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

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