Phase I Vandetanib Plus Capecitabine, Oxaliplatin and Bevacizumab for Metastatic Colorectal Cancer

Inclusion Criteria:

   - Provision of signed informed consent.

   - Female and or male age 18 years and over.

   - Negative pregnancy test for women of childbearing potential.

   - Histologically or cytologically confirmed adenocarcinoma of the colon or rectum.

   - Patients with a history of colorectal adenocarcinoma treated by surgical resection who
   develop radiological or clinical evidence of metastatic cancer do not require separate
   histological or cytological confirmation of metastatic disease unless an interval of >
   5 years has elapsed between the primary surgery and the development of metastatic
   disease. Clinicians should consider biopsy of lesions to establish diagnosis of
   metastatic colorectal adenocarcinoma if there is substantial clinical ambiguity
   regarding the nature or source of apparent metastases.

   - A primary or metastatic lesion measurable in at least one dimension by RECIST criteria
   within 4 weeks prior to entry of study

   - WHO performance status of 0-2

   - Laboratory values<= 2 weeks prior to randomization:

Absolute Neutrophil Count (ANC) >=1.5 x 10^9/L (>=1500/mm^3) Platelets (PLT) >=100 x 10^9/L
(>=100,000/mm^3) Hemoglobin (Hgb) >=9 g/dL Serum creatinine <=1.5 x ULN Serum bilirubin
<=1.5 x ULN Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT)
<=2.5 x ULN (<=5 x ULN if liver metastases present). Note: ERCP or percutaneous stenting
may be used to normalize the liver function tests.

Negative or trace for proteinuria based on dip stick reading OR, if documentation of +1
result for protein on dip stick reading, then total urinary protein <=500 mg and measured
creatinine clearance (CrCl) >=50 mL/min from a 24-hour urine collection

• Life expectancy >12 weeks

Exclusion Criteria:

• Laboratory results:

Serum bilirubin >1.5 x the upper limit of reference range (ULRR) Serum creatinine >1.5 x
ULRR or creatinine clearance >= 50 mL/minute (calculated by Cockcroft-Gault formula.)
Potassium <4.0 mmol/L despite supplementation; serum calcium (ionized or adjusted for
albumin,) or magnesium out of normal range despite supplementation.

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 x ULRR or alkaline
phosphatase (ALP) >2.5 x ULRR, or >5x ULRR if judged by the investigator to be related to
liver metastases

   - Evidence of severe or uncontrolled systemic disease or any concurrent condition which
   in the Investigator's opinion makes it undesirable for the patient to participate in
   the trial or which would jeopardize compliance with the protocol.

   - Clinically significant cardiac event such as myocardial infarction; New York Heart
   Association (NYHA) classification of heart disease >= 2 within 3 months before entry;
   or presence of cardiac disease that, in the opinion of the Investigator, increases the
   risk of ventricular arrhythmia.

   - History of arrhythmia (multifocal premature ventricular contractions (PVCs), bigeminy,
   trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) which is
   symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained
   ventricular tachycardia. Atrial fibrillation, controlled on medication, is not
   excluded.

   - Previous history of QTc prolongation as a result from other medication that required
   discontinuation of that medication.

   - Congenital long QT syndrome, or 1st degree relative with unexplained sudden death
   under 40 years of age.

   - Presence of left bundle branch block (LBBB.)

   - QTc with Bazett's correction that is unmeasurable, or <480 msec on screening ECG. If a
   patient has QTc >= 480 msec on screening ECG, the screen ECG may be repeated twice (at
   least 24 hours apart). The average QTc from the three screening ECGs must be <480 msec
   in order for the patient to be eligible for the study.)

   - Any concomitant medication that may cause QTc prolongation, induce Torsades de Pointes
   or induce CYP3A4 function

   - Hypertension not controlled by medical therapy (systolic blood pressure greater than
   160 mm Hg or diastolic blood pressure greater than 100 mm Hg)

   - Currently active diarrhea that may affect the ability of the patient to absorb the
   vandetanib or tolerate diarrhea.

   - Women who are currently pregnant or breastfeeding.

   - Previous or current malignancies of other histologies within the last 5 years, with
   the exception of cervical carcinoma in situ and adequately treated basal cell or
   squamous cell carcinoma of the skin

   - Receipt of any investigational agents within 30 days prior to commencing study
   treatment

   - Last dose of prior chemotherapy discontinued less than 4 weeks before the start of
   study therapy

   - Last radiation therapy within the last 4 weeks before the start of study therapy,
   except palliative radiotherapy

   - Any unresolved toxicity greater than CTC grade 1 from previous anti-cancer therapy

   - Previous enrollment or randomization of treatment in the present study

   - Major surgery within 4 weeks, or incompletely healed surgical incision before starting
   study therapy