Vorolanib Plus Sintilimab for Advanced Renal Cell Carcinoma After Failure of Prior Immune Checkpoint Inhibitors Based Combination Therapy

This Phase II trial assesses Vorolanib and Sintilimab for advanced renal cell carcinoma after previous therapy failure. Participants receive the treatment until disease progression, intolerable side effects, death, or withdrawal. The primary endpoint is progression-free survival (PFS).

This is a Phase II, multicenter, single-arm clinical trial designed to assess the efficacy and safety of Vorolanib in combination with Sintilimab in treating advanced renal cell carcinoma following the failure of prior immune checkpoint inhibitors based combination therapy. Participants will continue to receive Vorolanib and Sintilimab until disease progression, development of unacceptable toxic effects, death, or if the physician or patient decides to withdraw from the study. The primary endpoint is progression-free survival (PFS) according to RECIST v1.1 criteria as evaluated by the investigators.

Eligibility Criteria:
Inclusion Criteria:

1. Age ≥18 years and ≤75 years, any gender.
2. Histologically confirmed diagnosis of renal cell carcinoma.
3. Diagnosis of metastatic renal cell carcinoma or TNM stage IV (according to the 2017 TNM staging system). Evidence of distant metastasis by imaging or pathology.
4. Prior immune checkpoint inhibitors based combination therapy, dual immune combination, or immune monotherapy with disease progression, or who have received second/third line targeted monotherapy, immune monotherapy, or a change in immune-based combination therapy after failure of one of the above therapies for no more than 1 month and have completed the washout period. ECOG performance status ≤2.
5. Life expectancy of at least 3 months.
6. Signed informed consent and ability to comply with the protocol-specified visits and procedures.
7. Agreement to provide tumor tissue and blood specimens required for the study.
8. Adequate organ and bone marrow function as follows: absolute neutrophil count (ANC) ≥1×10\^9/L, platelets (PLT) ≥50×10\^9/L, hemoglobin (HGB) ≥80g/L; liver function: serum total bilirubin (TBIL) ≤3 times the upper limit of normal (ULN), alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤5 times ULN, serum albumin (ALB) ≥20 g/L; renal function: serum creatinine (Cr) ≤3×ULN.

Exclusion Criteria:

1. Pathologically diagnosed with non-renal cell carcinoma, collecting duct carcinoma.
2. First-line treatment with targeted monotherapy, or progression after first-line immune checkpoint inhibitors based combination therapy, followed by more than 1 month of treatment with targeted therapies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies, or anti-CTLA-4 antibodies specifically targeting T cell co-stimulation or checkpoint pathways and/or incomplete washout period.
3. Active brain metastases.
4. Personal history of other malignant tumors within 3 years with a different primary site or histology than that being evaluated in this study, excluding patients with well-controlled basal cell carcinoma, squamous cell carcinoma, or cervical intraepithelial neoplasia.
5. Major surgery or severe trauma within 4 weeks prior to enrollment.
6. Subjects with conditions requiring systemic corticosteroids (\>10mg/day prednisone or equivalent) or other immunosuppressive medications within 14 days prior to initial study drug administration. Subjects with inactive autoimmune disease are allowed to receive local, ophthalmic, intra-articular, intranasal, inhaled corticosteroids, or adrenal replacement steroids (\>10mg/day prednisone dose or equivalent).
7. Known or suspected active autoimmune disease (congenital or acquired), such as interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, thyroiditis, etc. Subjects with type 1 diabetes, thyroid dysfunction requiring only hormone replacement therapy, skin diseases (such as vitiligo, psoriasis, or alopecia) that do not require systemic treatment, or conditions expected not to recur in the absence of external triggering factors are allowed to participate in this study. Known allogeneic organ transplant (excluding corneal transplant) or allogeneic hematopoietic stem cell transplant.
8. Allergy to any component of monoclonal antibodies.
9. Uncontrolled other severe diseases, including but not limited to:

   1. Severe infection in the active or poorly controlled clinical phase;
   2. HIV infection (HIV antibody positive);
   3. Acute or chronic active hepatitis B (HBsAg positive and HBV DNA \>1\*103/ml) or acute or chronic active hepatitis C (HCV antibody positive and HCV RNA \>15IU/ml);
   4. Active pulmonary tuberculosis, etc.
10. NYHA class III-IV congestive heart failure, persistent symptomatic arrhythmia, uncontrolled atrial fibrillation; multiple echocardiographic assessments of left ventricular ejection fraction (LVEF) lower than the lower limit of normal.
11. Uncontrolled hypertension (systolic blood pressure ≥160mmHg and/or diastolic blood pressure ≥100mmHg);
12. Any arterial thrombosis, embolism, or ischemia in the past 6 months prior to enrollment, such as myocardial infarction, unstable angina, cerebrovascular accident or transient ischemic attack, etc.;
13. Diseases requiring warfarin (coumarin) anticoagulant therapy;
14. Uncontrolled hypercalcemia (calcium ion \>1.5 mmol/L or calcium \>12 mg/dL or corrected serum calcium \>ULN), or symptomatic hypercalcemia requiring continued bisphosphonate therapy;
15. Uncontrolled adrenal insufficiency;
16. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months;
17. Severe, non-healing wounds or ulcers;
18. Gastrointestinal diseases with impaired gastrointestinal function (such as malabsorption, ulcerative disease, uncontrollable nausea, vomiting, diarrhea, or small bowel resection);
19. Other acute or chronic diseases, mental illnesses, or laboratory abnormalities that may lead to the following outcomes: increased risk associated with study participation or drug administration, or interference with interpretation of study results, and deemed ineligible for study participation at the discretion of the investigator;
20. Pregnant or lactating women.