A Study of Setanaxib Co-Administered With Pembrolizumab in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of Head and Neck (SCCHN)

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:

• Absolute neutrophil count ≥1,000/mm3 (≥ 1.0×109/L).
• Platelet count ≥100,000/mm3 (≥ 100×109/L).
• 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.
• Total bilirubin ≤1.5×upper limit of normal (ULN) (if associated with liver metastases or Gilbert's disease, ≤3×ULN).
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3×ULN.
• 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.

• 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."
• 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.
• 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:

• Patients with vitiligo or alopecia.
• Any chronic skin condition that does not require systemic therapy.
• 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:

• Unstable angina within 6 months prior to Screening
• Myocardial infarction, coronary artery bypass graft surgery, or coronary angioplasty within 6 months prior to Screening
• Cerebrovascular accident within 6 months prior to Screening
• 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.