Urothelial cancer of the bladder, upper urinary tract or urethra. MedDRA version: 20.0 Level: LLT Classification code 10046714 Term: Urothelial carcinoma bladder System Organ Class: 100000004864 MedDRA version: 20.0 Level: LLT Classification code 10046723 Term: Urothelial carcinoma ureter System Organ Class: 100000004864 MedDRA version: 20.0 Level: LLT Classification code 10046728 Term: Urothelial carcinoma urethra System Organ Class: 100000004864
Conditions
Interventions
Trade Name: Bavencio
Product Name: Avelumab
Product Code: Not applicable
Pharmaceutical Form: Concentrate for solution for infusion
Sponsors
Erasmus MC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Age = 18 years. 2. Have histologically confirmed urothelial carcinoma of the bladder, upper urinary tract or urethra; a maximum of 50% of aberrant histology is allowed. 3. Have clinical stage cT4NxM0 or cTxN1-N3M0 as assessed by bimanual examination under anaesthesia, CT scan, MRI scan or PET-CT scan. 4. Have at least stable disease after a minimum of 3 or a maximum of 4 cycles of induction chemotherapy with Cisplatin / Carboplatin + Gemcitabine according to RECIST v1.1. 5. Are fit and willing to undergo radical surgery with removal of lymph node template including all affected lymph nodes and the primary tumor. 6. World Health Organisation performance status of 0-2. 7. Provide written informed consent. 8. Negative pregnancy test in women with childbearing potential. 9. Adequate bone marrow function, including: a. Absolute neutrophil count (ANC) =1,500/mm3 or 1.5 x 109/L; b. Platelets =100 x 109/L; c. Hemoglobin =5.6 mmol/L (may have been transfused). 10. Adequate renal function, defined as estimated creatinine clearance =30 mL/min as calculated by the CKD-EPI eGFR. 11. Adequate liver function, including: a. Total serum bilirubin =1.5 x upper limit of normal (ULN); b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =2.5 x ULN. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 38 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 20
Exclusion criteria
Exclusion criteria: 1. Predominant (>50%) non-urothelial carcinoma histology in the diagnostic endoresection specimen of the bladder, urethra or upper urinary tract. 2. Any test for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating acute or chronic infection. 3. Have an estimated creatinin clearance as assessed by the CKD-EPI eGFR of 2 NCI CTCAE v5.0). 6. A diagnosis of any other malignancy within 2 years prior to inclusion, except for adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the breast or of the cervix, low grade prostate cancer on surveillance without any plans for treatment intervention, or prostate cancer that has been adequately treated with prostatectomy or radiotherapy and currently with no evidence of disease. 7. =2 cycles of induction platinum-based chemotherapy received. 8. Progression of disease during or following induction platinum-based chemotherapy, as assessed by RECIST v1.1. 9. Distant metastatic disease. 10. Previous pelvic radiation therapy. 11. Breastfeeding women. 12. Bilateral upper urinary tract urothelial carcinoma. 13. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible. 14. Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, or symptomatic pulmonary embolism. 15. Active infection requiring systemic therapy. 16. Known severe hypersensitivity reactions to monoclonal antibodies (Grade 3), any history of anaphylaxis, or uncontrolled asthma (ie, 3 or more features of asthma symptom control per the Global Initiative for Asthma 2015). 17. Known prior or suspected hypersensitivity to avelumab. 18. Current use of immunosuppressive medication, EXCEPT the following: a. Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection); b. Systemic corticosteroids at (equivalent) doses of maximum 10 mg prednisone; c. Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication). 19. Diagnosis of prior immunodeficiency or organ transplant requiring immunosuppressive therapy, or known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness. 20. Vaccination within 4 weeks of the first dose of study treatment and while on trial is prohibited except for administration of inactivate vaccines (for example, inactivated influenza vaccines) or mRNA vaccines (for example, COVID-19 vaccines). 21. Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, and pneumonitis; psychiatric condition including recent (within the past year) or active suicidal ideation or behaviour; or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry int
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To demonstrate the benefit of sequential chemo-immunotherapy in increasing the number of patients reaching a pathological complete response (pCR) at radical surgery in patients with locally advanced irresectable (stage cT4NxM0) or clinically node-positive (stage cTxN1-N3M0) UC whose disease did not progress on or following completion of platinum-containing chemotherapy. The primary end point is the pCR rate, which is defined as the proportion of patients with absence of residual urothelial cancer cells (carcinoma in situ is allowed) in the surgical resection specimen, stage ypT0N0 / ypTisN0.;Secondary Objective: - The two-year progression-free, cancer-specific and overall survival, defined as the time from 1st administration of avelumab until two years of follow-up are completed or until: death, cancer-specific death, radiological progression as assessed by cross-sectional imaging, or abortion of radical surgery due to peri-operative irresectable primary tumor or presence of metastatic disease. - Safety and tolerability of preoperative avelumab as assessed by the CTCAE v5.0. - Clavien-Dindo surgical complications within 30 and 90 days from date of surgery. - The rate of non-invasive urothelial cancer in the surgical resection specimen, stage ypT0N0/ypTisN0/ypTaN0/ypT1N0. - The proportion of patients in whom radical surgery is delayed >8 weeks after day 14 of the last administration of avelumab due to immune-related toxicity. ;Primary end point(s): Pathological complete response rate, defined as the proportion of patients without residual urothelial cancer in the surgical resection specimen, ypT0N0 (carcinoma situ is allowed), in the intention-to-treat analysis. ;Timepoint(s) of evaluation of this end point: Surgery | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Progression-free, cancer-specific and overall survival at 24 months, calculated from the time of 1st administration of avelumab. - Safety and tolerability of preoperative avelumab as assessed by the CTCAE v5.0. - Clavien-Dindo surgical complications (within 30 and 90 days from date of surgery). - The rate of non-invasive urothelial cancer in the surgical resection specimen, stage ypT0N0/ypTisN0/ypTaN0/ypT1N0. - The proportion of patients in whom radical surgery is delayed >8 weeks after last administration of avelumab due to toxicity.;Timepoint(s) of evaluation of this end point: - 24 months - 30 and 90 days from date of surgery - surgery - >8 weeks after last administration of avelumab | — |
Countries
Netherlands
Contacts
Public ContactCoordinating investigator
Erasmus MC
Outcome results
None listed