Inclusion Criteria:

• Age ≥18 years

• Histologically proven urothelial carcinoma (AJCC 2017) of the bladder (BCa) or upper urothelial tract (UTUC), that has progressed despite enfortumab vedotin and pembrolizumab treatment NOTEs: Primary or secondary progression are allowed, therapies are not required to be concurrent or immediately antecedent to enrollment).

• Measurable disease per RECIST v1.1

• Eastern Cooperative Oncology Group (ECOG) performance status Grade 0, 1, or 2

• Adequate bone marrow, liver, and renal function (obtained ≤30 days prior to registration):

  • Hemoglobin >7.0 g/dL

  • Platelet count ≥75,000/mm3

  • Alanine aminotransferase (ALT) OR aspartate transaminase (AST) ≤3.5 x ULN OR total bilirubin ≤ 3x ULN OR direct bilirubin ≤3x ULN

  • Estimated GFR ≥15 ml/min

• Negative pregnancy test ≤8 days prior to registration, for persons of childbearing potential only.

• Provide written informed consent

• Ability to complete questionnaire(s) by themselves or with assistance.

• Willingness to undergo treatment on either treatment arm (Group A: TPE + EV/ pembro; OR Group B: next line standard of care)

• Willingness to provide mandatory blood and fluid specimens for correlative research Willingness to provide tissue specimens for correlative research

• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study)

Exclusion Criteria:

• Any of the following because this study involves an investigational agent, the genotoxic, mutagenic, and teratogenic effects of which on the developing fetus and newborn are unknown

  • Pregnant persons

  • Nursing persons

  • Persons of childbearing potential or able to father a child who are unwilling to employ adequate contraception

• Any of the following histologic variants/divergent differentiation: Any amount of neuroendocrine, micropapillary, or signet ring cell features

  • Active malignancies (i.e., progressing or requiring treatment change ≤24 months before registration) other than the disease being treated under study EXCEPTIONS:

  • Skin cancer (melanoma or non-melanoma) that is considered completely cured

  • Non-invasive cervical cancer that is considered completely cured

  • Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ considered to have a very low risk of recurrence

  • Localized prostate cancer (T1c/T2N0M0):

    • Gleason score 6, treated by either surgery or ablation ≤24 months prior to registration or untreated and under active surveillance

    • Gleason score 3+4 that has been treated (may include surgery or ablation) ≤24 months prior to registration and considered to have a very low risk of recurrence (i.e., cT1c or pT2 on prostatectomy specimen)

• History of uncontrolled cardiovascular disease including any of the following ≤6 months prior to registration:

  • significant cardiovascular disease (NYHA Class ≥III, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, myocardial infarction, ventricular fibrillation, Torsades de Pointes, cerebrovascular accident, or transient ischemic attack

  • Psychiatric illness/social situations (e.g., substance abuse) that would limit compliance with study requirements.

• Any condition for which, in the opinion of the Investigator, participation would not be in the best interest of the participants (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 05/16/2025. Questions regarding updates should be directed to the study team contact.