sEphB4-HSA With RT+Chemo or Cetux in Patients With Intermediate to High Risk LAHNSCC
Condition: Squamous Cell Carcinoma of Head and Neck
MeSH terms: Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): sEphB4-HSA with chemotherapy; Cetuximab; Radiation Therapy
Intervention type(s): Drug; Drug; Radiation
Intervention description(s): sEphB4-HSA is a fusion protein combining the soluble extracellular EphB4 domain with albumin that targets the ephrin B2 receptor, which is thought to mediate resistance to EGFR-targeted therapy, and acts as a radiosensitizer by enhancing DNA damage and promoting apoptosis. Concurrent chemotherapy drug (either cisplatin or carboplatin): Per treating physician discretion, and treatment plan is based per NCCN guidelines. These can be administered in tri-weekly or weekly doses during the radiation period. The participant will receive the first infusion on Day 15 (+/- 3 days).; Loading dose 400 mg/m2 on D9 Concurrent dose 250mg/m2 weekly D15± 3 day window; 6930 cGy IMRT starting D15-D18
Intervention MeSH terms: Cetuximab
Intervention model: Single Group Assignment
Intervention model description: This study will be enrolled using a 3+3 model. All patients will receive a fixed loading dose of 10 mg/kg to be followed by the assigned dose level during the concurrent phase. The 3+3 design model applies only to the concurrent phase. An expansion cohort of 6 patients will be added for testing biological endpoints.
Masking: None (Open Label)
Primary purpose: Treatment