Overview

This phase II trial compares therapeutic plasma exchange followed by enfortumab vedotin and pembrolizumab to standard of care next-line therapy for the treatment of patients with bladder or upper urinary tract cancers that have spread from where they first started (primary site) to other places in the body (metastatic) and that have not responded to previous treatment (refractory). TPE is a process that slowly removes a patient's blood through an intravenous or central line. The blood is sent through a machine that separates the plasma (the liquid part of blood) from other blood components (red cells, white cells, platelets). The plasma is then removed. The remaining blood components are combined with replacement fluid and returned to the patient's bloodstream through the intravenous or central line. Enfortumab vedotin is a monoclonal antibody, enfortumab, linked to an anticancer drug called vedotin. It works by helping the immune system to slow or stop the growth of cancer cells. Enfortumab attaches to a protein called nectin-4 on cancer cells in a targeted way and delivers vedotin to kill them. It is a type of antibody-drug conjugate. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Treatment with enfortumab vedotin and pembrolizumab is already approved by the Food and Drug Administration for the treatment of bladder cancer, but TPE is not. Combining TPE with enfortumab vedotin and pembrolizumab may work better than standard of care options for treating metastatic and refractory bladder and urinary tract cancers.

Eligibility

Inclusion Criteria:

• Age ≥ 18 years
• Histologically proven urothelial carcinoma [American Joint Committee on Cancer (AJCC) 2017] of the bladder (BCa) or upper urothelial tract (UTUC), that has progressed despite enfortumab vedotin and pembrolizumab treatment
  • NOTE: Primary or secondary progression are allowed, therapies are not required to be concurrent or immediately antecedent to enrollment)
• Measurable disease per RECIST version (v)1.1
• Eastern Cooperative Oncology Group (ECOG) performance status grade 0, 1, or 2
• Hemoglobin > 7.0 g/dL (obtained ≤ 30 days prior to registration)
• Platelet count ≥ 75,000/mm^3 (obtained ≤ 30 days prior to registration)
• Alanine aminotransferase (ALT) OR aspartate transaminase (AST) ≤ 3.5 x upper limit of normal (ULN) OR total bilirubin ≤ 3 x ULN OR direct bilirubin ≤ 3 x ULN (obtained ≤ 30 days prior to registration)
• Estimated glomerular filtration rate (GFR) ≥ 15 ml/min (obtained ≤ 30 days prior to registration)
• 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 [New York Heart Association (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