sEphB4-HSA With RT+Chemo or Cetux in Patients With Intermediate to High Risk LAHNSCC
sEphB4-HSA With RT+Chemo or Cetux in Patients With Intermediate to High Risk LAHNSCC
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.