Efficacy and Safety of Neoadjuvant Cadonilimab Plus High-Dose Recombinant Human Interferon α1b in Stage III/IV Melanoma.

Efficacy and Safety of Neoadjuvant Cadonilimab Plus High-Dose Recombinant Human Interferon α1b in Stage III/IV Melanoma: A Single-Center, Open-Label, Phase Ib Trial

1. Primary Objective

   To evaluate the efficacy and safety of cadonilimab in combination with high-dose recombinant human interferon α1b injection as neoadjuvant therapy in patients with stage III/IV melanoma. Assessments include:

   Target lesion response (complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD]) Objective response rate (ORR) Pathological response rate (pathological complete response [pCR], near pCR, pathological partial response [pPR], pathological non-response [pNR]) Incidence of all adverse events (AEs) and serious adverse events (SAEs) Changes from baseline in physical examinations, vital signs, and laboratory test results.

2. Exploratory Objectives To investigate the correlation between treatment efficacy/patient outcomes and:PD-L1 expression in tumor tissue CD8+ T-cell infiltration Tumor mutational burden (TMB).

3. Study Significance To conduct a preliminary exploration in support of future multicenter clinical studies.

Inclusion Criteria:

• Voluntarily participate in this trial, sign the informed consent form, and be between 18 and 75 years of age, regardless of gender.

• Patients with histopathologically or cytologically confirmed stage III or resectable stage IV malignant melanoma.

  • Stage III is defined as the presence of at least one clinically accessible lymph node metastasis or in-transit metastasis.
  • Resectable stage IV is defined as a single distant metastasis, excluding brain metastases or any other metastases that cannot be completely surgically resected.
  • Mucosal or ocular melanomas are excluded.
  • Melanomas of unknown primary origin are excluded.

• Have not received treatment with PD-1, PD-L1, or PD-L2 antibodies, anti-CTLA4 antibodies, interferon (IFN), targeted therapy, radiotherapy, or systemic chemotherapy within the past month.

• Have an expected survival period of ≥ 6 months.

• Have at least one measurable lesion according to RECIST version 1.1.

• Have an ECOG performance status score of 0 or 1.

• Have adequate organ function, as indicated by the following laboratory values (within 4 weeks prior to the start of study treatment):

  1. Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L

  2. Platelets ≥ 100 × 10⁹/L

  3. Hemoglobin ≥ 90 g/L (no blood transfusion within 14 days prior to enrollment)

  4. Serum creatinine ≤ 1.5 × upper limit of normal (ULN)

  5. Serum total bilirubin ≤ 1.5 × ULN

  6. AST (SGOT) and ALT (SGPT) ≤ 2.5 × ULN or ≤ 5 × ULN (for patients with liver metastases)

  7. Prothrombin time (PT)/International Normalized Ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN (unless the subject is receiving anticoagulant therapy, in which case PT or aPTT must be within the therapeutic range intended for the anticoagulant used).

     8.Female patients of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to receiving the first dose of the study drug.

     9.Female patients enrolled in the study must be willing to use appropriate contraception methods until 12 months after the last dose of the study drug.

     Exclusion Criteria:

• The patient is currently participating, or has participated within 4 weeks prior to the first dose of the study drug, in another interventional clinical trial of drugs or medical devices.

• The patient has received any anti-tumor therapy within the past month, including but not limited to chemotherapy, radiotherapy, immunotherapy (e.g., anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies, or any other antibody targeting T-cell co-regulatory pathways), etc.

• The patient has received systemic steroid therapy (>10 mg/kg prednisone or equivalent) within two weeks prior to the first dose, or any other form of immunosuppressive medication.

• The patient has a known history of hematologic malignancy, primary brain tumor, sarcoma, or another primary solid tumor, unless the patient has been cured and has had no evidence of recurrence for 5 years. Exceptions include cured basal cell carcinoma of the skin and carcinoma in situ of the cervix.

• The patient has known central nervous system metastases and/or carcinomatous meningitis.

• The patient has a history of severe hypersensitivity to another monoclonal antibody (mAb) therapy.

• The patient has had an active autoimmune disease requiring systemic treatment (e.g., with corticosteroids or immunosuppressive drugs) within the past 2 years, and related replacement therapies (e.g., thyroxine, insulin, or physiologic corticosteroid replacement for renal or pituitary insufficiency). Exceptions include patients with vitiligo, type I diabetes, childhood asthma/atopy.

• Other severe, uncontrolled concomitant diseases that may affect protocol compliance or interpretation of results, including active opportunistic or advanced (severe) infections; uncontrolled diabetes; cardiovascular disease (e.g., Class III or IV heart failure as defined by the New York Heart Association classification, second-degree or greater heart block, myocardial infarction within the past 6 months, unstable arrhythmias or unstable angina, cerebral infarction within 3 months); pulmonary disease (interstitial lung disease, obstructive pulmonary disease, history of symptomatic bronchospasm); HIV positivity; HCV positivity; HBsAg or HBcAb positivity with detectable HBV DNA (quantitative limit ≥500 IU/mL); or a documented history of tuberculosis.

• The patient has received a live vaccine within 4 weeks prior to the first dose; hematopoietic growth factors (e.g., colony-stimulating factors, erythropoietin) within 2 weeks prior to treatment initiation; or major surgical procedures (excluding diagnostic surgery) within 2 weeks prior to treatment initiation.

• The patient has a known psychiatric or substance use disorder that would interfere with cooperation with trial requirements.

• The patient is pregnant or breastfeeding, or plans to become pregnant or father a child during the study period.

• Any other severe, acute, or chronic medical or laboratory abnormality that, in the investigator's judgment, could increase the risk associated with study participation or could interfere with the interpretation of study results.