This is a randomised, double-blind, placebo-controlled, multicentre, global Phase III trial comparing the efficacy of adjuvant oral lapatinib versus placebo in high-risk subjects with head and neck cancer following surgery. Lapatinib or placebo will be administered post-operatively in combination with chemoradiotherapy followed by maintenance with lapatinib or placebo for 1 year. The primary goal is to determine if lapatinib is effective at reducing the recurrence of the disease in these high-risk patients.

A Randomised, Double-Blind, Placebo-Controlled, Multi-centre, Phase III Study of Post-Operative Adjuvant Lapatinib or Placebo and Concurrent Chemoradiotherapy Followed by Maintenance Lapatinib or Placebo Monotherapy in High-Risk Subjects with Resected Squamous Cell Carcinoma of the Head and Neck (SCCHN)

• Drug: Lapatinib
  Dual ErbB1/2 inhibitor
  Other Name: Lapatinib
• Other: Placebo
  Placebo
• Radiation: Chemoradiation
  Radiation plus platinum based chemotherapy

• Placebo+Chemoradiation: Placebo Comparator
  Interventions:

  • Other: Placebo
  • Radiation: Chemoradiation
• Lapatinib+Chemoradiation: Experimental
  Interventions:

  • Drug: Lapatinib
  • Radiation: Chemoradiation

Inclusion Criteria:

• Willing and able to sign a written informed consent.
• Histologically confirmed diagnosis of SCCHN of one of the following sites: oral cavity, oropharynx, hypopharynx and larynx.
• Pathological Stage II, III or IVa (according to AJCC cancer staging criteria [Green, 2002]) with no evidence of gross residual disease, and at least one of the following high risk factors by pathology:
• Extracapsular extension of nodal disease
• Positive resection margin (5 mm or less)
• Primary surgery with a curative intent completed within 4-6 weeks (and no later than 7 weeks) prior to randomization. The extent of surgical resection will follow accepted criteria for adequate excision [Helliwell, 2005]. Surgical margins are divided into 'mucosal' and 'deep', and for each category the resection margin (R) is classified as:
• Clear : (R0) > 5mm.
• Close: (R1) 1 - 5mm.
• Involved: (R2) <1mm
• Complete recovery from the surgical procedure allowing for appropriate radiotherapy. Radiation therapy is required to start as soon as adequate healing has occurred. This is normally around 4-6 weeks but no later than 9 weeks after surgery.
• Adequate tumour specimen from archived or resected tissue must be available for IHC evaluation of ErbB1 expression levels in a central laboratory and subsequent biomarker analysis.
• Male or female, between 18 and 70 years of age [Bourhis, 2006].

Criteria for female subjects or female partners of male subjects:

Non-child-bearing potential (i.e., a woman with functioning ovaries who has a current documented tubal ligation or hysterectomy or a woman who is menopausal); or

Child-bearing potential (i.e. a woman with functioning ovaries and no documented impairment of oviductal or uterine function that would cause sterility. This category includes women with oligomenorrhoea (even severe), women who are perimenopausal and young women who have begun to menstruate), who have a negative serum pregnancy test at screening, and agree to one of the following:

Complete abstinence from intercourse from the time of the screening pregnancy test until 28 days after the final dose of test article; or

Consistent and correct use of one of the following acceptable methods of birth control:

Male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female subject; or Oral contraceptives (either combined or progestogen only), or Injectable progestogen-only contraceptives or Implants of levonorgestrel, or Any intrauterine device with a documented failure rate of less than 1% per year; or Barrier methods (e.g. condoms, diaphragms, caps) only if used in combination with one of the above acceptable methods.

• ECOG performance status 0, 1 or 2
• Adequate haematology, renal and hepatic function Absolute neutrophil count ≥ 1,500/μL, platelets ≥ 100,000/μL Haemoglobin ≥ 9 gm/dL (5mmol/L) Calculated creatinine clearance ≥60 ml/min as determined by the modified method of Cockcroft and Gault.

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

Total bilirubin ≤ 2.0 mg/dL

• Left ventricular ejection fraction (LVEF) above the lower limits of the institutional normal range as measured by ECHO (if ECHO cannot be performed or if the Investigator feels it is not conclusive to evaluate LVEF, then a MUGA scan should be performed).
• Able to swallow and retain tablets whole or swallow a suspension of tablets dissolved in water at study inclusion.

The use 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).

• Life expectancy of at least 6 months in the best judgement of the investigator
• Current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, or stable chronic liver disease per investigator assessment).

Exclusion Criteria:

• Nasopharyngeal, paranasal sinuses or nasal cavity tumours
• Head and neck cancer with histology other than squamous cell carcinoma.
• Evidence of distant metastases or gross post-operative residual disease.
• Evidence of second primary tumour.
• Any prior or current anticancer treatment of any kind - except the primary surgical resection. This will include but is not limited to: prior tyrosine kinase inhibitors, prior neoadjuvant therapy, prior radiotherapy or use of any investigational agent.
• Concurrent treatment with an investigational agent or participation in another clinical trial.
• Concurrent use of CYP3A4 inducers or inhibitors while on lapatinib/placebo. A standard 3 to 5 day course of dexamethasone for the prevention of cisplatin induced nausea and vomiting is permitted. In addition glucocorticoid daily doses (oral) 1.5mg dexamethasone (or equivalent) are allowed.
• Subjects with known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure;
• Pregnant or lactating females
• 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;
• Peripheral neuropathy ≥ grade 2
• Mal-absorption syndrome, disease significantly affecting GI function, or major resection of the stomach or bowel, that could affect absorption of lapatinib.
• History of allergic reactions to relevant diuretics or anti-emetics (e.g 5-HT3 antagonists) to be administered with cisplatin chemotherapy
• History of allergic reactions attributed to compounds of similar chemical composition (quinazolines) to lapatinib
• The investigator considers the subject unfit for the study as a result of the medical interview, physical examinations, or screening investigations