A Phase II Study of Nab-Paclitaxel Combined With Retlirafusp Alfa and Apatinib in Patients With Advanced Mucosal Melanoma

Inclusion Criteria:

1. Age ≥ 18 years.

2. Histopathologically confirmed unresectable or metastatic mucosal melanoma.

3. Subjects must provide 5 paraffin-embedded tissue sections obtained prior to treatment for immune microenvironment (immune infiltration) scoring.

4. The Eastern Cooperative Oncology Group (ECOG) scoring system in the United States has a score range of 0-1.

5. No prior systemic therapy. Patients who developed recurrence or metastasis more than 6 months after discontinuation of adjuvant therapy are excluded from this criterion (i.e., such patients are eligible).

6. Presence of at least one measurable lesion according to RECIST 1.1 criteria.

7. No history of immunosuppressive drug use within 6 months prior to enrollment.

8. Adequate hematologic and organ function, meeting the following laboratory criteria:

   i. Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L; ii. Platelet count ≥ 100 × 10⁹/L; iii. Hemoglobin > 9.0 g/dL; iv. Serum creatinine ≤ 1.5 × ULN, or creatinine clearance (CrCl) ≥ 40 mL/min; v. AST/ALT ≤ 3 × ULN; vi. Total bilirubin ≤ 1.5 × ULN.

9. No active bleeding.

10. Urine protein ≤ 1+ or < 1 g/24h.

11. Women of childbearing potential must have a negative serum or urine pregnancy test and agree to use adequate contraception (barrier method or oral contraceptives) during the study.

Exclusion Criteria:

1. Patients with active autoimmune disease. Note: Patients with vitiligo, type I diabetes mellitus, or hypothyroidism due to Hashimoto's thyroiditis requiring only hormone replacement therapy may be enrolled if there is no obvious evidence of recurrence.
2. Patients requiring systemic corticosteroid therapy (> 10 mg prednisone [or equivalent] per day) or other immunosuppressive agents within 14 days after enrollment. Note: Inhaled or topical corticosteroids, or adrenal hormone replacement therapy (> 10 mg prednisone [or equivalent] per day) are acceptable for patients without obvious autoimmune disease.
3. Patients with concurrent other malignancy requiring anti-tumor therapy cannot be enrolled in this study. However, if the malignancy has achieved complete remission for two years or more, and no additional anti-tumor therapy is required during the study period, enrollment may be considered.
4. Patients who, in the investigator's judgment, are medically, psychologically, or physiologically unable to complete this study or to understand the patient information.
5. Prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, anti-TGF-β, or other agents targeting T-cell co-stimulatory or immune regulatory pathways.
6. Prior treatment with taxanes, platinum-based agents, or anti-angiogenic agents.
7. Presence of untreated CNS metastases, or CNS metastases requiring corticosteroids for edema control.
8. Tumor invasion of major blood vessels (e.g., carotid artery, aorta), concurrent active ulcer, or history of gastrointestinal bleeding.
9. History of myocardial infarction or stroke within the past 6 months.
10. Positive HIV test or confirmed diagnosis of acquired immunodeficiency syndrome (AIDS).
11. Uncontrolled hypertension, commonly defined as: systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg despite optimized antihypertensive therapy, or requiring ≥ 2 antihypertensive agents without achieving target.
12. Cardiac arrhythmias requiring pharmacological or device intervention, affecting hemodynamic stability, or posing a risk of sudden death, including but not limited to uncontrolled rapid atrial fibrillation, ventricular tachycardia, atrioventricular block, and QTc ≥ 500 ms.
13. Uncontrolled heart failure, defined as NYHA class III-IV, or persistent significant symptoms despite optimized therapy, or recent need for hospitalization or intravenous therapy, or significantly reduced left ventricular ejection fraction (e.g., < 40-50%).
14. Patients with a history of severe (≥ G3) immune-related adverse events (irAEs) involving major organs, such as immune-mediated hepatitis, pneumonitis, myocarditis, colitis, or central nervous system toxicity.
15. Presence of unhealed wounds.
16. Allergy to the study drug or its components.
17. Pregnant or lactating women.