M6620 Plus Standard Treatment in Oesophageal and Other Cancer

INCLUSION CRITERIA: For Stage A1: 1. Histologically confirmed adenocarcinoma or squamous cell carcinoma of the oesophagus (not including cervical oesophagus) 2. Tumor length 15cm or less 3. Any stage of disease that is unsuitable for radical CRT or surgery but suitable for palliative RT 4. Baseline investigations available: staging CT scan (within 42 days before first study dose) and endoscopy 5. Previous chemotherapy treatment completed 28 days before first study dose 6. No oesophageal stent in-situ 7. Any gender, aged ≥16 years. 8. Life expectancy of at least 12 weeks 9. ECOG performance score of 0-1 10. Able to comply with protocol fully - absence of any physical, psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial 11. Able to give written (signed and dated) informed consent according to GCP before registration 12. Hematological and biochemical indices within the ranges below: * Haemoglobin: ≥8.0g/dL * Platelet count : ≥100x10\^9/L * Absolute neutrophil count: ≥1.5x10\^9/L * Total bilirubin: ≤1.5 x upper limit of normal unless the subject has known or suspected Gilbert's syndrome * AST/ALT: ≤2.5 times the upper limit of normal; ≤5 times if liver metastases * Estimated glomerular filtration rate: ≥40ml/min For Stage A2: 1. Any histologically confirmed advanced solid tumor that is metastatic or unresectable where Investigator considers Cisplatin and Capecitabine based regimen as appropriate. 2. Baseline investigations available: staging CT scan (within 35 days before first study dose) 3. Previous chemotherapy treatment completed 28 days before first study dose 4. Any gender, aged ≥16 years 5. Life expectancy of at least 12 weeks 6. ECOG performance score of 0-1 7. Able to comply with protocol fully - absence of any physical, psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial 8. Able to give written (signed and dated) informed consent according to GCP before registration 9. Hematological and biochemical indices within the ranges below: * Haemoglobin: ≥10.0g/dL * Platelet count : ≥100x10\^9/L * Absolute neutrophil count: ≥1.5x10\^9/L * Total bilirubin: ≤1.5 x upper limit of normal unless the subject has known or suspected Gilbert's syndrome * AST/ALT: ≤2.5 times the upper limit of normal; ≤5 times if liver metastases * Ca, Mg, Phosphate: within normal limits * Estimated glomerular filtration rate: ≥60ml/min For Stage B: 1. Histologically confirmed adenocarcinoma or squamous cell carcinoma of the oesophagus including Siewert type 1 or 2 tumors with ≤2cm gastric mucosal extension (not including cervical oesophagus) 2. Tumor length 7cm or less 3. Suitable for radical CRT and surgery not an option due to being medically unfit or unsuitable for surgery or patient choice 4. No oesophageal stent in-situ 5. Endoscopically or radiologically documented measurable disease 6. Diagnostic PET CT scan\* 7. Staging CT scan\* \*either CT or PET CT scan within 42 days of first study dose 8. Adequate respiratory and cardiac function tests for safe delivery of CRT in the opinion of the Principle Investigator, specifically cardiac ejection fraction ≥60% and lung function FEV1\>1 litre or 40% of predicted value or KCO (DLCO/VA) \>40% predicted value. 9. Any gender, aged ≥16 years 10. ECOG performance score of 0-1 11. Able to comply with protocol fully - absence of any physical, psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial 12. Able to give written (signed and dated) informed consent according to GCP before registration 13. Haematological and biochemical indices within the ranges below: * Haemoglobin: ≥10.0g/dL * Platelet count : ≥100x10\^9/L * Absolute neutrophil count: ≥1.5x10\^9/L * Total bilirubin: ≤1.5 x upper limit of normal unless the subject has known or suspected Gilbert's syndrome * AST/ALT: ≤2.5 times the upper limit of normal; ≤5 times if liver metastases * Ca, Mg, Phosphate: within normal limits * Estimated glomerular filtration rate: ≥60ml/min EXCLUSION CRITERIA: 1. Pregnant or breast-feeding women, or women of childbearing potential unless highly effective contraception is used 2. Untreated and multiple brain metastases 3. Clinically significant cardiovascular event within 6 months before study entry to include: a) congestive heart failure requiring therapy, b) unstable angina pectoris, c) myocardial infarction, d) class II/III/IV cardiac disease (New York Heart Association), e) presence of severe valvular heart disease, f) presence of ventricular arrhythmia requiring treatment 4. History of arrhythmia that is symptomatic or requires treatment (CTCAE 3), symptomatic or uncontrolled atrial fibrillation, despite treatment, or asymptomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by medication are permitted. 5. Uncontrolled hypertension (blood pressure ≥160/100 despite optimal therapy) 6. Second or third degree heart block with or without symptoms 7. QTc \>450msec in adult male and \>470 msec in adult females (by Fridericia's correction) not due to electrolyte abnormality and that does not resolve with correction of electrolytes. 8. History of congenital long QT syndrome 9. History of torsades de pointes (or any concurrent medication with a known risk of inducing torsades de pointes) 10. Trachea-oesophageal fistula or invasion of the tracheo-bronchial tree 11. Treatment with any other investigational agent, or participation in another clinical trial within 28 days prior to the start of treatment 12. Strong CYP3A inhibitors and inducers or haemopoietic growth factors within 14 days before first dose of M6620 (Berzosertib) 13. HER2 gastro-oesophageal positive cancer where anti-Her2 therapies may be more appropriate (however patients who have failed anti-HER2 therapy may be eligible for stage A1 and A2) 14. Unable to have or unwilling to change to low molecular weight heparin instead of Warfarin 15. Other psychological, social or medical condition, physical examination finding or a laboratory abnormality that the Investigator considers would make the patient a poor trial candidate or could interfere with protocol compliance or the interpretation of trial results. 16. Any other active malignancy, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and non-melanoma skin lesions. 17. Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV. Additional Exclusion Criteria for Stage A1 and B: 1\) Previous radiotherapy to thorax or upper abdomen Additional exclusion criteria for Stage A2 and B: 1. History of hand-foot syndrome 2. History of hearing impairment 3. Live vaccine received within 30 days prior to treatment start 4. Complete or Partial DPD deficiency Additional Exclusion Criteria for Stage B: 1\) Previous chemotherapy