Objectives:~Primary:~• To determine the change in pY-STAT3 H-score in tumor tissue in post-treatment resection specimens versus pre-treatment biopsy specimens.~Secondary:~To determine the safety and tolerability of pre-surgery TTI-101 in patients with Stage II-IV HPV-negative HNSCC who are planned for definitive local surgery with or without radiation.~To determine the individual pre/post treatment changes in pY-STAT3 H-scores in epithelial and stromal tumor cells.~To determine the pathologic response rate to pre-surgery TTI-101.~To determine the overall response rate (ORR) to pre-surgery TTI-101 using RECIST v1.1 criteria.~To determine the disease free, disease specific and overall survival (DFS, DSS, OS) after pre-surgery TTI-101 treatment and SOC surgery.~Exploratory:~To evaluate the effects of pre-surgery TTI-101 on circulating and tumor-infiltrating immunocytes, and on the intratumoral expression of PD-1 along with other immune related molecules.~To compare outcome measures (response rate and survival) in control versus TTI-101-treated patients.~To determine the association of immunologic changes with treatment response.~To determine the association of pharmacokinetic (PK) measures with treatment response.
To learn if TTI-101 can reduce the growth of HPV-negative squamous cell carcinomas of the head and neck when given before standard of care surgery.