Sequential intravesical mitomycin-C and gemcitabine therapy for BCG-unresponsive high-risk non-muscle-invasive bladder cancer: protocol for a prospective, open-label, single-arm, multicentre phase II (IMGeS) study
9 affiliations
- 1Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (the Republic of)
- 2Department of Urology, Seoul St Mary's Hospital, The Catholic University of Korea, Seoul, Korea (the Republic of)
- 3Department of Urology, Pusan National University Hospital, College of Medicine, Pusan National University, Busan, Korea (the Republic of)
- 4Department of Urology, National Cancer Center, Goyang, Korea (the Republic of)
- 5Biostatistics Collaboration Team, Research Institute, National Cancer Center, Goyang, Korea (the Republic of)
- 6Department of Urology, Korea University Hospital, Seoul, Korea (the Republic of)
- 7Department of Urology, Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
- 8Department of Urology, Chonnam National University Medical School, Hwasun, Korea (the Republic of)
- 9Department of Urology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea (the Republic of)
Abstract
Introduction: Radical cystectomy (RC) is the standard treatment for high-risk non-muscle-invasive bladder cancer (HR NMIBC) unresponsive to adequate BCG therapy; however, many patients are ineligible or decline surgery. Current Food and Drug Administration-approved bladder-preserving therapies—including immune checkpoint inhibitors, viral gene therapy, and cytokine-based regimens—are under investigation but show limited efficacy, safety concerns, high costs and are mainly restricted to carcinoma in situ. Both intravesical mitomycin-C (MMC) and gemcitabine (GEM) as monotherapy have proven effective salvage monotherapies for BCG-unresponsive HR NMIBC and their sequential use (MMC/GEM) may offer mechanistic synergy. Prospective evidence supporting the clinical effectiveness and feasibility of sequential MMC/GEM as an effective salvage therapy for BCG-unresponsive HR NMIBC patients remains limited and insufficiently substantiated.
Methods and analysis: We designed the IMGeS study, a prospective, open-label, multicentre, single-arm phase II trial to assess the efficacy and safety of sequential intravesical MMC/GEM in patients with histologically confirmed BCG-unresponsive HR NMIBC per American Urological Association criteria who are unsuitable for or decline RC. Key exclusions include muscle-invasive or metastatic disease, upper tract urothelial carcinoma, prior intravesical MMC or GEM within 2 years (except a single immediate postoperative dose) and other predominant histological subtypes. Eligible, consenting patients undergo a 6-week induction phase of intravesical sequential MMC (40 mg/20 mL) followed by GEM (2000 mg/50 mL), starting 1–4 weeks after transurethral resection of bladder tumour. Each drug is retained in the bladder for 1–2 hours. Patients without recurrence at the 3-month evaluation then receive monthly maintenance therapy for up to 12 months. The primary endpoint is 1-year high-risk recurrence-free survival (HR RFS). Key secondary endpoints include additional time-to-event measures such as progression-free, cystectomy-free, cancer-specific and overall survival, as well as safety, tolerability and patient-reported outcomes. Exploratory endpoints encompass predictive multi-omics biomarker analyses of tumour tissue, urine and blood samples collected during the study. Assuming a historical 1-year RFS rate of 20% with valrubicin and an anticipated 1-year HR RFS rate of 35% for intravesical sequential MMC/GEM, 73 patients are needed to achieve 90% power using a one-sample log-rank test at a two-sided 5% significance level. Accounting for a maximum dropout rate of 10%, a total of 82 patients will be enrolled across eight centres in South Korea.
Ethics and dissemination: This study protocol was approved by the National Cancer Center Institutional Review Board (NCC2024-0026) and the ethics committees of all participating centres. Written informed consent will be obtained from all participants or their legal guardians. The findings will be disseminated through publication in peer-reviewed journals and presentation at academic conferences.
Trial registration number: NCT06388720
Protocol version: V.2.1 (14 July 2025).
Related
- Predictability of symptom changes following hemithyroidectomy due to compression symptoms assessed by specific questionnaires: prospective multicentre study.
- Vibroacoustic lung therapy and early postoperative oxygenation after cardiac surgery: a multicentre prospective study
- Safety and efficiency of the HEART-GP strategy with point-of-care high-sensitivity troponin testing for acute chest pain in out-of-hours primary care: a prospective multicentre diagnostic accuracy study
- Evaluation of the Efficacy and Safety of Combination Therapy of Vamha and Myrha in the Management of PMOS: An Open-Label, Randomized, Multicentre, Comparative, Prospective Clinical Study
- An explainable artificial intelligence system for prognostic assessment and decision support in diabetic foot ulcer care: a multicentre derivation and validation study with prospective randomised evaluation
BibTeX
@article{lee2026sequential,
title = {{Sequential intravesical mitomycin-C and gemcitabine therapy for BCG-unresponsive high-risk non-muscle-invasive bladder cancer: protocol for a prospective, open-label, single-arm, multicentre phase II (IMGeS) study}},
author = {Hye Won Lee and Yong Hyun Park and Kyung Hwan Kim and Eui Hyun Jung and Geehyun Song and Hyung Ho Lee and Dong Eun Lee and Seok Ho Kang and Byung Chang Jeong and Won Sik Ham and Seung Il Jung and Jong Jin Oh and Ho Kyung Seo},
journal = {BMJ Open},
year = {2026},
month = oct,
doi = {10.1136/bmjopen-2026-117239},
url = {https://bmjopen.bmj.com/lookup/doi/10.1136/bmjopen-2026-117239},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Sequential intravesical mitomycin-C and gemcitabine therapy for BCG-unresponsive high-risk non-muscle-invasive bladder cancer: protocol for a prospective, open-label, single-arm, multicentre phase II (IMGeS) study
AU - Hye Won Lee
AU - Yong Hyun Park
AU - Kyung Hwan Kim
AU - Eui Hyun Jung
AU - Geehyun Song
AU - Hyung Ho Lee
AU - Dong Eun Lee
AU - Seok Ho Kang
AU - Byung Chang Jeong
AU - Won Sik Ham
AU - Seung Il Jung
AU - Jong Jin Oh
AU - Ho Kyung Seo
PY - 2026
DA - 2026/10/29
JO - BMJ Open
DO - 10.1136/bmjopen-2026-117239
UR - https://bmjopen.bmj.com/lookup/doi/10.1136/bmjopen-2026-117239
AB - Introduction: Radical cystectomy (RC) is the standard treatment for high-risk non-muscle-invasive bladder cancer (HR NMIBC) unresponsive to adequate BCG therapy; however, many patients are ineligible or decline surgery. Current Food and Drug Administration-approved bladder-preserving therapies—including immune checkpoint inhibitors, viral gene therapy, and cytokine-based regimens—are under investigation but show limited efficacy, safety concerns, high costs and are mainly restricted to carcinoma in situ. Both intravesical mitomycin-C (MMC) and gemcitabine (GEM) as monotherapy have proven effective salvage monotherapies for BCG-unresponsive HR NMIBC and their sequential use (MMC/GEM) may offer mechanistic synergy. Prospective evidence supporting the clinical effectiveness and feasibility of sequential MMC/GEM as an effective salvage therapy for BCG-unresponsive HR NMIBC patients remains limited and insufficiently substantiated. Methods and analysis: We designed the IMGeS study, a prospective, open-label, multicentre, single-arm phase II trial to assess the efficacy and safety of sequential intravesical MMC/GEM in patients with histologically confirmed BCG-unresponsive HR NMIBC per American Urological Association criteria who are unsuitable for or decline RC. Key exclusions include muscle-invasive or metastatic disease, upper tract urothelial carcinoma, prior intravesical MMC or GEM within 2 years (except a single immediate postoperative dose) and other predominant histological subtypes. Eligible, consenting patients undergo a 6-week induction phase of intravesical sequential MMC (40 mg/20 mL) followed by GEM (2000 mg/50 mL), starting 1–4 weeks after transurethral resection of bladder tumour. Each drug is retained in the bladder for 1–2 hours. Patients without recurrence at the 3-month evaluation then receive monthly maintenance therapy for up to 12 months. The primary endpoint is 1-year high-risk recurrence-free survival (HR RFS). Key secondary endpoints include additional time-to-event measures such as progression-free, cystectomy-free, cancer-specific and overall survival, as well as safety, tolerability and patient-reported outcomes. Exploratory endpoints encompass predictive multi-omics biomarker analyses of tumour tissue, urine and blood samples collected during the study. Assuming a historical 1-year RFS rate of 20% with valrubicin and an anticipated 1-year HR RFS rate of 35% for intravesical sequential MMC/GEM, 73 patients are needed to achieve 90% power using a one-sample log-rank test at a two-sided 5% significance level. Accounting for a maximum dropout rate of 10%, a total of 82 patients will be enrolled across eight centres in South Korea. Ethics and dissemination: This study protocol was approved by the National Cancer Center Institutional Review Board (NCC2024-0026) and the ethics committees of all participating centres. Written informed consent will be obtained from all participants or their legal guardians. The findings will be disseminated through publication in peer-reviewed journals and presentation at academic conferences. Trial registration number: NCT06388720 Protocol version: V.2.1 (14 July 2025).
SN - 2044-6055
SN - 2044-6055
ER -