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 phase II, multicenter, single-arm, open-label study evaluates first-line ipilimumab N01 plus sintilimab and lenvatinib in patients with locally advanced or metastatic TFE3-rearranged renal cell carcinoma (TFE3-rRCC), a rare subtype lacking established first-line systemic therapy. Eligible patients (age ≥14 years, ECOG ≤2, measurable disease per RECIST v1.1, no prior systemic therapy) will receive ipilimumab N01 1 mg/kg Q6W for 4 cycles, sintilimab 200 mg Q3W for up to 35 cycles, and lenvatinib 12 mg or 8 mg QD continuously. The primary endpoint is objective response rate (ORR) per RECIST v1.1. Secondary endpoints include disease control rate, duration of response, progression-free survival, overall survival, safety per NCI CTCAE v5.0, and quality of life. Exploratory biomarker analyses will assess potential predictors of treatment response.

Study Overview

• Status: Not yet recruiting
• Conditions: Immunotherapy; Molecular Targeted Therapy; Renal Cell Carcinoma (Kidney Cancer)
• Intervention / Treatment: Drug: Ipilimumab Injection; Drug: Sintilimab injection; Drug: Lenvatinib

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 66
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Hao Zeng, Doctor; Phone Number: +86-18980602129; Email: kucaizeng@163.com

Study Locations

• China
  • Chengdu, China
    • West China Hospital, Chengdu, Sichuan 610000
    • Contact: Xingming Zhang, Doctor; Phone Number: +86-18782258490; Email: Jarmin@scu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥14 years, any gender.
2. Histologically confirmed locally advanced or metastatic TFE3-rearranged renal cell carcinoma (TFE3-rRCC) by FISH and/or next-generation sequencing.
3. Stage IV disease per the 2017 8th edition TNM staging system.
4. 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).
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
6. Life expectancy ≥3 months.
7. Signed informed consent and ability to comply with study visits and procedures.
8. Willingness to provide tumor tissue and blood specimens for correlative studies.
9. 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:

1. Active central nervous system metastases.
2. 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.
3. Major surgery or severe trauma within 4 weeks prior to enrollment.
4. 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).
5. 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.
6. Known hypersensitivity to ipilimumab N01, sintilimab, or lenvatinib.

7. 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.

8. 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.
9. Pregnant or lactating women.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Combination treatment group; Participants receive ipilimumab 1 mg/kg intravenously every 6 weeks for the first 4 cycles (induction phase) in combination with sintilimab 200 mg intravenously every 3 weeks for up to 35 cycles (approximately 2 years), plus 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.

Drug: Ipilimumab Injection; A human monoclonal antibody targeting CTLA-4.; Other Names: Ipilimumab; Drug: Sintilimab injection; Recombinant human-derived immunoglobulin G (IgG4)-type anti-programmed cell death receptor-1 (PD-1) monoclonal antibody, by binding to PD-1 and blocking PD-1 binding to PD-L1 and PD-L2, disarms the immunosuppressive effect, activates T-cell function, and enhances T-cell immunosurveillance and killing ability against tumors to generate tumor immune response.; Other Names: Sintilimab; Drug: Lenvatinib; A multi-target tyrosine kinase inhibitor (VEGFR1-3, FGFR1-4, PDGFRα, KIT, RET).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	Objective response rate is the proportion of participates with complete response (CR) or partial response (PR), based on RECIST1.1.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	Progression-free survival is assessed by investigators based on RECIST1.1, including disease progression or death from any cause.	3 years
Overall Survival (OS)	Overall survival is the time from starting treatment to still being alive.	3 years
Adverse Events (AEs)	Adverse events are the incidence of treatment-emergent adverse events as assessed by CTCAE v5.0, including type and severity.	3 years
Disease Control Rate (DCR)	Disease control rate is the proportion of participates with complete response (CR), partial response (PR) or stable disease (SD), based on RECIST1.1.	3 years
Duration of Response (DoR)	Duration of response is the time from first response (complete or partial response) to disease progression or death.	3 years
Cancer-Specific Survival (CSS)	The period from the time the patient was diagnosed with the tumor or began treatment until death directly caused by the tumor	3 years
Quality of Life, European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30（EORTC QLQ-C30）	Used to assess the multi-dimensional impact of cancer treatment on the quality of life of patients	3 years
Functional Assessment of Cancer Therapy Kidney Syndrome Index-Disease-Related Symptoms （FKSI-DRS）	Used to assess the impact of specific symptoms related to kidney cancer on quality of life	3 years
European Quality of Life （EuroQOL）	Used to assess the current overall health status of the patient	3 years
Visual Analogue Scale（VAS）	Used to assess the pain condition and severity of the patients	3 years

Collaborators and Investigators

• Sponsor: West China Hospital
• Investigators: Principal Investigator: Hao Zeng, Doctor, West China Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: July 15, 2026
• First Submitted That Met QC Criteria: July 15, 2026
• First Posted (Actual): July 20, 2026

Study Record Updates

• Last Update Posted (Actual): July 20, 2026
• Last Update Submitted That Met QC Criteria: July 15, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Sintilimab; lenvatinib; ipilimumab
• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Urologic Neoplasms; Carcinoma; Carcinoma, Renal Cell; Kidney Neoplasms; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Ipilimumab; sintilimab; lenvatinib
• Other Study ID Numbers: LIST

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: There is a plan to make IPD and related data dictionaries available.
• IPD Sharing Time Frame: Data would be available starting from the time when summary data are published or otherwise made available, for 3 years.
• IPD Sharing Access Criteria: Other researchers access the data by sending an email to our PI.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No