Patient description: The patient is a 60 year old man complaining of frequent headaches, generalized bone pain and difficulty chewing that started 6 years ago and is worsening. Examination shows bilateral swellings around the molars. The swellings have increased since his last examination. Several extraoral lesions are detected in the head and face. The swellings are non-tender and attached to the underlying bone. Further evaluation shows increased uptake of radioactive substance as well as an increase in urinary pyridinoline. His serum alkaline phosphatase is 300 IU/L (the normal range is 44- 147 IU/L). His family history is only significant for hypertension in his mother and DM type 2 in his father. The diagnosis of Paget's Disease of Bone was confirmed and Bisphosphonate will be started as first-line therapy.

Clinical trial eligibility criteria: eligible ages (years): 18.0-100.0,  Squamous Cell Carcinoma of Head and Neck Provision to sign and date the consent form. 2. Stated willingness to comply with all study procedures and be available for the duration of the study. 3. Patients must be willing to consent for two mandatory biopsies to be collected at baseline and again one week after the loading dose of sEphB4-HSA. A third optional biopsy will be collected if feasible 5-10 days after initiation of radiation treatment. 4. Be a male or female aged 18-100. 5. Pathologically confirmed (from the primary lesion and/or regional lymph nodes) squamous cell carcinoma of the oropharynx, hypopharynx, oral cavity, unknown primary, or larynx. 6. High risk, locally advanced HNSCC which may any of the following by AJCC 8th Edition Stage III Hypopharyngeal Carcinoma AJCC v8 Stage III Laryngeal Cancer AJCC v8 Stage III Lip and Oral Cavity Cancer AJCC v8 Stage III Oropharyngeal (p16-Negative) Carcinoma AJCC v8 or Stage III Oropharyngeal (p16-positive) Carcinoma ≥ 10 pack-years history of smoking Stage IVA Hypopharyngeal Carcinoma AJCC v8 Stage IVA Laryngeal Cancer AJCC v8 Stage IVA Lip and Oral Cavity Cancer AJCC v8 Stage IVA Oropharyngeal (p16-Negative) Carcinoma AJCC v8 or Stage IVA Oropharyngeal (p16-positive) Carcinoma ≥ 10 pack-years history of smoking Stage IVB Hypopharyngeal Carcinoma AJCC v8  Pregnant, attempting to conceive, lactating, or declining to use appropriate contraception for duration of study. 2. Hypertension that is uncontrolled (requiring 3+ antihypertensive medications to control). 3. Hypertension at screening (SBP ≥140mmHg or DBP ≥90mmHg, corresponding to Stage 2 according to JNC 7). 4. Prior history of allergic or infusion reaction to cetuximab or sEphB4. 5. Febrile illness within 7 days prior to enrollment. 6. Concomitant use of EGFR-directed therapies (besides cetuximab given as part of this trial), including erlotinib, gefitinib. 7. Major surgery (excluding tumor biopsy) within 4 weeks prior to start of study treatment. 8. Prior unrelated malignancy requiring current active treatment within 3 years prior to enrollment with exceptions of cervical carcinoma in situ, basal cell carcinoma of skin, resected T1-T2N0M0 differentiated thyroid cancers, Ta bladder cancer, prostatic adenocarcinoma of low or intermediate risk (per NCCN criteria). 9. Treatment with another investigational drug or other intervention within 30 days of treatment start. 10. Resectable oral cavity primary site 11. p16-positive carcinoma of the oropharynx or unknown primary that are T0-3, N0-1 (AJCC 8th Edition) AND ≤ 10 pack-year smoking history 12. Stage IVC (M1) disease per AJCC 8th edition. 13. Prior receipt of systemic chemotherapy for the study cancer (including "induction" or "neoadjuvant" chemotherapy) within 60 days of diagnosis; prior chemotherapy for a different cancer diagnosis is allowed. 14. Any severe, active comorbidity, defined as follows Cardiovascular disease or cerebrovascular disease, for example cerebrovascular accidents or myocardial infarction ≤ 6 months prior to study enrollment, unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure (CHF), or serious cardiac arrhythmia uncontrolled by medication or with the potential to interfere with protocol treatment Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to enrollment History or evidence upon physical/neurological examination of central nervous system disease (e.g., seizures) unrelated to cancer unless adequately controlled by medication Acute bacterial or fungal infection requiring intravenous antibiotics within 7 days of enrollment Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days of registration Patients known to be HIV positive or have active viral hepatitis, defined as positive HCV quantitative titers and/or +Hep B sAg and +IgM anti-HepB. Confirmatory testing is not required for the study