This open-label, randomised, multicentre, phase 2 study (OHAI-NMIBC-01) compares toripalimab plus sequential intravesical gemcitabine followed by mitomycin C (GEM→MMC) with toripalimab alone in adults with BCG-unresponsive or BCG-intolerant high-risk non-muscle-invasive bladder cancer (HR-NMIBC). Two prespecified cohorts are analysed: (1) CIS cohort (CIS with/without Ta/T1) and (2) non-CIS cohort (high-risk Ta/T1 without CIS). In the combination arm, intravesical GEM→MMC is given weekly for 6 weeks (induction) and, for patients without recurrence at the first tumour assessment (\~month 3), monthly maintenance continues up to 24 months or until progression/unacceptable toxicity; toripalimab IV every 3 weeks starts during the first intravesical cycle and continues up to 24 months or until progression/unacceptable toxicity. The monotherapy arm receives toripalimab IV every 3 weeks up to 24 months or until progression/unacceptable toxicity. Cystoscopy and urine cytology are performed every 3 months; imaging every 24 weeks. Primary endpoints are 3-month complete response (CR) rate in the CIS cohort and median recurrence-free survival (RFS) in the non-CIS cohort. Secondary endpoints include landmark CR, PFS and OS, RFS/HG-RFS landmarks in the non-CIS cohort, and safety (CTCAE v5.0). Exploratory analyses will assess outcomes by protocol-defined PD-L1 status. Approximately 106 participants will be enrolled at multiple sites in China.
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).
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;
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.
Parallel
Toripalimab
DrugPD-1 inhibitor administered intravenously every 3 weeks (Q3W) for up to 24 months. Starts during the first intravesical treatment cycle.
Gemcitabine (GEM)
DrugIntravesical instillation as part of a sequential regimen with mitomycin C: weekly for 6 weeks (induction); if no recurrence at first tumour assessment (\~month 3), maintenance instillations continue monthly up to 24 months.
Mitomycin C (MMC)
DrugIntravesical instillation immediately after intravesical gemcitabine in the same visit (sequential regimen): weekly for 6 weeks (induction); if eligible, monthly maintenance up to 24 months.
Complete Response (CR) Rate at Month 3 in the CIS Cohort
Proportion of participants in the CIS cohort achieving CR at month 3. 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.
Median Recurrence-Free Survival (RFS) in the Non-CIS Cohort
RFS is time to high-grade Ta recurrence, any T1, or new CIS, whichever occurs first. Recurrence requires cystoscopic suspicion confirmed by histopathology; if cytology becomes positive before histologic confirmation, the recurrence date is set at the first positive cytology once recurrence is subsequently confirmed. Death from any cause before documented recurrence is counted as an event.
CR Rates at Months 6, 12, 18, and 24 in the CIS Cohort
Proportion of participants in the CIS cohort with CR at the specified time points using the protocol CR definition.
Progression-Free Survival (PFS) Rates at Months 6, 12, 18, and 24 in the CIS Cohort
Proportion without progression at each time point. Progression is defined as lamina propria invasion from Ta/CIS to T1, or progression to ≥T2, or new nodal or distant metastasis.
Overall Survival at Month 24, EOT+6 Months, and EOT+12 Months in the CIS Cohort
Survival status at prespecified landmarks.
Incidence of Adverse Events in the CIS Cohort
Participants with treatment-emergent AEs and grade ≥3 AEs (MedDRA; CTCAE v5.0). Immune-related and instillation-related events summarised.
CR Rate at Month 3 in PD-L1-Positive Participants in the CIS Cohort
Proportion of PD-L1-positive participants in the CIS cohort who achieve CR at Month 3. CR is met by any of: (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.
CR Rate at Month 3 in PD-L1-Negative Participants in the CIS Cohort
Proportion of PD-L1-negative participants in the CIS cohort who achieve CR at Month 3; CR definition as above.
Median Recurrence-Free Survival in PD-L1-Positive Participants in the Non-CIS Cohort
RFS is time from randomisation/start of treatment to high-grade Ta recurrence, any T1, or new CIS, whichever occurs first. Recurrence requires cystoscopic suspicion confirmed by histopathology; if cytology becomes positive before histologic confirmation, the event date is the first positive cytology once recurrence is subsequently confirmed. Death before recurrence counts as an event.
Median Recurrence-Free Survival in PD-L1-Negative Participants in the Non-CIS Cohort
RFS definition and event-dating rules as above.
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