Brief Title
Checkpoint Inhibition and Chemoradiotherapy as Bladder Sparing Treatment in UC
Official Title
A Phase 2 Clinical Study to Assess Efficacy of Induction Ipilimumab/Nivolumab to Spare the Bladder in Urothelial Bladder Cancer
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 and bladder function.
Key secondary endpoints are overall survival (OS), recurrence-free survival (RFS),
feasibility to proceed to chemoradiation, safety, QoL, and bladder function.
Study Phase
Phase 2
Study Type
Interventional
Primary Outcome
Efficacy defined as bladder-intact event-free survival (BI-EFS)
Secondary Outcome
Recurrence-free survival (RFS)
Condition
Urothelial Carcinoma
Intervention
Ipilimumab + nivolumab
Study Arms / Comparison Groups
Induction with heckpoint inhibition followed by consolidative chemoradiation
Description: Checkpoint inhibition and chemoradiation
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
50
Start Date
January 4, 2022
Completion Date
December 1, 2027
Primary Completion Date
September 1, 2024
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.
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
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Location Countries
Netherlands
Location Countries
Netherlands
Administrative Informations
NCT ID
NCT05200988
Organization ID
M21IDB
Responsible Party
Sponsor
Study Sponsor
The Netherlands Cancer Institute
Collaborators
Bristol-Myers Squibb
Study Sponsor
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Verification Date
January 2022