Dual Inhibition of EGFR With Afatinib and Cetuximab in the Treatment of Advanced Squamous Cell Cancers of the Head and Neck

Patients with recurrent/metastatic squamous cell carcinoma of the head and neck, who are
previously treated with a platinum based regimen or with an immune checkpoint inhibitor will
be eligible for participation on the study. After a baseline evaluation and biopsy, they will
be treated with weekly IV cetuximab and daily oral afatinib. Biopsy will be repeated where
feasible after 4 weeks on therapy and again at disease progression or end of treatment.
Treatment will continue until disease progression or development of grade 3 or higher drug
related toxicities that fail to resolve to Grade 1 despite appropriate supportive care.

Inclusion Criteria:

- Histologically confirmed squamous cell carcinoma of the head and neck that is
metastatic, recurrent or locally advanced and not treatable with curative intent.

- Previous treatment with a platinum-based regimen or immune checkpoint inhibitor or
both.2-week washout period prior to treatment start will be required.

- Patients who have experienced progression of disease within 6 months following
completion of a platinum-based chemoradiation in the definitive or adjuvant setting
will be permitted.

- Prior cetuximab permitted if it was given as part of multi-modality therapy for
initial treatment of locally advanced disease.

- Measurable disease based on RECIST v 1.1. Baseline measurements and evaluations must
be obtained within 4 weeks of enrollment. Disease in previously irradiated sites is
considered measurable if there has been unequivocal disease progression or
biopsy-proven residual carcinoma following radiation therapy.

- ECOG performance status ≤2

- Adequate organ function, defined as all of the following:

- Hemoglobin ≥ 8 g/dl.

- Absolute neutrophil count (ANC) ≥1500 / mm3. (ANC >1000/mm3 may be considered in
special circumstances such as benign cyclical neutropenia as judged by the
investigator and in discussion with the sponsor).

- Platelet count ≥75,000 / mm3.

- Estimated creatinine clearance > 45ml / min.

- Total Bilirubin ≤ 1.5 times upper limit of (institutional/central) normal (Patients
with Gilbert's syndrome total bilirubin must be ≤4 times institutional upper limit of
normal).

- Aspartate amino transferase (AST) or alanine amino transferase (ALT) ≤ three times the
upper limit of (institutional/central) normal (ULN) (if related to liver metastases ≤
five times ULN).

- Ability to understand and the willingness to sign a written informed consent that is
consistent with ICH-GCP guidelines.

- Negative urine or serum pregnancy test for women of childbearing potential

Exclusion Criteria:

- Prior erlotinib, gefitinib or lapatinib therapy or prior exposure to any
investigational EGFR or panErbB reversible or irreversible inhibitor or any prior
panitumumab or investigational EGFR-directed monoclonal antibody.

- Radiotherapy within 2 weeks prior to enrollment. Palliative radiation to target organs
may be allowed up to 2 weeks prior to enrollment, as long as there are other target
lesions that can be monitored for response to study treatment.

- Known hypersensitivity to afatinib or its excipients

- Women of child-bearing potential (WOCBP) and men who are able to father a child,
unwilling to be abstinent or use highly effective methods of birth control prior to
study entry, for the duration of study participation and for at least 4 weeks after
treatment has ended.

- Women who are pregnant, nursing, or who plan to become pregnant while in the trial.

- Any history of or concomitant condition that, in the opinion of the Investigator,
would compromise the patient's ability to comply with the study or interfere with the
evaluation of the efficacy and safety of the test drug.

- Concomitant malignancies at other sites that are being actively treated with systemic
therapy

- Requiring treatment with any of the prohibited concomitant medications that cannot be
stopped for the duration of trial participation.

- Clinically significant interstitial lung disease.

- Known history of untreated viral hepatitis or HIV.

- Patients with parenchymal brain metastases are not eligible, unless they have
completed local therapy

- Leptomeningeal carcinomatosis