Chemoablation Or Bladder Resection With Adjuvant Chemotherapy in Recurrent Non-Muscle Invasive Bladder Cancer (COBRA-NMIBC)

The investigartors will conduct a randomized, multinational study with the aim to assess if the efficacy of a dose dense chemoablation with Mitomycin C (MMC) with adjuvant BCG in non-responding patients is superior regarding long term effect compared to standard treatment with trans urethral resection of bladder tumors (TURBT) and adjuvant intravesical instillation therapy in patients with recurrent Ta LG tumors.

The study is a natural follow-up study following the pivotal NICSA trial supported by the Danish Cancer Society that has lead to the initial change in the European guidelines. In order to not only be comparable to current standard, but also to improve clinical outcome and furthermore confirm the previous findings, the investigators here suggest to implement at patient tailored approach through a new multicenter RCT.

The investigators hypothesize that chemoablation with MMC in patients with recurrent Ta LG tumors will result in a permanent low recurrence rate in patients with complete response, whereas patients without complete response can be selected for adjuvant BCG which theoretically is more efficient in this select patient group. This will potentially result in a more favorable long term recurrence free survival (RFS) rate compared to the current standard regimen where all patients are treated with TURBT and adjuvant instillation therapy.

The incidence of bladder cancer in Denmark is almost 2,000 per year. Of these, 75% have non-muscle invasive bladder cancer (NMIBC). The yearly recurrence rate of NMIBC is approximately 35% and the disease is therefore one of the most costly cancers to manage on a per patient basis, due to the cost of operative procedures, follow-up cystoscopies and instillation therapies

Study Overview

• Status: Recruiting
• Conditions: Non-Muscle Invasive Bladder Cancer
• Intervention / Treatment: Drug: Mitomycin c

• Study Type: Interventional
• Enrollment (Estimated): 272
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Pernille Kingo, PhD, Dr; Phone Number: 0045 78 45 00 00; Email: pernking@rm.dk
• Study Contact Backup: Name: Vibeke Morrison, Rn, Msc Nurs; Email: vimorr@rm.dk

Study Locations

• Denmark
  • Aalborg, Denmark
    • Not yet recruiting
    • Aalborg University Hospital
    • Contact: Knud Fabrin, MD; Email: knf@rn.dk
  • Aarhus N, Denmark, 8200
    • Recruiting
    • Aarhus University Hospital
    • Contact: Pernille Skjold Kingo Assosiate prof., Senior consultant, PhD; Phone Number: +45 30915600; Email: perkin@rm.dk
  • Herlev, Denmark
    • Recruiting
    • Herlev and Gentofte Hospital
    • Contact: Ann K Bersang, MD; Email: ann.kortbaek.bersang@regionh.dk
  • Roskilde, Denmark
    • Recruiting
    • Zealand University Hospital, Roskilde
    • Contact: Juan L Vásquez, PhD; Email: Julv@regionsjaelland.dk
• Iceland
  • Reykjavik, Iceland
    • Not yet recruiting
    • Landspitali University Hospital
    • Contact: Sigurður Guðjónsson, PhD; Email: sigugud@landspitali.is
• Norway
  • Bergen, Norway
    • Not yet recruiting
    • Haukeland University Hospital
    • Contact: Gigja Gudbrandsdottir, PhD; Email: gigja.gudbrandsdottir@helse-bergen.no
  • Tønsberg, Norway
    • Not yet recruiting
    • Vestfold Hospital Trust
    • Contact: Erik S Haug, MD; Email: Erik.haug@siv.no
• Sweden
  • Uddevalla, Sweden
    • Not yet recruiting
    • NU Hospital Group
    • Contact: Suleiman Abuhasanein, MD; Email: suleiman.abuhasanein@vgregion.se

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Tumour recurrence after previous urothelial tumour of Ta low-grade
• Tumours smaller than 2 cm in diameter
• Negative urine cytology (optional)
• ≥18 years of age
• Ability to understand and comprehend the provided written and oral information
• Has provided written consent

Exclusion Criteria:

• Known history of invasive tumour of the bladder (T1+)
• Known history of CIS of the bladder
• Previous MMC or BCG-treatment except for single instillations following previous TURBTs
• Known allergy or intolerance to MMC
• Solid tumour with suspicions of invasion
• Tumour in the bladder neck or urethra
• Suspicion of CIS (positive cytology with high-grade neoplastic cells combined with suspicious flat lesions seen at cystoscopy)
• Small bladder volume (less than 100 ml) or incontinence
• Prior radiation therapy to the pelvic area, as radiation affects the bladder function and instillation therapy is a suboptimal treatment for this patient group
• Acute cystitis
• Pregnancy or breast-feeding
• Averse to using secure contraception with regard to men with partners and premenopausal women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Chemoablation; Patients will undergo dose dense chemoablation with MMC three times per week for two weeks (six instillations in total) followed by flexible cystoscopy eight weeks later. If no tumour can be identified (complete response), patients will receive monthly MMC maintenance instillations for 6 months (six instillations in total) and then continue in the outpatient follow-up programme, according to European guidelines. If tumour regression is observed without complete response or there is no response, a TURBT or outpatient biopsy and tumour fulguration will be performed followed by adjuvant BCG with induction therapy and 1 year maintenance (6 weekly instillations as induction followed by 3 weekly instillations as maintenance at 3, 6, and 12 months or 4, 8 and 12 months as is standard for site ).	Drug: Mitomycin c; Chemoablation
No Intervention: Control; Patients will have TURBT or outpatient biopsy and tumour fulguration performed, followed by standard intravesical instillation therapy according to tumour histology: MMC once a week for six weeks with a monthly maintenance instillation for six months in low-grade tumours. For high-grade tumours BCG will be utilised once a week for six weeks followed by 1-year maintenance consisting of one weekly instillation for three weeks after 3, 6, and 12 months or 4, 8 and 12 months as is standard for site.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Two-year Recurrence Free Survival	This is defined as event of first recurrence following treatment but not including the recurrence diagnosed at the time of inclusion or persisting tumour following chemoablation.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Five-year RFS	This is defined as event of first recurrence following treatment but not including the recurrence diagnosed at the time of inclusion or persisting tumour following chemoablation.	5 years
Number of patients in need of a TURBT or tumour fulguration in the outpatient clinic in the first two years following randomisation	need for TURBT/fulgaration	2 years
Number of tumours at first recurrence based on the following intervals: 1, 2-7, > 8	tumour number	5 years
Number of TURBTs per patient in the first two and five years of follow-up based on the following intervals: 1, 2-5, 5-10 and multiple	number of TURBTs	5 years
Five-year progression free survival	(progression defined as progression to T1-tumour, T2+-tumour, or cystectomy irrespectively of indication)	5 years
Five-year overall survival	survival	5 years
Number of patients completing assigned intervention	completing assigned intervention	2 years
Serious adverse events related to MMC treatment during neoadjuvant or adjuvant therapy	SAE's	2 years

Collaborators and Investigators

• Sponsor: Jakob Kristian Jakobsen
• Collaborators: Danish Cancer Society; medac GmbH

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2025
• Primary Completion (Estimated): February 1, 2029
• Study Completion (Estimated): February 1, 2032

Study Registration Dates

• First Submitted: January 14, 2025
• First Submitted That Met QC Criteria: January 14, 2025
• First Posted (Actual): January 17, 2025

Study Record Updates

• Last Update Posted (Estimated): October 3, 2025
• Last Update Submitted That Met QC Criteria: September 30, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Recurrence; Ta low.grade; Chemoablation
• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Disease Attributes; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Urologic Neoplasms; Carcinoma; Urinary Bladder Diseases; Urinary Bladder Neoplasms; Pathological Conditions, Signs and Symptoms; Non-Muscle Invasive Bladder Neoplasms; Recurrence; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indoles; Quinones; Azirines; Mitomycins; Indolequinones; Mitomycin
• Other Study ID Numbers: COBRA NMIBC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No