A Study Investigating the Efficacy and Safety of the Combination of Iparomlimab and Tuvonralimab With or Without Chemotherapy in Second-line and Subsequent Treatments for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

A Study Investigating the Efficacy and Safety of the Combination of Iparomlimab and Tuvonralimab With or Without Chemotherapy in Second-line and Subsequent Treatments for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

This is a single-arm, open-label, phase II study to evaluate the efficacy and safety of the combination of the antibodies iparomlimab and tuvonralimab, administered with or without chemotherapy, in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) who have progressed after receiving at least one line of systemic therapy.

The study includes a safety run-in phase with approximately three patients, which may be expanded to six if a dose-limiting toxicity is observed. Patients are then assigned to either combination antibody monotherapy or combination antibody plus chemotherapy, based on PD-L1 combined positive score (CPS), symptom burden, disease characteristics and patient preference.

Monotherapy involves iparomlimab and tuvonralimab (5 mg/kg on day 1, every 3 weeks).

Combination therapy involves the same antibody regimen plus up to six cycles of platinum (carboplatin at an area under the curve (AUC) of 5 or cisplatin at 75 mg/m²) plus docetaxel (75 mg/m²) or paclitaxel (135-175 mg/m²), followed by antibody monotherapy maintenance.

The primary objective is to assess the objective response rate (ORR) according to RECIST 1.1. The secondary objectives are to evaluate the disease control rate (DCR), the 6-month progression-free survival (PFS) rate, the 6-month overall survival (OS) rate and the safety profile. Exploratory objectives include the association of tumour biomarkers (PD-L1 expression and tumour mutation burden) with efficacy.

Inclusion Criteria:

1. Sign a written informed consent form before any trial-related procedures are performed；
2. Ages 18 to 75, regardless of gender；
3. ECOG performance status of 0-2；
4. Pathologically confirmed recurrent or metastatic squamous cell carcinoma of the head and neck, including the oropharynx, oral cavity, hypopharynx, or larynx；
5. Has received systemic therapy for recurrent or metastatic HNSCC；
6. Expected survival time > 3 months；
7. At least one measurable lesion according to the RECIST 1.1 criteria
8. All acute toxicities resulting from prior anticancer therapy must have resolved to Grade 0-1 (according to NCI CTCAE Version 5.0) or to a level acceptable under the inclusion/exclusion criteria；
9. Total triiodothyronine (T3) or free T3 and free thyroxine (T4) are within the normal range. (These levels may be controlled by thyroid replacement therapy.) Asymptomatic subjects with abnormal T3, free T3, or free T4 levels may be enrolled；
10. Patients must have adequate organ and bone marrow function, and laboratory test results within 7 days prior to grouping must meet the following requirements (conditions must not be met by administering any blood components, cell growth factors, albumin, or other corrective medications within 14 days prior to obtaining the laboratory tests), as follows: 1) Complete blood count (CBC): Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L; Platelet count (PLT) ≥ 75 × 10⁹/L (≥ 50 × 10⁹/L for patients with cirrhosis or splenomegaly); Hemoglobin (HGB) ≥ 90 g/L; 2) Liver function: Serum total bilirubin (TBIL) ≤ 1.5×upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5×ULN; 3) Renal function: Serum creatinine (Cr) ≤ 1.5×ULN or creatinine clearance (CCr) ≥ 50 mL/min (Cockcroft-Gault formula); Qualitative urine protein ≤ 1+; if qualitative urine protein is ≥ 2+, a 24-hour urine protein quantification test must be performed; if the 24-hour urine protein quantification is < 1 g, it is acceptable; Coagulation function: International Normalized Ratio (INR) and Activated Partial Thromboplastin Time (APTT) ≤ 2 times the upper limit of normal (ULN).

Exclusion Criteria:

1.A confirmed history of other types of cancer unrelated to the target cancer in this study (head and neck squamous cell carcinoma)； 2.Subjects with central nervous system metastases or brain metastases； 3.Patients with acute or chronic active hepatitis B or C; those with hepatitis B virus (HBV) DNA > 1,000 IU/mL who have failed antiviral therapy; those with hepatitis C virus (HCV) RNA > 10³ copies/mL who have been assessed as unsuitable for immunotherapy; and those who are simultaneously positive for hepatitis B surface antigen (HBsAg) and anti-HCV antibodies； 4.Any life-threatening bleeding episode within the past 3 months, including those requiring blood transfusion, surgery, or local treatment, or ongoing medication； 5.A history of arterial or venous thromboembolic events within the past 6 months, including myocardial infarction, unstable angina, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis, or any other serious thromboembolic event. Implantable venous access ports or catheter-related thrombosis, or superficial vein thrombosis, unless the thrombus is stable following conventional anticoagulation therapy. Prophylactic use of low-dose low-molecular-weight heparin (e.g., enoxaparin 40 mg/day) is permitted； 6.Use of aspirin (> 325 mg/day) or other drugs known to inhibit platelet function, such as dipyridamole or clopidogrel, for 10 consecutive days within 2 weeks prior to the first dose； 7.Symptomatic congestive heart failure (New York Heart Association Class II-IV). Symptomatic or poorly controlled arrhythmias. History of congenital long QT syndrome or a corrected QTc > 500 ms on screening (calculated using the Fridericia formula)； 8.A severe bleeding tendency or coagulation disorder, or currently undergoing thrombolytic therapy； 9.A history of gastrointestinal perforation and/or fistula within the past 6 months; a history of intestinal obstruction (including partial intestinal obstruction requiring parenteral nutrition); extensive intestinal resection (partial colectomy or extensive small bowel resection complicated by chronic diarrhea); Crohn's disease; ulcerative colitis; or long-term chronic diarrhea； 10.A history of or current pulmonary conditions such as pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, drug-induced pneumonia, or severe impairment of lung function； 11.Known history of alcohol abuse, psychotropic substance abuse, or drug use； 12.A history of specific neurological or psychiatric disorders, such as epilepsy, dementia, schizophrenia, etc； 13.Active pulmonary tuberculosis (TB), individuals currently undergoing antituberculosis treatment, or those who received antituberculosis treatment within one year prior to the first dose； 14.Individuals infected with human immunodeficiency virus (HIV) (HIV-1/2 antibody-positive) and individuals with known syphilis； 15.Active severe infections or infections that are not well clinically controlled. Severe infections within 4 weeks prior to the first dose, including but not limited to hospitalization due to complications from infection, bacteremia, or severe pneumonia； 16.Active autoimmune disease requiring systemic treatment (e.g., disease-modifying antirheumatic drugs, corticosteroids, or immunosuppressants) within 2 years prior to the first dose. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroids for adrenal or pituitary insufficiency) is permitted. Known history of primary immunodeficiency. Patients who are only positive for autoimmune antibodies must be evaluated by the investigator to determine whether an autoimmune disease is present； 17.Use of immunosuppressive drugs within 4 weeks prior to the first dose, excluding topical corticosteroids administered via nasal spray, inhalation, or other routes, or systemic corticosteroids at physiological doses (i.e., no more than 10 mg/day of prednisone or an equivalent dose of other corticosteroids); temporary use of corticosteroids to treat dyspnea associated with conditions such as asthma or chronic obstructive pulmonary disease is permitted； 18.Within 4 weeks prior to the first dose, or if the patient is scheduled to receive an attenuated live vaccine during the study； 19.Major surgery (craniotomy, thoracotomy, or laparotomy) within 4 weeks prior to the first dose, or unhealed wounds, ulcers, or fractures. Tissue biopsy or other minor surgical procedures within 7 days prior to the first dose, excluding venipuncture or catheter placement for the purpose of intravenous infusion； 20.Uncontrolled or uncorrectable metabolic disorders, other non-malignant organ diseases, systemic diseases, or secondary reactions to cancer, which may result in a higher medical risk and/or uncertainty regarding survival prognosis； 21.A diagnosis of another malignancy within 5 years prior to the first dose, excluding curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and/or carcinoma in situ that has been curatively resected. If another malignancy or hepatocellular carcinoma was diagnosed more than 5 years prior to dosing, a pathological or cytological diagnosis of the recurrent or metastatic lesions is required； 22.A history of severe allergic reactions to study drug components (such as the epa-loritovireli combination antibody, platinum agents, docetaxel, or paclitaxel)； 23.Has received treatment in another clinical trial or is currently participating in another clinical study within 4 weeks prior to the first dose； 24.Pregnant or breastfeeding patients； 25.Other acute or chronic medical conditions, psychiatric disorders, or abnormal laboratory test results that may lead to the following: increased risks associated with study participation or administration of the study drug, or interference with the interpretation of study results; and, in the investigator's judgment, render the patient ineligible for participation in this study.

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