Efficacy Study Comparing ZD6474 in Combination With Pemetrexed and Pemetrexed Alone in 2nd Line NSCLC Patients

Inclusion Criteria:

* Provision of informed consent
* Female or male aged 18 years or above
* Histologic or cytologic confirmation of locally advanced or metastatic NSCLC (stage IIIB or IV) on entry into study
* Failure of 1st line anti-cancer therapy (either radiological documentation of disease progression or due to toxicity) or subsequent relapse of disease following 1st line therapy
* WHO Performance status 0 - 2
* One or more measurable lesions at least 10 mm in the longest diameter (LD) by spiral CT scan or 20 mm with conventional techniques according to RECIST criteria. Previously irradiated lesions will not be considered measurable.
* Life expectancy of 12 weeks or longer
* Negative pregnancy test for women of childbearing potential only

Exclusion Criteria:

* Mixed small cell and non-small cell lung cancer histology
* Patients have received 2nd-line or subsequent anti-cancer therapy
* Prior treatment with pemetrexed
* Prior treatment with VEGFR TKIs (previous treatment with bevacizumab \[Avastin\] is permitted)
* Known or suspected brain metastases or spinal cord compression, unless treated at least 4 weeks before entry, and stable without steroid treatment for 10 days
* The last radiation therapy within 4 weeks before the start of study therapy, not including local palliative radiation
* The last dose of prior chemotherapy or other anti-cancer therapy is discontinued less than 3 weeks before the start of study therapy (6 weeks for nitrosoureas, mitomycin, and suramin)
* Major surgery within 4 weeks before entry, or incompletely healed surgical incision
* Neutrophils \<1.5 x 109/L or platelets \<100 x 109/L
* Serum bilirubin \>1.5 x the upper limit of reference range (ULRR)
* Creatinine clearance \<50 ml/min calculated by either Cockcroft -Gault, 24 hours urine collection, EDTA scan or other validated methods
* Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>2.5 x ULRR in the absence of liver metastases, or \> 5 x ULRR in the presence of liver metastases
* Alkaline phosphatase (ALP) \>2.5 x ULRR in the absence of liver metastases, or \>5 x ULRR in the presence of liver metastases
* Current active gastrointestinal disease that may affect the ability of the patient to absorb ZD6474 or tolerate diarrhoea
* 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 study or which would jeopardize compliance with the protocol
* Any unresolved toxicity greater than CTCAE Grade 2 from previous anti-cancer therapy
* Significant cardiovascular event (e.g., myocardial infarction, superior vena cava \[SVC\] syndrome), 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
* Congenital long QT syndrome or 1st degree relative with unexplained sudden death under 40 years of age
* QT prolongation with other medications that required discontinuation of that medication
* Presence of left bundle branch block (LBBB)
* QTc with Bazett's correction unmeasurable or ≥ 480 msec on screening ECG (Note: If a patient has QTc interval ≥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) Patients who are receiving a drug that has a risk of QTc prolongation are eligible if QTc is \<460 msec.
* Potassium \<4.0 mmol/L despite supplementation; serum calcium (or ionized or adjusted for albumin), or magnesium out of normal range despite supplementation
* Women who are pregnant or breast-feeding
* Any concomitant medications that may cause QTc prolongation or induce Torsades de Pointes or induce CYP3A4 function. Drugs that have a risk of QTc prolongation, that in the investigator's opinion cannot be discontinued, are allowed, but only of the QTc is \<460 msec
* Hypertension not controlled by medical therapy (systolic blood pressure greater than 160 millimetre of mercury \[mmHg\] or diastolic blood pressure greater than 100 mmHg)
* Previous or current malignancies of other histologies within the last 5 years, with the exception of in situ carcinoma of the cervix and adequately treated basal cell or squamous cell carcinoma of the skin
* Treatment with a non-approved or investigational drug within 30 days before Day 1 of study treatment
* Concomitant use of yellow fever vaccine or any live attenuated vaccines