Description
This is a single-center, single-arm phase II clinical study designed to evaluate the efficacy and safety of Iparomlimab and Tuvonralimab combined with cetuximab in patients with locally advanced resectable oral squamous cell carcinoma.
The treatment regimen for the experimental group is as follows:
The recommended dose of epalorestivolimab is 5 mg/kg. Cetuximab is administered at an initial dose of 400 mg/m² followed by 250 mg/m² once weekly, or alternatively cetuximab 500 mg/m² once every 2 weeks, via intravenous infusion. Each treatment cycle lasts 21 days, with 3 cycles administered preoperatively. Patients will undergo surgical resection at 3 weeks ± 7 days after completion of neoadjuvant therapy, followed by concurrent radiotherapy or chemoradiotherapy at 6 weeks ± 2 weeks postoperatively.
One clinical tumor imaging assessment will be performed preoperatively per RECIST v1.1 (Appendix 4). In addition, clinically required assessments including vital signs, physical examination, complete blood count, urinalysis, liver and renal function tests, serum electrolytes, thyroid function, electrocardiogram, ECOG performance status, and quality-of-life questionnaires will be completed on Day 1 of each treatment cycle (refer to the study flowchart for specific assessments at each visit). Subjects with hepatitis virus carriage will have viral load monitoring every 2 to 4 treatment cycles.
If PD is assessed per RECIST v1.1 but the subject remains clinically stable or the investigator judges that continued treatment may still benefit the subject, reassessment may be performed 4 weeks later using irRECIST. Treatment may be continued if no progressive disease is identified on reassessment.
Eligibility criteria
Inclusion Criteria:
* \- Aged 18-75 years, male or female;
* Histopathologically confirmed primary stage Ⅲ-Ⅳa surgically resectable oral squamous cell carcinoma, with measurable lesions (≥10 mm on spiral CT, meeting RECIST 1.1 criteria);
* ECOG performance status of 0 or 1;
* Expected survival ≥12 weeks;
* At least one measurable lesion per RECIST 1.1. Previously irradiated lesions may serve as measurable lesions provided disease progression has occurred;
* Availability of tumor tissue for PD-L1 testing (paraffin-embedded specimens obtained within 2 years or fresh tumor tissue);
* Adequate organ function assessed within 14 days prior to the first dose of study drug, defined as:
* Hematology: absolute neutrophil count (ANC) ≥1.5×10⁹/L, platelets (PLT) ≥100×10⁹/L, hemoglobin (HB) ≥9 g/dL (no blood transfusion or component transfusion within 14 days before testing);
* Hepatic: serum total bilirubin (TBIL) ≤1.5 × upper limit of normal (ULN); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN (AST and ALT ≤5 × ULN permitted in the presence of liver metastases);
* Renal: serum creatinine \<1.5 × ULN, or creatinine clearance ≥60 mL/min; blood urea nitrogen ≤200 mg/L;
* Thyroid-stimulating hormone (TSH) ≤1 × ULN. If TSH is abnormal, free triiodothyronine (FT3) and free thyroxine (FT4) shall be evaluated; subjects with normal FT3 and FT4 may be enrolled;
* Urine protein ≤1+. If urine protein \>1+, 24-hour urine protein quantification is required, with total urinary protein ≤1 g;
* Normal cardiac function: normal electrocardiogram (ECG) or ECG abnormalities of no clinical significance; left ventricular ejection fraction (LVEF) \>50% on echocardiography.
* Female subjects of reproductive potential must have a negative serum pregnancy test before the first dose of study drug;
* Male or female subjects of reproductive potential must use highly effective contraceptive methods throughout the study (e.g., oral contraceptives, intrauterine devices, abstinence, or barrier contraception combined with spermicide), and continue contraception for 90 days after treatment completion;
* Subjects voluntarily participate in the study, sign the informed consent form, demonstrate good compliance, and agree to follow-up.
Exclusion Criteria:
* \- Presence of distant metastatic lesions or locally unresectable disease (stage Ⅳb or Ⅳc);
* Prior primary nasopharyngeal carcinoma;
* Participation in another investigational drug/therapy clinical trial within 4 weeks before the first study drug dose;
* Major surgery within 4 weeks before the first study drug dose, or unresolved adverse effects from such surgery; receipt of live vaccine or immunotherapy within 4 weeks; radiotherapy within 2 weeks;
* Concurrent receipt of any other anti-tumor therapy;
* Active autoimmune disease or history of autoimmune disease (including but not limited to autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism; vitiligo not requiring systemic therapy is allowed; childhood asthma fully resolved with no intervention required in adulthood is allowed; asthma requiring bronchodilator treatment is excluded);
* Current use of immunosuppressants or systemic corticosteroids for immunosuppressive purposes (\>10 mg/day prednisone or equivalent), continued within 2 weeks prior to enrollment;
* History of other malignant tumors within the past 5 years, except cured basal cell carcinoma of the skin, cutaneous squamous cell carcinoma, early prostate cancer, and carcinoma in situ of the cervix;
* Administration of hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) or erythropoietin within 1 week before the first study drug dose;
* Prior treatment with anti-PD-1/PD-L1/PD-L2/CTLA-4 antibodies or agonist/antagonist agents targeting T-cell receptors (e.g., OX40, CD137);
* Positive human immunodeficiency virus (HIV) antibody or \*Treponema pallidum\* antibody;
* Active hepatitis B or hepatitis C infection:
* If HBsAg or HBcAb is positive, HBV DNA testing will be performed (enrollment excluded if above ULN);
* If HCV antibody is positive, HCV RNA testing will be performed (enrollment excluded if above ULN);
* Known hypersensitivity to recombinant humanized anti-PD-1 monoclonal antibody or its components;
* Active pulmonary disease (interstitial pneumonia, pneumonia, obstructive pulmonary disease, asthma) or history of active tuberculosis;
* Any uncontrolled clinical conditions, including but not limited to:
* Persistent or active (severe) infection;
* Poorly controlled hypertension (persistent blood pressure \>150/90 mmHg);
* Uncontrolled diabetes mellitus;
* Cardiac disease (New York Heart Association grade Ⅲ/Ⅳ congestive heart failure or cardiac block);
* Events occurring within 6 months before first dose: deep vein thrombosis or pulmonary embolism; myocardial infarction; severe or unstable arrhythmia or angina; percutaneous coronary intervention, acute coronary syndrome, coronary artery bypass grafting; cerebrovascular accident, transient ischemic attack, cerebral embolism;
* Prior stem cell transplantation or solid organ transplantation;
* History of substance abuse that cannot be discontinued, or history of psychiatric disorders;
* Other severe, acute or chronic medical conditions or laboratory abnormalities that, in the investigator's judgment, may increase risks associated with study participation or interfere with interpretation of study results;
* Poor compliance or other conditions deemed by the investigator to render the subject unsuitable for trial participation.