Is Prolonged Systemic Immunotherapy Necessary After Achieving Tumor-free Status in Patients With Extensive Transurethrally Unresectable Very-high-risk NMIBC?

Official title

Randomized Trial of Active Surveillance Versus Continued Systemic Immunotherapy After Achieving Tumor-Free Status in Extensive Transurethrally Unresectable Very-High-Risk NMIBC

Overview

Patients with extensive transurethrally unresectable very-high-risk non-muscle-invasive bladder cancer (NMIBC) may achieve a tumor-free status after systemic immunotherapy-based bladder-sparing treatment combined with transurethral resection of bladder tumor (TURBT). However, the optimal duration of systemic immunotherapy after achieving a tumor-free status remains uncertain. Prolonged treatment may increase toxicity, treatment burden, and cost, while some patients may maintain durable disease control without continued therapy. This randomized study aims to evaluate whether active surveillance after achieving tumor-free status is a feasible alternative to continued systemic immunotherapy in patients with extensive transurethrally unresectable very-high-risk NMIBC. Patients will initially receive systemic immunotherapy-based treatment followed by disease evaluation using cystoscopy with biopsy and/or TURBT, urine cytology, urinary tumor DNA (utDNA), and imaging assessments. Patients who achieve tumor-free status after treatment and complete resection of visible disease will be randomized to either active surveillance or continued systemic immunotherapy. The study will evaluate recurrence outcomes, bladder preservation, progression, safety, and patient management strategies following achievement of tumor-free status. The trial also aims to explore the role of urinary tumor DNA in identifying patients who may safely undergo treatment de-escalation and active surveillance.

Interventions

• Behavioral Active Surveillance
  Patients undergo protocol-defined surveillance after achieving tumor-free status, including cystoscopy, biopsy as clinically indicated, urine cytology, urinary tumor DNA testing, and imaging assessments, without continued systemic PD-1/PD-L1 inhibitor therapy unless disease recurrence or progression occurs.
• Drug PD-1/PD-L1 Inhibitor-Based Systemic Immunotherapy
  Patients continue protocol-defined systemic PD-1/PD-L1 inhibitor therapy after achieving tumor-free status for up to approximately 1 year, with ongoing surveillance including cystoscopy, urine cytology, urinary tumor DNA testing, and imaging assessments.

Primary outcome measures

• Bladder-intact event-free survival (BI-EFS) [Time frame: Up to 2 years from randomization]

Secondary outcome measures (5)

• Recurrence-free survival (RFS) [Time frame: Up to 2 years from randomization]
• Progression-free survival (PFS) [Time frame: Up to 2 years from randomization]
• Radical cystectomy-free survival (RCFS) [Time frame: Up to 2 years from randomization]
• Overall survival (OS) [Time frame: Up to 2 years from randomization]
• Incidence of treatment-related adverse events [Time frame: Up to 2 years from randomization]

Eligibility criteria

Inclusion criteria

• Has histologically confirmed very-high-risk non-muscle-invasive urothelial carcinoma of the bladder.
• Has transurethrally unresectable bladder tumor, defined as visually incomplete TURBT and/or extensive high-volume disease considered unsuitable for complete and oncologically adequate transurethral resection.
• Has undergone cystoscopy and TURBT evaluation before study enrollment.
• Has received systemic PD-1/PD-L1 inhibitor-based bladder-sparing therapy before randomization.
• Has achieved tumor-free status before randomization, defined as:

• No visible bladder tumor on cystoscopy;
• Negative bladder biopsy and/or TURBT pathology;
• Negative urine cytology;
• Negative urinary tumor DNA (utDNA);
• No radiographic evidence of progression or metastasis.
• Has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
• Has adequate organ function.
• Has provided written informed consent.

Cohort A Only

• Achieved tumor-free status at the initial response evaluation after induction systemic therapy.
• Maintained tumor-free status after additional systemic therapy before randomization.

Cohort B Only

• Did not achieve tumor-free status at the initial response evaluation because of residual non-muscle-invasive disease.
• Subsequently underwent complete TURBT/resection of residual disease followed by additional systemic therapy.
• Achieved tumor-free status at the second response evaluation before randomization.

Exclusion criteria

• Has muscle-invasive bladder cancer (≥T2), locally advanced unresectable disease, nodal disease, or distant metastasis.
• Has concurrent upper tract urothelial carcinoma.
• Has persistent visible tumor, positive bladder pathology, positive urine cytology, or positive utDNA before randomization.
• Has received prior systemic immunotherapy for metastatic urothelial carcinoma.
• Has active autoimmune disease requiring systemic treatment.
• Is receiving systemic immunosuppressive therapy.
• Has uncontrolled infection requiring systemic therapy.
• Has another active malignancy requiring systemic treatment.
• Has known active hepatitis B, hepatitis C, human immunodeficiency virus infection, or active tuberculosis.
• Has pregnancy or breastfeeding.
• Has any medical or psychiatric condition that, in the investigator's judgment, would interfere with study participation or interpretation of results.

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 · 4 centers

• The Second Hospital of Tianjin Medical University — Tianjin
• General Hospital of Tianjin Medical University — Tianjin
• Tianjin Hospital — Tianjin
• Xingtai People's Hospital — Xingtai

Identifiers

NCT: NCT07625527 · Truce-LB03

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗