet
BIOLOGICALPembrolizumab
200 mg IV infusion
DRUGPlacebo
Oral tablets
Sponsors
Calliditas Therapeutics Suisse SA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Percentage Change in Tumour Size | Baseline to at least 15 weeks and up to 51 weeks | Defined as the best percentage change from Baseline in the sum of diameters of target lesions, as assessed by RECIST v1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Cancer-associated Fibroblasts (CAFs) Level in Tumour Tissue | Baseline up to approximately 9 weeks | Changes within treatment groups (ie, across paired tissue samples) and between treatment groups summarized both descriptively and as adjusted mean difference between treatment groups. |
| Change From Baseline in the Number of Cluster of Differentiation 8 (CD8+) Tumour Infiltrating Lymphocytes (TILs) in Tumour Tissue | Baseline up to approximately 9 weeks | Changes within treatment groups (ie, across paired tissue samples) and between treatment groups summarized both descriptively and as adjusted mean difference between treatment groups. |
| Change From Baseline in the Number of Regulatory T-cells in Tumour Tissue | Baseline up to approximately 9 weeks | Changes within treatment groups (ie, across paired tissue samples) and between treatment groups summarized both descriptively and as adjusted mean difference between treatment groups. |
| Overall Response Rate (ORR) | Baseline up to approximately 12 months | Proportion of the patients who have a complete response (CR) or partial response (PR) per RECIST v1.1 will be used to access ORR. |
| Duration of Response (DoR) | Baseline up to approximately 12 months | 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. |
| Disease Control Rate (DCR) | Baseline up to approximately 12 months | 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. |
| Overall Survival (OS) | Baseline up to 12 months | 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. |
| Number of Participants With Adverse Events (AEs) | Baseline up to approximately 21 months | 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). |
| Number of Participants With Adverse Events of Special Interest (AESI) | Baseline up to approximately 21 months | AESI include Anaemia and Hypothyroidism. |
| Progression Free Survival (PFS) | Baseline up to approximately 21 months | Defined as time from randomisation to the first documented disease progression per RECIST v1.1 or death due to any cause, whichever occurs first. |
| Change From Baseline in CAFs Cell Type Abundance Based on Gene Expression Profiles | Baseline up to approximately 9 weeks | 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. |
| Change From Baseline in CD8+ TILs Cell Type Abundance Based on Gene Expression Profiles | Baseline up to approximately 9 weeks | 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. 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. |
| Change From Baseline in Regulatory T-cell Abundance Based on Gene Expression Profiles | Baseline up to approximately 9 weeks | 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. 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. |
| Area Under The Concentration-time Curve Over a 24-hour Period at Steady State (AUC[0-24]-ss) of Setanaxib | Baseline, Week 3, week 9, week 24, week 51 | — |
| Area Under The Concentration-time Curve Over a 24-hour Period at Steady State (AUC24-ss) of GKT138184 | Baseline, Week 3, week 9, week 24, week 51 | — |
| Minimum Plasma Concentration at Steady State (Cmax-ss) of Setanaxib | Baseline, Week 3, week 9, week 24, week 51 | — |
| Minimum Plasma Concentration at Steady State (Cmin-ss) of GKT138184 | Baseline, Week 3, week 9, week 24, week 51 | — |
| Maximum Plasma Concentration at Steady State (Cmax-ss) of Setanaxib | Baseline, Week 3, week 9, week 24, week 51 | — |
| Maximum Plasma Concentration at Steady State (Cmax-ss) of GKT138184 | Baseline up to approximately 26 months | — |
| Levels of Programmed Death-ligand 1 (PD-L1) Expression in Tumour Tissue | Baseline up to approximately 9 weeks | 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. |
Countries
France, Germany, Italy, Poland, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 | 27 |
| 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 | 28 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 3 |
| Overall Study | Clinical disease progression | 0 | 1 |
| Overall Study | Death | 1 | 2 |
| Overall Study | Patient and Investigator decision | 1 | 0 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Progressive Disease | 15 | 14 |
| Overall Study | Still On-Treatment | 6 | 6 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo and Pembrolizumab 200 mg | Setanaxib 1600 mg and Pembrolizumab 200 mg |
|---|---|---|---|
| Age, Continuous | 64.8 years STANDARD_DEVIATION 10.19 | 65.0 years STANDARD_DEVIATION 10.54 | 64.6 years STANDARD_DEVIATION 10 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 3 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 11 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 31 Participants | 14 Participants | 17 Participants |
| Human papillomavirus (HPV) Status Negative | 45 Participants | 23 Participants | 22 Participants |
| Human papillomavirus (HPV) Status Positive | 10 Participants | 5 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 16 Participants | 6 Participants | 10 Participants |
| Race (NIH/OMB) White | 38 Participants | 22 Participants | 16 Participants |
| Sex: Female, Male Female | 15 Participants | 10 Participants | 5 Participants |
| Sex: Female, Male Male | 40 Participants | 18 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 27 | 13 / 28 |
| other Total, other adverse events | 27 / 27 | 23 / 28 |
| serious Total, serious adverse events | 8 / 27 | 10 / 28 |
Outcome results
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.
Time frame: Baseline to at least 15 weeks and up to 51 weeks
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Best Percentage Change in Tumour Size | -7.88 Percentage change from baseline | Standard Error 9.323 |
| Placebo and Pembrolizumab 200 mg | Best Percentage Change in Tumour Size | -12.93 Percentage change from baseline | Standard Error 8.977 |
Comparison: 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%.p-value: 0.700880% CI: [-11.98, 22]ANCOVA
Secondary
Area Under The Concentration-time Curve Over a 24-hour Period at Steady State (AUC[0-24]-ss) of Setanaxib
Time frame: Baseline, Week 3, week 9, week 24, week 51
Population: PK analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Area Under The Concentration-time Curve Over a 24-hour Period at Steady State (AUC[0-24]-ss) of Setanaxib | 240.41 ug*h*mL-¹ | Geometric Coefficient of Variation 28.86 |
Secondary
Area Under The Concentration-time Curve Over a 24-hour Period at Steady State (AUC24-ss) of GKT138184
Time frame: Baseline, Week 3, week 9, week 24, week 51
Population: PK analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Area Under The Concentration-time Curve Over a 24-hour Period at Steady State (AUC24-ss) of GKT138184 | 50.2 ug*h*mL-¹ | Geometric Coefficient of Variation 41.49 |
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.
Time frame: Baseline up to approximately 9 weeks
Population: Full Analysis Set with paired observations
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Change From Baseline in CAFs Cell Type Abundance Based on Gene Expression Profiles | Screening | 0.87 CIBERSORTx Absolute Abundance ratio | Standard Deviation 0.88 |
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Change From Baseline in CAFs Cell Type Abundance Based on Gene Expression Profiles | Week 9 | 0.98 CIBERSORTx Absolute Abundance ratio | Standard Deviation 0.99 |
| Placebo and Pembrolizumab 200 mg | Change From Baseline in CAFs Cell Type Abundance Based on Gene Expression Profiles | Screening | 0.74 CIBERSORTx Absolute Abundance ratio | Standard Deviation 0.787 |
| Placebo and Pembrolizumab 200 mg | Change From Baseline in CAFs Cell Type Abundance Based on Gene Expression Profiles | Week 9 | 0.56 CIBERSORTx Absolute Abundance ratio | Standard Deviation 0.581 |
Comparison: Within group test of hypothesis that screening and week 9 values are equal.p-value: 0.22Wilcoxon signed rank test
Comparison: Within group test of hypothesis that screening and week 9 values are equal.p-value: 0.2Wilcoxon signed rank test
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.
Time frame: Baseline up to approximately 9 weeks
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Change From Baseline in Cancer-associated Fibroblasts (CAFs) Level in Tumour Tissue | Baseline | 58.13 % positivity of tumour stromal component | Standard Deviation 37.006 |
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Change From Baseline in Cancer-associated Fibroblasts (CAFs) Level in Tumour Tissue | Week 9 | 50.50 % positivity of tumour stromal component | Standard Deviation 31.023 |
| Placebo and Pembrolizumab 200 mg | Change From Baseline in Cancer-associated Fibroblasts (CAFs) Level in Tumour Tissue | Baseline | 52.00 % positivity of tumour stromal component | Standard Deviation 23.357 |
| Placebo and Pembrolizumab 200 mg | Change From Baseline in Cancer-associated Fibroblasts (CAFs) Level in Tumour Tissue | Week 9 | 36.50 % positivity of tumour stromal component | Standard Deviation 30.373 |
Comparison: Null Hypothesis: Mean difference in postbaseline CAF levels does not differ between treatment groups. ANCOVA model is on postbaseline CAFs level with a fixed factor for treatment and a covariate for baseline.p-value: 0.298680% CI: [-2.3, 21.3]ANCOVA
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. 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.
Time frame: Baseline up to approximately 9 weeks
Population: Full Analysis Set with paired observations
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Change From Baseline in CD8+ TILs Cell Type Abundance Based on Gene Expression Profiles | Screening | 0.03 CIBERSORTx Absolute Abundance ratio | Standard Deviation 0.03 |
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Change From Baseline in CD8+ TILs Cell Type Abundance Based on Gene Expression Profiles | Week 9 | 0.07 CIBERSORTx Absolute Abundance ratio | Standard Deviation 0.063 |
| Placebo and Pembrolizumab 200 mg | Change From Baseline in CD8+ TILs Cell Type Abundance Based on Gene Expression Profiles | Screening | 0.04 CIBERSORTx Absolute Abundance ratio | Standard Deviation 0.044 |
| Placebo and Pembrolizumab 200 mg | Change From Baseline in CD8+ TILs Cell Type Abundance Based on Gene Expression Profiles | Week 9 | 0.02 CIBERSORTx Absolute Abundance ratio | Standard Deviation 0.033 |
Comparison: Within group test of hypothesis that screening and week 9 values are equal.p-value: 0.037Wilcoxon signed rank test
Comparison: Within group test of hypothesis that screening and week 9 values are equal.p-value: 0.123Wilcoxon signed rank test
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. 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.
Time frame: Baseline up to approximately 9 weeks
Population: Full Analysis Set with paired observations
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Change From Baseline in Regulatory T-cell Abundance Based on Gene Expression Profiles | Screening | 0.01 CIBERSORTx Absolute Abundance ratio | Standard Deviation 0.012 |
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Change From Baseline in Regulatory T-cell Abundance Based on Gene Expression Profiles | Week 9 | 0.01 CIBERSORTx Absolute Abundance ratio | Standard Deviation 0.016 |
| Placebo and Pembrolizumab 200 mg | Change From Baseline in Regulatory T-cell Abundance Based on Gene Expression Profiles | Screening | 0.02 CIBERSORTx Absolute Abundance ratio | Standard Deviation 0.033 |
| Placebo and Pembrolizumab 200 mg | Change From Baseline in Regulatory T-cell Abundance Based on Gene Expression Profiles | Week 9 | 0.03 CIBERSORTx Absolute Abundance ratio | Standard Deviation 0.054 |
Comparison: Within group test of hypothesis that screening and week 9 values are equal.p-value: 0.41Wilcoxon signed rank test
Comparison: Within group test of hypothesis that screening and week 9 values are equal.p-value: 0.11Wilcoxon signed rank test
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.
Time frame: Baseline up to approximately 9 weeks
Population: Full Analysis Set)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Change From Baseline in the Number of Cluster of Differentiation 8 (CD8+) Tumour Infiltrating Lymphocytes (TILs) in Tumour Tissue | Baseline | 18.13 cells/High Power Field (HPF) | Standard Deviation 8.901 |
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Change From Baseline in the Number of Cluster of Differentiation 8 (CD8+) Tumour Infiltrating Lymphocytes (TILs) in Tumour Tissue | Week 9 | 41.14 cells/High Power Field (HPF) | Standard Deviation 34.535 |
| Placebo and Pembrolizumab 200 mg | Change From Baseline in the Number of Cluster of Differentiation 8 (CD8+) Tumour Infiltrating Lymphocytes (TILs) in Tumour Tissue | Baseline | 21.34 cells/High Power Field (HPF) | Standard Deviation 19.789 |
| Placebo and Pembrolizumab 200 mg | Change From Baseline in the Number of Cluster of Differentiation 8 (CD8+) Tumour Infiltrating Lymphocytes (TILs) in Tumour Tissue | Week 9 | 38.30 cells/High Power Field (HPF) | Standard Deviation 26.553 |
Comparison: Null Hypothesis: Mean difference in postbaseline CD8+ TILs does not differ between treatment groups. ANCOVA model is on postbaseline CD8+ TILs level with a fixed factor for treatment and a covariate for baseline.p-value: 0.591880% CI: [-9.86, 23.52]ANCOVA
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.
Time frame: Baseline up to approximately 9 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Change From Baseline in the Number of Regulatory T-cells in Tumour Tissue | Baseline | 9.75 cells/High Power Field (HPF) | Standard Deviation 9.955 |
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Change From Baseline in the Number of Regulatory T-cells in Tumour Tissue | Week 9 | 21.14 cells/High Power Field (HPF) | Standard Deviation 22.879 |
| Placebo and Pembrolizumab 200 mg | Change From Baseline in the Number of Regulatory T-cells in Tumour Tissue | Baseline | 24.36 cells/High Power Field (HPF) | Standard Deviation 27.104 |
| Placebo and Pembrolizumab 200 mg | Change From Baseline in the Number of Regulatory T-cells in Tumour Tissue | Week 9 | 30.16 cells/High Power Field (HPF) | Standard Deviation 38.866 |
Comparison: Null Hypothesis: Mean difference in postbaseline number of regulatory T-cells in tumour tissue does not differ between treatment groups. ANCOVA model is on postbaseline number of regulatory T-cells in tumour tissue level with a fixed factor for treatment and a covariate for baseline.p-value: 0.213580% CI: [-0.34, 22.02]ANCOVA
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.
Time frame: Baseline up to approximately 12 months
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Disease Control Rate (DCR) | 70.4 percentage of participants |
| Placebo and Pembrolizumab 200 mg | Disease Control Rate (DCR) | 50 percentage of 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.
Time frame: Baseline up to approximately 12 months
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Duration of Response (DoR) | Duration of Response 25% Percentile | 170 days |
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Duration of Response (DoR) | Duration of Response 50% Percentile | NA days |
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Duration of Response (DoR) | Duration of Response 75% Percentile | NA days |
| Placebo and Pembrolizumab 200 mg | Duration of Response (DoR) | Duration of Response 25% Percentile | 46 days |
| Placebo and Pembrolizumab 200 mg | Duration of Response (DoR) | Duration of Response 50% Percentile | 79 days |
| Placebo and Pembrolizumab 200 mg | Duration of Response (DoR) | Duration of Response 75% Percentile | 300 days |
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.
Time frame: Baseline up to approximately 9 weeks
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Levels of Programmed Death-ligand 1 (PD-L1) Expression in Tumour Tissue | Baseline | 19.73 ratio | Standard Deviation 29.408 |
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Levels of Programmed Death-ligand 1 (PD-L1) Expression in Tumour Tissue | Week 9 | 42.27 ratio | Standard Deviation 37.641 |
| Placebo and Pembrolizumab 200 mg | Levels of Programmed Death-ligand 1 (PD-L1) Expression in Tumour Tissue | Baseline | 13.14 ratio | Standard Deviation 25.149 |
| Placebo and Pembrolizumab 200 mg | Levels of Programmed Death-ligand 1 (PD-L1) Expression in Tumour Tissue | Week 9 | 18.57 ratio | Standard Deviation 15.999 |
Comparison: Null Hypothesis: Mean difference in postbaseline PD-L1 combined positive score (CPS) does not differ between treatment groups. ANCOVA model is on postbaseline PD-L1 CPS with a fixed factor for treatment and a covariate for baseline. Threshold for statistical significance = 0.2.p-value: 0.078280% CI: [5.17, 30.36]ANCOVA
Secondary
Maximum Plasma Concentration at Steady State (Cmax-ss) of GKT138184
Time frame: Baseline up to approximately 26 months
Population: PK analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Maximum Plasma Concentration at Steady State (Cmax-ss) of GKT138184 | 3.74 ug*mL-¹ | Geometric Coefficient of Variation 34.33 |
Secondary
Maximum Plasma Concentration at Steady State (Cmax-ss) of Setanaxib
Time frame: Baseline, Week 3, week 9, week 24, week 51
Population: PK analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Maximum Plasma Concentration at Steady State (Cmax-ss) of Setanaxib | 26.24 ug*mL-¹ | Geometric Coefficient of Variation 24.84 |
Secondary
Minimum Plasma Concentration at Steady State (Cmax-ss) of Setanaxib
Time frame: Baseline, Week 3, week 9, week 24, week 51
Population: PK analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Minimum Plasma Concentration at Steady State (Cmax-ss) of Setanaxib | 2.14 ug*mL-¹ | Geometric Coefficient of Variation 85.71 |
Secondary
Minimum Plasma Concentration at Steady State (Cmin-ss) of GKT138184
Time frame: Baseline, Week 3, week 9, week 24, week 51
Population: PK analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Minimum Plasma Concentration at Steady State (Cmin-ss) of GKT138184 | 0.76 ug*mL-¹ | Geometric Coefficient of Variation 68.98 |
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).
Time frame: Baseline up to approximately 21 months
Population: Safety Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Number of Participants With Adverse Events (AEs) | 27 Participants |
| Placebo and Pembrolizumab 200 mg | Number of Participants With Adverse Events (AEs) | 26 Participants |
Secondary
Number of Participants With Adverse Events of Special Interest (AESI)
AESI include Anaemia and Hypothyroidism.
Time frame: Baseline up to approximately 21 months
Population: Safety Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Number of Participants With Adverse Events of Special Interest (AESI) | 5 Participants |
| Placebo and Pembrolizumab 200 mg | Number of Participants With Adverse Events of Special Interest (AESI) | 5 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.
Time frame: Baseline up to approximately 12 months
Population: Full Analysis Set
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Overall Response Rate (ORR) | Partial Response | 8 Participants |
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Overall Response Rate (ORR) | Progressive Disease | 7 Participants |
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Overall Response Rate (ORR) | Stable Disease | 10 Participants |
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Overall Response Rate (ORR) | Not Evaluable | 1 Participants |
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Overall Response Rate (ORR) | Complete Response | 1 Participants |
| Placebo and Pembrolizumab 200 mg | Overall Response Rate (ORR) | Not Evaluable | 0 Participants |
| Placebo and Pembrolizumab 200 mg | Overall Response Rate (ORR) | Complete Response | 0 Participants |
| Placebo and Pembrolizumab 200 mg | Overall Response Rate (ORR) | Partial Response | 9 Participants |
| Placebo and Pembrolizumab 200 mg | Overall Response Rate (ORR) | Stable Disease | 5 Participants |
| Placebo and Pembrolizumab 200 mg | Overall Response Rate (ORR) | Progressive Disease | 14 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.
Time frame: Baseline up to 12 months
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Overall Survival (OS) | 3 Months | 96 percentage of participants |
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Overall Survival (OS) | 9 Months | 88 percentage of participants |
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Overall Survival (OS) | 6 Months | 92 percentage of participants |
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Overall Survival (OS) | 12 Months | 46 percentage of participants |
| Placebo and Pembrolizumab 200 mg | Overall Survival (OS) | 6 Months | 68 percentage of participants |
| Placebo and Pembrolizumab 200 mg | Overall Survival (OS) | 3 Months | 79 percentage of participants |
| Placebo and Pembrolizumab 200 mg | Overall Survival (OS) | 12 Months | 42 percentage of participants |
| Placebo and Pembrolizumab 200 mg | Overall Survival (OS) | 9 Months | 58 percentage of participants |
Comparison: No formal test of significance undertaken.80% CI: [0.24, 0.85]
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.
Time frame: Baseline up to approximately 21 months
Population: Full Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Setanaxib 1600 mg and Pembrolizumab 200 mg | Progression Free Survival (PFS) | 151 days |
| Placebo and Pembrolizumab 200 mg | Progression Free Survival (PFS) | 87 days |
Comparison: Null hypothesis: The risk for progression, as defined by RECIST v1.1, is the same between treatment groups. If the true hazard ratio is 0.5, approximately 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\<0.2p-value: 0.102380% CI: [0.38, 0.89]Regression, Cox