EV + Toripalimab vs GC as Neoadjuvant Therapy in Locally Advanced/High-Risk MIBC

Official title

A Phase II, Two-arm, Open-label, Multicenter, Randomized Controlled Clinical Study Evaluating the Safety and Efficacy of Enfortumab Vedotin Combined With Toripalimab Versus Gemcitabine Combined With Cisplatin in the Neoadjuvant Treatment of Patients With Locally Advanced/High-risk Muscle-invasive Bladder Cancer

Overview

The purpose of this Phase II, open-label, multicenter, randomized controlled study is to evaluate the efficacy and safety of Enfortumab Vedotin in combination with Toripalimab compared to Gemcitabine plus Cisplatin. This regimen is evaluated as a neoadjuvant treatment for patients with locally advanced or high-risk muscle-invasive bladder cancer. Participants will be randomly assigned in a 1:1 ratio to one of two cohorts. Cohort A will receive Enfortumab Vedotin and Toripalimab for 3 treatment cycles. Cohort B will receive Gemcitabine and Cisplatin for 3 treatment cycles. Following the neoadjuvant treatment phase, patients will undergo radical cystectomy and pelvic lymph node dissection. The primary endpoint of the study is the 1-year Event-Free Survival (EFS) rate. Secondary endpoints include pathological downstaging rate (pDR), pathological complete response (pCR), Disease-Free Survival (DFS), Overall Survival (OS), and the assessment of adverse events. Additionally, the study will evaluate the relationship between treatment efficacy and the expression of PD-L1 and Nectin-4 in tumor tissues.

Interventions

• Drug enfortumab vedotin (EV)
  Enfortumab Vedotin is administered intravenously at a dose of 1.25 mg/kg on Day 1 and Day 8 of each 21-day cycle for a total of 3 cycles
• Drug Toripalimab
  Toripalimab is administered intravenously at a dose of 240 mg on Day 1 of each 21-day cycle for a total of 3 cycles.
• Drug Gemcitabine (Chemotherapy)
  Gemcitabine is administered intravenously at a dose of 1000 mg/m² on Day 1 and Day 8 of each 21-day cycle for a total of 3 cycles.
• Drug Cisplatin
  Cisplatin is administered intravenously at a dose of 70 mg/m² on Day 1 of each 21-day cycle for a total of 3 cycles.

Primary outcome measures

• 1-Year Event-Free Survival (EFS) Rate [Time frame: Up to 1 year post-surgery]

Secondary outcome measures (6)

• Pathological Complete Response (pCR) Rate [Time frame: At the time of radical surgery (Expected to be within 4-6 weeks after the last cycle of neoadjuvant therapy)]
• Pathological Downstaging Rate (pDR) [Time frame: At the time of radical surgery (Expected to be within 4-6 weeks after the last cycle of neoadjuvant therapy)]
• Disease-Free Survival (DFS) [Time frame: From the date of radical surgery up to study completion (Assessed every 12 weeks for the first 48 weeks, then every 24 weeks, estimated up to 3 years)]
• Overall Survival (OS) [Time frame: From the date of randomization up to study completion (Assessed every 12 weeks, estimated up to 3 years)]
• Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) [Time frame: From the first dose of study drug up to 28 days after the last dose (or before starting new anti-tumor therapy, whichever is earlier)]
• Biomarker Expression: Nectin-4 and PD-L1 [Time frame: Baseline (Screening) and at the time of radical surgery]

Eligibility criteria

Inclusion criteria

• Voluntarily agree to participate in the study and sign the informed consent form (ICF).
• Age ≥ 18 and ≤ 80 years at the time of signing the ICF.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Histologically confirmed muscle-invasive urothelial carcinoma of the bladder, with variant histology components comprising < 50%.
• Radiographically confirmed non-metastatic urothelial carcinoma (M0). Clinical stage must be locally advanced or possess high-risk features, including at least one of the following: clinical stage cT3-T4aNxM0, or definitive high-risk cT2 (e.g., accompanied by tumor-related hydronephrosis, lymphovascular invasion).
• Participants must be evaluated as fit for and scheduled to undergo radical surgery, and clinically fit to tolerate cisplatin-based chemotherapy.
• Able to provide tumor tissue samples (at least 5 unstained slides, or paraffin scrolls/blocks).
• Expected life expectancy of at least 12 weeks.
• Adequate organ function, defined by the following laboratory values (obtained without blood transfusion within 14 days or growth factor support within 7 days prior to testing): Absolute neutrophil count (ANC) ≥ 1.5 × 10\^9/L; Platelet count (PLT) ≥ 100 × 10\^9/L; Hemoglobin (Hb) ≥ 90 g/L; Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × Upper Limit of Normal (ULN); Total bilirubin (TBIL) ≤ 1.5 × ULN; International Normalized Ratio (INR) ≤ 1.5 × ULN; Creatinine clearance ≥ 60 mL/min (calculated using the Cockcroft-Gault formula); Left ventricular ejection fraction (LVEF) ≥ 50%; QTcF interval ≤ 480 ms.
• Female participants of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose of study treatment and must be willing to use highly effective contraception during the study and for 180 days after the last dose.
• Male participants with female partners of childbearing potential must be surgically sterile or willing to use highly effective contraception during the study and for 180 days after the last dose.
• Able to understand and comply with study visits, treatment plans, laboratory tests, and other study procedures.

Exclusion criteria

• Prior systemic anti-tumor therapy for urothelial carcinoma, including radiotherapy, chemotherapy, targeted therapy, or biological therapy (except for intravesical instillation therapy).
• Prior treatment with PD-1/PD-L1 inhibitors or antibody-drug conjugates (ADCs).
• Active malignancies other than urothelial carcinoma within 3 years prior to the first dose, except for curatively treated malignancies (e.g., basal or squamous cell skin cancer, localized low-risk prostate cancer, papillary thyroid cancer, carcinoma in situ of the cervix, ductal carcinoma in situ of the breast).
• Active autoimmune disease requiring systemic treatment (e.g., use of disease-modifying agents, corticosteroids, or immunosuppressants) within 2 years prior to the first dose; or received high-dose steroids (>10 mg/day prednisone equivalent) or other immunosuppressive medications within 14 days prior to the first dose. (Physiological replacement therapies are permitted).
• Severe thromboembolic events or severe cardiovascular/cerebrovascular diseases within 1 year prior to the first dose, including but not limited to myocardial infarction, unstable angina, pulmonary embolism, cerebral hemorrhage, cerebral infarction, and deep vein thrombosis.
• Major surgical procedure within 28 days prior to the first dose; or cystoscopy/ureteroscopy biopsy or intravesical therapy within 7 days prior to the first dose.
• Peripheral neuropathy ≥ Grade 2.
• Severe dry eye syndrome, active keratitis, corneal ulcers, or conditions assessed by the investigator as increasing the risk of corneal disease and unsuitable for participation.
• Active infections, including: Positive HBsAg with HBV-DNA copy number ≥ 500 IU/mL; Positive HCV antibody with positive HCV-RNA; Positive HIV antibody; Active tuberculosis infection; Other active infections requiring systemic therapy within 7 days prior to the first dose.
• Other severe or uncontrolled diseases, including but not limited to: Severe respiratory diseases (e.g., moderate-to-severe interstitial or obstructive pulmonary disease, severe asthma); New York Heart Association (NYHA) Class III or IV heart failure; HbA1c ≥ 8% (except for participants whose fasting blood glucose is stably controlled at ≤ 10 mmol/L with medication); Poorly controlled hypertension (systolic BP ≥ 160 mmHg and/or diastolic BP ≥ 100 mmHg); Large pleural effusion or ascites requiring symptomatic treatment within 14 days prior to the first dose.
• Receipt of live vaccines within 28 days prior to the first dose or plans to receive live vaccines during the study.
• Prior allogeneic hematopoietic stem cell transplantation or solid organ transplantation.
• Use of strong CYP3A4 inhibitors or inducers within 14 days prior to the first dose.
• Known severe hypersensitivity or intolerance to the study drugs or any of their excipients.
• Substance abuse or psychiatric disorders that may interfere with study compliance.
• Any other condition that, in the opinion of the investigator, makes the participant unsuitable for the study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Peking University Third Hospital — Beijing

Identifiers

NCT: NCT07647289 · LM2025412 · M20250227 · IRB00006761

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗