Renal Cell Carcinoma (Kidney Cancer), Immunotherapy, Molecular Targeted Therapy
Conditions
Keywords
Sintilimab, ipilimumab, lenvatinib
Brief summary
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.
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.
Interventions
A human monoclonal antibody targeting CTLA-4.
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.
DRUGLenvatinib
A multi-target tyrosine kinase inhibitor (VEGFR1-3, FGFR1-4, PDGFRα, KIT, RET).
Sponsors
West China Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
14 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | 3 years | Objective response rate is the proportion of participates with complete response (CR) or partial response (PR), based on RECIST1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events (AEs) | 3 years | Adverse events are the incidence of treatment-emergent adverse events as assessed by CTCAE v5.0, including type and severity. |
| Overall Survival (OS) | 3 years | Overall survival is the time from starting treatment to still being alive. |
| Progression-Free Survival (PFS) | 3 years | Progression-free survival is assessed by investigators based on RECIST1.1, including disease progression or death from any cause. |
| Disease Control Rate (DCR) | 3 years | Disease control rate is the proportion of participates with complete response (CR), partial response (PR) or stable disease (SD), based on RECIST1.1. |
| Duration of Response (DoR) | 3 years | Duration of response is the time from first response (complete or partial response) to disease progression or death. |
| Cancer-Specific Survival (CSS) | 3 years | The period from the time the patient was diagnosed with the tumor or began treatment until death directly caused by the tumor |
| Quality of Life, European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30（EORTC QLQ-C30） | 3 years | Used to assess the multi-dimensional impact of cancer treatment on the quality of life of patients |
| Functional Assessment of Cancer Therapy Kidney Syndrome Index-Disease-Related Symptoms （FKSI-DRS） | 3 years | Used to assess the impact of specific symptoms related to kidney cancer on quality of life |
| European Quality of Life （EuroQOL） | 3 years | Used to assess the current overall health status of the patient |
| Visual Analogue Scale（VAS） | 3 years | Used to assess the pain condition and severity of the patients |
Countries
China
Contacts
CONTACTHao Zeng, Doctor
PRINCIPAL_INVESTIGATORHao Zeng, Doctor
West China Hospital
Outcome results
None listed