Dual REctcal Angiogenesis or MEK Inhibition radioTHERAPY Trial

Inclusion criteria

Inc Criteria: * Histologically confirmed rectal adenocarcinoma * MRI (magnetic resonance imaging) and triphasic CT (computerised tomography) defined locally advanced rectal cancer: * Mesorectal fascia involved or * Mesorectal fascia threatened or * Any T3 tumours \< 5cm from the anal verge * Primary resection unlikely to achieve clear margins * No previous chemotherapy or radiotherapy for rectal cancer * Bone marrow function: absolute neutrophil count ≥1.5 x109/l and platelet count \>100 x109/l * Hepatobiliary function: serum bilirubin \<1.5 x upper limit of normal (ULN); serum ALP \<5 x ULN; serum transaminase (AST or ALT) \<2.5 x ULN * Renal function: Serum creatinine clearance \>50mL/min by either Cockcroft-Gault formula or EDTA (ethylenediaminetetraacetic acid) clearance * ECOG PS(Eastern Cooperative Oncology Group Performance Status) 0-1 * Disease can be encompassed within a radical radiotherapy treatment volume * No pre-existing condition which would deter radiotherapy, e.g. fistulas, severe ulcerative colitis, Crohn's disease, prior adhesions * For women of child-bearing potential a negative pregnancy test is required and adequate contraceptive precautions such as a condom for their partner must be used. For men - adequate contraception must be used. * Fit to receive all study treatments * Able to comply with oral medication and protocol * Signed, written and dated informed consent. * Life expectancy ≥ 3 months. Exc Criteria: * Concurrent uncontrolled medical illness, or other previous/current malignant disease likely to interfere with protocol treatments * Age\<18 * Any pregnant, lactating women or potentially childbearing patients not using adequate contraception * Previous chemotherapy or radiotherapy for rectal cancer * Metastatic disease * ECOG PS\>1 * Patients who have very significant small bowel delineated within the radiation fields. * Current or impending rectal obstruction (unless defunctioning stoma present), metallic colonic rectal stent in situ * Pelvic sepsis. * Uncontrolled cardiac, respiratory or other disease, or any serious medical or psychiatric disorder that would preclude trial therapy or informed consent. * Cardiac conditions as follows: * Uncontrolled hypertension (resting BP ≥150/95mmHg despite optimal therapy) * Heart failure NYHA Class II or above * Prior or current cardiomyopathy * Atrial fibrillation with heart rate \>100 bpm * Unstable ischaemic heart disease * Refractory nausea and vomiting, chronic gastrointestinal diseases, or significant bowel resection that would preclude adequate absorption of trial drug * Patients who are deemed unsuitable for surgery because of co-morbidity or coagulation problems. * Recent (\<14 days) major thoracic or abdominal surgery prior to entry into the study or a surgical incision that is not fully healed which would prevent administration of study treatment * Known DPD (dihydropyrimidine dehydrogenase)deficiency * Patients suffering from any condition that may affect the absorption of capecitabine or IMP (investigational medical product) * Any evidence of severe or uncontrolled systemic disease, active infection, active bleeding diatheses or renal transplant, including any patient known to have Hep B, Hep C or HIV * Mean QTc with Bazetts correction \>470msec in screening ECG or history of familial long QT syndrome EXC CRITERIA (AZD6244 cohorts) * KRAS (Kirsten ras sarcoma viral oncogene) wild-type * Prior treatment with a MEK inhibitor * Baseline LVEF (left ventricular ejection fraction) ≤50% EXC CRITERIA (Cediranib cohorts) * Known hypersensitivity to Cediranib or any of its excipients * Greater than +1 proteinuria on two consecutive dipsticks taken no less than 1 week apart unless urinary protein \< 1.5g in a 24 hr period or protein/creatinine ratio \< 1.5. * Significant haemorrhage (\>30mL bleeding/episode in previous 3 months) or haemoptysis (\>5mL fresh blood in previous 4 weeks) * APTT ratio \> 1.5 x ULN * Arterial thromboembolic event (including ischemic attack) in the previous 12 months