Checkpoint Inhibition and Chemoradiotherapy as Bladder Sparing Treatment in UC

NCT05200988 | Active Not Recruiting Phase 2

• 1 other identifier: M21IDB
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 3

Brief 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.

Conditions

Urothelial Carcinoma; Bladder Cancer

Outcome Measures

Primary Outcomes (1)

• 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.

  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)

  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)

  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)

  From the initiation of the study drug untill the the start of CRT

• Change in patient reported outcome regarding quality of life (QoL)

  From screening until two years after finalizing chemoradiation

• Patient reported outcome regarding bladder function

  From screening until two years after finalizing chemoradiation

Other Outcomes (2)

• Radiological tumor evaluation by mpMRI

  mpMRI assessments will be done at baseline and at 56 ±7 days after treatment initiation. BI-EFS, RFS and OS will be determined as mentioned above and collected at the moment of primary analysis.

• Translational

  TMB and PD-L1 will be determined on baseline tissue. BI-EFS, RFS and OS will be determined as mentioned above.

Study Arms (1)

Induction with heckpoint inhibition followed by consolidative chemoradiation

EXPERIMENTAL

Checkpoint inhibition and chemoradiation

Drug: Ipilimumab + nivolumab

Interventions

Ipilimumab + nivolumab DRUG

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

Also known as: Yervoy, Opdivo

Induction with heckpoint inhibition followed by consolidative chemoradiation

Eligibility Criteria

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

You may qualify if:

• 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.
• World Health Organization (WHO) performance Status 0 or 1.
• Urothelial cancer is the dominant histology (\>70%). A small cell component is not allowed.
• 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.

You may not qualify if:

• 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
• 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.
• 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.

Sponsors & Collaborators

• The Netherlands Cancer Institute: lead
• Bristol-Myers Squibb: collaborator

Study Sites (3)

Antoni van Leeuwenhoek ziekenhuis

Amsterdam, 1066CX, Netherlands

Location

Erasmus Medical Center

Rotterdam, Netherlands

Location

Universitair Medisch Centrum Utrecht

Utrecht, Netherlands

Location

Related Publications (1)

• Stockem 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.

  PMID: 37711193 DERIVED

MeSH Terms

Conditions

Carcinoma, Transitional Cell; Urinary Bladder Neoplasms

Interventions

Ipilimumab; Nivolumab

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Design

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

Model Details: Multicenter, open-label, phase 2 clinical trial

Study Record Dates

• First Submitted: October 14, 2021
• First Posted: January 21, 2022
• Study Start: March 14, 2022
• Primary Completion: September 5, 2025
• Study Completion (Estimated): September 5, 2027
• Last Updated: March 18, 2024

Record last verified: 2024-03

Locations

NL (3)