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

NCT07189793 | Not Yet Recruiting Phase 2

• 1 other identifier: KY2025-352
• Study Type: interventional
• Target: 106
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Carcinoma in Situ of Bladder; Non-Muscle-Invasive Bladder Cancer

Keywords

NMIBC; High-Risk NMIBC; BCG-Unresponsive; BCG-Intolerant; BCG Failure; Carcinoma in Situ (CIS); Intravesical Therapy; Ta; T1; Gemcitabine; Mitomycin C; GEM-MMC; Toripalimab; PD-1 Inhibitor; Bladder-Sparing

Outcome Measures

Primary Outcomes (2)

• 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.

  Baseline to Month 3

• 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.

  From randomisation/start of treatment to first event, assessed up to 24 months

Secondary Outcomes (9)

• CR Rates at Months 6, 12, 18, and 24 in the CIS Cohort

  Baseline to months 6, 12, 18, and 24

• Progression-Free Survival (PFS) Rates at Months 6, 12, 18, and 24 in the CIS Cohort

  Baseline to months 6, 12, 18, and 24

• Overall Survival at Month 24, EOT+6 Months, and EOT+12 Months in the CIS Cohort

  Baseline to Month 24, EOT+6 months, and EOT+12 months

• Incidence of Adverse Events in the CIS Cohort

  From first dose/instillation to 90 days post-last dose/instillation (≈ up to 27 months)

• Recurrence-Free Survival Rates at Months 6, 12, 18, and 24 in the Non-CIS Cohort

  Baseline to months 6, 12, 18, and 24

Other Outcomes (4)

• CR Rate at Month 3 in PD-L1-Positive Participants in the CIS Cohort

  Baseline to Month 3

• CR Rate at Month 3 in PD-L1-Negative Participants in the CIS Cohort

  Baseline to Month 3

• Median Recurrence-Free Survival in PD-L1-Positive Participants in the Non-CIS Cohort

  From randomisation/start of treatment to first event, up to 24 months

Study Arms (2)

Combination: Toripalimab + Intravesical GEM-MMC

EXPERIMENTAL

Toripalimab IV Q3W starting with the first intravesical cycle, plus sequential intravesical gemcitabine followed by mitomycin C in the same visit. Induction weekly ×6; if no recurrence at first tumour assessment (\~month 3), monthly maintenance up to 24 months.

Drug: Toripalimab; Drug: Gemcitabine (GEM); Drug: Mitomycin C (MMC)

Monotherapy: Toripalimab Alone

ACTIVE COMPARATOR

Toripalimab IV every 3 weeks (Q3W) up to 24 months or until disease progression, unacceptable toxicity, or withdrawal; no intravesical chemotherapy.

Drug: Toripalimab

Interventions

Toripalimab DRUG

PD-1 inhibitor administered intravenously every 3 weeks (Q3W) for up to 24 months. Starts during the first intravesical treatment cycle.

Also known as: JS001, Tuoyi

Combination: Toripalimab + Intravesical GEM-MMC; Monotherapy: Toripalimab Alone

Gemcitabine (GEM) DRUG

Intravesical 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.

Also known as: GEM

Combination: Toripalimab + Intravesical GEM-MMC

Mitomycin C (MMC) DRUG

Intravesical instillation immediately after intravesical gemcitabine in the same visit (sequential regimen): weekly for 6 weeks (induction); if eligible, monthly maintenance up to 24 months.

Combination: Toripalimab + Intravesical GEM-MMC

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• First Affiliated Hospital of Wenzhou Medical University: lead

Study Sites (1)

The First Affiliated Hospital of Wenzhou Medical University

Wenzhou, Zhejiang, 325000, China

Location

Related Publications (6)

• Holzbeierlein JM, Bixler BR, Buckley DI, Chang SS, Holmes R, James AC, Kirkby E, McKiernan JM, Schuckman AK. Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline: 2024 Amendment. J Urol. 2024 Apr;211(4):533-538. doi: 10.1097/JU.0000000000003846. Epub 2024 Jan 24.

  PMID: 38265030 BACKGROUND

• Lightfoot AJ, Breyer BN, Rosevear HM, Erickson BA, Konety BR, O'Donnell MA. Multi-institutional analysis of sequential intravesical gemcitabine and mitomycin C chemotherapy for non-muscle invasive bladder cancer. Urol Oncol. 2014 Jan;32(1):35.e15-9. doi: 10.1016/j.urolonc.2013.01.009. Epub 2013 Mar 17.

  PMID: 23510863 BACKGROUND

• Breyer BN, Whitson JM, Carroll PR, Konety BR. Sequential intravesical gemcitabine and mitomycin C chemotherapy regimen in patients with non-muscle invasive bladder cancer. Urol Oncol. 2010 Sep-Oct;28(5):510-4. doi: 10.1016/j.urolonc.2008.11.019. Epub 2009 Jan 26.

  PMID: 19171491 BACKGROUND

• Black PC, Tangen CM, Singh P, McConkey DJ, Lucia MS, Lowrance WT, Koshkin VS, Stratton KL, Bivalacqua TJ, Kassouf W, Porten SP, Bangs R, Plets M, Thompson IM Jr, Lerner SP. Phase 2 Trial of Atezolizumab in Bacillus Calmette-Guerin-unresponsive High-risk Non-muscle-invasive Bladder Cancer: SWOG S1605. Eur Urol. 2023 Dec;84(6):536-544. doi: 10.1016/j.eururo.2023.08.004. Epub 2023 Aug 16.

  PMID: 37596191 BACKGROUND

• Necchi A, Roumiguie M, Kamat AM, Shore ND, Boormans JL, Esen AA, Lebret T, Kandori S, Bajorin DF, Krieger LEM, Niglio SA, Uchio EM, Seo HK, de Wit R, Singer EA, Grivas P, Nishiyama H, Li H, Baranwal P, Van den Sigtenhorst-Fijlstra M, Kapadia E, Kulkarni GS. Pembrolizumab monotherapy for high-risk non-muscle-invasive bladder cancer without carcinoma in situ and unresponsive to BCG (KEYNOTE-057): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2024 Jun;25(6):720-730. doi: 10.1016/S1470-2045(24)00178-5. Epub 2024 May 10.

  PMID: 38740030 BACKGROUND

• Balar AV, Kamat AM, Kulkarni GS, Uchio EM, Boormans JL, Roumiguie M, Krieger LEM, Singer EA, Bajorin DF, Grivas P, Seo HK, Nishiyama H, Konety BR, Li H, Nam K, Kapadia E, Frenkl T, de Wit R. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 2021 Jul;22(7):919-930. doi: 10.1016/S1470-2045(21)00147-9. Epub 2021 May 26.

  PMID: 34051177 BACKGROUND

Related Links

• EAU Guidelines on Non-muscle-invasive Bladder Cancer (TaT1 and CIS)

MeSH Terms

Conditions

Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Non-Muscle Invasive Bladder Neoplasms; Carcinoma in Situ

Interventions

toripalimab; Gemcitabine; Mitomycin

Condition Hierarchy (Ancestors)

Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Mitomycins; Indolequinones; Quinones; Organic Chemicals; Azirines; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Central Study Contacts

Qi Lin, MM

CONTACT

+8615205771010; devillynch@126.com

Wei Chen, MD

CONTACT

+8613857771505; wzmuchenwei@163.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Two-arm, 1:1 randomised, open-label, parallel-group phase 2 trial comparing toripalimab plus sequential intravesical gemcitabine→mitomycin C with toripalimab alone in adults with BCG-unresponsive or BCG-intolerant high-risk NMIBC. Randomisation stratified by CIS status, stage (Ta vs T1), BCG failure subtype, and study centre. Treatment up to 24 months.

Study Record Dates

• First Submitted: September 17, 2025
• First Posted: September 24, 2025
• Study Start: October 1, 2025
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): October 1, 2028
• Last Updated: September 24, 2025

Record last verified: 2025-09

Locations

CN (1)