A Study of Pembrolizumab (MK-3475) Versus Paclitaxel, Docetaxel, or Vinflunine for Participants With Advanced Urothelial Cancer (MK-3475-045/KEYNOTE-045)
Condition: Urothelial Cancer
Intervention: pembrolizumab; paclitaxel; vinflunine; docetaxel
Intervention description: IV infusion; IV infusion; IV infusion; IV infusion
Intervention MeSH terms: Paclitaxel; Docetaxel; Pembrolizumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 542.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Programmed Cell Death-1 (PD1, PD-1); Programmed Death-Ligand 1 (PDL1, PD-L1); Bladder cancer

Summary:

      Participants with metastatic or locally advanced/unresectable urothelial cancer that has
      recurred or progressed following platinum-based chemotherapy will be randomly assigned to
      receive Investigator's choice of paclitaxel, docetaxel, or vinflunine (Control), or
      pembrolizumab. The primary study hypotheses are that pembrolizumab will prolong Overall
      Survival (OS) and Progression-free Survival (PFS) compared to paclitaxel, docetaxel, or
      vinflunine.
    

Eligibility criteria:

        Inclusion criteria:

          -  Histologically- or cytologically-confirmed diagnosis of urothelial cancer of the renal
             pelvis, ureter, bladder, or urethra, that is transitional cell or mixed
             transitional/non-transitional (predominantly transitional) cell type

          -  Progression or recurrence of urothelial cancer following a first-line
             platinum-containing regimen (e.g cisplatin, carboplatin) for metastatic or inoperable
             locally advanced disease; or adjuvant platinum-based therapy following cystectomy for
             localized muscle-invasive urothelial cancer with recurrence/progression <=12 months
             following completion of therapy; or neoadjuvant platinum-containing therapy prior to
             cystectomy for localized muscle-invasive urothelial cancer with recurrence <=12 months
             following completion of therapy

          -  No more than 2 prior lines of systemic chemotherapy for metastatic urothelial cancer

          -  Able to provide tissue for biomarker analysis from an archival tissue sample or newly
             obtained core or excisional biopsy of a tumor lesion not previously irradiated

          -  Measureable disease

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

          -  Adequate organ function

          -  Female participants of childbearing potential have a negative urine or serum pregnancy
             test; or are surgically sterile, or willing to use 2 acceptable methods of birth
             control, or abstain from heterosexual activity for the course of the study through 120
             days after the last dose of pembrolizumab or 180 days after the last dose of
             paclitaxel, docetaxel, or vinflunine

          -  Male participants must be willing to use an adequate method of contraception starting
             with the first dose of study medication through 120 days after the last dose of
             pembrolizumab or 180 days after the last dose of paclitaxel, docetaxel, or vinflunine

        Exclusion criteria:

          -  Urothelial cancer that is suitable for local therapy administered with curative intent

          -  Currently participating in or has participated in a study of an investigational agent
             or using an investigational device within 4 weeks prior to the first dose of trial
             medication

          -  Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form
             of immunosuppressive therapy within 7 days prior to the first dose of study medication

          -  Anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or not
             recovered from adverse events due to agents administered more than 4 weeks earlier

          -  Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2
             weeks of study Day 1 or not recovered from adverse events due to a previously
             administered agent

          -  Prior therapy with all choices of active comparator

          -  Known additional malignancy that is progressing or requires active treatment with the
             exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin
             that has undergone potentially curative therapy or in situ cancer; or prostate cancer
             that was identified incidentally following cystoprostatectomy for bladder cancer that
             is Stage T2N0M0 or lower, Gleason score<= 6, or prostatic-specific antigen (PSA)
             undetectable

          -  Known active central nervous system (CNS) metastases and/or carcinomatous meningitis

          -  Active autoimmune disease requiring systemic treatment within the past 3 months or a
             documented history of clinically severe autoimmune disease, or a syndrome that
             requires systemic or immunosuppressive agents

          -  Active cardiac disease

          -  Evidence of interstitial lung disease or active non-infectious pneumonitis

          -  Active infection requiring systemic therapy

          -  History of severe hypersensitivity reaction to paclitaxel, docetaxel, or to other
             drugs formulated with polysorbate 80 or polyoxyethylated castor oil, or to vinflunine
             or other vinca alkaloids

          -  Requires ongoing therapy with a medication that is a strong inhibitor or inducer of
             the cytochrome 3A4 (CYP3A4) enzymes

          -  Pregnant, breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the screening visit through 120 days
             after the last dose of pembrolizumab or 180 days after the last dose of paclitaxel,
             docetaxel, or vinflunine

          -  Prior therapy with an anti-programmed cell death 1 (PD-1) or anti-PD-Ligand 1 agent,
             or with an agent directed to another co-inhibitory T-cell receptor

          -  Human immunodeficiency virus (HIV)

          -  Active hepatitis B or hepatitis C

          -  Received a live virus vaccine within 30 days of planned start of trial treatment