A Randomised, Open-label, Phase III Study to Evaluate the Efficacy and Safety of Oral Afatinib (BIBW 2992) Versus Intravenous Methotrexate in Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma Who Have Progressed After Platinum-based Therapy
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 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
1. Progressive disease within three months after completion of curatively intended
treatment for locoregionally advanced or for metastatic head and neck squamous cell
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. Re-challenge with the first line regimen after a temporary
break is considered a second line regimen only in case of progression within the
4. Prior treatment with EGFR-targeted small molecules.
5. Treatment with any investigational drug or anti-cancer therapy less than four 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
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).
10. 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
11. Known lesion or signs of brain metastasis.
12. Known pre-existing interstitial lung disease (ILD).
13. 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.
14. Cardiac left ventricular dysfunction with resting ejection fraction
normal (LLN) of investigational site (if no LLN is defined at the site the lower
limit is 50%).
15. 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.
16. 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.
17. Other significant disease that in the investigator's opinion would exclude the
subject from the trial.
18. 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
19. 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
20. Pregnancy or breast feeding.
21. Known or suspected hypersensitivity to any of the study medications or their
22. Any past or present history of areca/betel-nut chewing or its derivatives for a
cumulative duration of more than 3 months
23. Patients unable to comply with the protocol, in the opinion of the investigator.