Renal Adjuvant MultiPle Arm Randomised Trial

Inclusion Criteria:

1. Histologically proven RCC (all cell types of RCC are eligible, except for pureoncocytoma, collecting duct, medullary and transitional cell cancer [TCC]); noevidence of residual macroscopic disease on post-operative CT scan after resection ofRCC. Patients with treated bilateral synchronous RCCs are eligible.

2. At the start of recruitment patients with Leibovich score 3-11 will be eligible forrandomisation. MRC CTU at UCL will monitor accrual and stop recruiting intermediaterisk patients (Leibovich Score 3-5) after three years or when intermediate riskpatients contribute 25% of the total accrual target, whichever is earlier. Recruitmentof patients with Leibovich Score 6 11 will continue until the accrual target isreached.

3. Patients should have had surgery at least 28 days but no more than 91 days prior totheir randomisation date.

4. Post-operative scans should be performed within 28 days prior to randomisation.

5. Patients with microscopically positive resection margins after radical nephrectomy atthe nephrectomy bed, renal vein or inferior vena cava are eligible provided thepost-operative CT scan shows no evidence of residual macroscopic disease.

6. WHO Performance Status 0 or 1.

7. Patient has archival FFPE pathology tissue available, and agrees to provide at leastone sample (FFPE tumour block from nephrectomy, or a minimum of 10 unstained slides),as well as a baseline EDTA blood sample for future translational research).

8. Adequate normal organ and marrow function

9. Haemoglobin ≥9.0g/dL (transfusions will be allowed within 2 weeks prior torandomisation in order to achieve the entry criteria).

10. Absolute neutrophil count (ANC) ≥1.5 x 109/L (≥1500 per mm3).

11. Platelet count ≥100 x 109 (≥100,000 per mm3).

12. Bilirubin ≤1.5 x ULN (This will not apply to subjects with confirmed Gilbert'ssyndrome (i.e., persistent or recurrent hyperbilirubinemia that is predominantlyunconjugated in the absence of haemolysis or hepatic pathology), who will beallowed only in consultation with their physician).

13. AST/ALT ≤2.5 x ULN.

14. Calculated Creatinine Clearance level >40mL/min by Cockcroft Gault formula (usingactual body weight).

15. 12-lead ECG on which QTcF must be <450 ms. In case of clinically significant ECGabnormalities, including a QTcF value ≥450 ms, two additional 12-lead ECGs should beobtained over a brief period (e.g., 30 minutes) to confirm the finding. Patients areonly eligible if a QTcF of <450ms is confirmed

16. Subjects must be ≥18 years of age.

17. Written informed consent obtained from the patient.

18. Both men and women enrolled in this trial must be in agreement with trial policy oncontraception during the treatment phase of the study and 6 months afterwards. Eggdonation, sperm donation and breastfeeding must be avoided.

19. Evidence of post-menopausal status or negative serum HCG pregnancy test for female premenopausal patients. Women will be considered post-menopausal if they have beenamenorrhoeic for 12 months without an alternative medical cause. The following agespecific requirements apply:

20. Women <50 years of age will be considered post-menopausal if they have beenamenorrhoeic for 12 months or more following cessation of exogenous hormonaltreatments and if they have luteinising hormone and follicle-stimulating hormonelevels in the post-menopausal range for the institution or underwent surgicalsterilisation (bilateral oophorectomy or hysterectomy).

21. Women ≥50 years of age will be considered post-menopausal if they have beenamenorrhoeic for 12 months or more following cessation of all exogenous hormonaltreatments, had radiation-induced menopause with last menses >1 year ago, hadchemotherapy induced menopause with last menses >1 year ago, or underwentsurgical sterilisation (bilateral oophorectomy, bilateral salpingectomy, orhysterectomy).

Exclusion Criteria:

1. Previous diagnosis of RCC.

2. Metastatic or macroscopic residual disease.

3. Patients with positive resection margins after partial nephrectomy.

4. Patients with a single pulmonary nodule ≥5mm diameter are not eligible unless thenodule has had a definite benign diagnosis. Patients with multiple small, less than 5mm nodules may be eligible if nodules have been shown to be radiologically stable forat least 8 weeks.

5. Prior anticancer treatment (other than nephrectomy) for RCC.

6. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with theexception of alopecia, vitiligo, and the laboratory values defined in the inclusioncriteria

7. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis afterconsultation with the Study Physician.

8. Patients with irreversible toxicity not reasonably expected to be exacerbated bytreatment with durvalumab or tremelimumab may be included only after consultationwith the Study Physician.

9. History of another primary malignancy except for:

10. Malignancy treated with curative intent and with no known active disease ≥5 yearsbefore the first dose of IP and of low potential risk for recurrence.

11. Adequately treated non-melanoma skin cancer or lentigo maligna without evidenceof disease.

12. Adequately treated carcinoma in situ without evidence of disease.

13. History of leptomeningeal carcinomatosis.

14. Concurrent enrolment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow up period of an interventionalstudy.

15. Major surgical procedure (as defined by the Investigator) within 28 days prior to thestart of treatment. Local surgery of isolated lesions for palliative intent isacceptable.

16. Current or prior use of immunosuppressive medication within 14 days before the firstdose of durvalumab or tremelimumab, with the exceptions of intranasal and inhaledcorticosteroids or systemic corticosteroids at physiological doses, which are not toexceed 10 mg/day of prednisone, or an equivalent corticosteroid.

17. Active or prior documented autoimmune or inflammatory disorders (includinginflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [withthe exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoidarthritis, hypophysitis, uveitis, etc]). The following are exceptions to thiscriterion:

18. Patients with vitiligo or alopecia

19. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable onhormone replacement

20. Any chronic skin condition that does not require systemic therapy

21. Patients without active disease in the last 5 years may be included but onlyafter consultation with the RAMPART Trial Management Team

22. Patients with coeliac disease controlled by diet alone

23. A history of immunodeficiency syndrome. Please consult the MRC CTU at UCL on anindividual basis if there is any uncertainty.

24. History of allogeneic organ transplant.

25. Uncontrolled intercurrent illness including, but not limited to:

26. Ongoing or active infection of any kind (patients who are exhibiting symptomsconsistent with COVID-19, or who have tested positive, should not be randomisedinto the study until they are asymptomatic and at least 14 days after a positivetest)

27. Symptomatic congestive heart failure

28. Uncontrolled hypertension

29. Unstable angina pectoris

30. Uncontrolled cardiac arrhythmia

31. Active peptic ulcer disease or gastritis

32. Active bleeding diatheses

33. Psychiatric illness or social situations that would limit compliance with studyrequirements or compromise the ability of the subject to give written informedconsent.

34. Active infection including

35. Tuberculosis (clinical evaluation that includes clinical history, physicalexamination and radiographic findings, and TB testing in line with localpractice)

36. Hepatitis B (known positive HBV surface antigen (HBsAg) result). Patients with apast or resolved HBV infection (defined as the presence of hepatitis B coreantibody [anti HBc] and absence of HBsAg) are eligible.

37. Hepatitis C

38. Human immunodeficiency virus (positive HIV 1/2 antibodies). Note: Patientspositive for hepatitis C (HCV) antibody are eligible only if polymerase chainreaction is negative for HCV RNA.

39. Receipt of live attenuated vaccine within 30 days prior to the start of treatment.Note: Patients, if enrolled, should not receive live vaccine while receivinginvestigational medicinal product and up to 30 days after the last dose ofinvestigational medicinal product.

40. Pregnant or breastfeeding patients.

41. Any condition that, in the opinion of the investigator, would interfere withevaluation of study treatment or interpretation of patient safety or study results.

42. Known allergy or hypersensitivity to durvalumab or tremelimumab, or any of theirexcipients.

43. Previous investigational medicinal product assignment in the present study.

44. Clinically significant pneumonitis or fibrosis.