AVELUMAB for Metastatic urothelial cancer | Locally advanced urothelial cancer

Inclusion criteria

• {"criterion_text":"- Informed consent obtained before any study-specific procedures. Patients must be able to understand and be willing to sign a written informed consent\n- Adequate bone-marrow, liver, and renal function as assessed by the following laboratory requirements conducted within 7 days of starting to study treatment: a Creatinine value <2.5 mg/dl and creatinine clearance > 30 ml/min evaluated by the Cockcroft-Gault Formula. b Total bilirubin ≤1∙5 × the upper limit of normal (ULN); Synopsis_SELECTIO-UC_Version 1.0 of 29 May 2024 5 / 12 c Alanine aminotransferase and aspartate aminotransferase ≤2 × ULN (≤5 × ULN for patients with liver involvement of their cancer); d International normalized ratio (INR) and partial thromboplastin time (PTT) ≤1∙5 × ULN. Subjects who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate if no prior evidence of an underlying abnormality in coagulation parameters exists. Close monitoring of at least weekly evaluations will be performed until INR and PTT are stable based on a pre-dose measurement as defined by the local standard of care; e Platelet count ≥100 000/mm3, hemoglobin >9 g/dl, absolute neutrophil count >1,500/mm3; f Alkaline phosphatase limit ≤2∙5 × ULN (≤5 × ULN for patients with liver involvement of their cancer)\n- Male or female patient ≥18 years of age\n- Histological or cytological documentation of urothelial cancer\n- Available tumor tissue for analysis\n- Measurable disease according to Response Evaluation Criteria in Solid Tumors criteria, version 1.1\n- Eastern Cooperative Oncology Group performance status of ≤2. (Patients with ECOG PS of 2 were required to also meet the additional criteria: hemoglobin ≥10 g/dL, GFR ≥50mL/min, may not have NYHA class III heart failure)\n- Life expectancy of at least 6 months\n- Eligible to standard chemotherapy with cisplatin or carboplatin + gemcitabine as per clinical practice\n- Women of childbearing potential and men must agree to use adequate contraception since signing of the informed consent form until at least 180 days after the last dose of chemotherapy and 30 days after the last dose of avelumab. The investigator or a designated associate is requested to advise the subject how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommend method (or combination of methods) as per standard of care"}

Exclusion criteria

• {"criterion_text":"- Previous treatment for metastatic or locally advanced disease\n- Any autoimmune disease that contraindicates the use of maintenance immunotherapy in case of stable or responsive disease to chemotherapy\n- Seizure disorder requiring medication\n- Symptomatic metastatic brain or meningeal tumors unless the patient is >2 months from definitive therapy, has a negative imaging study within 4 weeks of study entry and is clinically stable with respect to the tumor at the time of study entry. Also, the patient must not be undergoing acute steroid therapy or tapering (chronic steroid therapy is acceptable provided that the dose is stable for 1 month before and after screening radiographic studies)\n- History of organ allograft\n- Evidence or history of bleeding diathesis. Any hemorrhage or bleeding event of CTCAE grade 3 or higher within 4 weeks of start of study medication\n- Non-healing wound, ulcer, or bone fracture\n- Renal failure requiring hemodialysis or peritoneal dialysis\n- Any illness or medical conditions that are unstable or could jeopardize the safety of the patient and his or her compliance in the study\n- Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed\n- Participation to another clinical trial at the time of the enrollment\n- Previous adjuvant therapy within 1 year from the diagnosis of metastatic disease\n- Prior treatment with immunotherapy\n- Previous or concurrent cancer that is distinct in primary site or histology from urothelial cancer within 3 years before enrollment EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer and pT2 prostate cancer with PSA<0.01\n- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication\n- Pregnancy or breast-feeding. Women in childbearing potential must have a pregnancy test performed a maximum of 7 days before start of treatment, and a negative result must be documented before start of treatment\n- Any cardiological condition among: a Congestive heart failure of New York Heart Association class 3 or worse. b Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months). Myocardial infarction less than 6 months before start of study drug. c Cardiac arrhythmias requiring anti-arrhythmic therapy (betablockers or digoxin are permitted). Synopsis_SELECTIO-UC_Version 1.0 of 29 May 2024 6 / 12 d Uncontrolled hypertension (systolic blood pressure >150 mmHg or diastolic pressure >90 mmHg despite optimal medical management). e Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), pulmonary embolism within the 4 months before start of study medication\n- Ongoing infection higher than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 grade 2\n- Known history of human immunodeficiency (HIV) virus infection or known history of chronic hepatitis B or C"}

Primary endpoints

• {"endpoint_text":"- To assess the difference in ORR defined as the percentage of patients who achieve PR or CR as measured by RECIST 1.1, to the platinum-based chemotherapy between patients with metastatic or locally advanced urothelial cancer with or without DDR genes alterations. Radiological confirmation of the response is not required","definition_or_measurement_approach":"ORR defined as the percentage of patients who achieve PR or CR as measured by RECIST 1.1; radiological confirmation of the response is not required"}

Secondary endpoints

• {"endpoint_text":"- To evaluate the PFS defined as the time elapsed from start of investigational treatment to the documentation of investigatorassessed disease progression, according to RECIST 1.1, or death due to any cause, whichever occurs first in patients with or without DDR genes alterations","definition_or_measurement_approach":"PFS defined as time from start of investigational treatment to investigator-assessed disease progression per RECIST 1.1 or death from any cause"}
• {"endpoint_text":"- To evaluate the OS defined as time elapsed from start of investigational treatment to the date of death due to any cause in patients with or without DDR genes alterations","definition_or_measurement_approach":"OS defined as time from start of investigational treatment to date of death due to any cause"}
• {"endpoint_text":"- To evaluate the ORR defined as the percentage of patients who achieve PR or CR as measured by RECIST 1.1 criteria in patients with or without DDR genes alterations between those treated with carboplatin o cisplatin","definition_or_measurement_approach":"ORR per RECIST 1.1 (PR or CR) compared between patients treated with carboplatin or cisplatin"}
• {"endpoint_text":"- To evaluate the disease control rate (DCR) defined as the percentage of patients who achieve stable disease (SD) or PR or CR as measured by RECIST 1.1 criteria in patients with or without DDR genes alterations between those treated with carboplatin o cisplatin","definition_or_measurement_approach":"DCR defined as percentage achieving SD, PR, or CR per RECIST 1.1, compared between carboplatin and cisplatin groups"}
• {"endpoint_text":"- To evaluate the incidence of chemo-related adverse events in patients with or without DDR genes alterations graded according to NCI CTCAE version 5.0","definition_or_measurement_approach":"Incidence of chemotherapy-related adverse events graded per NCI CTCAE v5.0"}
• {"endpoint_text":"- Translational endpoint: to describe the incidence of DDR alteration found in NGS analysis performed among the eligible patients","definition_or_measurement_approach":"Incidence of DDR alterations identified by NGS analysis among eligible patients"}
• {"endpoint_text":"- Traslational endpoint: To describe the expression of Nectin4, PDL1, Trop2 and Her2 proteins in tumor tissue","definition_or_measurement_approach":"Descriptive assessment of Nectin4, PDL1, Trop2 and Her2 protein expression in tumor tissue (translational analyses)"}

Italy

Earliest CTIS Part Ii Submission Date

18-10-2024

Latest Decision Or Authorization Date

28-05-2025

Processing Time Days

222

Number Of Sites

23

Number Of Participants

135

Primary sponsor

Full Name

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Italy

Third parties

• {"country":"","full_name":"Merck KGaA","duties_or_roles":"Source of monetary support","organisation_type":""}