Safety study of AZD8931 for oesophago-gastric cancer

INTERVENTION: Dose Escalation ? In the dose escalation phase of the study patients with metastatic or inoperable disease will be recruited and no surgery is planned. Patients who successfully complete the screening will receive AZD8931 monotherapy for three days (days ‐3 to ‐1) [20mg bd in cohort 1, 40 mg bd in cohort 2 and 60 mg bd in cohort 3]. Xelox chemotherapy will be added in on day 4 of AZD8931 treatment AZD8931 tablets will be taken orally, continuously, twice daily. Patients will receive oxaliplatin and capecitabine on day one of every cycle every 21 days. Oxaliplatin will be given at 130 mg/m2 IV in 250‐500 ml of 5% glucose over 2 hours. Capecitabine 1250mg/m2/day will be given orally in two divided doses continuously from days 1‐21 of each 3 week cycle. In this phase patients will receive a maximum of 8 cycles of daily AZD8931 in combination with Xelox. AZD8931 may be continued following cessation of the Xelox, providing the patient has no evidence of tumour progression and continues to tolerate treatment. Dose Expansion ‐ In the dose expansion phase of the trial, we propose a randomised component. Patients will receive two cycles of Xelox chemotherapy ± AZD8931 prior to undergoing an oesophago‐gastrectomy. Twenty patients will receive Xelox and AZD8931 and 10 patients Xelox alone. The expectation is that this randomisation will allow us to assess any additive toxicity due to the combination of AZD8931 and Xelox over the toxicities associated with the Xelox backbone of chemotherapy alone. AZD8931 monotherapy will be used as maintenance therapy, in patients who were randomised to the combination and who have successful surgery, for a maximum of 12 months starting 6 to 12 weeks after surgery. Patients may therefore receive treatment for 58 weeks over a maximum 18 months period. Maintenance Phase ‐ To investigate the safety and feasibility of maintaining patients on AZD8931, to reduce the risk of recurrence, patients who have successful surgery will be allowed to CONDITION: Upper gastro‐intestinal cancer ; Cancer ; Malignant neoplasm of oesophagus PRIMARY OUTCOME: 1. Assessment of efficacy for the combination of AZD8931 + Xelox in patients with operable OG carcinoma ; 2. 6‐month progression‐free survival rate ; 3. R0 resection rate ; 4. Progression free and overall survival SECONDARY OUTCOME: 1. Pharmacokinetics (PK) of AZD8931 when co‐administered with Xelox; 2. Serum AZD8931 concentration; 3. Tolerability of post‐operative maintenance therapy with AZD8931; 4. Adverse events using CTCAE v4.03 ; 5. Number of patients starting maintenance therapy INCLUSION CRITERIA: 1. Age = 18 years 2. WHO performance status 01 3. Adequate respiratory and cardiac function 4. Able to give informed consent and be capable of cooperating with protocol 5. Haematological and biochemical indices within the ranges shown below: 5.1. Haemoglobin (Hb) =10g/dl 5.2. Neutrophils = 1500/µl 5.3. Platelet count = 100.000/µl 5.4. AST or ALT = 3 ULN, alkaline phosphatase = 2x ULN 5.5. Serum Bilirubin = 1.5 ULN 5.6. Creatinine Clearance = 50ml/min 6. Able to swallow oral medication 7. Women of child bearing potential must use an acceptable method of contraception during the study, and have a negative pregnancy test 8. Male patients must use a barrier method of contraception ‐ male condom (female condom or diaphragm are not acceptable) during the study. 9. For the dose escalation phase patients with locally advanced or metastatic oesophageal or gastro‐oesophageal junction adenocarcinoma (including Siewert