RegoNivo vs Standard of Care Chemotherapy in AGOC

Inclusion Criteria

• Adults (18 years or over) with metastatic or locally recurrent gastro-oesophageal cancer which:
• has arisen in any primary gastro-oesophageal site (oesophago-gastric junction (GOJ) or stomach); and
• is of adenocarcinoma or undifferentiated carcinoma histology; and
• is evaluable according to Response Evaluation Criteria in Solid Tumours (RECIST Version 1.1) by computed tomography (CT) scan performed within 21 days prior to randomisation. A lesion in a previously irradiated area is eligible to be considered as measurable disease as long as there is objective evidence of progression of the lesion prior to study enrolment; and
• has failed or been intolerant to a minimum of 2 lines of prior anti-cancer therapy for recurrent/metastatic disease which must have included at least one platinum agent and one fluoropyrimidine analogue. Note: Neoadjuvant or adjuvant chemotherapy or chemoradiotherapy will be considered as first line treatment where people have relapsed or progressed within 6 months of completing treatment; Radiosensitising chemotherapy given solely for this purpose concurrent with palliative radiation will not be considered as a line of treatment. Ramucirumab monotherapy, or immunotherapy with a checkpoint inhibitor, will be considered a line of treatment.
• HER2-positive participants must have received trastuzumab
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (Appendix 1).
• Ability to swallow oral medication.
• Adequate bone marrow function (Platelets ≥100x109/L; Absolute Neutrophil Count (ANC) ≥1.5x109/L and Haemoglobin ≥ 9.0g/dL).
• Adequate renal function (Creatinine clearance >50 ml/min) based on either the Cockcroft-Gault formula (Appendix 2), 24-hour urine or Glomerular Filtration Rate (GFR) scan; and serum creatinine ≤1.5 x Upper Limit of Normal (ULN).
• Adequate liver function (Serum total bilirubin ≤1.5 x ULN, and INR ≤ 1.5 x ULN, and Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP) ≤2.5 x ULN (≤ 5 x ULN for participants with liver metastases)). Participants being treated with an anti-coagulant, such as warfarin or heparin, will be allowed to participate provided that no prior evidence of an underlying abnormality in these parameters exists.
• Willing and able to comply with all study requirements, including treatment, timing, and/or nature of required assessments and follow-up.
• Study treatment both planned and able to start within 7 days after randomisation (note: subjects randomised on a Friday should commence treatment no earlier than the following Monday)
• Signed, written informed consent

Exclusion Criteria

• Known allergy to the investigational product drug class or excipients in the regorafenib and/or nivolumab
• Poorly-controlled hypertension (systolic blood pressure >140mmHg or diastolic pressure> 90mmHg despite optimal medical management).
• Participants with known, uncontrolled malabsorption syndromes
• Any prior anti-VEGF targeted therapy using small molecule VEGF TKIs (e.g. apatinib). Prior anti-VEGF targeted monoclonal antibody therapies (e.g. bevacizumab and ramucirumab) are permitted.
• Any prior use of more than one immune checkpoint inhibitor
• Treatment with any previous drug therapy within 2 weeks prior to first dose of study treatment. This includes any investigational therapy.
• Use of biological response modifiers, such as granulocyte colony stimulating factor (G-CSF), within 3 weeks prior to randomisation.
• Concurrent treatment with strong CYP3A4 inhibitors or inducers.
• Palliative radiotherapy, unless more than 14 days have elapsed between completion of radiation and the date of registration, and adverse events resulting from radiation have resolved to < Grade 2 according to CTCAE V5.0
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization
• Arterial thrombotic or ischaemic events, such as cerebrovascular accident, within 6 months prior to randomization.
• Venous thrombotic events and pulmonary embolism within 3 months prior to randomization
• Any haemorrhage or bleeding event ≥ Grade 3 according to CTCAE v5.0 within 4 weeks prior to randomization.
• Non-healing wound, ulcer, or bone fracture.
• Interstitial lung disease with ongoing signs and symptoms
• Clinical hyperthyroidism or hypothyroidism. Note: non-clinically significant abnormal TFTs (abnormal TSH and abnormal T3 and/or abnormal T4) considered to be due to sick euthyroid syndrome is allowed.
• Persistent proteinuria of ≥ Grade 3 according to CTCAE v5.0 (equivalent to > 3.5g of protein over 24 hour measured on either a random specimen or 24 hour collection.
• Uncontrolled metastatic disease to the central nervous system. To be eligible, known CNS metastases should have been treated with surgery and/or radiotherapy and the patient should have been receiving a stable dose of steroids for at least 2 weeks prior to randomization, with no deterioration in neurological symptoms during this time.
• History of another malignancy within 2 years prior to randomization. Participants with the following are eligible for this study:
• curatively treated cervical carcinoma in situ,
• non-melanomatous carcinoma of the skin,
• superficial bladder tumours (T1a [Non-invasive tumour], and Tis [Carcinoma in situ]),
• treated thyroid papillary cancer
• Any significant active infection, including chronic active hepatitis B, hepatitis C, or HIV. Testing for these is not mandatory unless clinically indicated. Participants with known Hepatitis B/C infection will be allowed to participate providing evidence of viral suppression has been documented and the patient remains on appropriate anti-viral therapy.
• Patients with acute coronary syndrome (including myocardial infarction and unstable angina), and with a history of coronary angioplasty or stent placement performed within 6 months before enrolment
• Patients with a ≥ grade 3 active infection according to CTCAE version 5.0
• Patients with concurrent autoimmune disease, or a history of chronic or recurrent autoimmune disease
• Patients who require systemic corticosteroids (excluding temporary usage for tests, prophylactic administration for allergic reactions, or to alleviate swelling associated with radiotherapy; if used as replacement therapy e.g. ≤ 10 mg prednisolone or dexamethasone ≤ 2 mg per day) or immunosuppressants, or who have received such a therapy < 14 days prior to randomisation
• Patients with a seizure disorder who require pharmacotherapy
• Serious medical or psychiatric condition(s) that might limit the ability of the patient to comply with the protocol.
• Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to randomization. Men must have been surgically sterilized or use a barrier method of contraception.