Checkpoint Inhibition and Chemoradiotherapy as Bladder Sparing Treatment in UC

NCT ID: NCT05200988

Last Updated: 2024-03-18

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 50 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-03-14
• Study Completion Date: 2027-09-05

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.

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Induction with heckpoint inhibition followed by consolidative chemoradiation

Checkpoint inhibition and chemoradiation

Group Type: EXPERIMENTAL

Ipilimumab + nivolumab

Intervention Type: 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

Interventions

Ipilimumab + nivolumab

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

Intervention Type: DRUG

Other Intervention Names

Yervoy; Opdivo

Eligibility Criteria

Inclusion Criteria

1. Willing and able to provide informed consent

2. Age ≥ 18 years

3. 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.

4. Lymph nodes should be amenable for inclusion into the radiation field.

5. World Health Organization (WHO) performance Status 0 or 1.

6. Urothelial cancer is the dominant histology (>70%). A small cell component is not allowed.

7. Formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks from diagnostic TUR available.

8. 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

9. Negative pregnancy test (βHCG in urine or blood) for female patients of childbearing potential within 2 weeks prior to day 1 of start immunotherapy.

10. 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.

Exclusion Criteria

1. Previous pelvic irradiation

2. Upper tract urothelial cancer

3. Extensive carcinoma in situ (CIS) of the bladder

4. Bilateral hydronephrosis

5. Previous intravenous chemotherapy for bladder cancer

6. Contra-indication to one of the study treatment components, or mpMRI

7. 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.

8. Documented history of severe autoimmune disease (e.g. inflammatory bowel disease, myasthenia gravis).

9. Prior CTLA-4 or PD-(L)1 -targeting immunotherapy.

10. Known history of Human Immunodeficiency Virus, active tuberculosis, or other active infection requiring therapy at the time of inclusion.

11. Positive tests for Hepatitis B surface antigen or Hepatitis C ribonucleic acid (RNA)

12. Underlying medical conditions that, in the investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of adverse events

13. 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.

14. Use of other investigational drugs four weeks before study drug administration

15. 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.

16. Pregnant and lactating female patients.

17. 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.

18. 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bristol-Myers Squibb

INDUSTRY

Sponsor Role: collaborator

The Netherlands Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Antoni van Leeuwenhoek ziekenhuis

Amsterdam, , Netherlands

Erasmus Medical Center

Rotterdam, , Netherlands

Universitair Medisch Centrum Utrecht

Utrecht, , Netherlands

Countries

Netherlands

References

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.

Reference Type: DERIVED

PMID: 37711193 (View on PubMed)

Other Identifiers

M21IDB

Identifier Type: -

Identifier Source: org_study_id