Toripalimab ± Sequential Intravesical Gemcitabine-Mitomycin C for BCG-Unresponsive/-Intolerant High-Risk NMIBC: Open-Label Randomized Phase 2 Study

Rationale and Objectives. A substantial proportion of HR-NMIBC patients are BCG-unresponsive or BCG-intolerant and face early high-grade recurrence and consideration of cystectomy. This trial evaluates whether adding sequential intravesical chemotherapy (gemcitabine followed by mitomycin C in the same visit) to systemic PD-1 blockade (toripalimab) improves outcomes versus toripalimab alone.

Design. Prospective, open-label, randomised (1:1), parallel-group, phase 2 study at multiple centres in China. Treatment continues until recurrence/progression, unacceptable toxicity, withdrawal, or completion of 24 months.

Interventions.

Arm A (Combination): Toripalimab 240 mg IV every 3 weeks (Q3W) up to 24 months plus intravesical GEM→MMC: gemcitabine 1,000 mg retained ~60 min and drained, then mitomycin C 40 mg retained ~60 min; administered weekly for 6 weeks (induction) and then maintenance every 4 weeks (Q4W) up to month 24 if no high-grade recurrence.

Arm B (Monotherapy): Toripalimab 240 mg IV Q3W up to 24 months.

Assessments. Cystoscopy and urine cytology at months 3, 6, 9, 12 and every 3 months thereafter; abdominopelvic/upper-tract CT or MRI every 24 weeks; routine laboratory tests prior to dosing/instillation. (Exploratory tissue/urine/blood sampling may be performed per protocol.)

Primary Endpoints.

CIS cohort: CR rate at month 3 (proportion). CR is met by any of the following protocol-specified scenarios indicating no high-grade bladder disease: (a) negative urine cytology and negative cystoscopy; (b) negative cytology with cystoscopic lesions that are benign or low-grade Ta on biopsy; or (c) negative cystoscopy with positive cytology attributed to tumour in the upper tract or prostatic urethra and random bladder biopsies negative.

Non-CIS cohort: Median RFS, defined as time from start of treatment to high-grade Ta recurrence, any T1, or new CIS. Recurrence requires cystoscopic suspicion confirmed by histopathology; if cytology becomes positive prior to histologic confirmation, the recurrence date is set at the first positive cytology once recurrence is subsequently confirmed.

Secondary Endpoints.

CIS cohort: CR rates at months 6, 12, 18, and 24; PFS rates at the same landmarks (progression defined as lamina propria invasion from Ta/CIS to T1, progression to ≥T2, or new nodal/distant metastasis); OS at month 24, EOT+6 months, and EOT+12 months; incidence of adverse events (AEs).

Non-CIS cohort: RFS rates at months 6, 12, 18, and 24; high-grade RFS (HG-RFS) rates at the same landmarks (high-grade recurrence defined as Tis or Ta/T1 high-grade, or muscle-invasive disease at TURBT or cystectomy); PFS rates at months 6/12/18/24; OS at month 24, EOT+6 months, and EOT+12 months; AE incidence.

Exploratory Endpoints.

CIS cohort: 3-month CR rate in PD-L1-positive and PD-L1-negative subgroups (per protocol-specified assay and criteria; no prespecified CPS threshold).

Non-CIS cohort: Median RFS in PD-L1-positive and PD-L1-negative subgroups (recurrence definitions as above).

Sample Size and Oversight. Approximately 106 participants will be randomised 1:1. Safety will be monitored throughout; a Data Monitoring Committee oversees participant protection and study conduct.

Inclusion criteria

• Age ≥18 years; sex: all; signed written informed consent by the participant or legally authorised representative.
• Histologically confirmed high-risk non-muscle-invasive bladder cancer (HR-NMIBC), defined as any T1, high-grade Ta, and/or carcinoma in situ (CIS).
• BCG-intolerant (unable to continue BCG because of severe adverse reactions) or meeting at least one definition of BCG treatment failure:

• Persistent or recurrent CIS within 12 months after completion of adequate BCG (with or without concomitant NMIBC);
• Recurrent high-grade Ta/T1 within 6 months after completion of adequate BCG;
• High-grade T1 at the first evaluation after BCG induction (~3 months);
• Ta high-grade and/or CIS present or recurrent at ~3 months after receiving ≥5 BCG instillations.

Adequate BCG, for the purposes of this protocol, is defined as receipt of at least 5 of 6 induction instillations (maintenance not required).

• ECOG performance status 0-2.
• Adequate organ function per protocol laboratory criteria.
• No intravesical chemotherapy or immunotherapy between the most recent cystoscopy/TURBT and study start; a single immediate postoperative intravesical chemotherapy at the time of the most recent cystoscopy/TURBT is allowed during screening per local practice.
• Willing and able to comply with study procedures.

Exclusion criteria

• Muscle-invasive bladder cancer (T2-T4).
• Low-grade (LG) recurrence during or after BCG therapy.
• Concomitant upper tract urothelial carcinoma, or lymph-node/distant metastasis.
• Indwelling ureteral stent or known vesicoureteral reflux.
• Contraindications to intravesical instillation, including within 2 weeks after TURBT, bladder perforation, symptomatic urinary tract infection, or gross haematuria.
• Known hypersensitivity or contraindication to gemcitabine, mitomycin C, or toripalimab.
• Systemic chemotherapy, small-molecule targeted therapy, or radiotherapy within 2 weeks before first study treatment.
• Prior immune checkpoint inhibitor therapy.
• Pregnant, planning pregnancy, or breastfeeding women.
• Ongoing acute or chronic systemic infection, or history of active tuberculosis.
• Other malignancy requiring active treatment.
• Any condition that, in the investigator's judgment, makes participation not in the patient's best interest or could confound study results.

Study Population Adults with BCG-unresponsive or BCG-intolerant HR-NMIBC treated at participating centres in China.