Clinical trial NCT01160926 (phase 1, status: terminated)
Conditions: rectal cancer
ICD codes: C05.2, C10.0, C16.0, C16.4, C17.0, C17.1, C17.2
Drugs: azd6244, cediranib (azd2171)
SMILES: CN1C=NC2=C1C=C(C(O)=NOCCO)C(NC1=C(Cl)C=C(Br)C=C1)=C2F, COC1=CC2=C(C=C1OCCCN1CCCC1)N=CN=C2OC1=C(F)C2=C(NC(C)=C2)C=C1
Reason stopped: 
    2 dlts had been reported from first 4 patients on lowest possible dose cohort.
  
Eligibility 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