• STAGE A1 - Determine the best tolerated M6620 treatment schedule (or phase II recommended dose), administered concomitantly with radiotherapy only in the palliative treatment of oesophageal cancer [ Time Frame: Week 9 ]
  Highest treatment schedule resulting in less than 25% dose limiting toxicity rate
• STAGE A2 - Determine the best tolerated M6620 treatment schedule (or phase II recommended dose) administered concomitantly with chemotherapy (Cisplatin and Capecitabine) only in the palliative treatment of solid cancer [ Time Frame: Week 4 ]
  Highest treatment schedule resulting in less than 30% dose limiting toxicity rate
• STAGE B - Determine the best tolerated M6620 treatment schedule (or phase II recommended dose) administered concomitantly with radiotherapy (dCRT) in combination with Cisplatin and Capecitabine in the radical treatment of oesophageal cancer [ Time Frame: Up to Week 24 ]
  Highest treatment schedule resulting in less than 45% dose limiting toxicity rate

• STAGE A1 - To determine the number of toxicities grade ≥3 (according to CTCAE v4.03) and the length of time these toxicities take to resolve when M6620 is administered concomitantly with RT only in the palliative treatment of oesophageal cancer [ Time Frame: During radiotherapy weeks 1-3, week 4, 9 and 12 ]
  To determine the safety and toxicity profile of M6620 administered concomitantly with RT only in the palliative treatment of oesophageal cancer
• STAGE A1 - To determine if M6620 can be delivered in combination with palliative radiotherapy by the proportion of patients completing at least 75%, 90% and 100% of the planned radiotherapy dose [ Time Frame: End of radiotherapy, end of week 3 ]
  Proportion of patients completing at least 75%, 90% and 100% of the planned radiotherapy dose
• STAGE A1 - Efficacy of the combination (M6620 and radiotherapy), measured by objective tumour response [ Time Frame: 12 weeks, 6 and 12 months ]
  Objective tumor response as evaluated by CT scan as quantified by RECIST 1.1. PFS and OS from D1
• STAGE A2 -To determine the number of toxicities grade ≥3 (according to CTCAE v4.03) and the time they take to resolve when M6620 is administered concomitantly with chemotherapy (Cisplatin and Capecitabine) only in the palliative treatment of solid cancer [ Time Frame: During chemotherapy week 1-18, week 20, 26 ]
  To determine the safety and toxicity profile of M6620 administered concomitantly with chemotherapy (Cisplatin and Capecitabine) only in the palliative treatment of solid cancer
• STAGE A2 - To determine if M6620 can be delivered in combination with palliative chemotherapy by the proportion of patients completing at least 75%, 90% and 100% of the planned dose [ Time Frame: End of chemotherapy, week 18 ]
  Proportion of patients completing at least 75%, 90% and 100% of the planned dose
• STAGE A2 - Efficacy of the combination (M6620 and chemotherapy), measured by objective tumour response [ Time Frame: Week 6, 12, 18, 26 and 12 months ]
  Objective tumor response as evaluated by CT scan and quantified by RECIST 1.1; PFS and OS from D1; in field radiotherapy control
• STAGE B -To determine the number of toxicities grade ≥3 (according to CTCAE v4.03) & the time they take to resolve when M6620 is administered concomitantly with dCRT (radiotherapy, cisplatin & capecitabine) in the radical treatment of oesophageal cancer [ Time Frame: Up to week 24 ]
  To determine safety and toxicity profile of M6620 administered concomitantly with dCRT in combination with cisplatin and capecitabine in the radical treatment of oesophageal cancer
• STAGE B - To measure the the proportion of patients completing at least 80% of the planned chemotherapy dose and at least 20 fractions of radiotherapy in order to determine tolerance and ability to deliver M6620 in combination with standard dCRT [ Time Frame: End of induction chemotherapy and dCRT. End of week 11. ]
  To determine the tolerance and ability to deliver M6620 in combination with standard dCRT
• STAGE B - To measure objective tumor response as evaluated by CT scan and quantified by RECIST 1.1 and endoscopic biopsy findings [ Time Frame: 24 weeks, 12 and 24 months ]
  To determine the efficacy of the long term safety of the treatment combination

• STAGE A2 - To measure M6620 area under the plasma concentration time curve using blood samples when delivered after Capecitabine and Cisplatin [ Time Frame: 1st dose of M6620 (C1D2) at the following timepoints: BOI, at 0.5 hours before EOI, at EOI and at 0.5, 1, 2,6, 23, 47 hours after EOI. For C1D9 and C1D16 doses at the following timepoints: BOI and EOI ]
  To enable evaluation of pharmacokinetics of M6620 when administered in combination with Cisplatin and Capecitabine
• STAGE A2 - To measure M6620 Cmax (observed peak plasma concentration) using blood samples when delivered after Capecitabine and Cisplatin administration [ Time Frame: 1st dose of M6620 (C1D2) at the following timepoints: BOI, at 0.5 hours before EOI, at EOI and at 0.5, 1, 2,6, 23, 47 hours after EOI. For C1D9 and C1D16 doses at the following timepoints: BOI and EOI ]
  To enable evaluation of pharmacokinetics of M6620 when administered in combination with Cisplatin and Capecitabine
• STAGE B - To explore target effects in tissue by measuring the change in level of ATR inhibition and apoptosis in M6620 treated tissue using IHC [ Time Frame: Biopsies and blood samples at baseline, week 7 and 24 ]
  To explore change in level of ATR inhibition and apoptosis in M6620 treated tissue
• STAGE B - To explore target effects in tissue by assessing genotyping of tumours obtained from biopsies and blood samples [ Time Frame: Biopsies and blood samples at baseline, week 7 and 24 ]
  To explore change in level of ATR inhibition and apoptosis in M6620 treated tissue
• STAGE B - To explore target effects in tissue by aiming to identify markers for oesophageal cancer in the blood [ Time Frame: Biopsies and blood samples at baseline, week 7 and 24 ]
  To explore change in level of ATR inhibition and apoptosis in M6620 treated tissue

There is strong scientific rationale for combining ATR inhibitors with DNA damaging agents such as radiation and cisplatin. In particular, ATR inhibition has been shown to be cytotoxic to tumor cells with an impaired DNA damage response, such as those with deficiency in the ATM- or p53 pathway. The high incidence of p53 mutations and the fact that cisplatin and radiation are key therapeutics, makes oesophageal cancer an attractive tumor type to test the activity of an ATR inhibitor. Given the reported synthetic lethal relationship between ATM and ATR, it is likely that ATR inhibition in an ATM- or p53- deficient background will offer a specific and effective way of targeting OAC and SCC of the oesophagus, and enhance the current standard of care.

The trial will be divided into three stages. Stage A1 will explore the combination of M6620 plus radiotherapy in the palliative setting and Stage A2 will explore the combination of M6620 plus chemotherapy in the palliative setting. Stage B, will explore the combination of all 3 (M6620 plus chemoradiotherapy in the radical setting).

In Stage A1 of the study M6620 will be combined with radiotherapy for the first time and the starting dose will be 140mg/m2 M6620, which has been well-tolerated. M6620 will be administered with daily palliative radiotherapy during this stage in order to study the specific interaction of M6620 with radiotherapy (acting as the DNA damaging agent during this trial stage).

In Stage A2 of the study, M6620 will be combined with Cisplatin and Capecitabine combination chemotherapy for the first time; with a starting dose of 90mg/m2 M6620. M6620 will be administered 24 hours post cisplatin infusion, aiming to achieve maximum treatment benefit. Stage A1 and A2 together will help give an indication of a toxicity profile before administration with chemoradiotherapy (Stage B).

• Oesophageal Adenocarcinoma
• Squamous Cell Carcinoma
• Solid Tumor

• Drug: M6620
  M6620 is an unlicensed small molecule ATR inhibitor which can be used in combination with DNA damaging agents. In pre-clinical models it has substantial activity when given with DNA damaging drugs or ionising radiation. The clinical agent (M6620) is currently studied in a phase I trial in Oxford and other centres in combination with gemcitabine, cisplatin, gemcitabine/cisplatin and cisplatin/etoposide.
• Drug: Cisplatin
  Cisplatin is a platinum based chemotherapy drug licensed to treat a number of different types of cancer. Cisplatin use is not considered standard practice in Stage A2 & B, therefore Cisplatin is considered an investigational medicinal product for the purpose of this trial.
• Drug: Capecitabine
  Capecitabine is a chemotherapy drug licensed to treat a number of different types of cancer, it is a noncytotoxic pre-cursor of the cytotoxic 5-fluourouracil. Capecitabine use is not considered standard practice in Stage A2 & B, therefore Capecitabine is considered an investigational medicinal product for the purpose of this trial.
• Radiation: Radiotherapy
  Stage A1 uses palliative radiotherapy. Stage B uses definitive radiotherapy.

INCLUSION CRITERIA:

For Stage A1:

1. Histologically confirmed adenocarcinoma or squamous cell carcinoma of the oesophagus (not including cervical oesophagus)
2. Tumor length 10cm 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 have given (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. 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 either Fridericia's or Bazett'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 haemopoetic growth factors within 14 days before first dose of M6620
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

Additional Exclusion Criteria for Stage B:

1) Previous chemotherapy