An Exploratory Study on the Failure of Immunotherapy With Vorolanib Combined With Everolimus

Prior treatment

• Previously only received single-drug targeted drug therapy against VEGF/VEGFR or mTOR；
• Subjects currently receiving antitumor therapy (e.g., chemotherapy, radiation therapy, immunotherapy, biotherapy, hormone therapy, surgery, and/or tumor embolization, but excluding local radiation therapy for bone metastases) may be enrolled if they have a half-life of 5 years after the end of drug therapy；
• Progression after previous mTOR therapy (monotherapy or combination)；
• Myocardial infarction, percutaneous coronary intervention, acute coronary syndrome, coronary artery bypass grafting, New York Heart Association (NYHA) class III/IV congestive heart failure, cerebrovascular accident, transient ischemic attack, or rest leg claudication occurring within the 12 months prior to randomization;
• Deep vein thrombosis or pulmonary embolism occurring within 6 months prior to randomization;
• Any major surgery performed within 4 weeks prior to randomization;
• Active autoimmune diseases requiring systemic treatment in the past two years (such as treatment with disease-modifying drugs, corticosteroids, or immunosuppressants);
• Any condition affecting the subject's ability to swallow medication or any condition affecting the absorption or pharmacokinetics of the investigational drug, including any history of gastrointestinal resection or surgery;

Other illness

• Conditions of the subjects' organ systems:
  • Presence of significant pleural effusion or ascites with clinical symptoms requiring symptomatic treatment; brain metastases, or epidural metastases;
• Subjects who have had other malignancies within the past 5 years (excluding non-melanoma skin cancer, cervical carcinoma in situ, or successfully treated basal cell carcinoma or squamous cell carcinoma);
• Any uncontrolled clinical issues, including but not limited to, persistent or active infections, uncontrolled diabetes, decompensated liver cirrhosis;
• A clear history of mental illness that hinders understanding of the informed consent and compliance with the study protocol;
• Patients infected with the human immunodeficiency virus (HIV);
• Subjects known to be allergic to similar drugs;
• The presence of severe pulmonary disease, history of asthma or COPD, and pulmonary function tests indicating moderate to severe impairment.

• Clear cell carcinoma of the kidney is confirmed by pathology (histology or cytology);
• Have received systemic anti-tumor therapy with no more than 2 targeted drugs (excluding mTOR inhibitors) and 1 immune checkpoint inhibitor and failed treatment;
• Not less than 3 weeks after receiving the last systemic anti-tumor therapy (chemotherapy, radiotherapy, targeted therapy, biotherapy or endocrine therapy), Or not less than 5 half-lives since the last systemic antitumor treatment; And treatment-related toxicity was recovered to meet the laboratory test requirements for this study;
• ECOG score ≤ 1;
• Over 18 years old, and less than or equal to 75 years old; a life expectancy of more than 12 weeks
• According to RECIST 1.1 criteria: at least one measurable lesion;
• Organ function levels must meet the following requirements:
  • Bone marrow: blood test results must show hemoglobin ≥ 80 g/L, platelets ≥ 90 x 10\^9/L, absolute neutrophil count ≥ 1.5 x 10\^9/L; Liver: serum bilirubin ≤ 1.5 times the upper limit of normal, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times the upper limit of normal (if there is liver metastasis, AST and ALT ≤ 5 times the upper limit of normal are allowed); Serum creatinine \< 1.5 times the upper limit of normal; Urinary protein ≤ 2+, if urinary protein \> 2+, a 24-hour urine protein test must be collected with a total amount ≤ 2 grams; Well-controlled hypertensive patients; Echocardiogram shows left ventricular ejection fraction greater than 40%;
• For women of childbearing potential, the serum pregnancy test must be negative within 7 days prior to randomization;
• All enrolled subjects (regardless of gender) must use effective barrier contraceptive methods throughout the treatment period and for 4 weeks after treatment ends;
• Subjects must have the ability to understand and voluntarily sign the informed consent form, and the signing of the informed consent must occur prior to any study procedure.