A Trial of Durvalumab (MEDI 4736) in Combination With Extended Neoadjuvant Regimens in Rectal Cancer

Inclusion Criteria (Main trial): 1. Be willing and able to provide written informed consent for the trial. 2. Willingness to comply with scheduled visits, treatment plans and laboratory tests and other trial procedures including willingness to provide repeated biopsy samples of tumour via flexible sigmoidoscopy. 3. Age 18 or over on the day of signing informed consent. 4. Histologically confirmed non-metastatic, locally advanced rectal adenocarcinoma deemed appropriate for radical treatment. 5. Non-metastatic disease confirmed with CT of chest/abdomen and pelvis. 6. The rectal tumour must have at least one of the following high risk criteria on MRI scan: cT3b+ OR EMVI positive, OR Primary tumour or morphologically malignant lymph node at 2mm or less from the mesorectal fascia or beyond the mesorectal fascia OR Low rectal tumour and the consensus of the multi-disciplinary meeting is that abdomino-perineal excision would be required for sufficient surgical management. 7. ECOG performance status 0-1 8. No contra-indication to treatment with pelvic radiotherapy. 9. Primary disease which can be encompassed within a radical radiotherapy treatment volume. 10. Adequate haematological and biochemical function Exclusion Criteria (Main trial): 1. Patients with Dihydroppyrimidine Dehydrogenase (DPD) deficiency (any degree). 2. Unable to have MRI assessment. 3. Patient weight less than or equal to 30kg. 4. Previous pelvic radiotherapy 5. Metastatic disease defined by CT (includes resectable metastases). 6. Previous treatment with immunotherapy. 7. Previous treatment with chemotherapy for the treatment of current malignancy or treatment with chemotherapy within the last 5 years for a separate malignancy (unless that malignancy was treated squamous/basal cell skin cancer, treated early stage cervical cancer or treated/biochemically stable, organ confined prostate cancer). 8. History of a separate malignancy in the last 5 years (other than treated squamous/basal cell skin cancer, treated early stage cervical cancer or treated/biochemically stable, organ confined prostate cancer). 9. Pregnant or lactating females or males unwilling to use a highly effective method of contraception. Women of childbearing potential, and men with female partners of childbearing potential, must agree to use adequate contraceptive measures (see section 9.1.12) for the duration of the study and for 6 months after the completion of study treatment. 10. Major surgery within 28 days prior to trial entry 11. Prolongation of corrected QT (QTc) interval to \>470 msec when electrolyte balance is normal. 12. If a patient has had a recent occurrence (within 3-6 months) of a major thromboembolic event, such as pulmonary embolism or proximal deep vein thrombosis, they must be stable on therapeutic anticoagulation. Subjects with a history of clinically non-significant thromboembolic events, not requiring anticoagulation, are allowed on study. 13. Active inflammatory bowel disease affecting the colon and rectum based on previous endoscopy and defined as active by ongoing drug treatment. 14. Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., levothyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible. 15. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisolone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial drug. 16. Has a history of (non-infectious) interstitial pneumonia or pneumonitis that required steroids or current pneumonitis. 17. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. 18. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 19. Has received a live vaccine within 30 days prior to the first dose of trial drug. 21. Any patients receiving treatment with brivudine, sorivudine and analogues or patients who have not stopped these drugs at least 4 weeks prior to start of study treatment 22. Any patient with severe diarrhoea (defined as ≥ grade 3 diarrhoea despite maximum supportive measures and exclusion of underlying infection). 20. Known hypersensitivity for any component of any study drug. 21. Administration of any investigational drug within 28 days or 5 half-lives, whichever is longer, prior to receiving the first dose of trial treatment. 22. Uncontrolled Chronic Heart Failure (CHF), or history of myocardial infarction (MI), unstable angina, stroke, or transient ischemia within previous 6 months. 23. Patients with known malabsorption or inability to comply with oral medication. 24. Patients with known human immunodeficiency virus (HIV1/2). This is an exclusion criteria because the blood samples from these patients cannot be processed at the translational laboratories linked with this trial. Screening for HIV is not required for this trial. 25. Patients with known Hepatitis B or Hepatitis C. This is an exclusion criteria as the blood samples from these patients cannot be processed at the translational laboratories linked with this trial. Screening for hepatitis B or C is not required for this trial. 26. Receiving systemic steroid therapy or any other form of immunosuppressive therapy within 14 days prior to the first dose of trial treatment. Includes prior organ transplantation including allogenic stem-cell transplant.