Urothelial CarcinomaPhase 2Indi-BladeNCT05200988
Checkpoint Inhibition and Chemoradiotherapy as Bladder Sparing Treatment in UC
A Phase 2 study testing Ipilimumab + nivolumab in people with Urothelial Carcinoma and Bladder Cancer, run by The Netherlands Cancer Institute at 3 sites in Netherlands.
Trial summary
This is a single-armed, multicenter, non-blinded phase 2 study to assess efficacy of induction ipilimumab + nivolumab followed by chemoradiation to spare the bladder in urothelial bladder cancer. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Urothelial Carcinoma, Bladder Cancer
- What is being tested?
- Ipilimumab + nivolumab
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 50 participants
- Where
- 3 sitesNetherlands
- Study dates
- 14 Mar 2022to 5 Sep 2027
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Willing and able to provide informed consent
- Age ≥ 18 years
- Patients with cT2-4aN0-2M0 urothelial bladder cancer, who are amendable for chemoradiation and who are seeking an alternative to radical cystectomy and/or patients who are medically unfit for surgery.
- Lymph nodes should be amenable for inclusion into the radiation field.
- World Health Organization (WHO) performance Status 0 or 1.
- Urothelial cancer is the dominant histology (>70%). A small cell component is not allowed.
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- Formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks from diagnostic TUR available.
- Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109/L, Neutrophils ≥1.0x109/L, Platelets ≥100 x109/L, Hemoglobin ≥5.5 mmol/L, GFR>30 ml/min as per Cockcroft-Gault formula, AST ≤ 2.5 x ULN, ALT ≤2.5 x ULN, Bilirubin ≤1.5 X ULN
- Negative pregnancy test (βHCG in urine or blood) for female patients of childbearing potential within 2 weeks prior to day 1 of start immunotherapy.
- Highly effective contraception for both male and female subjects if the risk of conception exists. Female patients of childbearing potential must comply with contraception methods as requested by the study protocol.
Who cannot join
- Previous pelvic irradiation
- Upper tract urothelial cancer
- Extensive carcinoma in situ (CIS) of the bladder
- Bilateral hydronephrosis
- Previous intravenous chemotherapy for bladder cancer
- Contra-indication to one of the study treatment components, or mpMRI
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- Subjects with active autoimmune disease in the past 2 years. Patients with diabetes mellitus, properly controlled hypothyroidism or hyperthyroidism, vitiligo, psoriasis or other mild skin disease can still be included.
- Documented history of severe autoimmune disease (e.g. inflammatory bowel disease, myasthenia gravis).
- Prior CTLA-4 or PD-(L)1 -targeting immunotherapy.
- Known history of Human Immunodeficiency Virus, active tuberculosis, or other active infection requiring therapy at the time of inclusion.
- Positive tests for Hepatitis B surface antigen or Hepatitis C ribonucleic acid (RNA)
- Underlying medical conditions that, in the investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of adverse events
- Medical condition requiring the use of immunosuppressive medications, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) will be allowed.
- Use of other investigational drugs four weeks before study drug administration
- Malignancy, other than urothelial cancer, in the previous 2 years, with a high chance of recurrence (estimated >10%). Patients with low risk prostate cancer (defined as Stage T1/T2a, Gleason score ≤ 6, and PSA ≤ 10 ng/mL) who are treatment-naive and undergoing active surveillance are eligible.
- Pregnant and lactating female patients.
- Major pelvic surgical procedure within 4 weeks prior to enrolment or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis.
- Severe infections within 2 weeks prior to enrolment in the study including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia.
Trial locations and contacts
3 sites in 1 country.
Netherlands3 sites
Antoni van Leeuwenhoek ziekenhuis
Amsterdam, 1066CX
Erasmus Medical Center
Rotterdam
Universitair Medisch Centrum Utrecht
Utrecht
About this study
Official title: A Phase 2 Clinical Study to Assess Efficacy of Induction Ipilimumab/Nivolumab to Spare the Bladder in Urothelial Bladder Cancer
This is a single-armed, multicenter, non-blinded phase 2 study to assess efficacy of induction ipilimumab + nivolumab followed by chemoradiation to spare the bladder in urothelial bladder cancer.
Read the detailed description
This is a phase 2 study in which fifty adult patients with cT2-4aN0-2 urothelial bladder cancer, who are amenable for chemoradiation, will be included. Lymph nodes should be amenable for inclusion into the radiation field.
Included patients will be treated with three cycles of checkpoint inhibition: ipilimumab 3mg/kg on day 1, ipilimumab 3 mg/kg plus nivolumab 1 mg/kg on day 22, and nivolumab 3 mg/kg on day 43.
Response of this induction therapy will be evaluated by cystoscopy, mpMRI and a CT scan.
Patients will then be treated by radiation to the bladder and involved nodes, in combination with mitomycine C (day 1, 12 mg/m2, maximum dose of 20 mg) and either daily capecitabin or intravenous 5-FU in week 1 and 4. Radiotherapy will be delivered using Volumetric Modulated Arc Therapy delivering a dose of 50Gy to the whole bladder with a simultaneous tumor boost of 60Gy to the tumor bed.
The primary endpoint is efficacy, defined as bladder-intact event-free survival (BI-EFS). Events consist of death by any cause; muscle-invasive, upper urinary tract, nodal or distant recurrence, cystectomy, or switch to cisplatin-based chemotherapy.
The first evaluation after completion of chemoradiation will be after three months. Further follow-up visits will take place 6, 12, 18, 24, 30, and 36 months after completion of chemoradiation. During these visits, focused physical examination, cystoscopy and a CT chest-abdomen will be performed, combined with registration of treatment-related adverse events and a questionnaire for evaluating QoL, bladder function and long-term effects of immunotherapy on QoL.
Key secondary endpoints are overall survival (OS), recurrence-free survival (RFS), feasibility to proceed to chemoradiation, safety, QoL, and bladder function.
- Conditions
- Urothelial Carcinoma, Bladder Cancer
- Being tested
- Ipilimumab + nivolumab
- Medical subject headings
- Carcinoma, Transitional Cell, Urinary Bladder Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ipilimumab + nivolumabDrug
Also called Yervoy, Opdivo
Induction with immune checkpoint blockade: ipilimumab 3mg/kg on day 1, pilimumab 3mg/kg plus nivolumab 1mg/kg on day 22, and nivolumab 3mg/kg on day 43
Response evaluation after the last cycle of checkpoint inhibition.
Chemoradiation will start 10-12 weeks after start of checkpoint inhibition according to the following scheme:
- Mitoycine C (12mg/m2) on the first day of radiotherapy, followed by either 5-fluorouracil intravenously (500mg/m2) five days a week during week one and four of radiation, or oral capecitabin (2x825mg/m2) every day during the radiation period
- Radiation with a preference for a four-week schedule, in which 55 Gy will be administered using intensity modulated radiation therapy
| Study group | Role | What they receive |
|---|---|---|
| Induction with heckpoint inhibition followed by consolidative chemoradiation | Experimental | Checkpoint inhibition and chemoradiation Receives: Drug: Ipilimumab + nivolumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Efficacy defined as bladder-intact event-free survival (BI-EFS)
Events are defined as death by any cause, muscle-invasive, upper urinary tract, nodal or distant recurrence, cystectomy, or switch to cisplatin-based chemotherapy.
Measured: From initiation of study drug until event, defined as described above, whichever comes first. Patients without an event are censored at time of last cystoscopy/last CT scan. Assessed at primary analysis and subsequently at a minimum of 3yrs follow-up.
Secondary outcomes (5)
Recurrence-free survival (RFS)
RFS is defined as time from start of therapy until the following events: muscle-invasive bladder or upper urinary tract recurrence, locoregional or distant metastases, switch to cisplatin-based chemotherapy or death by any cause.
Measured: From start of therapy until one of the events mentioned above, whichever comes first. RFS will be assessed at the primary analysis and subsequently at a minimum of 3 years follow-up for all patients
Overall survival (OS)
OS is defined as the time between the date of enrollment and the date of death.
Measured: From date of enrollment until date of death. OS will be assessed at the primary analysis and subsequently at a minimum of 3 years follow-up for all patients.
Feasibility to proceed to chemoradiation (CRT)
Percentage of patients able to proceed to CRT
Measured: From the initiation of the study drug untill the the start of CRT
Change in patient reported outcome regarding quality of life (QoL)
QoL will be assessed using the EORTC QLQ-C30 and an unvalidated immunotherapy-related QoL questionnaire developed by and used in the Netherlands Cancer Institute. These will be provided to evaluate changes from baseline in QoL and evaluate long-term effects of immunotherapy on QoL using both multi-item scale and single-item scales. A graph showing the change from baseline to three timepoints will be reported: 56 ±7 days after treatment initiation and at 3, 6, 12,18 and 24 months after finalizing chemoradiotherapy.
Measured: From screening until two years after finalizing chemoradiation
Patient reported outcome regarding bladder function
Questionnaires for bladder function (EORTC-QLQ-BLM30)will be provided, resulting in a score on a four point scale. A graph showing the change from baseline to six timepoints will be reported: 56 ±7 days after treatment initiation and at 3, 6, 12,18 and 24 months after finalizing chemoradiotherapy.
Measured: From screening until two years after finalizing chemoradiation
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Jan 2022
- Study start14 Mar 2022
- Primary completion5 Sep 2025 (estimated)
- Study completion5 Sep 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Urothelial CarcinomaStudies of the same condition, open and under way.
- More trials run by The Netherlands Cancer InstituteThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Multicenter, open-label, phase 2 clinical trial
- Masking
- None (open label)
- Enrolment
- 50 participants (estimated)
Sponsor and investigators
- Lead sponsor
- The Netherlands Cancer Institute
- Sponsor type
- University, hospital or other
- Collaborators
- Bristol-Myers Squibb
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05200988
- Sponsor's protocol ID
- M21IDB
- Acronym
- Indi-Blade
- Status last verified
- Mar 2024
- First submitted
- 14 Oct 2021
- Last updated
- 18 Mar 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Mellema JJ, Stockem CF, Herberts C, Cheung SK, Vis DJ, van Rhijn BWG, Mertens LS, Boellaard TN, van Montfoort ML, Balduzzi S, de Feijter JM, van der Mijn JCK, Sharma S, El Naggar AC, Boormans JL, Franckena M, Meijer RP, Noteboom JL, Schaake EE, Robbrecht DGJ, Suelmann BBM, van der Heijden MS. Ipilimumab and nivolumab followed by chemoradiotherapy as bladder-sparing treatment in muscle-invasive bladder cancer: a phase 2 trial. Nat Med. 2026 Apr;32(4):1241-1248. doi: 10.1038/s41591-026-04271-3. Epub 2026 Feb 27.
PubMed 41760951Stockem CF, Mellema JJJ, van Rhijn BWG, Boellaard TN, van Montfoort ML, Balduzzi S, Boormans JL, Franckena M, Meijer RP, Robbrecht DGJ, Suelmann BBM, Schaake EE, van der Heijden MS. Induction therapy with ipilimumab and nivolumab followed by consolidative chemoradiation as organ-sparing treatment in urothelial bladder cancer: study protocol of the INDIBLADE trial. Front Oncol. 2023 Aug 29;13:1246603. doi: 10.3389/fonc.2023.1246603. eCollection 2023.
PubMed 37711193
Study at a glance
From the registry record, last updated by the sponsor on 18 Mar 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 2 Clinical Study to Assess Efficacy of Induction Ipilimumab/Nivolumab to Spare the Bladder in Urothelial Bladder Cancer
- ClinicalTrials.gov ID
- NCT05200988
- Acronym / sponsor ID
- Indi-Blade / M21IDB
- Conditions
- Urothelial Carcinoma, Bladder Cancer
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 50 participants (estimated)
- Lead sponsor
- The Netherlands Cancer InstituteUniversity, hospital or other
- Collaborators
- Bristol-Myers Squibb
- Study start
- 14 Mar 2022 (actual)
- Primary completion
- 5 Sep 2025 (estimated)
- Study completion
- 5 Sep 2027 (estimated)
- First posted
- 21 Jan 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a single-armed, multicenter, non-blinded phase 2 study to assess efficacy of induction ipilimumab + nivolumab followed by chemoradiation to spare the bladder in urothelial bladder cancer.
Detailed description
This is a phase 2 study in which fifty adult patients with cT2-4aN0-2 urothelial bladder cancer, who are amenable for chemoradiation, will be included. Lymph nodes should be amenable for inclusion into the radiation field.
Included patients will be treated with three cycles of checkpoint inhibition: ipilimumab 3mg/kg on day 1, ipilimumab 3 mg/kg plus nivolumab 1 mg/kg on day 22, and nivolumab 3 mg/kg on day 43.
Response of this induction therapy will be evaluated by cystoscopy, mpMRI and a CT scan.
Patients will then be treated by radiation to the bladder and involved nodes, in combination with mitomycine C (day 1, 12 mg/m2, maximum dose of 20 mg) and either daily capecitabin or intravenous 5-FU in week 1 and 4. Radiotherapy will be delivered using Volumetric Modulated Arc Therapy delivering a dose of 50Gy to the whole bladder with a simultaneous tumor boost of 60Gy to the tumor bed.
The primary endpoint is efficacy, defined as bladder-intact event-free survival (BI-EFS). Events consist of death by any cause; muscle-invasive, upper urinary tract, nodal or distant recurrence, cystectomy, or switch to cisplatin-based chemotherapy.
The first evaluation after completion of chemoradiation will be after three months. Further follow-up visits will take place 6, 12, 18, 24, 30, and 36 months after completion of chemoradiation. During these visits, focused physical examination, cystoscopy and a CT chest-abdomen will be performed, combined with registration of treatment-related adverse events and a questionnaire for evaluating QoL, bladder function and long-term effects of immunotherapy on QoL.
Key secondary endpoints are overall survival (OS), recurrence-free survival (RFS), feasibility to proceed to chemoradiation, safety, QoL, and bladder function.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Multicenter, open-label, phase 2 clinical trial
| Arm | Type | Receives |
|---|---|---|
| Induction with heckpoint inhibition followed by consolidative chemoradiation | Experimental | Drug: Ipilimumab + nivolumabCheckpoint inhibition and chemoradiation |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Willing and able to provide informed consent
- Age ≥ 18 years
- Patients with cT2-4aN0-2M0 urothelial bladder cancer, who are amendable for chemoradiation and who are seeking an alternative to radical cystectomy and/or patients who are medically unfit for surgery.
- Lymph nodes should be amenable for inclusion into the radiation field.
- World Health Organization (WHO) performance Status 0 or 1.
Key exclusion criteria (18 listed)
- Previous pelvic irradiation
- Upper tract urothelial cancer
- Extensive carcinoma in situ (CIS) of the bladder
- Bilateral hydronephrosis
- Previous intravenous chemotherapy for bladder cancer
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ipilimumab + nivolumabAlso: Yervoy, OpdivoInduction with immune checkpoint blockade: ipilimumab 3mg/kg on day 1, pilimumab 3mg/kg plus nivolumab 1mg/kg on day 22, and nivolumab 3mg/kg on day 43 Response evaluation after the last cycle of checkpoint inhibition. Chemoradiation will start 10-12 weeks after start of checkpoint inhibition according to the following scheme: * Mitoycine C (12mg/m2) on the first day of radiotherapy, followed by either 5-fluorouracil intravenously (500mg/m2) five days a week during week one and four of radiation, or oral capecitabin (2x825mg/m2) every day during the radiation period * Radiation with a preference for a four-week schedule, in which 55 Gy will be administered using intensity modulated radiation therapy | Drug | Induction with heckpoint inhibition followed by consolidative chemoradiation |
Primary outcome
Efficacy defined as bladder-intact event-free survival (BI-EFS)
Time frame: From initiation of study drug until event, defined as described above, whichever comes first. Patients without an event are censored at time of last cystoscopy/last CT scan. Assessed at primary analysis and subsequently at a minimum of 3yrs follow-up.
Events are defined as death by any cause, muscle-invasive, upper urinary tract, nodal or distant recurrence, cystectomy, or switch to cisplatin-based chemotherapy.
5 secondary outcomes
Recurrence-free survival (RFS)
Time frame: From start of therapy until one of the events mentioned above, whichever comes first. RFS will be assessed at the primary analysis and subsequently at a minimum of 3 years follow-up for all patients
Overall survival (OS)
Time frame: From date of enrollment until date of death. OS will be assessed at the primary analysis and subsequently at a minimum of 3 years follow-up for all patients.
Feasibility to proceed to chemoradiation (CRT)
Time frame: From the initiation of the study drug untill the the start of CRT
Change in patient reported outcome regarding quality of life (QoL)
Time frame: From screening until two years after finalizing chemoradiation
Patient reported outcome regarding bladder function
Time frame: From screening until two years after finalizing chemoradiation
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Mar 2024.
- Derived from this study: PubMed 41760951Mellema JJ, Stockem CF, Herberts C, Cheung SK, Vis DJ, van Rhijn BWG, Mertens LS, Boellaard TN, van Montfoort ML, Balduzzi S, de Feijter JM, van der Mijn JCK, Sharma S, El Naggar AC, Boormans JL, Franckena M, Meijer RP, Noteboom JL, Schaake EE, Robbrecht DGJ, Suelmann BBM, van der Heijden MS. Ipilimumab and nivolumab followed by chemoradiotherapy as bladder-sparing treatment in muscle-invasive bladder cancer: a phase 2 trial. Nat Med. 2026 Apr;32(4):1241-1248. doi: 10.1038/s41591-026-04271-3. Epub 2026 Feb 27.
- Derived from this study: PubMed 37711193Stockem CF, Mellema JJJ, van Rhijn BWG, Boellaard TN, van Montfoort ML, Balduzzi S, Boormans JL, Franckena M, Meijer RP, Robbrecht DGJ, Suelmann BBM, Schaake EE, van der Heijden MS. Induction therapy with ipilimumab and nivolumab followed by consolidative chemoradiation as organ-sparing treatment in urothelial bladder cancer: study protocol of the INDIBLADE trial. Front Oncol. 2023 Aug 29;13:1246603. doi: 10.3389/fonc.2023.1246603. eCollection 2023.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Ipilimumab + nivolumab in people with Urothelial Carcinoma and Bladder Cancer, run by The Netherlands Cancer Institute at 3 sites in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 18 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Efficacy defined as bladder-intact event-free survival (BI-EFS) (time frame: From initiation of study drug until event, defined as described above, whichever comes first. Patients without an event are censored at time of last cystoscopy/last CT scan. Assessed at primary analysis and subsequently at a minimum of 3yrs follow-up.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05200988, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Mar 2024.