Treatment of Recurrent/Metastatic Head and Neck Cancer

Inclusion Criteria:

• The subject voluntarily enrolls in the study, signs the informed consent form, and has good compliance.
• Aged 18 to 75 years inclusive (calculated on the date of informed consent signing).
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1.
• Expected survival > 12 weeks.
• Subjects with histologically or cytologically confirmed recurrent/metastatic head and neck cancer (R/M HNC) and no indication for curative local therapy.head and neck cancer (HNC)
• At least one measurable lesion per RECIST 1.1 criteria. If the target lesion is within the prior radiotherapy field, the lesion must be confirmed as progressive disease.

• Adequate major organ function, meeting the following laboratory criteria (no blood transfusion within 14 days prior to screening; no hematopoietic growth factors or other corrective medications administered within 7 days prior to screening):

  • Hemoglobin (HGB) ≥ 90 g/L;
  • Absolute neutrophil count (NEUT) ≥ 1.5×10⁹/L;
  • Platelet count (PLT) ≥ 100×10⁹/L;
  • Total bilirubin (TBIL) ≤ 1.5×upper limit of normal (ULN); ≤ 2.0×ULN in subjects with liver metastasis;
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5×ULN; ≤ 5.0×ULN in subjects with liver metastasis;
  • Creatinine clearance (CCR) ≥ 50 mL/min (calculated using the standard Cockcroft-Gault formula). For subjects not receiving platinum-containing chemotherapy, serum creatinine (Cr) ≤ 1.3×ULN is also acceptable.
  • Serum albumin ≥ 30 g/L;
  • Prothrombin time (PT), activated partial thromboplastin time (APTT) and international normalized ratio (INR) ≤ 1.5×ULN (in subjects not receiving anticoagulant therapy).
• Echocardiographic assessment: left ventricular ejection fraction (LVEF) ≥ 50%.
• Females of childbearing potential agree to use effective contraception during the study and for 6 months after study completion; serum or urine pregnancy test must be negative within 7 days prior to enrollment. Males agree to use effective contraception during the study and for 6 months after study completion (see Section 5.5 for details).

Additional criteria for Expansion Cohort 1 and Cohort 2:

• Has received at least one line of systemic therapy for recurrent/metastatic disease, including platinum-based chemotherapy and anti-programmed cell death protein 1 / programmed cell death ligand 1 (anti-PD-1/L1) therapy.

Systemic therapy administered as part of multimodal treatment for locally advanced disease (including neoadjuvant/induction, concurrent, adjuvant/consolidation therapy), with disease recurrence or progression during chemotherapy/immunotherapy or within 6 months after the last dose, shall be defined as first-line chemotherapy/immunotherapy failure.

• No prior exposure to paclitaxel and its novel formulations (e.g., albumin-bound paclitaxel) (Cohort 2 only).

Additional criteria for Expansion Cohort 3

• No prior systemic therapy for recurrent/metastatic disease. Systemic therapy as part of multimodal treatment for locally advanced disease (including induction/neoadjuvant therapy, concurrent systemic therapy with curative radiotherapy, adjuvant/consolidation therapy) is excluded, provided that the interval from completion of such therapy to disease recurrence/progression exceeds 6 months.

Exclusion Criteria:

• Current or history of other malignant tumors. The following two conditions are allowed for enrollment:

Other malignant tumors treated with surgery alone with continuous 5-year disease-free survival (DFS); cured carcinoma in situ of cervix, non-melanoma skin cancer and superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invading basement membrane)].

• Diseases that interfere with subcutaneous injection or venous blood collection.
• Adverse reactions from prior treatment have not recovered to ≤Grade 1 per CTCAE Version 6.0, except Grade 2 alopecia, Grade 2 peripheral neurotoxicity (Cohort 1 only), Grade 2 anemia, non-clinically significant asymptomatic Grade 2 laboratory abnormalities, hypothyroidism stabilized by hormone replacement therapy, and other toxicities deemed to have no safety risk by the investigator.
• Major surgical treatment, significant traumatic injury within 4 weeks prior to the first dose, or planned major surgery during the study treatment period (excluding protocol-specified surgeries); or unhealed wounds or fractures for a long time.

Major surgery is defined as Grade 3 or above surgeries in the 2022 National Surgery Classification Catalogue.

• Any bleeding event ≥Grade 3 per CTCAE within 4 weeks prior to the first dose.
• Arterial/venous thromboembolic events within 6 months prior to the first dose, including cerebrovascular accidents (including transient ischemic attack, excluding lacunar cerebral infarction). Implantable venous port/catheter-related thrombosis or superficial venous thrombosis shall not be regarded as "severe" thromboembolism); deep venous thrombosis and pulmonary embolism.
• Active and poorly controlled viral hepatitis. Subjects meeting the following criteria may undergo screening:

HBsAg-positive subjects must have Hepatitis B Virus Deoxyribonucleic Acid (HBV) DNA <500 IU/mL (or 2500 copies/mL), and agree to receive anti-HBV therapy throughout the study.

HCV-infected subjects (HCV Ab or HCV RNA positive): HCV viral RNA ≤upper limit of normal, and continue approved antiviral therapy during the study.

• Active syphilis requiring treatment.
• Active pulmonary tuberculosis, history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonia/radiation pneumonitis requiring treatment, active pneumonia with obvious clinical symptoms; history of interstitial lung disease (ILD) requiring previous treatment, or current interstitial lung disease.
• History of psychoactive substance abuse without abstinence, or mental disorders.
• Planned or prior allogeneic bone marrow transplantation or solid organ transplantation.
• History of hepatic encephalopathy.

• Severe cardiovascular diseases, including any of the following:

  • Cardiac insufficiency ≥New York Heart Association (NYHA) Class II, or echocardiography showing left ventricular ejection fraction (LVEF) <50%.
  • History of clinically significant ventricular arrhythmia (e.g., sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes), or arrhythmia requiring continuous antiarrhythmic medication. Subjects with stable atrial fibrillation controlled by β-blockers alone may be enrolled after investigator's assessment.
  • Unstable angina pectoris.
  • Myocardial infarction within 12 months. Subjects who received interventional treatment more than 6 months ago without sequelae may be enrolled.
  • Corrected QT interval (QTc): >450 ms in males, >470 ms in females. If QTc is abnormal, three consecutive measurements at an interval >2 minutes shall be performed and the average value adopted. Correction methods include Fridericia formula or Bazett formula.
  • History or family history of congenital long QT syndrome.
• Active or uncontrolled severe infection (≥CTCAE Grade 2 infection).
• Renal failure requiring hemodialysis or peritoneal dialysis.
• History of immunodeficiency, including HIV positivity, or other acquired/congenital immunodeficiency diseases.
• Uncontrolled autoimmune diseases requiring immunosuppressive agents or systemic corticosteroids for immunosuppressive purposes, and still requiring such treatment within 7 days prior to the first dose.

Exclusion does not apply to subjects receiving prednisone <10 mg daily or equivalent dose of other corticosteroids.

• Epilepsy requiring treatment.
• Poorly controlled diabetes [fasting blood glucose (FBG)>10 mmol/L].

• Tumor-related conditions and prior therapies:

  • Received chemotherapy, immunotherapy, small-molecule targeted therapy within 3 weeks prior to the first dose, or still within 5 half-lives of the drug (whichever is longer). The washout period is calculated from the date of the last treatment.

Prior local radiotherapy is allowed if: radiotherapy completed >4 weeks prior to study treatment initiation (>2 weeks for brain radiotherapy); target lesion selected in this study is outside the radiotherapy field; or target lesion within radiotherapy field with confirmed progression.

• Received proprietary Chinese medicines with anti-tumor indications specified in National Medical Products Administration approved drug instructions within 1 week prior to the first dose (including Compound Mylabris Capsule, Kang'ai Injection, Kanglaite Capsule/Injection, Aidi Injection, Brucea Javanica Oil Injection/Capsule, Xiaoaiping Tablets/Injection, Huachansu Capsule, etc.).
• Imaging (CT/MRI) shows tumor invasion of major blood vessels, or the investigator judges that the tumor is highly likely to invade major blood vessels and cause fatal massive hemorrhage during subsequent study treatment.
• Uncontrolled recurrent pleural effusion, pericardial effusion or moderate to severe ascites requiring repeated drainage (as assessed by investigator).
• Known spinal cord compression, meningeal metastasis/carcinomatous meningitis, brain metastasis with symptoms, or brain metastasis with symptomatic/radiographic control duration <4 weeks; still requiring steroids or dehydrating agents within 2 weeks prior to study treatment initiation.

Subjects with newly diagnosed or progressive brain metastasis at screening shall be re-examined after at least 4 weeks to confirm stability.

• Known hypersensitivity to study drug or excipients.
• Received more than 2 lines of systemic therapy for recurrent/metastatic disease (Cohort 1 and Cohort 2).
• Prior treatment with EGFR-targeted antibodies/Antibody-Drug Conjugates (ADCs). Exclusion does not apply to subjects who received cetuximab or nimotuzumab during curative radiotherapy for locally advanced disease, with disease recurrence/progression occurring >6 months after completion of curative radiotherapy and the last dose.
• Prior treatment with more than one immune checkpoint inhibitor, or prior Transforming Growth Factor Beta targeted therapy (Cohort 3).
• Participated in another anti-tumor clinical trial and received investigational drugs within 4 weeks prior to the first dose.
• Conditions judged by the investigator to pose serious risks to subject safety or impair completion of the study.