Single-Arm Phase II Trial of Dual Inhibition of EGFR With Afatinib and Cetuximab With Correlative Studies in the Second-Line Treatment of Recurrent or Metastatic 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 or recurrent and not treatable with curative intent.
• Previous progression on or intolerance to one line of therapy - either platinum or immunotherapy (pembrolizumab or nivolumab). Prior chemotherapy in the induction, organ preservation or adjuvant setting permitted if it was completed more than 4 months prior to enrollment on the current study.
• Prior cetuximab permitted if it was given for no more than 9 doses in combination with radiation therapy or chemoradiation therapy for initial treatment of locally advanced disease and completed at least 4 months prior to study enrollment.
• Measurable disease based on RECIST v 1.1.
• ECOG performance status ≤2
• Adequate organ function, defined as all of the following:
• Hemoglobin ≥ 9 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).
• Recovered from any previous therapy related toxicity to ≤Grade 1 or baseline at study entry (except for stable sensory neuropathy ≤Grade 2 and alopecia).
• 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.
• Hormonal treatment within 2 weeks prior to start of study treatment (continued use of anti-androgens and/or gonadorelin analogues for treatment of prostate cancer permitted) Radiotherapy within 4 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.
• Major surgery within 4 weeks before starting study treatment or scheduled for surgery during the projected course of the study.
• Known hypersensitivity to afatinib or its excipients
• History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of ≥ 3, unstable angina or poorly controlled arrhythmia as determined by the investigator. Myocardial infarction within 6 months.
• 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 that result in a low failure rate of less than 1% per year when used consistently and correctly 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.
• Previous or concomitant malignancies at other sites, except effectively treated non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ or effectively treated malignancy that has been in remission for more than 3 years and is considered to be cured.
• Requiring treatment with any of the prohibited concomitant medications that cannot be stopped for the duration of trial participation.
• Known pre-existing interstitial lung disease.
• Any history or presence of poorly controlled gastrointestinal disorders that could affect the absorption of the study drug (e.g. Crohn's disease, ulcerative colitis, chronic diarrhea, malabsorption).
• Active hepatitis B infection (defined as presence of HepB sAg and/ or Hep B DNA), active hepatitis C infection (defined as presence of Hep C RNA) and/or known HIV carrier.
• Patients with brain or subdural metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids, anti-convulsants or have been on stable dose of corticosteroids for at least 4 weeks before starting study treatment. Any symptoms attributed to brain metastases must be stable for at least 4 weeks before starting study treatment.
• Leptomeningeal carcinomatosis, diagnosed on cytology or appropriate imaging.