Sintilimab Plus Hypofractionated Radiotherapy Followed by Chemoradiotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma

Sintilimab Combined With Hypofractionated Radiotherapy Followed by Chemoradiotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma: A Multicenter, Single-Arm, Phase II Clinical Study

Most patients with head and neck squamous cell carcinoma (HNSCC) are diagnosed with locally advanced disease. While cisplatin-based chemoradiotherapy remains the standard-of-care treatment for this patient population, it is still associated with a high rate of disease recurrence. Given the relatively high mutational burden of HNSCC, immunotherapy has emerged as a promising therapeutic strategy. The addition of PD-1 inhibitors to induction chemotherapy has been shown to improve antitumor responses without increasing treatment-related toxicity. In addition, radiotherapy can further potentiate systemic antitumor immune responses.

Sintilimab, a PD-1 monoclonal antibody, has demonstrated robust antitumor activity across multiple solid malignancies. Early clinical evidence indicates a synergistic antitumor effect when combined with hypofractionated radiotherapy. Nevertheless, clinical data regarding the combination of sintilimab with chemoradiotherapy in locally advanced HNSCC remain limited.

Accordingly, we designed a multicenter, single-arm phase II trial to evaluate the efficacy and safety of sintilimab in combination with definitive chemoradiotherapy for patients with locally advanced HNSCC.

Inclusion Criteria:

• 1. Provide written informed consent and understand and agree to comply with study requirements and the study visit schedule.

  2. Male or female subjects aged ≥18 and ≤75 years at the time of signing the informed consent form.

  3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1.

  4. Histologically or cytologically confirmed stage III IVB head and neck squamous cell carcinoma as assessed by the investigator.

  5. No prior systemic therapy for head and neck squamous cell carcinoma (including chemotherapy, EGFR monoclonal antibodies, anti PD 1 or anti PD L1 antibodies, anti CTLA 4 antibodies and other immune checkpoint inhibitors).

  6. At least one measurable target lesion per RECIST version 1.1 criteria. 7. Expected survival time ≥12 weeks. 8. Adequate bone marrow and organ function (no administration of any cellular/blood components, colony stimulating factors or cytokines within 14 days prior to laboratory testing):

  1. Hematology: Absolute neutrophil count (ANC) ≥1.5×10⁹/L or within normal range; Platelet count (PLT) ≥100×10⁹/L; Hemoglobin (HGB) ≥90 g/L.

  2. Hepatic function: Total bilirubin (TBIL) ≤1.5×ULN; For subjects with Gilbert's syndrome, TBIL ≤3×ULN; For subjects without liver metastasis, AST and ALT ≤2.5×ULN; For subjects with liver metastasis, AST and ALT ≤5×ULN; Albumin (ALB) ≥28 g/L.

  3. Renal function: Serum creatinine (Cr) ≤1.5×ULN, or creatinine clearance rate (CCR) ≥60 mL/min (calculated by Cockcroft Gault formula or measured via 24 hour urine collection); Urinalysis showing urinary protein <2+. Subjects with baseline urinary protein ≥2+ must undergo 24 hour urine collection with 24 hour urinary protein <1 g (if both assays are performed, the 24 hour urine result will be used for eligibility determination).

  4. Coagulation function: International normalized ratio (INR) ≤1.5; Activated partial thromboplastin time (APTT) ≤1.5×ULN.

     9. Male and female subjects of non childbearing potential, or those who agree to use at least one highly effective contraceptive method during the study (starting 14 days prior to screening or first study drug administration, whichever occurs earlier, continuing for 180 days after the last dose of study drug).

     Exclusion Criteria:

• 1. History of hypersensitivity to PD 1 agents or platinum containing components.

  2. History or concurrent presence of other malignancies (except for malignancies cured with no relapse for more than 5 years, including basal cell carcinoma, carcinoma in situ of the cervix, and papillary thyroid carcinoma).

  3. Uncontrolled clinical cardiac symptoms or diseases, including:

  a. New York Heart Association (NYHA) class II or higher heart failure. b. Unstable angina pectoris. c. Myocardial infarction within the past 12 months. d. Clinically significant supraventricular or ventricular arrhythmias requiring clinical intervention.

  4. Prior treatment history, including:

  1. Previous treatment with anti PD 1, anti PD L1, or anti CTLA 4 antibodies.

  2. Use of any investigational drug within 4 weeks prior to the first dose of study drug.

  3. Concurrent participation in another clinical trial, unless it is an observational (non interventional) clinical study.

  4. Patients requiring systemic corticosteroid therapy (≥10 mg prednisone equivalent dose per day) or other immunosuppressive agents within 2 weeks before the first dose of study drug, except for local inflammation, hypersensitivity, and prophylaxis for nausea and vomiting. Other special situations should be discussed with the investigator. In the absence of active autoimmune disease, inhaled or topical corticosteroids, or adrenal hormone replacement doses equivalent to >10 mg/day prednisone are permitted.

  5. Patients who have received anti tumor vaccines or live vaccines within 4 weeks prior to the first dose of study drug.

  6. Patients who have undergone major surgery or sustained severe trauma within 4 weeks prior to the first dose of study drug.

     5. Not recovered to ≤ Grade 1 from previous anti tumor therapy according to Common Terminology Criteria for Adverse Events (CTCAE) (alopecia and residual neuropathy related to prior platinum based therapy are excluded), or failing to meet the levels specified in inclusion/exclusion criteria.

     6. Severe infection (CTCAE grade >2) within 4 weeks prior to the first dose of study drug, including severe pneumonia, bacteremia, complicated infections requiring hospitalization, active pulmonary inflammation on baseline chest imaging, infectious signs and symptoms within 4 weeks before first study drug administration, or infections requiring oral or intravenous antibiotic therapy.

     7. Active autoimmune disease or history of autoimmune disease (such as interstitial pneumonitis, colitis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism, including but not limited to these diseases or syndromes). However, patients with autoimmune hypothyroidism receiving stable dose thyroid hormone replacement and patients with type 1 diabetes mellitus treated with stable dose insulin are not excluded. Patients with vitiligo or childhood onset asthma/hypersensitivity that resolves without intervention in adulthood are also eligible.

     8. History of immunodeficiency, including positive HIV test result, history of acquired or congenital immunodeficiency diseases, or history of organ allotransplantation or allogeneic bone marrow transplantation.

     9. History of interstitial lung disease (excluding radiation pneumonitis that has not received corticosteroid therapy) or non infectious pneumonitis.

     10. Evidence of active tuberculosis infection based on medical history or CT scan; active tuberculosis infection within 1 year prior to enrollment; or history of active tuberculosis more than 1 year previously without standard of care treatment.

     11. Patients with active hepatitis B (HBV DNA ≥500 IU/mL or 2500 copies/mL) or active hepatitis C (anti HCV positive with HCV RNA above the lower limit of detection).

     12. History of substance abuse, alcohol abuse, or drug addiction. 13. Pregnant or lactating women. 14. Subjects with other factors that, in the investigator's opinion, may lead to premature study termination, such as other severe concurrent illnesses (including psychiatric disorders), significant laboratory abnormalities, family or social factors that may compromise subject safety or data collection.