WIRE

To be included in the trial the participant must meet all of the following criteria:

• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and 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, within 6 weeks prior to consent.

• Allow access to archival FFPE tumour tissue from biopsy and nephrectomy.

• Have a surgically resectable tumour as determined by the treating Urologist

• T1b or above, any N status, M0, OR have any T or N status, M1 (but if M1, the participant must be deemed suitable for cytoreductive nephrectomy at time of enrolment).

• 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-PD-1, or anti-PD-L1 antibodies, including durvalumab), nor prior treatment with an mammalian target of rapamycin (mTOR) inhibitor (including, but not limited to everolimus, temsirolimus, or sirolimus). Prior cytokine therapy (eg, IL-2, IFN-α) or treatment with cytotoxics is allowed.

• At least 1 measurable lesion according to RECIST Version 1.1 at screening that can be accurately assessed at screening by - MRI 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.

• 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 ≥30mL/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.

• Evidence of post-menopausal status or negative serum pregnancy test for female pre-menopausal 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 amenorrheic 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 28 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 partners of male participants should also be willing to use a highly effective form of contraception (see Section 11.12 for 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 OLAPARIB CONTAINING ARMS:

• Haemoglobin must be ≥ 100 g/L

• If abnormalities in the Full Blood Count (and it is clinically indicated): Peripheral blood smear with no features of myelodysplastic syndrome or acute myeloid leukaemia

• Serum creatinine must be ≤1.5x the institutional ULN concurrent with creatinine clearance ≥51mL/min (calculated by Cockcroft and Gault equation as above) or based on a 24 hour urine creatinine clearance test.

SPECIFIC INCLUSION CRITERIA FOR OLAPARIB PLUS CEDIRANIB ARM ONLY:

• Urine protein: creatinine ratio (UPC) ≤1 OR ≤2+ proteinuria on two consecutive dipsticks taken no less than 1 week apart. Patients with 2+ proteinuria on dipstick must also have UPC <0.5 on 2 consecutive samples.

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):

• cT1a N0 M0-staged Renal Cell Cancer

• Participants with 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, durvalumab 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 durvalumab.

• 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 (non-interventional 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.

• 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 melena in the past 120 days priort 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 consent:

  • myocardial infarction,

  • 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 day 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 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 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) 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.

  • For DURVALUMAB-CONTAINING arms only: Participant with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the investigator.

• Women who are pregnant, or are lactating or breastfeeding.

  • Women of childbearing potential and male participants who are unwilling to use adequate contraception from consent and for 3 months after the last dose of trial drug.

• Participants with contraindication to MRI including; contraindicated metallic implants, contraindicated coronary stents and pacemakers. Inability to lie flat or still in an MRI scanner for whatever reason (e.g., claustrophobia).

• Judgement by the Investigator that the participant should not participate in the trial.

• Involvement in the planning and/or conduct of the trial

• Previous allogeneic bone marrow transplant or double umbilical cord blood transplantation.

SPECIFIC EXCLUSION CRITERIA FOR CEDIRANIB AND/OR OLAPARIB CONTAINING ARMS:

• Current use or anticipated need for treatment with drugs that are known potent CYP3A4 inhibitors, or inducers or substrates for CYP1A2.

• Concomitant medications known to prolong the QT interval or with factors that increase the risk of QTc prolongation or risk of arrhythmic events (such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age), history of Torsades de pointes.

• Resting ECG indicating uncontrolled, potentially reversible cardiac conditions as judged by the investigator (eg., unstable ischaemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation >500ms, electrolyte disturbances, resting QTc of ≥470ms (Fridericia; as per local reading), etc.) on two or more time points within a 24 hour period or family history of long QT syndrome.

• Requirement of anticoagulant therapy with oral vitamin K antagonists.

  • Therapeutic use of low molecular weight heparin is allowed.

• Poorly controlled hypertension (persistently elevated > 150/100mmHg (or > 140/90 FOR OLAPARIB PLUS CEDIRANIB ARM ONLY), either systolic or diastolic or both, despite anti-hypertensive medication)

• Clinically significant signs and/or symptoms of bowel obstruction within 3 months prior to starting treatment

• History of intra-abdominal abscess within 3 months prior to starting the first dose of trial treatment

• History of GI perforation. Participants with a history of abdominal fistula will be considered eligible if the fistula was surgically repaired, there has been no evidence of fistula for at least 6 months prior to starting the first dose of trial treatment, and participant is deemed to be at low risk of recurrent fistula

SPECIFIC EXCLUSION CRITERIA FOR CEDIRANIB MONOTHERAPY OR COMBINATION THERAPY ARMS ONLY:

• Left ventricular ejection fraction (LVEF) < lower limit of normal (LLN) per institutional guidelines, or <55%, if threshold for normal not otherwise specified by institutional guidelines, for participants with the below risk factors (an Echocardiogram should be performed at baseline and if clinically indicated):

  • Prior treatment with anthracyclines

  • Prior treatment with trastuzumab

  • Prior central thoracic RT, including exposure of heart to therapeutic doses of ionising RTM

  • Prior history of other significant impaired cardiac function

SPECIFIC EXCLUSION CRITERIA FOR DURVALUMAB CONTAINING ARMS ONLY:

• Receipt of live, attenuated vaccine within the last 30 days. Note: enrolled participants should not receive live, attenuated vaccine while receiving durvalumab nor within 30 days of last dose of durvalumab.

• Active or prior documented autoimmune or inflammatory disorders (except vitiligo), for example:

  • Intestinal: Inflammatory Bowel Disease (Colitis (including ulcerative colitis), Crohn’s Disease), Diverticulitis (with the exception of Diverticulosis), Coeliac Disease (except participants with coeliac disease controlled by diet alone), irritable Bowel Disease

  • 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 (eg, 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.

  • 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.

  • Tumour necrosis factor alpha (TNF-α) blockers

  • Participants with autoimmune conditions without active disease in the past 5 years may be included but only after discussion with the Trial Medical 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 durvalumab may be included only after consultation with the Chief Investigator.