Ipilimumab N01 Plus Sintilimab and Lenvatinib as First-line Therapy for Locally Advanced or Metastatic TFE3-Rearranged Renal Cell Carcinoma: A Prospective, Multicenter, Single-Arm, Phase II Clinical Trial

Prior treatment

• Major surgery or severe trauma within 4 weeks prior to enrollment.
• Systemic corticosteroids (\>10 mg/day prednisone equivalent) or other immunosuppressive agents within 14 days before first dose (topical, ophthalmic, intra-articular, intranasal, inhaled, or physiologic replacement steroids are permitted).

Other illness

• History of other malignancies within 3 years (different primary site or histology), except well-controlled basal cell carcinoma, squamous cell carcinoma, or cervical carcinoma in situ.
• Known or suspected active autoimmune disease (e.g., interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, thyroiditis), except type 1 diabetes, hypothyroidism requiring hormone replacement only, or skin conditions not requiring systemic treatment. Known allogeneic organ transplant (except corneal) or allogeneic hematopoietic stem cell transplant.
• Known hypersensitivity to ipilimumab N01, sintilimab, or lenvatinib.

Lab values

• Uncontrolled severe comorbidities including:
  • Active or poorly controlled severe infection. HIV infection. Active hepatitis B (HBsAg-positive and HBV DNA \>1×10³ IU/mL) or active hepatitis C (HCV antibody-positive and HCV RNA \>15 IU/mL).
  • Active pulmonary tuberculosis. New York Heart Association Class III-IV congestive heart failure, symptomatic arrhythmia, uncontrolled atrial fibrillation, or left ventricular ejection fraction below the lower limit of normal.
  • Uncontrolled arterial hypertension (systolic ≥160 mmHg or diastolic ≥100 mmHg). Arterial thrombosis, embolism, or ischemia within 6 months (e.g., myocardial infarction, unstable angina, cerebrovascular accident, transient ischemic attack).
  • Uncontrolled adrenal insufficiency. Severe, non-healing wounds or ulcers; gastrointestinal disorders impairing absorption; active uncontrolled bleeding or high bleeding risk (e.g., esophageal/gastric varices requiring intervention); or unstable anticoagulation with clinically significant bleeding.
• Any other acute or chronic medical or psychiatric condition, or laboratory abnormality, that in the opinion of the investigator increases the risk associated with study participation, may interfere with interpretation of study results, or makes the patient unsuitable for the study.

Other

• Active central nervous system metastases.
• Pregnant or lactating women.

• Age ≥14 years, any gender.
• Histologically confirmed locally advanced or metastatic TFE3-rearranged renal cell carcinoma (TFE3-rRCC) by FISH and/or next-generation sequencing.
• Stage IV disease per the 2017 8th edition TNM staging system.
• No prior systemic therapy with immune checkpoint inhibitors (PD-1/PD-L1 inhibitors) or targeted agents (TKI, mTORi); prior targeted therapy ≤1 month is allowed after an adequate washout (5.5 half-lives).
• Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
• Life expectancy ≥3 months.
• Signed informed consent and ability to comply with study visits and procedures.
• Willingness to provide tumor tissue and blood specimens for correlative studies.
• Adequate organ and bone marrow function within 14 days prior to enrollment:
  • Hematology: ANC ≥1.5×10⁹/L, platelets ≥100×10⁹/L, hemoglobin ≥90 g/L. Hepatic: TBIL ≤1.5×ULN, ALT/AST ≤2.5×ULN, albumin ≥20 g/L. Renal: serum creatinine ≤1.5×ULN or creatinine clearance ≥50 mL/min.