• Determine the safety profile, tolerability and (MTD) of ZD6474 in combination with radiation therapy (RT) and ZD6474 in combination with RT and cisplatin chemo. [ Time Frame: 16 Months ] [ Designated as safety issue: Yes ]
  

• Define the objective tumor response rates (ORR), disease control rate (DCR), and locoregional control rates (LRCR) per Response Evaluation Criteria in Solid Tumors (RECIST). [ Time Frame: 16 Months ] [ Designated as safety issue: No ]
  
• Assess rate of locoregional recurrence (LRR) and distant disease recurrence at 2 years. [ Time Frame: 16 Months ] [ Designated as safety issue: No ]
  
• Investigate whether there is any change in the steady state exposure to ZD6474 due to RT or RT cisplatin or the method of administration. [ Time Frame: 16 Months ] [ Designated as safety issue: No ]
  
• Investigate whether there is any change in the exposure to cisplatin due to ZD6474 as assessed by total platinum. [ Time Frame: 16 Months ] [ Designated as safety issue: No ]
  

Inclusion Criteria:

1. Provision of informed consent.
2. Female or male aged 18 years and over
3. Histologically or cytologically confirmed (from the primary lesion and/or lymph nodes) squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx that has not been previously treated or resected.
4. Stage III to IV disease, with no proven hematogenous metastatic disease.
5. WHO performance status of 0-1
6. One or more measurable lesion at least 10 mm in the longest diameter by spiral CT scan or 20 mm with conventional techniques (according to RECIST guidelines)
7. Patients with history of non-melanoma skin cancer, or previous malignancies treated at 3 years prior to the current tumor from which the patient has remained continually disease-free and patients with in situ carcinoma of the cervix and adequately treated basal cell or squamous cell carcinoma of the skin are eligible
8. Life expectancy of >/= 12 weeks
9. Negative pregnancy test for women of childbearing potential

Exclusion Criteria:

1. Presence of simultaneous primary tumors
2. Women who are currently breast-feeding
3. Men or women unwilling to use an acceptable method of contraception while on study
4. Major surgery within 4 weeks, or incompletely healed surgical incision
5. Any concomitant medications that may affect QTc or induce CYP3A4 function and cannot be discontinued
6. Any previous anti-cancer therapy given for treatment of current diagnosis
7. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >1.5 x ULRR or alkaline phosphatase > 2.5 x ULRR
8. Serum bilirubin > ULRR
9. Serum creatinine > 1.5 x ULRR or creatinine clearance </= 50 mL/minute (calculated by Cockcroft-Gault formula)
10. Significant cardiac event (eg. myocardial infarction, super vena cava (SVC) syndrome), within 3 months before entry, or presence of cardiac disease that in the opinion of the Investigator increases the risk of ventricular arrhythmia
11. 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 permitted
12. Congenital long QT syndrome or a 1st degree relative with an unexplained sudden death under 40 years of age (except for Sudden Infant Death Syndrome)
13. QT prolongation with other medications that required discontinuation of that medication
14. Presence of left bundle branch block (LBBB).
15. QTc with Bazett's correction unmeasurable or >/= 480 msec on screening ECG (Note: If a patient has QTc interval >/= 480 msec on the screening ECG, two additional ECGs should be done [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)
16. Potassium 3.5 - 5.0 mEq/L; serum calcium (ionized or adjusted for albumin), or magnesium out of normal range despite supplementation
17. Hypertension not controlled by medical therapy (systolic blood pressure greater than 140 millimeter of mercury mmHg or diastolic blood pressure greater than 90mm Hg)
18. 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
19. Participation in an investigational study, or receipt of an investigational drug, within the past 30 days and during study.
20. Involvement in the planning and conduct of the study (applies to both AstraZeneca staff or staff at the investigational site)
21. Previous enrollment in the present study
22. Exclusion Criteria (applicable to Treatment Regimen 2 only) Any of the following is regarded as a criterion for exclusion from the study for patients who are assigned to receive cisplatin chemotherapy
23. Pre-existing neuropathy CTCAE grade 2 or worse
24. Known severe hypersensitivity to cisplatin or any of the excipients of the product
25. Evidence of pre-existing moderate to severe decline of hearing capacity
26. Neutrophils < 1.5 x 10^9/L or platelets < 100 x 10^9/L
27. Creatinine clearance </= 60 mL/minute (calculated by Cockcroft-Gault formula)