A Trial of Palliative Chemotherapy, Radiation and Immune Treatment for Oesophageal Cancer: PALEO Study

Inclusion Criteria: 1. Males and females \> 18 years of age. 2. Biopsy proven adenocarcinoma or squamous cell carcinoma of the esophagus or gastro-oesophageal junction 3. Oligometastatic disease (1-5 lesions outside the primary tumour radiotherapy field on FDG-PET scan), or locoregionally advanced disease unsuitable for either surgical resection or radical chemoradiotherapy 4. Symptomatic dysphagia (Mellow score greater than 0) 5. ECOG performance status 0-2 6. Anticipated life expectancy of greater than 12 weeks. 7. Body weight of greater than 30kg. 8. Adequate bone marrow function, with values within the ranges specified below. Blood transfusions are permissible. 1. White blood cell count greater than or equal to 2 x (10 to the power of 9)/L 2. Absolute neutrophil count greater than or equal to 1.5 x (10 to the power of 9)/L 3. Platelets greater than or equal to 100 x (10 to the power of 9)/L 4. Haemoglobin greater than or equal to 90g/L 9. Adequate liver function, with values within the ranges specified below: 1. Alanine transferase less than or equal to 2.5 x upper limit of normal (ULN) 2. Aspartate transferase less than or equal to 2.5 x ULN 3. Total bilirubin less than or equal to 1.5 x ULN (except patients with Gilbert's Syndrome, who can have total bilirubin less than or equal to 5 x ULN) 10. Adequate renal function, with values within the ranges specified below. Note that an estimated renal function of greater than 125mL/min by the Cockroft-Gault formula must not be used for carboplatin dosing, and must instead be determined using a direct method. 1. Serum creatinine less than or equal to 1.5 x ULN 2. Creatinine clearance (CrCl) greater than or equal to 40 mL/min using Cockroft-Gault formula 11. Tumour tissue (formalin-fixed, paraffin embedded) should be available for PD-L1 and mismatch repair (MMR) protein expression and can be provided as a block or slides (archival tissue is acceptable). Blocks prepared from cytological samples, where tumour cell number is sufficient, are also acceptable. Patients will not be selected by PD-L1 or MMR status. 12. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments. 13. Signed, written and informed consent. Exclusion Criteria: 1. Bulky or organ-threatening metastatic disease requiring upfront higher dose chemotherapy in the judgement of the treating clinician. 2. Known tumour HER2 positivity (IHC 2+ or more and HER2 gene amplification on in situ hybridisation) if oligometastatic disease. 3. Previous systemic therapy for oesophageal or GOJ carcinoma. 4. Previous thoracic radiotherapy. Prior palliative radiotherapy to bony metastases is permitted. 5. Esophageal stent in situ. 6. Known tracheo-oesophageal fistula. 7. Known leptomeningeal or brain metastases. 8. Major surgical procedure (as defined by the Investigator) within 28 days prior to first day of study treatment. Note: Local surgery of isolated lesions for palliative intent is permitted. 9. History of another malignancy within the last 3 years, with the exception of adequately treated non-melanomatous skin cancer, carcinoma in situ and superficial transitional cell carcinoma of the bladder. 10. Prior therapy with an anti-PD1, 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. 11. Sensory neuropathy of grade 2 or higher severity per CTCAE v5.0. 12. History of allergy or hypersensitivity to study drug components, or other contraindications to any of the study drugs. Active or prior documented autoimmune disorders (including inflammatory bowel disease \[e.g., ulcerative colitis or Crohn's disease\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis\], Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc). Patients with the following conditions are exceptions to this criterion: 1. Vitiligo or alopecia. 2. Hypothyroidism (e.g., following Hashimoto syndrome) stable on thyroid hormone replacement. 3. Any chronic skin condition (e.g. psoriasis) that does not require systemic therapy. 4. Type 1 diabetes mellitus. 5. Coeliac disease controlled by diet alone. Patients without active autoimmune disease in the last 5 years may also be included but only after consultation with the Chief Principal Investigators. 13. Any condition requiring continuous systemic treatment with either regular corticosteroids (\>10mg daily prednisone or equivalent dose of an alternative corticosteroid) or other immunosuppressive medications within 14 days of study drug administration. Intranasal, inhaled or topical steroids, and adrenal replacement steroid doses \>10mg daily oral prednisone equivalent, are permitted in the absence of active autoimmune disease. 14. Positive test for hepatitis B surface antigen (HBsAg) indicating acute or chronic infection. Participants with a past or resolved HBV infection (defined as the presence of anti-HBc and absence of HBsAg) are eligible. 15. Positive test for hepatitis C virus antibody (HCV antibody) , unless polymerase chain reaction is negative for HCV RNA. 16. History of other significant, or active, infection, including HIV or tuberculosis (TB). HIV testing is not mandatory unless clinically indicated. Clinical evaluation for active TB may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice. 17. Receipt of a transplanted solid organ (kidney, liver, heart or lung) or of an allogeneic bone marrow transplant. 18. Receipt of a live attenuated vaccine within 30 days prior to registration. 19. Use of alternative or traditional medicines within 14 days prior to registration. 20. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring adverse events or compromise the ability of the patient to give written informed consent. 21. Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or use a reliable means of contraception to avoid pregnancy for 90 days after the last dose of durvalumab. Women of childbearing potential must have a negative pregnancy test within 24 hours prior to trial registration. Men must have been surgically sterilized or use a double barrier method of contraception if they are sexually active with a woman of childbearing potential for a period of 180 days after the last dose of durvalumab and chemotherapy, or 90 days after the last dose of durvalumab monotherapy (whichever is the longer time period). Sperm donation is not permitted for 180 days after the last dose of durvalumab and chemotherapy, or 90 days after the last dose of durvalumab monotherapy (whichever is the longer time period).