Avelumab Maintenance Versus Best Supportive Care After Second-Line Platinum-Based Chemotherapy in Metastatic Urothelial Carcinoma (AVESEC Trial)

Trial ID: 2025-524077-16-00
Protocol: GOIRC-02-2025
Sponsor: G.O.I.R.C. Gruppo Oncologico Italiano Di Ricerca Clinica

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Diseases & Conditions

Transitional cell carcinoma metastatic

Objectives

The primary objective is to assess progression-free survival by blinded independent central review with maintenance avelumab 800 mg intravenously every 2 weeks versus best supportive care in patients with advanced or metastatic urothelial carcinoma who achieved partial response, complete response, or stable disease after second-line platinum-based chemotherapy following progression on first-line pembrolizumab plus enfortumab vedotin. This endpoint is clinically relevant because it measures the ability of maintenance treatment to delay disease progression. Secondary objectives are to evaluate overall survival, investigator-assessed progression-free survival, antitumor activity according to RECIST v1.1, overall safety, and patient-reported outcomes using FBlSI and EQ-5D.

Participants

The sponsor did not provide the total number of participants. The study population included male and female patients aged 18 years or older with histologically or cytologically confirmed metastatic or locally advanced unresectable urothelial carcinoma of the bladder or upper tract with predominant transitional cell carcinoma. Eligible participants had stable disease, partial response, or complete response after completion of 3 to 6 cycles of second-line platinum-based chemotherapy, following prior first-line enfortumab vedotin plus pembrolizumab. The trial population was selected according to predefined inclusion criteria, including measurable disease by RECIST v1.1, ECOG performance status 0 or 1, stable medical condition, adequate organ and bone marrow function, and an estimated life expectancy of at least 3 months. For individuals of fertile age, use of highly effective contraception was required, and a negative serum pregnancy test was required for females of childbearing potential. No additional lifestyle considerations were provided.

Plans and Procedures

This is a phase 4, randomized, controlled trial in metastatic urothelial carcinoma evaluating maintenance avelumab 800 mg intravenous administration every 2 weeks versus best supportive care after response or stable disease to second-line platinum-based chemotherapy. The primary endpoint is blinded independent central review progression-free survival, with secondary assessments including investigator-assessed progression-free survival, objective response, duration of response, disease control, safety, patient-reported outcomes, overall survival, and 1-year progression-free survival. The overall trial duration is planned from 2026-05-04 to 2030-11-04. Study participation begins with a screening visit to confirm eligibility, including disease status, prior treatment history, performance status, organ function, and pregnancy testing where applicable. Eligible participants then enter the treatment and follow-up period, during which study visits are performed to assess efficacy, safety, laboratory parameters, and other protocol-defined outcomes. An end-of-study visit is performed at completion of study participation. Expected participant involvement continues for the duration of the study unless early termination occurs because of disease progression, unacceptable toxicity, withdrawal of consent, noncompliance with study procedures, intercurrent illness, or other protocol-defined reasons.

Treatment

The investigational treatment is avelumab, administered as an intravenous dose of 800 mg every 2 weeks. The trial evaluates maintenance treatment with avelumab after response or stable disease to second-line platinum-based chemotherapy in advanced or metastatic urothelial carcinoma. The source data do not specify the pharmaceutical form. Administration is by intravenous route on a Q2W schedule. No additional dosing modifications or compliance monitoring procedures are specified in the source data.

The non-experimental treatment is best supportive care, used as the comparator in the study. No further details regarding its components, dosing schedule, or administration procedures are provided in the source data.

Efficacy

Efficacy will be assessed primarily by progression-free survival based on blinded independent central review in patients with metastatic urothelial carcinoma receiving maintenance avelumab 800 mg intravenously every 2 weeks versus best supportive care. The treatment effect will be compared between arms using a one-sided log-rank test, and quantified using the hazard ratio estimated from a Cox proportional hazards model with corresponding confidence intervals. Secondary efficacy assessments will include investigator-assessed PFS, objective response rate, duration of response, disease control rate assessed per RECIST v1.1 by blinded independent central review and investigator, overall survival, and 1-year PFS based on blinded independent central review per RECIST v1.1. Patient-reported outcomes will also be evaluated for bladder cancer symptom, functioning, global quality of life, time to deterioration using the NCCN- FACT FBlSI, and health status using the EQ-5D.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Histologically or cytologically-confirmed diagnosis of metastatic or locally advanced unresectable urothelial carcinoma of the bladder or upper tract with predominant transitional cell carcinoma.
Have received first-line of therapy consisting in enfortumab vedotin plus pembrolizumab and second-line of therapy with cisplatin or carboplatin plus gemcitabine (at least 3 cycles). Adjuvant or neoadjuvant chemotherapy is allowed if completed by >12 months.
Have not progressed per RECIST v1.1 guidelines (stable disease, partial response, complete response) following completion of 3-6 cycles of second-line chemotherapy.
Have measurable disease by RECIST v1.1 as assessed by the investigator
Estimated life expectancy of at least 3 months.
Willing and able to comply to study visits and procedures and be available for the duration of the study.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
Adequate organ and bone marrow function, including: a. Absolute neutrophil count (ANC) ≥1,500/mm3 or 1.5 x 109/L ; b. Platelets ≥100,000/mm3 or 100 x 109/L; c. Hemoglobin ≥9 g/dL (may have been transfused); d. Estimated creatinine clearance ≥30 mL/min calculated using the Cockcroft-Gault equation; e. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN); f. Total bilirubin ≤1.5 x ULN. For subjects with Gilbert's disease, ≤3 mg/dL.
Serum pregnancy test (for females of childbearing potential) negative at screening.
If in fertile age, must agree to use highly effective methods of contraception (licensed hormonal methods for female patients and condom for male patients) throughout the study and for at least 30 days after the last dose.
Male or female ≥18 years.
Signed informed consent documenting that the patient has been informed on all the aspects of the study.
Stable medical condition, including the absence of acute exacerbations of chronic illnesses, serious infections, or major surgery within 4 weeks before registration, and otherwise noted in other inclusion/exclusion criteria

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Exclusion Criteria

Patients whose disease progressed by RECIST v1.1 on second-line chemotherapy for urothelial cancer
Prior grade ≥3 per National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) toxicity from an immune-checkpoint inhibitor (thyroid toxicity excluded).
Persisting toxicity related to prior therapy (CTCAE Grade > 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator’s judgment are acceptable
Patients with known symptomatic central nervous system (SNC) metastases requiring steroids. Patients are eligible if treatment (radiation or surgery) for SNC metastases has been completed by at least 4 weeks before first study dose and have recovered from acute effects of treatment and are neurologically stable.
Has had major surgery within 4 weeks prior to first study dose. Complete wound healing must have occurred independently from the time passed
Has received prior radiotherapy within 2 weeks prior to first study dose. Prior palliative radiotherapy to metastatic bone lesion(s) is permitted, provided it has been completed at least 48 hours prior to first study dose.
Active autoimmune disease requiring high-dose steroids or immunosuppressive treatment. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible
Diagnosis of any other malignancy within 5 years prior to randomization, except for radically treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of the cervix, or low-grade (Gleason 6) prostate cancer on surveillance
Participation in other studies involving investigational drug(s) within 4 weeks prior to randomization with the exception of observational studies
Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
Known prior severe hypersensitivity to study drug or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (CTCAE Grade ≥3).
Current or prior use of immunosuppressive medication within 7 days prior to randomization, EXCEPT the following: a) intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection); b) systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c) steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).
Active and/or uncontrolled infection. The following exceptions apply: a. Participants with HIV infection are eligible if they are on effective antiretroviral therapy with undetectable viral load within 6 months, provided there is no expected drug-drug interaction. b. Participants with evidence of chronic HBV infection are eligible if the HBV viral load is undetectable on suppressive therapy (if indicated), and if they have ALT, AST, and total bilirubin levels < ULN, and provided there is no expected drug-drug interaction. c. Participants with a history of HCV infection are eligible if they have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load, and if they have ALT, AST, and total bilirubin levels < ULN.
Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behaviour; or laboratory abnormalities 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.
Prior organ transplantation including allogenic stem-cell transplantation
Vaccination within 4 weeks of the first dose of study treatment and while on trial is prohibited except for administration of inactivate vaccines (eg, inactivated influenza vaccines)
Pregnant or lactating female patients; male patients able to father children, and female patients of childbearing potential who are unwilling or unable to use 2 highly effective methods of contraception for the duration of the study and for at least 60 days after the last dose of study drug.