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