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

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.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

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

   1. Persistent or recurrent CIS within 12 months after completion of adequate BCG (with or without concomitant NMIBC);
   2. Recurrent high-grade Ta/T1 within 6 months after completion of adequate BCG;
   3. High-grade T1 at the first evaluation after BCG induction (\~3 months);
   4. 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).
4. ECOG performance status 0-2.
5. Adequate organ function per protocol laboratory criteria.
6. 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.
7. Willing and able to comply with study procedures.

Exclusion Criteria:

1. Muscle-invasive bladder cancer (T2-T4).
2. Low-grade (LG) recurrence during or after BCG therapy.
3. Concomitant upper tract urothelial carcinoma, or lymph-node/distant metastasis.
4. Indwelling ureteral stent or known vesicoureteral reflux.
5. Contraindications to intravesical instillation, including within 2 weeks after TURBT, bladder perforation, symptomatic urinary tract infection, or gross haematuria.
6. Known hypersensitivity or contraindication to gemcitabine, mitomycin C, or toripalimab.
7. Systemic chemotherapy, small-molecule targeted therapy, or radiotherapy within 2 weeks before first study treatment.
8. Prior immune checkpoint inhibitor therapy.
9. Pregnant, planning pregnancy, or breastfeeding women.
10. Ongoing acute or chronic systemic infection, or history of active tuberculosis.
11. Other malignancy requiring active treatment.
12. 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.

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