Cryoablation Plus Camrelizumab for Advanced Soft Tissue Sarcoma

A Prospective, Single-Center, Single-Arm Phase II Clinical Trial of Cryoablation Combined With Camrelizumab in the Treatment of Advanced or Unresectable Soft Tissue Sarcoma Refractory to Standard Therapy

The main purpose of this trial is to investigate and evaluate the efficacy of cryoablation combined with camrelizumab treatment to patients with advanced or inoperable soft tissue sarcomas after standard treatment failure.

Soft tissue sarcoma is a malignant tumor originating from mesenchymal tissues, characterized by high heterogeneity. It accounts for 15% to 20% of malignant solid tumors in children and 1% in adults. Although its incidence rate is relatively low, most cases are highly malignant and carry a poor prognosis, with a 5-year survival rate of less than 20% for advanced patients.

In recent years, tumor immunotherapy has emerged as a promising approach for treating malignant tumors alongside surgery, chemotherapy, and radiotherapy. This approach mainly includes immune checkpoint blockade, immunomodulators, adoptive cellular immunotherapy, and tumor vaccines. Among these, PD-1/PD-L1 immune checkpoint inhibitors have shown good efficacy in various solid tumors, such as non-small cell lung cancer and malignant melanoma. PD-1 antibodies have also demonstrated some efficacy in specific types of soft tissue sarcomas, including pleomorphic undifferentiated sarcoma and alveolar soft part sarcoma.

Tumor cryoablation therapy has been successfully applied for local control in multiple tumor types. Cryoablation involves freezing and rewarming, which physically damages tumor tissues. The freeze-thaw process causes tumor cell rupture, generating specific tumor antigens and triggering both specific and non-specific anti-tumor immune responses. This therapy offers precise targeting with a short recovery period.

By cryoablating tumor lesions locally, tumor-specific antigens are generated, enabling the immune system to recognize tumor cells more effectively. Meanwhile, camrelizumab is administered to enhance the immune cells' ability to target and destroy tumor cells. This study primarily aims to evaluate the efficacy and safety of cryoablation combined with the PD-1 antibody camrelizumab in the treatment of advanced or inoperable soft tissue sarcomas that have failed standard treatment, providing a basis for Phase III clinical research.

Inclusion Criteria:

1. Before any procedures related to the research program, including screening and evaluation stage, signed informed consent.
2. Age≥14 years old, and≤70 years old ;
3. Pathologically diagnosed as soft tissue sarcomas, and staging for advanced or unresectable patients ;
4. Patients with standard treatment (such as chemotherapy) failure ;
5. No previous treatment with PD-1 antibody ; or those who have previously received PD-1 antibody therapy and progressed at least half a year later;
6. According to the RECIST1.1 standard, there are ≥3 measurable lesions; the distribution sites of multiple lesions are in ≤3 organs (which may include the abdominopelvic cavity, extremities, liver, lungs, pleura, etc.); the size of the target lesions is 1.0 - 5.0 cm.
7. ECOG score 0-1 ( see Appendix ) and expected survival time greater than 3 months ;
8. Patients with brain metastasis who were stable for at least one month after treatment and who do not require the use of glucocorticoids can be included.
9. echocardiography showed left ventricular ejection fraction ≥ 50 %;
10. The results of laboratory tests should meet at least the following indicators :

（1）White blood cell count ≥ 3.0 × 109 / L; （2）absolute neutrophil count ( ANC ) ≥ 1.5 × 109 / L ( without GCSF support ) ; （3）absolute lymphocyte count ( ALC ) ≥ 1.0 × 109 / L; （4）platelet ( PLT ) ≥ 75 × 109 / L; （5）hemoglobin ≥ 10g / dL ( no blood transfusion in the past 7 days ) ; （6）Prothrombin time or INR ≤ 1.5x normal upper limit time, unless receiving anticoagulant therapy; （7）partial thromboplastin time ( APTT ) ≤ 1.5x normal upper limit time, unless receiving anticoagulant therapy; （8）serum creatinine ≤ 1.5 × ULN ( upper limit of normal ) ; 24-hour creatinine clearance rate ≥ 60 mL / min; （9）Aspartate Aminotransferase (AST/SGOT) ≤ 2 × ULN or 5×ULN (for patients with liver metastases).; （10）Alanine Aminotransferase (ALT/SGPT) ≤ 2 × ULN or 5×ULN (for patients with liver metastases).; （11）total bilirubin ( TBIL ) ≤ 1 × ULN 11. Females with fertility were negative in pregnancy test before treatment ; consent must be given to the use of contraception or the prohibition of same-sex or opposite-sex sexual activity during treatment.

12. During the whole experiment, we can regularly go to the research institutions to carry out relevant testing, evaluation and management.

Exclusion Criteria:

1. Concurrently having other malignant tumors within 5 years.;
2. Patients who received major surgeries, conventional chemotherapy, large-area radiotherapy, biotherapy or interventional ablation therapy for anti-tumor treatment within 4 weeks before entering the trial;
3. known for any component of this test treatment will produce allergic reactions ;
4. No recovery from previous surgery or treatment-related adverse reactions to < Level 2 CTCAE;
5. Uncontrolled hypertension ( systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 90 mmHg ) or clinically significant cardiovascular and cerebrovascular diseases ( such as activity ), such as cerebrovascular accident ( within 6 months before the signing of informed consent ), myocardial infarction ( within 6 months before the signing of informed consent ), unstable angina, New York Heart Association ( Appendix ) grade II or above congestive heart failure, or severe arrhythmia can not be controlled with drugs or have a potential impact on research and treatment ; the electrocardiogram showed obvious abnormality or average QTc interval ≥ 450 milliseconds in three consecutive times.
6. Combined with other serious organic diseases and mental disorders;
7. Patients with systemic active infections requiring treatment, including active tuberculosis, known HIV-positive patients or clinically active hepatitis A, B, and C patients, in the case of chronic hepatitis B virus infection, the HBV-DNA level should be ≤ 10E3.
8. Patients with autoimmune diseases : patients with a history of inflammatory bowel disease and a history of autoimmune diseases ( such as systemic lupus erythematosus, vasculitis, and invasive lung disease ) that were judged by the researchers to be unsuitable for this study need to be excluded. (Patients with vitiligo and those with Hashimoto's thyroiditis with normal thyroid function will not be excluded.)
9. During the 4 weeks prior to therapy, if there has been use of chronic systemic corticosteroids, hydroxyurea, immunomodulatory drugs (such as interleukin-2, α or γ interferons, GM-CSF, mTOR inhibitors, cyclosporine, thymosin, etc.).
10. History of organ transplantation, autologous / allogeneic stem cell transplantation and renal replacement therapy;
11. known uncontrolled diabetes, pulmonary fibrosis, interstitial lung disease, acute lung disease or liver failure;
12. Known alcohol and/or drug abuse;
13. Pregnant or lactating women;
14. With any researchers determine that may damage the test carried out in the coexistence of medical conditions or diseases of the test;
15. No legal capacity / limited capacity.