The goal of this clinical trial is to evaluate the efficacy and safety of a novel combination therapy for locally advanced head and neck squamous cell carcinoma (HNSCC). The therapy combines the JAK1 inhibitor Sulfamethoxazole, the anti-PD-L1 antibody Adebrelimab, and chemotherapy (Nab-paclitaxel + Cisplatin) as a neoadjuvant treatment (given before surgery). The main questions it aims to answer are:
* For patients with resectable locally advanced HNSCC: Can this combination improve the pathological complete response (pCR) rate (the absence of viable cancer cells in the surgical specimen) compared to current neoadjuvant therapies? * For patients with potentially resectable or unresectable locally advanced HNSCC: Can this combination improve the objective response rate (ORR) (the percentage of patients with significant tumor shrinkage), potentially making surgery possible or reducing its scope?
Researchers will also assess secondary outcomes including event-free survival (EFS), overall survival (OS), and the safety profile of the combination.
Participants will:
* Receive neoadjuvant treatment with the combination of Sulfamethoxazole, Adebrelimab, and chemotherapy. A key feature is the timed sequencing of the JAK inhibitor, which will be started on day 8 of each treatment cycle. * Be evaluated for surgery after the neoadjuvant treatment. For those who undergo surgery, the pathological response will be analyzed. * Have regular follow-up assessments, including imaging studies (such as CT or MRI scans) and safety monitoring, to evaluate long-term treatment response, survival, and side effects. * Provide tissue and/or blood samples for exploratory biomarker analysis (e.g., Interferon-Stimulated Gene signature) to help identify patients who benefit most from this treatment.
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).
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.
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.
History of other active malignancies or active infections (including tuberculosis and hepatitis); uncontrolled infections (HIV, HBV, HCV).
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.
Single group
cisplatin+ nab-paclitaxel +adebrelimab + imaxitinib
DrugTreatment is administered in 21-day cycles, with a response assessment after 2 cycles. On Day 1 of each cycle, patients receive cisplatin (60mg/m²) plus nab-paclitaxel (260mg/m²) concurrently with adebrelimab (1200mg). Starting from Day 8 through Day 21 of each cycle, patients orally take 4mg of imaxitinib daily.
Pathological Complete Response (pCR) Rate in Cohort A (Resectable)
The proportion of participants in Cohort A (resectable locally advanced HNSCC) who achieve a pathological complete response (pCR) upon histopathological examination of the surgical resection specimen after 2 cycles of neoadjuvant therapy. pCR is defined as the absence of viable tumor cells (ypT0 ypN0) as per College of American Pathologists (CAP) criteria.
Objective Response Rate (ORR) in Cohort B (Potentially Resectable)
The proportion of participants in Cohort B (potentially resectable locally advanced HNSCC) who achieve a best overall response of Complete Response (CR) or Partial Response (PR) according to RECIST 1.1 criteria, assessed via imaging (CT/MRI) after 2 cycles of neoadjuvant therapy.
Objective Response Rate (ORR) in Cohort C (Unresectable)
The proportion of participants in Cohort C (unresectable locally advanced HNSCC) who achieve a best overall response of Complete Response (CR) or Partial Response (PR) according to RECIST 1.1 criteria, assessed via imaging (CT/MRI) after 2 cycles of neoadjuvant therapy.
Event-Free Survival (EFS)
EFS is defined as the time from enrollment to the occurrence of any of the following events: disease progression that precludes planned curative surgery (for Cohorts A/B), local or regional recurrence after definitive therapy (surgery or radiotherapy), distant metastasis, or death from any cause.
Overall Survival (OS)
OS is defined as the time from enrollment to death from any cause.
Incidence of Treatment-Related Adverse Events (TRAEs)
The frequency and severity of all adverse events assessed as related to the study intervention (Adebrelimab, Sulfamethoxazole, cisplatin, and nab-paclitaxel). Severity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. This includes the incidence of serious adverse events (SAEs), adverse events leading to treatment discontinuation or dose reduction, and specific events of interest such as immune-related adverse events (irAEs) and hematological toxicities.
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