LUX-Head & Neck 2;A randomised, double-blind, placebo-controlled, phase III study to evaluate the efficacy and safety of afatinib (BIBW 2992) as adjuvant therapy after chemoradiotherapy in primary unresected patients with stage III, IVa, or IVb loco-regionally advanced head and neck squamous cell carcinoma

Head and neck cancers constitutes a group of biologically similar cancers
originating in the upper aerodigestive tract. Most head and neck cancers (>90%)
are squamous cell carcinomas (SCC). Head and neck squamous cell carcinoma
(HNSCC) is the 6th most common type of cancer with an incidence of
approximately 650,000 new cases worldwide each year, and its incidence is
rising rapidly in developing countries. Over expression of the epidermal growth
factor receptor (EGFR) is seen in the overwhelming majority of HNSCC. The EGFR
is a member of the human epidermal receptor (HER)/Erb-B family of receptor
tyrosine kinases that are responsible for signal transduction (R10-5898). EGFR
activation plays an important role in malignant cell proliferation,
angiogenesis, metastasis, and inhibition of apoptosis. Both EGFR over
expression and EGFR gene amplification are prognostic factors for shorter
progression free survival (PFS) and overall survival (OS).

About 50% of patients with HNSCC are diagnosed with loco-regionally advanced
(LA) disease (stages III-IVb) and have a 5-year survival rate varying from 10
to 75% depending on stage, site of primary tumour, HPV association, and other
known risk factors. Patients, who present with LA disease, stage III-IVb, are
treated with a combination of chemotherapy, surgery, or radiotherapy (RT).

After completion of CRT, the standard of care is no treatment. However, more
than 50% of patients with LA HNSCC will relapse. There is thus a pressing need
for the study of novel approaches and agents for this group of patients.

EGFR has been implicated in supporting oncogenesis and progression of human
solid tumours and is a promising target for anti-cancer therapy. Afatinib is a
second generation irreversible EGFR inhibitor. Possibly afatinib is a promising
agent for the maintenance of remission in patients with HNSCC following CRT.

The objective is to investigate the efficacy and safety of afatinib over
placebo when given as adjuvant therapy for patients with no evidence of disease
after CRT in primary unresected patients with LA SCC stage III or IVa/b of the
oral cavity, oropharynx, or hypopharynx, or larynx stage IVa/b. The main
objective of the trial is to test the superiority of afatinib as adjuvant
therapy vs. placebo in terms of disease free survival (DFS) for this trial
patient population.

After completion of CRT, the patients will have a Magnetic Resonance Imaging
(MRI) or
Computed Tomography (CT) scan and patients must have no evidence of disease
(NED) before randomisation.

Eligible patients will be randomised (2:1) to receive either afatinib or
placebo based on
stratification factors: Prior use of EGFR-targeted antibody therapy and nodal
status.

Patients will receive continuous daily treatment with oral afatinib or placebo
for one and a halve year or
until tumour recurrence, unacceptable AEs, or other reason necessitating
treatment withdrawal. The study medication will be dispensed every 4 weeks. The
starting dose of afatinib will be 40 mg once daily. In the event of no or
minimal drug-related AEs after four weeks of treatment or later, the dose
should be increased to 50 mg. As detailed in Section 4.1.4, dose reduction will
occur in the event of certain drug-related AEs.

During the treatment period, patients will visit the investigational site in
weeks one, two, and four, and then every four weeks for assessment of safety
parameters and AEs as outlined in the Flow Chart. Tumour recurrence will be
assessed regularly by MRI/CT scan until tumour recurrence or lost to follow-up.
Health related quality of life (HRQOL) will be assessed until tumour
recurrence. The end of treatment (EOT) information is obtained when the study
medication is discontinued. After the EOT visit, patients will continue in the
follow-up period. During the follow up period, data on vital status (survival),
ECOG performance status drug-related, HRQOL, AEs, and concomitant anti-cancer
therapy will be collected.

Patients come regularly for visits. In case a scan needs to be made the time
necessary is longer. Average estimation is 1-3 hours per visit.

Afatinib is not yet registered. Therefore unexpected side effects can occur.
Also, known side effects can occur. The scans will involve radiation. From
blooddrawing side effects can occur.