This study represents an innovative opportunity in the treatment of metastatic urothelial carcinoma

Phase II, multicenter, randomized, open-label, efficacy and safety study of maintenance avelumab compared to BSC in advanced or metastatic urothelial carcinoma patients not progressed on second-line platinum-based chemotherapy (carboplatin or cisplatin plus gemcitabine) pretreated with pembrolizumab plus enfortumab vedotin.

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:

  1. Absolute neutrophil count (ANC) ≥1,500/mm3 or 1.5 x 109/L;
  2. Platelets ≥100,000/mm3 or 100 x 109/L;
  3. Hemoglobin ≥9 g/dL (may have been transfused);
  4. Estimated creatinine clearance ≥30 mL/min calculated using the Cockcroft-Gault equation;
  5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN);
  6. 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 femle ≥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.

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:

  1. intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection);
  2. systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent;
  3. steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).

• Active and/or uncontrolled infection. The following exceptions apply:

  1. 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.
  2. 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.
  3. 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.