A Phase II Clinical Study of Multimodal Ablation Combined With Systemic Drug Therapy for Advanced Solid Tumors.

Inclusion Criteria i. Common eligibility criteria for all cohorts:

1\. Age between 18-80 years,gender not limited; 2. Patients with hepatic lesions amenable to ablation, all hepatic lesions \<5 cm in diameter; 3. Expected survival≥3 months; 4. ECOG performance status score of 0-1; 5. Within 14 days before the first dose,laboratory tests indicate adequate organ function:

a) Hematology:WBC≥3.0×10\^9/L;ANC≥1.5×10\^9/L;PLT≥75×10\^9/L;HGB≥90 g/L b) Liver function:Child-Pugh score≤7,AST≤5.0×ULN;ALT≤5.0×ULN;TBIL≤1.5×ULN c) Renal function:Cr≤1.5×ULN or CrCl≥60 mL/min d) Coagulation function:INR≤1.5×ULN(for patients on anticoagulant therapy,≤3×ULN,anticoagulants must be discontinued one week before ablation);APTT≤1.5×ULN ii. Additional eligibility criteria for each cohort:

1. Colorectal Cancer：

   a) Clinically or pathologically confirmed colorectal cancer with liver metastases that are unresectable, or the patient is intolerant to or refuses surgery; b) Patients who have failed standard second-line drug therapy.
2. Triple-negative breast cancer :

   1. Clinically or pathologically confirmed triple-negative breast cancer(triple-negative defined as\<1% nuclear staining for ER and PR expression and HER2 negative);
   2. Patients who have failed standard second-line drug therapy(including those who have failed PD-1 monoclonal antibody therapy, with progression within six months of adjuvant or neoadjuvant therapy considered as first-line therapy failure).
3. Melanoma :

   1. Clinically or pathologically confirmed melanoma liver metastasis, with inoperable or intolerable liver lesions or refusal of surgical resection;
   2. Patients who have failed standard first-line drug therapy.

Exclusion Criteria:

i. Common exclusion criteria for all cohorts:

1. Patients with known allergy or suspected allergy to the study drugs or similar drugs;
2. Patients who have participated in another clinical study and received at least one treatment within 4 weeks prior to enrollment;
3. History or concurrent presence of other malignant tumors(except for cured basal cell carcinoma of the skin,superficial bladder cancer,carcinoma in situ of the cervix,and papillary thyroid carcinoma);
4. Patients with immunodeficiency diseases within 7 days prior to the first dose,or currently receiving systemic corticosteroid therapy(≥10mg/day prednisone or equivalent dose of other corticosteroids),or other forms of immunosuppressive therapy;
5. Symptomatic central nervous system(CNS)metastases,or other evidence indicating that the CNS metastases have not been controlled,and deemed unsuitable for enrollment by the investigator;
6. Patients who have previously undergone organ or bone marrow transplantation;
7. Uncontrollable pleural effusion,pericardial effusion,or ascites causing respiratory syndrome(≥CTCAE grade 2 dyspnea);
8. Esophageal(gastric fundus)variceal rupture bleeding within the last month;
9. Other antitumor treatments outside the combined regimen,such as radiotherapy,systemic chemotherapy,etc.;
10. Clinically significant electrolyte abnormalities as judged by the investigator;
11. Insufficiency or failure of major organs;
12. Patients who have received systemic drug therapy,radiotherapy,or local liver treatment,with a time interval of less than 1 month since the last systemic treatment or local liver treatment;
13. Patients who have received immunotherapy and experienced grade 3 or higher immune-related adverse events(irAEs)(except for thyroid function abnormalities,blood sugar abnormalities);
14. Active or uncontrolled severe infections(≥CTCAE grade 2 infections);
15. Any other disease,clinically significant metabolic abnormalities,physical examination abnormalities,or laboratory test abnormalities that,in the investigator's judgment,may have a disease or condition that makes the patient unsuitable for the study drug,or may affect the interpretation of the study results,or may place the patient at high risk;
16. Pregnant or breastfeeding women,or women of childbearing age with a positive baseline pregnancy test;
17. Known human immunodeficiency virus(HIV)infection;known clinically significant liver disease history,including viral hepatitis\[known carriers of hepatitis B virus(HBV)must exclude active HBV infection,i.e.,HBV DNA positive(\>1×10\^4 copies/mL or\>2000 IU/mL);known hepatitis C virus(HCV)infection and HCV RNA positive(\>1×10\^3 copies/mL),or other hepatitis,cirrhosis;
18. Patients with severe heart,lung,liver,or kidney dysfunction,irreversible coagulation disorders,or other uncontrolled diseases(including hypertension or diabetes,active infections,mental illness,or social conditions that may affect patient compliance);
19. Other factors that may affect patient safety or trial compliance as judged by the investigator.

ii. Additional exclusion criteria for each cohort:

1. Colorectal Cancer :

   a) Patients with uncontrolled hypertension, defined as: patients with hypertension that cannot be well-controlled with a single antihypertensive agent (SBP ≥150 mmHg or DBP ≥100 mmHg); or patients who require two or more antihypertensive medications to control blood pressure.

   b）Patients with urine dipstick proteinuria ≥2+ and a 24-hour urinary protein level \>1.0 g.

   c）Patients with gastrointestinal diseases such as active gastric or duodenal ulcers, ulcerative colitis, or active bleeding from an unresected tumor; or other conditions judged by the investigator as potentially causing gastrointestinal bleeding or perforation.

   d）Patients with evidence or history of a significant bleeding tendency within 3 months prior to enrollment (e.g., bleeding \>30 mL, hematemesis, melena, hematochezia), hemoptysis (\>5 mL of fresh blood within 4 weeks), or a thromboembolic event (including stroke and/or transient ischemic attack) within the past 12 months.

   e）Patients with clinically significant cardiovascular disease, including but not limited to, acute myocardial infarction, severe/unstable angina, or coronary artery bypass grafting within 6 months prior to enrollment.

   f）Congestive heart failure of New York Heart Association (NYHA) class \> II; ventricular arrhythmias requiring medication; or an ECG showing a QTc interval ≥480 milliseconds.

   g）Patients who are unable to take fruquintinib orally.
2. Triple-negative breast cancer :

   a) Patients who have previously received pucotenlimab treatment;
3. Melanoma :

   1. Patients who have previously received pembrolizumab or toripalimab treatment;
   2. Patients currently have uncontrolled hypertension,defined as:patients with hypertension that cannot be well controlled with monotherapy(systolic blood pressure≥150 mmHg,or diastolic blood pressure≥100 mmHg);or patients using two or more antihypertensive drugs to control blood pressure;
   3. Urine routine indicates proteinuria≥2+,and 24-hour urine protein\>1.0g;
   4. Significant clinically meaningful cardiovascular diseases,including but not limited to acute myocardial infarction,severe/unstable angina,or coronary artery bypass grafting within 6 months before enrollment;
   5. Congestive heart failure New York Heart Association(NYHA)classification\>2;ventricular arrhythmias requiring drug treatment;electrocardiogram(ECG)showing QTc interval≥480 milliseconds.