LUX-Head&Neck 3: Afatinib (BIBW2992) Versus Methotrexate for the Treatment of Recurrent and/or Metastatic Head and Neck Squamous Cell Cancer After Platinum Based Chemotherapy

Inclusion criteria:

1. Histologically or cytologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx, which has recurred/metastasised and is not amenable for salvage surgery or radiotherapy.
2. Documented progressive disease based on investigator assessment according to RECIST, following receipt of a cisplatin and/or carboplatin and/or Nedaplatin based regimen administered for recurrent and/or metastatic disease independent of whether patient progressed during or after platinum based therapy.
3. Measurable disease according to RECIST (version 1.1).
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 at Visit 2.
5. Male and female patients age is 18 years or older
6. Signed and dated written informed consent that is in compliance with ICH-GCP and local law.

Exclusion criteria:

1. Progressive disease within three months after completion of curatively intended treatment for locoregionally advanced or for metastatic head and neck squamous cell cancer (HNSCC).
2. Primary tumour site nasopharynx (of any histology), sinuses, and/or salivary glands.
3. Any other than one previous platinum based systemic regimen given for recurrent and/or metastatic disease, with the exception of immunotherapy used either before or after platinum based treatment. Re-challenge with the platinum based regimen after a temporary break is considered an additional line regimen only in case of progression within the break.
4. Prior treatment with EGFR-targeted small molecules.
5. Treatment with any investigational drug less than four weeks or anti-cancer therapy less than three weeks prior to randomization (except palliative radiotherapy to bones to alleviate pain).
6. Unresolved chronic toxicity, other than hearing loss, tinnitus or dry mouth, CTCAE grade >2 from previous anti-cancer therapy or unresolved skin toxicities CTCAE grade >1 and/or diarrhoea CTCAE grade >1 caused by prior treatment with EGFR targeted antibodies.
7. Previous tumour bleeding CTCAE grade =3.
8. Requirement for treatment with any of the prohibited concomitant medications.
9. Major surgical or planned procedure less than four weeks prior to randomization (isolated biopsies are not considered as major surgical procedures).

Any other malignancy unless free of disease for at least five years except for:

1. Other HNSCC of a location as described in inclusion criterion number 1
2. Appropriately treated superficial basal cell skin cancer
3. Surgically cured cervical cancer in situ
4. For Korea: endoscopically cured superficial esophageal and/or gastric cancer is allowed
5. Known lesion or signs of brain metastasis.
6. Known pre-existing interstitial lung disease (ILD).
7. Clinically relevant cardiovascular abnormalities, as judged by the investigator, such as, but not limited to, uncontrolled hypertension, congestive heart failure NYHA classification =III, unstable angina, myocardial infarction within six months prior to randomization, or poorly controlled arrhythmia.
8. Significant or recent acute gastrointestinal disorders with diarrhoea as a major symptom in the opinion of the investigator, e.g. Crohn's disease, malabsorption or CTCAE grade >1 diarrhoea of any aetiology at randomization.
9. Known HIV, active hepatitis B, active hepatitis C, and/or other known severe infections, including but not limited to tuberculosis, as judged by the investigator.
10. Other significant disease that in the investigator's opinion would exclude the subject from the trial.

Screening laboratory values:

1. Absolute neutrophil count (ANC) <1.5x10^9/l
2. Platelet count <75x10^9/l
3. Total bilirubin >1.5 times the upper limit of normal (ULN)
4. Aspartate amino transferase (AST) or alanine amino transferase (ALT) >3 times the ULN (if related to liver metastases >5 times the ULN)
5. Calculated creatinine clearance <50 ml/min (as evidenced by using the Cockcroft-Gault formula).
6. Women of child-bearing potential and men who are able to father a child, unwilling to be abstinent or to use adequate contraception during the trial and for at least six months after end of treatment. Adequate methods of contraception and definition of child-bearing potential.
7. Pregnancy or breast feeding.
8. Known or suspected hypersensitivity to any of the study medications or their excipients.
9. Patients unable to comply with the protocol, in the opinion of the investigator.