WIRE

To be included in the trial the participant must meet all of the following criteria (note additional IMP-specific inclusions listed below the main inclusion criteria):
•    Capable of giving signed informed consent which includes compliance with the
•    requirements and restrictions listed in the informed consent form (ICF) and in this
•    protocol.
•    Aged ≥18 years and over.
•    Predicted life expectancy ≥ 16 weeks.
•    Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
•    Have biopsy proven clear cell RCC, either as part of the screening process or if undertaken prior to screening no more than 6 weeks prior to consent.
•    Allow access to archival Formalin-Fixed Paraffin-Embedded (FFPE) tumour tissue from any previous renal tumour biopsy
•    Have a surgically resectable tumour as determined by the treating urologist
•    Tumours of the following stage and/or size:
      -  T3 and T4 tumours at least 4 cm in size on imaging; or
      -  T2 tumours with biopsy proven ISUP/WHO grade 4 or sarcomatoid or rhabdoid components; or
      -  any T stage with unequivocal N1 or M1.
•    No prior exposure to PARP inhibitors (including but not limited to olaparib), tyrosine kinase inhibitors (including but not limited to cediranib, sunitinib, pazopanib, axitinib, bevacizumab and cabozantinib), immunotherapy or immune checkpoint inhibitors (including but not limited to other anti-CTLA-4, anti-TIGIT, anti-PD-1, or anti-PD-L1 antibodies), nor prior treatment with a mammalian target of rapamycin (mTOR) inhibitor (including, but not limited to everolimus, temsirolimus, or sirolimus). Prior cytokine therapy (e.g. IL-2, IFN-α) or treatment with cytotoxics is NOT allowed.
•     At least 1 measurable lesion according to RECIST Version 1.1 at screening that can be accurately assessed at screening by MRI (or CT if MRI is not possible) and is suitable for repeated assessment. A previously irradiated lesion cannot be considered a target lesion. Radiographic disease assessment can be performed up to 28 days prior to the first dose of trial treatment. It is acceptable for the measurable lesion to be planned for removal at surgery. CT reported RECIST assessments are acceptable at screening:
     -  for participants with chest metastases
     -  Where MRI is not possible
     -  Measurements cannot be obtained from MRI
•     Have adequate organ and marrow function, as defined below (measured within 28 days of first dose of trial medication):
     -  Haemoglobin ≥ 90 g/L
     -  Platelet count ≥ 100 x 109/L
     -  Neutrophil count ≥ 1.5 x 109/L
•    Creatinine clearance ≥45mL/min (calculated by Cockcroft and Gault equation: where estimated creatinine clearance = (140-age[years]) x weight (kg) (xF)a serum creatinine (mg/dL) x 72a where F=0.85 for females and 1 for males). Participants with 2+ proteinuria on dipstick must also have UPC <0.5 on 2 consecutive samples.
•     Adequate hepatic function:
     -  Alanine Aminotransferase (ALT) (SGPT) ≤2.5x the institutional upper limit of normal (ULN) unless liver metastases are present, in which case it must be ≤5x the institutional ULN, AND.
     -  AST ≤2.5x the institutional ULN unless liver metastases are present, in which case it must be ≤5x the institutional ULN, AND.
     -  Total bilirubin ≤1.5x the institutional ULN unless in the presence of known or suspected Gilbert’s syndrome- the inclusion of potential participants with known/suspected Gilbert’s syndrome must be discussed with the Trial Oncologist prior to their inclusion in the trial. For patients with known Gilbert’s syndrome the threshold for receiving rilvegostomig/volrustomig is total bilirubin ≤ 1.5x the institutional ULN.
•    Evidence of post-menopausal status or negative serum pregnancy test for female premenopausal participants. Women will be considered post-menopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age specific requirements apply:
     -  Women <50 years of age would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
     -  Women ≥50 years of age would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
•    For women of childbearing potential, a negative serum pregnancy test must be performed within 14 days of trial treatment and confirmed prior to treatment on Day 1. Male participants must be willing to use a condom during treatment and for 3 months after the last dose of trial treatment when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female participants and female partners of male participants should also be willing to use a highly effective form of contraception (see Section 11.8for acceptable methods) if they are of childbearing potential.
•     Participant is willing and able to comply with the protocol for the duration of the trial.
•     Adequately controlled thyroid function, with no symptoms of thyroid dysfunction
SPECIFIC INCLUSION CRITERIA FOR VOLRUSTOMIG:
•    Body weight (WT) > 35 kg
•    Adequate organ and marrow function (in the absence of transfusions or growth factor support within 14 days prior to enrolment).
•    Adequate hepatic function:
    -  Alanine Aminotransferase (ALT) (SGPT) ≤2.5x the institutional upper limit of normal (ULN) unless liver metastases are present, in which case it must be ≤3x the institutional ULN, AND
    -  AST ≤2.5x the institutional ULN unless liver metastases are present, in which case it must be ≤3x the institutional ULN.

The presence of any of the following core exclusion criteria will preclude participant inclusion (note additional IMP-specific exclusions listed below the main exclusion criteria):
•    cT1 N0 M0 renal cell carcinoma OR cT2 without biopsy proven ISUP/WHO grade 4 or sarcomatoid or rhabdoid components.
•    Participants with uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required.
•    Participants with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days prior to start of first dose of treatment.
•    History of leptomeningeal carcinomatosis.
•    Body weight ≤30kg
•    Contraindication to cediranib, olaparib, volrustomig and rilvegostomig or chimeric or humanized antibodies or fusion proteins (specifically participants with hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not enter the trial).
•    History of hypersensitivity to active or inactive excipients of cediranib, olaparib or volrustomig and rilvegostomig.
•    Other invasive malignancy within the last 2 years. Participants with previous history of malignancies with a negligible risk of metastasis or death and treated with expected curative intent are eligible at discretion of clinical team, for example:
     -  Carcinoma in situ of the cervix.
     -  Basal or squamous cell skin cancer.
     -  Localized low to intermediate risk prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse; or prostate cancer (Stage T1/T2a, Gleason ≤ 6 and PSA < 10 ng/mL) undergoing active surveillance and treatment naïve.
•    Major surgery within 4 weeks prior to first dose of trial drug (excluding placement of vascular access). If participants have undergone major surgery more than 4 weeks prior to the scheduled first dose of trial drug, they must have fully recovered from the procedure.
•    Minor surgery (not including the diagnostic biopsy) within 2 weeks prior to first dose of trial treatment
•    Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
•    Concurrent enrolment in another clinical trial unless it is an observational (noninterventional NOT involving CTIMPs) or translational clinical trial, or during the follow-up period of an interventional clinical trial.
•    Receipt of the last dose of anticancer therapy or radiotherapy, chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumour embolisation, monoclonal antibodies) ≤28 days prior to the first dose of trial drug. Palliative radiotherapy (including stereotactic radiosurgery) for RCC metastases is permitted.
•    Gastrointestinal abnormalities including:
     -  refractory nausea and vomiting,
     -  inability to take oral medication;
     -  requirement for intravenous alimentation;
     -  prior surgical procedures affecting absorption including total gastric resection;
     -  treatment for active peptic ulcer disease in the past 6 months prior to the first dose of trial treatment;
     -  active gastrointestinal bleeding, unrelated to cancer, as evidenced by haematemesis, haematochezia or melaena in the past 120 days prior to the first dose of trial treatment without evidence of resolution documented by endoscopy or colonoscopy;
     -  malabsorption syndromes.
•    Any of the following within 12 months prior to trial consent:
     -  myocardial infarction,
     -  clinically significant arrhythmia,
     -  uncontrolled angina,
     -  coronary/peripheral artery bypass graft,
     -  symptomatic congestive heart failure,
     -  cerebrovascular accident or transient ischemic attack,
     -  peripheral arterial embolus.
•    Current or prior use of immunosuppressive agents within 28 days prior to the first dose of trial treatment, including anti-TNF and anti-IL17 agents, with the exceptions of intranasal or inhaled corticosteroids, or systemic corticosteroids at physiological doses which are not to exceed 10mg/day prednisolone (or an equivalent corticosteroid). The following exceptions are allowed:
     -  Intranasal, inhaled, topical or local steroid injections (e.g. intra articular injection).
     -  Systemic corticosteroids at physiological doses not to exceed 10mg/day prednisolone (or equivalent).
     -  Steroids for premedication of hypersensitivity reactions (e.g. as CT scan premedication).
•    Immunocompromised participants (e.g., participants who are known to be serologically positive for human immunodeficiency virus (HIV) or have a history of active primary immunodeficiency).
•    Active infection including tuberculosis (clinical history, physical examination and radiographic findings, and Tuberculosis (TB) testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV1/2 antibodies).
     -  Participants with a past or resolved HBV infection (defined as: presence of hepatitis B core antibody -anti-HBc- and absence of hepatitis B surface antigen –HbsAg-) are eligible.
•    As judged by the Investigator, any participant considered a high medical risk, for example due to a serious uncontrolled medical or psychiatric disorder, non -malignant systemic disease or on-going or active infection.
•    Persistent toxicities (≥ Common Terminology Criteria for Adverse Event (CTCAE V5.0) grade 2) caused by previous cancer therapy, excluding alopecia and vitiligo.
     -  Participants with Grade ≥2 neuropathy will be evaluated on a case-by case basis after consultation with the Chief Investigator.
•    Judgement by the Investigator that the participant should not participate in the trial.
•    Involvement in the planning and/or conduct of the trial.

SPECIFIC EXCLUSION CRITERIA FOR VOLRUSTOMIG AND RILVEGOSTOMIG ARMS ONLY:
•    Participant with irreversible toxicity not reasonably expected to be exacerbated by treatment with volrustomig and rilvegostomig may be included only after consultation with the Trial Oncologist.
•    History of organ transplant that requires use of immunosuppressive medications or any medical condition in which immunosuppressive agents were administered, including but not limited to: systemic corticosteroids, methotrexate, azathioprine.
•    Receipt of live, attenuated vaccine within the last 30 days. Note: enrolled participants should not receive live, attenuated vaccine while receiving volrustomig or rilvegostomig nor within 30 days of last dose of volrustomig or rilvegostomig.
•    Active or prior documented autoimmune or inflammatory disorders (except vitiligo), for example: 
     -  Intestinal: Inflammatory Bowel Disease (Colitis (including ulcerative colitis), Crohn’s Disease), Diverticulitis, Coeliac Disease (except participants with coeliac disease controlled by diet alone),
     -  Vascular: any type of vasculitic disorder, e.g. Wegener syndrome, granulomatosis with polyangiitis.
     -  Endocrine: any endocrine alteration related to an autoimmune process e.g. Hashimoto syndrome, Grave’s disease. NOTE: participants with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement treatment may be included.
     -  Respiratory: Active Pneumonitis (of any origin: inflammatory or infectious), Sarcoidosis syndrome.
     -  Dermatological: Psoriasis, Lupus/SLE (unless the skin condition has never required systemic therapy).
     -  Other: Rheumatoid Arthritis, Hypophysitis, Uveitis.
     -  Participants with autoimmune conditions without active disease in the past 5 years may be included but only after discussion with the Trial Oncologist.
•    Participants with persistent toxicities (≥ Common Terminology Criteria for Adverse Event (CTCAE v 5.0) grade 2) caused by previous cancer therapy, excluding alopecia and vitiligo, which are not reasonably expected to be exacerbated by treatment with volrustomig and rilvegostomig may be included only after consultation with the Chief Investigator.