Avelumab for Locally advanced urothelial carcinoma

Inclusion criteria

• {"criterion_text":"- Age ≥ 18 years."}
• {"criterion_text":"- Adequate renal function, defined as estimated creatinine clearance ≥30 mL/min as calculated by the CKD-EPI eGFR."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Have histologically confirmed urothelial carcinoma of the bladder, upper urinary tract or urethra; a maximum of 50% of aberrant histology is allowed."}
• {"criterion_text":"- Have clinical stage cT4bNxM0 or cTxN1-N3M0 as assessed by bimanual examination under anaesthesia, CT scan, MRI scan or PET-CT scan."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Are fit and willing to undergo radical surgery with removal of lymph node template including all affected lymph nodes and the primary tumor."}
• {"criterion_text":"- World Health Organisation performance status of 0-2."}
• {"criterion_text":"- Provide written informed consent."}
• {"criterion_text":"- Negative pregnancy test in women with childbearing potential."}
• {"criterion_text":"- 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)."}

Exclusion criteria

• {"criterion_text":"- Predominant (>50%) non-urothelial carcinoma histology in the diagnostic endoresection specimen of the bladder, urethra or upper urinary tract."}
• {"criterion_text":"- 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)."}
• {"criterion_text":"- Diagnosis of prior immunodeficiency or organ transplant requiring immunosuppressive therapy, or known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness."}
• {"criterion_text":"- Any test for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating acute or chronic infection."}
• {"criterion_text":"- 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)."}
• {"criterion_text":"- Have an estimated creatinin clearance as assessed by the CKD-EPI eGFR of <30 ml/min."}
• {"criterion_text":"- Prior exposure to immune-mediated therapy with exclusion of Bacillus-Calmette Guérin intravesical instillations, including but not limited to other anti-CTLA-4, anti PD1, anti PD-L1, or anti-PD-L2 antibodies."}
• {"criterion_text":"- Persisting toxicity related to prior chemotherapy (Grade >2 NCI CTCAE v5.0)."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- ≤2 cycles of induction platinum-based chemotherapy received."}
• {"criterion_text":"- Progression of disease during or following induction platinum-based chemotherapy, as assessed by RECIST v1.1."}
• {"criterion_text":"- Previous pelvic radiation therapy."}
• {"criterion_text":"- Distant metastatic disease."}
• {"criterion_text":"- 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 into this study."}
• {"criterion_text":"- Breastfeeding women."}
• {"criterion_text":"- Bilateral upper urinary tract urothelial carcinoma."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Active infection requiring systemic therapy."}
• {"criterion_text":"- 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)."}
• {"criterion_text":"- Known prior or suspected hypersensitivity to avelumab."}

Primary endpoints

• {"endpoint_text":"- Pathological complete response rate, defined as the proportion of patients without residual UC in the surgical resection specimen, ypT0N0 (carcinoma situ is allowed), in the intention-to-treat analysis.","definition_or_measurement_approach":"defined as the proportion of patients without residual UC in the surgical resection specimen, ypT0N0 (carcinoma situ is allowed), in the intention-to-treat analysis."}

Secondary endpoints

• {"endpoint_text":"- Progression-free, cancer-specific and overall survival at 24 months, calculated from the time of 1st administration of avelumab.","definition_or_measurement_approach":"Calculated from the time of 1st administration of avelumab; survival outcomes at 24 months."}
• {"endpoint_text":"- Safety and tolerability of preoperative avelumab as assessed by the CTCAE v5.0 (Appendix 9).","definition_or_measurement_approach":"Assessed by CTCAE v5.0 (see Appendix 9)."}
• {"endpoint_text":"- Clavien-Dindo surgical complications (within 30 and 90 days from date of surgery) (Appendix 10).","definition_or_measurement_approach":"Assessed using Clavien-Dindo classification within 30 and 90 days after surgery (see Appendix 10)."}
• {"endpoint_text":"- The rate of non-invasive urothelial cancer in the surgical resection specimen, stage ypT0N0/ypTisN0/ypTaN0/ypT1N0.","definition_or_measurement_approach":"Proportion of surgical specimens with non-invasive urothelial cancer by pathological staging (ypT0N0/ypTisN0/ypTaN0/ypT1N0)."}
• {"endpoint_text":"- The proportion of patients in whom radical surgery is delayed >8 weeks after last administration of avelumab due to toxicity.","definition_or_measurement_approach":"Proportion of patients with radical surgery delayed >8 weeks after day 14 of the last administration of avelumab due to immune-related toxicity (or toxicity)."}

Netherlands

Earliest CTIS Part Ii Submission Date

24-10-2024

Latest Decision Or Authorization Date

17-03-2025

Processing Time Days

144

Number Of Sites

6

Number Of Participants

58

Primary sponsor

Full Name

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Netherlands