Exploratory Study With Parallel Controls on the Safety and Efficacy of Neoadjuvant Low Branched-Chain Amino Acid Diet in Combination With Anti-PD-1 Monoclonal Antibody for Stage III Melanoma

A Randomized, Double-Blind, Single-Center, Exploratory Study With Parallel Controls on the Safety and Efficacy of Neoadjuvant Low Branched-Chain Amino Acid Diet in Combination With Anti-PD-1 Monoclonal Antibody for Stage III Melanoma

1. Primary Objective:

   To evaluate the safety of a low branched-chain amino acid diet (60% of the normal dietary BCAA content) combined with anti-PD-1 monoclonal antibody as neoadjuvant therapy in patients with stage III melanoma, by documenting the incidence of all adverse events (AEs) and serious adverse events (SAEs), and analyzing changes from baseline in physical examinations, vital signs, and laboratory test results.

2. Secondary Objectives:

   To assess the pathological response rates (including pCR, near-pCR, pPR, and pNR) of the combination therapy in stage III melanoma; to evaluate the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and the immune-related RECIST (irRECIST) criteria; and to estimate event-free survival (EFS) and overall survival (OS) through long-term follow-up.

3. Exploratory Objectives:

To investigate the quality of life (QoL) in patients receiving the low BCAA diet combined with anti-PD-1 therapy; and to identify predictive biomarkers for treatment outcome differences, such as immune-related gene signatures (e.g., PD-L1 expression) and driver gene mutations in somatic variants.

Inclusion Criteria:

• Patients with histopathologically or cytologically confirmed Stage III malignant melanoma. Stage III is defined as the presence of at least one clinically accessible lymph node metastasis or in-transit metastasis. Patients with mucosal or ocular melanoma are excluded; those with melanoma of unknown primary are also excluded.

• No prior radiotherapy or systemic chemotherapy. No treatment with anti-PD-1, anti-PD-L1, anti-PD-L2 monoclonal antibodies, anti-CTLA-4 monoclonal antibody, interferon (IFN), or targeted agents within the last month.

• Life expectancy ≥ 6 months.

• At least one measurable lesion as defined by RECIST version 1.1.

• Patients must have provided written informed consent to participate voluntarily in this trial and must be between 18 and 75 years of age on the day of signing the consent form.

• ECOG (Eastern Cooperative Oncology Group) performance status score of 0 or 1.

• Adequate organ function as assessed by the following laboratory values (within 4 weeks prior to the start of study drug treatment):

  1. Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L
  2. Platelets ≥ 100 × 10⁹/L
  3. Hemoglobin ≥ 90 g/L (no 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 patient is on anticoagulant therapy, in which case PT or aPTT must be within the therapeutic range intended for the anticoagulant).

• For women of childbearing potential, a negative urine or serum pregnancy test within 7 days prior to receiving the first dose of the study drug.

• Female patients of childbearing potential who enroll in the study must be willing to use adequate contraception for up to 12 months after the last dose of the study drug.

Exclusion Criteria:

• The patient is currently participating, or has participated in a clinical trial of an investigational drug or medical device within 4 weeks prior to the first dose of the study drug.
• The patient has received any anti-tumor therapy within the past month, including but not limited to chemotherapy, radiotherapy, immunotherapy (such as 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 corticosteroid therapy (>10 mg/kg prednisone or equivalent) within two weeks prior to the first dose, or any other form of immunosuppressive therapy.
• The patient has a known history of hematologic malignancies, primary brain tumors, sarcoma, or other primary solid tumors, 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 (CNS) metastases and/or carcinomatous meningitis.
• The patient has a history of severe hypersensitivity reaction to another monoclonal antibody (mAb) therapy.
• The patient has an active autoimmune disease that has required systemic treatment in the past 2 years (e.g., with corticosteroids or immunosuppressive drugs). Replacement therapies (such as thyroxine, insulin, or physiologic corticosteroid replacement for adrenal or pituitary insufficiency) are not considered systemic treatments and are allowed. Exceptions include patients with vitiligo, type I diabetes mellitus, or childhood asthma/atopy.
• Any other severe, uncontrolled co-morbid condition that may compromise protocol compliance or interfere with the interpretation of results, including metabolic diseases, active opportunistic or advanced (severe) infections, 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), or pulmonary disease (interstitial lung disease, obstructive pulmonary disease, history of symptomatic bronchospasm). Also included are HIV positivity; HCV positivity; HBsAg or HBcAb positivity with detectable HBV DNA (quantitation limit: 500 IU/mL); or a known history of tuberculosis.
• The patient has received a live vaccine within 4 weeks prior to the first dose. The patient has received hematopoietic growth factors (e.g., colony-stimulating factors, erythropoietin) within 2 weeks prior to treatment initiation. The patient has undergone major surgical procedures (excluding diagnostic surgery) within 2 weeks prior to treatment initiation.
• The patient has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the trial.
• The patient is pregnant or breastfeeding, or plans to conceive or father children during the study period.
• Any other severe, acute, or chronic medical or psychiatric condition, or laboratory abnormality that, in the investigator's judgment, may increase the risk associated with study participation or may interfere with the interpretation of study results.