EGF105884 : A Randomized, Double-Blind, Placebo Controlled, Multicentre, Phase II Study of Oral Lapatinib in Combination With Concurrent Radiotherapy and Cisplatin Versus Radiotherapy and Cisplatin Alone, in Subjects With Stage III, IVA, B Squamous Cell Carcinoma of the Head and Neck (SCCHN)

A subject will be eligible for inclusion in this study only if all of the following criteria apply: 1)Willing and able to sign a written informed consent; 2)Histologically confirmed diagnosis of SCCHN of one or more of the following sites: oral cavity, oropharynx, hypopharynx and larynx; Multiple primary tumours will: •Have to be histologically proven; •Have to be anatomically distant and surrounded by normal tissue; 3) Subjects with stage III and IVA/IVB disease, who are to receive cisplatin chemotherapy and radiation therapy as primary treatment (total dose 65 Gy (IMRT) or 70 Gy (2D or 3D RT)); •Subjects T1N1 or T2N1 disease are excluded.

•Subjects with distant metastases, ie Stage IVC, are excluded.

4)Willing and able to have a tumour biopsy taken at screening; For patients who have had prior tumour biopsy, an adequate archived specimen must be available.

5)Male or female 18 years of age and above; Criteria for female subjects or female partners of male subjects: Non-child-bearing potential (i.e., women with functioning ovaries who have a current documented tubal ligation or hysterectomy, or women who are post- menopausal); Child-bearing potential (i.e. women with functioning ovaries and no documented impairment of oviductal or uterine function that would cause sterility.) This category includes women with oligomenorrhoea (severe), women who are perimenopausal, and young women who have begun to menstruate.

These subjects must have a negative serum pregnancy test at screening and agree to one of the following: A)Complete abstinence from intercourse from 2 weeks prior to administration of the first dose of study medication until 28 days after the final dose of study medication; or B)Consistent and correct use of one of the acceptable methods of birth control: 6)ECOG performance status 0, 1 or 2; 7)Subjects must have adequate haematological, renal and hepatic function; (a)Calculated creatinine clearance more than or equal to 60 ml/min (b)Absolute neutrophil count more than or equal to 1,500/µl, platelets more than or equal to 100,000/µl.

(c)Haemoglobin more than or equal to 9g/dL (5mmol/L).

(d)Aspartate (AST) and alanine transaminase (ALT) less than 3 times the upper limit of the normal range (ULN).

8)Left ventricular ejection fraction (LVEF) within the institutional normal ranges as measured by echocardiogram (ECHO) or Multigated Acquisition (MUGA) scan; 9)Able to swallow tablets whole or swallow a suspension of tablets dissolved in water at study inclusion; The use and timing of feeding tube is optional.

If necessary, the suspension may be administered via percutaneous endoscopic gastrostomy (PEG), percutaneous jejunostomy tube (J- Tube), or a nasogastric tube (NG or Dobhoff type tube).

10)Life expectancy of at least 6 months in the best judgment of the investigator.

A subject will not be eligible for inclusion in this study if any of the following criteria apply: 1) Nasopharyngeal, paranasal sinuses or nasal cavity tumours; 2) Any prior or current treatment for invasive head and neck cancer of any kind.

This will include but is not limited to: prior tyrosine kinase inhibitors, prior neoadjuvant therapy, prior surgical resection, or use of any investigational agent; 3) Concurrent use of CYP3A4 inducers or inhibitors.

A standard 3 to 5-day course of dexamethasone for the prevention of cisplatin-induced nausea and vomiting is permitted; 4) Serious cardiac illness or medical conditions including but not confined to: •History of documented congestive heart failure (CHF) or systolic dysfunction (LVEF less than Institutional LLN); •High-risk uncontrolled arrhythmias (ventricular tachycardia, high-grade AV-block, supraventricular arrhythmias which are not adequately rate-controlled); •Angina pectoris requiring antianginal medication; •Clinically significant valvular heart disease; •Evidence of transmural infarction on ECG; 5) History of another malignancy within the last 5 years, with the exception of completely resected basal or squamous cell skin cancer, or successfully treated in-situ carcinoma.

History of non-invasive lesion or in-situ carcinoma that was successfully treated with surgery, photodynamics or laser, will be permitted; 6) Peripheral neuropathy greater than or equal to grade 2; 7) Pregnant or lactating females (female subjects of child-bearing potential will undertake pregnancy testing at screening and during study completion/withdrawal visits); 8) Other concurrent serious diseases that may interfere with planned treatment including malabsorption syndrome, disease significantly affecting GI function, that could affect absorption of lapatinib; 9) History of allergic reactions to appropriate antiemetics (e.g. 5-HT3 antagonists) to be administered with platinum chemotherapy; 10) The investigator considers the subject unfit for the study as a result of the medical interview, physical examinations, or screening investigations; 11) Current active hepatic or biliary disease (with exception of patients with Gilberts syndrome, asymptomatic gallstones, or stable chronic liver disease per investigator assessment).