Table 1.

Eligibility Criteria

Inclusion criteria

Aged 18 years or over

Diagnosed with advanced (not amenable to curative surgery) or metastatic RCC

Histopathologically confirmed clear cell renal cell cancer (or with a component of clear cell)

Evidence of measurable disease as per RECIST v1.1

Life expectancy of ≥6 months

Karnofsky Performance Status (KPS) of at least 70%

Required laboratory values within 14 days prior to randomisation:   • WBC ≥ 2 × 109/L   • Neutrophils ≥1.5 × 109/L   • Platelets ≥100 × 109/L   • Haemoglobin > 9.0 g/dL   • Serum creatinine ≤1.5 x ULN or calculated creatinine clearance (CrCl) ≥ 40 mL/min (Cockcroft and Gault or Wright formula may be used according to local practice)   • AST and ALT ≤3 x ULN   • Total Bilirubin ≤1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 50 μmol/L)

Able to give written informed consent and willing to follow trial protocol

Women of childbearing potential (WOCBP) must:   • Use appropriate method(s) of contraception for 23 weeks after the last dose of investigational drug.   • Have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) before randomisation.

Men who are sexually active with WOCBP must agree to use any contraceptive method with a failure rate of less than 1% per year. Men who are sexually active with WOCBP must agree to adhere to contraception for a period of 31 weeks after the last dose of investigational product.

Exclusion criteria

Pregnant or breast feeding females.

Prior systemic therapy for RCC (previous participation in adjuvant studies allowed, providing the patient was on the observation/placebo arm – this may require unblinding of the patient)

Participants who have undergone any prior systemic anti-cancer treatment, including with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways (previous participation in adjuvant studies allowed, providing the patient was on the observation/placebo arm – this may require unblinding of the patient)

Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.

Participants who test positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.

Participants who test positive for human immunodeficiency virus (HIV) or have known acquired immunodeficiency syndrome (AIDS).

Untreated brain metastases or brain metastases treated only with whole brain radiotherapy. (Patients are eligible if previous brain metastases treated with complete surgical resection, Stereotactic Brain Radiation Therapy (SBRT), or gamma knife with no subsequent evidence of progression and asymptomatic).

Active, known or suspected autoimmune disease. (Subjects are permitted to enrol if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger).

Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of study drug administration. (Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease).

Uncontrolled adrenal insufficiency.

Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results.

Palliative radiotherapy less than 14 days prior to first dose of study drug.

Any history of hypersensitivity to any of the trial medications or excipients.

Poorly controlled or serious medical or psychiatric illness that, in the Investigator’s opinion, is likely to interfere with participation and/or compliance in this clinical trial.