A Study Testing Emactinib Sulfate With Chemotherapy and Immunotherapy Before Surgery for Advanced Head and Neck Cancer

Prior treatment

• Prior treatment with immunotherapy (anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 agents) or JAK inhibitors. History of severe allergic reactions to any component of monoclonal antibodies.
• Active autoimmune disease or condition requiring immunosuppressive therapy. Subjects requiring systemic corticosteroids or other immunosuppressive drugs prior to enrollment.

Other illness

• History of other active malignancies or active infections (including tuberculosis and hepatitis); uncontrolled infections (HIV, HBV, HCV).

Lab values

• Severe cardiac or pulmonary dysfunction, including severe cardiac insufficiency (e.g., NYHA Class III or higher) or severe pulmonary dysfunction (e.g., FEV1 \<50% predicted); history of thrombotic diseases, coagulation disorders (Prothrombin Time (PT) \>16 seconds, Activated Partial Thromboplastin Time (APTT) \>53 seconds, Thrombin Time (TT) \>21 seconds, Fibrinogen (FIB) \<1.5 g/L), bleeding tendency, or current thrombolytic/anticoagulant therapy.

Other

• Pregnant or lactating women. Subjects unwilling to use effective contraception during the study period.

• ECOG Performance Status of 0-1.
• Histologically and/or cytologically confirmed Stage III-IVA head and neck squamous cell carcinoma (oral cavity, oropharynx, hypopharynx, or larynx).
• Classified according to the Asia-Pacific multidisciplinary consensus (Y.Guo et al., Oral Oncol 2024):
  • Cohort A: Resectable\*\* (amenable to upfront surgery): T2N2-3M0, T3-4N0-2M0 (AJCC 8th edition).
  • Cohort B: Potentially Resectable:\*\* Cases with relative contraindications to surgery (e.g., cervical lesion directly invading skin, anterior 2/3 tongue tumor extending below the hyoid level, extension to the vallecula) or where surgery would cause significant disfigurement/functional loss, requiring discussion by an MDT (head \& neck surgery, radiology) to weigh risks vs. non-surgical options.
  • Cohort C: Unresectable: Tumor extensively invading skull base, extending to nasopharynx/deep nasopharyngeal wall, invading/encasing carotid artery, extending to mediastinal structures, prevertebral fascia, or cervical spine; T3-4 (N0-3) or any N2a-3 (T1-4) M0 (AJCC 8th edition).
• Biomarker: Peripheral blood flow cytometry analysis showing that PD-1+TIM-3+CD8+ exhausted T cells account for \>10% of CD8+ T cells.
• Adequate baseline organ function within 14 days prior to enrollment:
  • Hematological: White Blood Cell count (WBC) ≥4000/μL, Absolute Neutrophil Count (ANC) ≥2000/μL, Hemoglobin (HGB) ≥9 g/dL, Platelet count (PLT) ≥100,000/μL.
  • Renal: Serum creatinine \<1.5 times the Upper Limit of Normal (ULN) OR Creatinine Clearance (CrCl) \>60 mL/min (calculated by Cockcroft-Gault formula).
  • Hepatic: Total bilirubin ≤1.5x ULN (except subjects with Gilbert's syndrome, who may have total bilirubin \<3x ULN); Aspartate Aminotransferase (AST) / Alanine Aminotransferase (ALT) ≤3x ULN; Alkaline Phosphatase (ALP) ≤3x ULN; Albumin (ALB) ≥3 g/dL.
• Ability to understand and willingness to sign the Informed Consent Form. Subjects must be willing and able to comply with the protocol, including receiving treatments and scheduled visits/examinations, including follow-up.