A Study of the Combination of Cetuximab and Methotrexate in Recurrent or Metastatic Cancer of the Head and Neck

Inclusion Criteria:

* Cytologically/histologically-proven SCCHN
* Recurrent or metastatic SCCHN
* At least one measurable lesion as determined by RECIST v1.1 is required. Lesions in previously irradiated areas should not be considered measurable unless there is clear evidence of progression in such lesions since the radiotherapy.
* No prior systemic treatment for recurrent or metastatic disease
* Primary site: (1) oral cavity, (2) oropharynx, (3) hypopharynx, (4) larynx, or (5) unknown primary squamous cell carcinoma in the head and neck region presenting originally with lymph node metastases (N1-N3).
* Time between prior treatment and inclusion in the study (\> 3 months). Palliative RT in case of painful bone metastases is allowed in phase II and after 4 weeks in phase Ib
* Ineligible (due to medical co-morbidities) or intolerant to platinum-based therapy per medical history or refusing cisplatin-based chemotherapy by the patient
* WHO performance status 0-2.
* Age \>18 years
* Adequate organ function and laboratory parameters as defined by:

  * Absolute neutrophil count (ANC) ≥ 1.5 x 109 /L
  * Hemoglobin (Hb) ≥ 9 g/dl 5.6 mmol/l (which may be achieved by transfusion)
  * Platelets (PLT) ≥ 100 x 109/L
  * AST and ALT ≤ 2.5 x ULN (upper limit of normal)
  * Serum bilirubin ≤ 1.5 x ULN
  * Calculated creatinine clearance or MDRD \> 60ml/min
* Recovered from all adverse events (AEs) of previous anti-cancer therapies. AEs related to prior radiotherapy are allowed.
* Written informed consent

Exclusion Criteria:

* Serious active infections
* Patients (M/F) with reproductive potential not implementing adequate contraceptives measures
* Prior treatment with EGFR inhibitors or MTX
* Concomitant (or within 4 weeks before randomization) administration of any other experimental drug under investigation
* Concurrent treatment with any other anti-cancer therapy.
* Central nervous system involvement
* Lung fibrosis
* Pleural effusion or ascites or other third space effusions
* History of another malignancy within 2 years prior to starting study treatment, except cured basal cell carcinoma of the skin, excised carcinoma in situ of the cervix, or other head and neck cancer.
* Pregnancy or lactation
* Any other condition that would, in the Investigator's judgment, preclude patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g. infection/inflammation, intestinal obstruction, social/psychological complications.