Cryoablation Combined With Hepatic Arterial Infusion of Iparomlimab and Tuvonralimab (QL1706), Intravenous Dacarbazine, and Oral Lenvatinib in Patients With Liver Metastases From Malignant Melanoma: a Single-arm, Phase II, Prospective Trial

Prior treatment

• Liver metastases previously treated with radiotherapy, microwave ablation, radiofrequency ablation, or irreversible electroporation;
• Known central nervous system metastases that are clinically unstable, or acute meningitis (except patients with central nervous system metastases who have received treatment and are clinically stable).
  • Clinical stability requires all of the following:

Lab values

• Child-Pugh score \>= 7; decompensated liver function, such as massive ascites, gastric fundal or esophageal varices with upper gastrointestinal bleeding within the previous year, hepatic encephalopathy, or bilirubin encephalopathy;
• no new neurological symptoms, and previous neurological symptoms have returned to normal.
  • Previous treatment with immune checkpoint inhibitors complicated by grade 3 or higher immune-related adverse events;
  • Pregnant or breastfeeding women;
  • History of HIV infection;
  • History of another malignancy within 5 years (excluding early-stage basal cell carcinoma, carcinoma in situ of the cervix, and papillary thyroid carcinoma);
  • Any of the following within 12 months before study initiation: myocardial infarction, severe or unstable angina, congestive heart failure, cerebrovascular accident, or pulmonary embolism;
  • Severe hepatic or renal impairment; uncontrolled diabetes, pulmonary fibrosis, interstitial lung disease, or acute pulmonary disease; poorly controlled hypertension (systolic blood pressure \> 160 mmHg and/or diastolic blood pressure \> 90 mmHg); clinically significant cardiovascular or cerebrovascular disease, such as cerebrovascular accident or myocardial infarction within 6 months, unstable angina, NYHA class II or higher congestive heart failure, severe arrhythmia not controlled by medication, clinically significant electrocardiographic abnormalities on three consecutive recordings obtained at least 5 minutes apart, psychiatric disorders, or drug abuse; or any condition that the investigator considers likely to increase risk to the subject or interfere with study results;
  • History of organ transplantation;
  • Other severe acute or chronic physical or psychiatric illnesses, or laboratory abnormalities, that may increase study-related risk or interfere with interpretation of results and make the patient unsuitable for enrollment;
  • Uncontrolled concurrent diseases or infectious diseases. Patients with active hepatitis B must receive antiviral therapy to achieve HBV DNA \< 500 copies/mL and remain stable for at least 2 weeks before the investigator assesses eligibility, and must continue antiviral therapy throughout the study after enrollment;
  • History of severe adverse reactions to contrast agents;
  • Any active autoimmune disease, or a history of autoimmune disease judged by the investigator to make the patient unsuitable for this study, including but not limited to systemic lupus erythematosus, immune-related neuropathy, multiple sclerosis, Guillain-Barre syndrome, myasthenia gravis, connective tissue diseases, and inflammatory bowel disease including Crohn's disease and ulcerative colitis;
  • Previous treatment with lenvatinib or other multi-target tyrosine kinase inhibitors;
  • Previous systemic chemotherapy containing dacarbazine or temozolomide complicated by grade 3 or higher myelosuppression or hepatotoxicity during treatment;
  • Total intrahepatic lesion volume assessed by the investigator as exceeding 50% of the total liver volume;
  • Use of therapeutic anticoagulants (such as warfarin, direct oral anticoagulants, or low-molecular-weight heparin) or dual antiplatelet therapy (such as aspirin combined with clopidogrel) within 7 days before enrollment, if the medications cannot be safely discontinued and bridged before cryoablation and arterial infusion.

Other

• ECOG performance status score \>= 2;
• no new brain lesions and no enlargement of existing lesions, confirmed by MRI;
• no glucocorticoid treatment for at least 2 weeks;

• Age 18-70 years;
• Patients with pathologically confirmed metastatic malignant melanoma after failure of standard treatment;
• Presence of liver metastases, with at least one lesion assessed as suitable for cryoablation;
• The largest diameter of each intrahepatic metastatic lesion \< 5 cm;
• At least one target lesion suitable for efficacy assessment according to RECIST 1.1 (when no appropriate extrahepatic target lesion is available, a non-ablated intrahepatic lesion may serve as the observation lesion);
• ECOG performance status score of 0;
• No history of autoimmune disease;
• Life expectancy of more than 3 months;
• Laboratory test results meeting the following criteria:
  • Neutrophil count \>= 1.8 × 10⁹/L;
  • White blood cell count \>= 3.0 × 10⁹/L;
  • Platelet count \>= 100 × 10⁹/L; Hemoglobin \>= 90 g/L;
  • Serum ALT and AST \<= 2.5 × the upper limit of normal (ULN);
  • Serum creatinine \<= 1.5 × ULN;
  • INR \< 1.3 or prothrombin time \< ULN + 2 seconds;
  • Albumin \>= 35 g/L;
  • Total bilirubin \<= 1.0 × ULN.