Hyperthermic Intravesical Chemotherapy (HIVEC) in BCG-Non-Responsive High-Grade NMIBC Patients

Hyperthermic Intravesical Chemotherapy (HIVEC) In Patients With BCG-Non Responsive Or Intolerant High-Grade BCG-Infiltrating Non-Muscle-Infiltrating Bladder Cancer And Not Eligible For Radical Cystectomy: Phase II Study (SMG-Bladder 01).

This is a Phase II, prospective, single-arm, open-label clinical study evaluating hyperthermic intravesical chemotherapy (HIVEC) with Mitomycin C in patients with high-grade, non-muscle-invasive bladder cancer (NMIBC) who are BCG-non-responsive or BCG-intolerant and are ineligible for, or refuse, radical cystectomy. Mitomycin C is an approved medicinal product used within routine clinical practice and administered with a CE-marked recirculation device (BRS Combat system) that maintains the solution at approximately 43°C for 60 minutes. The treatment schedule consists of 6 weekly induction instillations followed by 9 monthly maintenance instillations.

The co-primary objectives are to describe the safety and toxicity profile of HIVEC, including treatment discontinuations due to procedure-related toxicity, and to estimate the 12-month recurrence-free survival (12moRFS). Secondary objectives include characterizing patterns of non-muscle-invasive and muscle-invasive recurrences, bladder cancer-specific survival, overall survival, and quality of life. Approximately 50 patients will be enrolled in this single-center pilot study to generate exploratory safety and efficacy data in this high-risk population and to support the design of future randomized trials

This is an interventional, prospective, single-center, single-arm, open-label, Phase II study conducted in patients with high-grade non-muscle-invasive urothelial carcinoma of the bladder (NMIBC) who are BCG-non-responsive or BCG-intolerant according to European Association of Urology criteria, and who are either not eligible for, or decline, radical cystectomy. Radical cystectomy remains the standard of care in this setting, but many patients are unfit because of age or comorbidities or are unwilling to undergo major surgery. Hyperthermic intravesical chemotherapy (HIVEC) has emerged as a potential alternative option for disease control in these high-risk patients. 

In this study, Mitomycin C 80 mg in 80 mL of sterile water is administered intravesically using the CE-marked BRS Combat recirculation system, which keeps the solution at a controlled temperature of about 43°C for 60 minutes. The treatment regimen includes an induction phase of 6 weekly instillations followed by a maintenance phase of 9 monthly instillations. Therapy may be discontinued earlier in the event of disease progression or unacceptable toxicity. Mitomycin C is purchased by the ASL Napoli 2 Nord as part of routine care, with costs reimbursed by the sponsor, while the device and related disposables are supplied on loan for use for the study. 

The co-primary endpoints are: (1) toxicity and safety, including the type, incidence, severity, and timing of adverse events graded according to NCI CTCAE v5.0 and PRO-CTCAE, and the proportion of patients who discontinue treatment due to procedure-related toxicity; and (2) 12-month recurrence-free survival (12moRFS), defined as the time from first instillation to recurrence or progression (Ta, T1, or CIS) or death from any cause, with estimates obtained using the Kaplan-Meier method. Secondary endpoints include the rate of Ta-T1 non-muscle-invasive recurrences, the proportion of muscle-invasive recurrences (≥T2), bladder cancer-specific survival, overall survival, and quality of life assessed with the EORTC QLQ-NMIBC24 questionnaire at predefined time points during treatment and follow-up. 

Approximately 50 patients will be enrolled between November 2025 and November 2026 at the Oncology and Urology Units of the "S. Maria delle Grazie" Hospital in Pozzuoli (ASL Napoli 2 Nord). Data will be recorded in an electronic database using anonymized patient codes. Statistical analyses will be primarily descriptive and exploratory, reflecting the monocentric, non-comparative design and the pilot nature of the study, with the aim of characterizing the safety profile of HIVEC and providing a preliminary estimate of 12-month recurrence-free survival and overall disease control in this population.

Inclusion Criteria:

• Age ≥ 18 years.
• Histologically confirmed high-grade non-muscle-invasive bladder cancer (NMIBC), including Ta, T1, and/or carcinoma in situ (CIS).
• BCG-unresponsive or BCG-intolerant disease according to international definitions (persistent or recurrent high-grade NMIBC after adequate BCG therapy).
• Patient is ineligible for, or refuses, radical cystectomy.
• Candidate for hyperthermic intravesical chemotherapy (HIVEC) according to clinical judgment.
• ECOG Performance Status 0-2.
• Adequate organ function according to institutional standards.
• Ability and willingness to comply with study procedures and follow-up schedule.
• Written informed consent obtained.

Exclusion Criteria:

• Muscle-invasive bladder cancer (≥ T2) or metastatic disease.
• Active urinary tract infection at baseline.
• Previous treatment with HIVEC or other intravesical hyperthermia systems.
• Known hypersensitivity to Mitomycin C or contraindications to intravesical chemotherapy.
• Active uncontrolled bleeding or gross hematuria preventing intravesical instillation.
• Upper urinary tract urothelial carcinoma.
• Pregnant or breastfeeding women.
• Any medical or psychological condition that, in the investigator's judgment, could interfere with study participation or compromise patient safety.