Dual REctcal Angiogenesis or MEK Inhibition radioTHERAPY Trial

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