This is a Phase I dose-escalation study of sEphB4-HSA in combination with chemotherapy, cetuximab and radiotherapy (RT). The purpose is to estimate the maximum tolerated dose (MTD) that can be administered concurrently with Cetuximab and radiation in patients with locally advanced, Stage III or IV A-B squamous cell carcinomas of the head or neck with a history of at least ten pack-years of smoking.

RT combined with the EGFR-targeted agent cetuximab represents a valuable alternative to platinum-based CRT and is FDA-approved for initial treatment of LAHNSCC, but outcomes remain unfavorable. Recently, EphB4 has emerged as another rational target. While minimally expressed in normal tissue, it is highly expressed in LAHNSCC and has been implicated in resistance to both EGFR-targeted therapy and to RT. Suppression of EphB4 in the preclinical setting has enhanced tumor death and enhanced radiosensitivity. The novel agent sEphB4-HSA is a fusion protein that binds the ligand for EphB4 and leads to inhibition of tumor proliferation and angiogenesis. It was well-tolerated as monotherapy in a phase I trial but has yet to be explored in combination with radiotherapy or EGFR-directed treatments. A combined modality approach adding sEphB4-HSA to standard-of-care RT plus cetuximab represents a rational, targeted approach for investigation in patients with high risk LAHNSS p16-negative or any patient with heavy smoking histories. Moreover, a short window period of sEphB4-HSA monotherapy between baseline biopsy and repeat biopsy prior to initiation of cetuximab with RT will both minimize potential treatment delay and allow for the identification of potential biomarkers of response to sEphB4-HSA. Finally, a third optional biopsy, to be done if feasible after initiation of cetuximab-radiation, will allow us to identify radiosensitization markers and potential markers for treatment de-escalation. MTD.

Inclusion Criteria:

1. 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 include 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
   • Stage IVB Laryngeal Cancer AJCC v8
   • Stage IVB Lip and Oral Cavity Cancer AJCC v8
   • Stage IVB Oropharyngeal (p16-Negative) Carcinoma AJCC v8 or Stage IVB Oropharyngeal (p16-positive) Carcinoma ≥ 10 pack-years history of smoking

7. Patient is not a candidate for definitive surgical resection

8. Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:

   • Hemoglobin ≥ 9.0 g/dL
   • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
   • White blood cells (WBC) > 3 x 109/L
   • Platelet count ≥ 100 x 109/L
   • Total bilirubin < 1.5 x institutional upper limit of normal
   • AST and ALT < 2.5 x institutional upper limit of normal

9. For women of childbearing potential, a negative serum pregnancy test within 28 day screening to confirm eligibility. (Note: Pregnancy test will be repeated within 48 hours prior to the first dose of sEphB4-HAS) .

10. ECOG performance status ≤ 2.

11. Be deemed ineligible by a medical oncologist to receive concurrent platinum-based chemotherapy with radiotherapy or patient refusal of platinum-based chemotherapy.

12. Be deemed eligible by a medical oncologist to receive cetuximab.

13. Agreement to exercise appropriate use of contraception, as indicated.

    • For females of reproductive potential: use of highly effective contraception from time of screening through 12 weeks following the final dose of study treatment (see section 8.5).
    • For males of reproductive potential: use of condoms from time of screening through 12 weeks following the final dose of study treatment.

14. Pretreatment imaging to include the following within 28 days of treatment initiation:

    CT Neck (with contrast unless contraindicated) with CT chest OR PET-CT. MRI of the neck with contrast (unless contraindicated) can replace CT neck.

    N.B.: a CT Neck performed for radiation planning and read by a radiologist may serve as appropriate staging and planning tools.

15. General history and physical examination by a radiation or medical oncologist within 28 days prior to enrollment.

16. Examination by an ENT or head and neck surgeon, including laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) within 56 days prior to enrollment.

17. Dental evaluation and, if applicable, prophylaxis per NCCN guidelines performed within 84 days of treatment initiation.

18. Eligible for definitive therapy.

Exclusion Criteria:

1. 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.