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

This prospective, multicenter, single-arm, open-label, phase II clinical trial evaluates the efficacy and safety of first-line ipilimumab N01 plus sintilimab and lenvatinib in patients with locally advanced or metastatic TFE3-rearranged renal cell carcinoma (TFE3-rRCC). TFE3-rRCC is a rare, aggressive renal cell carcinoma subtype with no established standard first-line systemic therapy. Preliminary retrospective data suggest that immune checkpoint inhibitor-based combination therapy may improve clinical outcomes in this population.

Eligible patients (age ≥14 years; ECOG performance status ≤2) must have histologically confirmed, locally advanced or metastatic TFE3-rRCC diagnosed by fluorescence in situ hybridization (FISH) and/or next-generation sequencing, with measurable disease per RECIST v1.1, and no prior systemic therapy (or prior targeted therapy ≤1 month with adequate washout). A total of 66 participants will be enrolled using a Simon two-stage optimal design (21 patients in stage 1; 39 in stage 2).

Participants will receive ipilimumab N01 1 mg/kg intravenously every 6 weeks for the first 4 cycles (induction); sintilimab 200 mg intravenously every 3 weeks for up to 35 cycles (approximately 2 years); and lenvatinib 12 mg (body weight ≥60 kg) or 8 mg (body weight <60 kg) orally once daily continuously until disease progression, unacceptable toxicity, or loss of clinical benefit.

The primary endpoint is objective response rate (ORR) assessed by investigators according to RECIST v1.1. Secondary endpoints include disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), cancer-specific survival (CSS), ORR and DCR per imRECIST, safety profile according to NCI CTCAE v5.0, and quality of life measured by EORTC QLQ-C30, FKSI-DRS, EuroQOL, and VAS. Exploratory analyses will evaluate biomarkers (tumor tissue PD-1, PD-L1, CD4, CD8, tumor-infiltrating lymphocytes, tumor mutational burden; peripheral blood cytokines, circulating tumor DNA, immune cell subsets by single-cell sequencing) and functional MRI sequences as potential predictors of treatment response.

Inclusion criteria

• 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.

Exclusion criteria

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