LEAP-011: This phase III trial is trying to determine whether it is better to give a type of immunotherapy (Pembrolizumab) alone or in combination with an oral drug (Lenvatinib) in people with urothelial cancers that have spread to other parts of the bodyA Phase 3, Randomized, Double-blind Study to Compare the Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Lenvatinib (E7080/MK-7902) Versus Pembrolizumab and Placebo as First Line Treatment for Locally Advanced or Metastatic Urothelial Carcinoma in Cisplatin-ineligible Participants Whose Tumors Express PD-L1, and in Participants Ineligible for Any Platinum-containing Chemotherapy Regardless of PD-L1 Expression

Exclusion

• Has disease that is suitable for local therapy administered with curative intent (e.g. chemotherapy and radiation for Stage 3 disease).
• Has tumor with any neuroendocrine or small cell component.
• Has a history of a gastrointestinal condition or procedure (e.g. gastric bypass, malabsorption) that, in the opinion of the investigator, may affect oral drug absorption.
• Has had major surgery within 3 weeks prior to the first dose of study treatment
• Has a pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula.
• Has radiographic evidence of major blood vessel invasion/infiltration, or has had clinically significant hemoptysis (≥0.5 teaspoon of bright red blood) or tumor bleeding within 2 weeks prior to the first dose of study treatment.
• Has had significant cardiovascular impairment within 12 months of the first dose of study treatment, such as history of New York Heart Association (NYHA) >Class II congestive heart failure, unstable angina, myocardial infarction or cerebrovascular accident (CVA)/stroke, cardiac revascularization procedure, or cardiac arrhythmia associated with hemodynamic instability.
• Has known intolerance or severe hypersensitivity (Grade ≥3) to pembrolizumab or lenvatinib or any of their excipients
• Has received lenvatinib as monotherapy or in combination with a programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitor or has previously been enrolled in a clinical study evaluating lenvatinib for bladder cancer, regardless of the treatment received.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 inhibitor, indoleamine-pyrrole 2,3 dioxygenase (IDO1) inhibitor, or agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4], OX 40, CD137), or any other antibody or drug targeting T-cell costimulatory pathways in the adjuvant or advanced/metastatic setting.
• Has received prior radiotherapy to a metastatic site without the use of chemotherapy radiosensitization within 3 weeks of the first dose of study treatment, with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks before the start of study treatment. Participants must have recovered from all radiation-related toxicities, and must not require corticosteroids.
• Has received a live vaccine within 30 days prior to the first dose of study treatment.
• In the investigator's judgment, has not recovered from toxicity or other complications from any major surgery prior to starting study treatment.
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
• Has history or presence of an abnormal electrocardiogram (ECG) that, in the investigator's opinion, is clinically meaningful.
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (at a dose exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to randomization.
• Has had an active malignancy (except locally advanced or metastatic UC) within the past 36 months. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) who have undergone potentially curative therapy are not excluded.
• Has a history of prostate cancer (T2NXMX or lower with Gleason score ≤7) treated with definitive intent (surgically or with radiation therapy) ≥1 year prior to study entry is acceptable, provided that the participant is considered prostate cancer-free.
• Has central nervous system (CNS) metastases, unless the participant has completed local therapy (e.g. whole brain radiation therapy, surgery, or radiosurgery) and has discontinued use of corticosteroids for this indication for ≥4 weeks before starting study treatment. Any signs (e.g. radiologic) or symptoms of CNS metastases must be stable for ≥4 weeks before starting study treatment.
• Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e, with disease-modifying agents, corticosteroids, or immunosuppressive drugs).
• Has a history of (non-infectious) pneumonitis that required systemic steroids, or current pneumonitis.
• Has an active infection requiring systemic therapy.
• Has a known history of human immunodeficiency virus (HIV) infection.
• Has a known history of or is positive for active hepatitis B virus (HBV) or has active hepatitis C virus (HCV).
• Has active tuberculosis (TB).
• Is receiving hemodialysis.
• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of pembrolizumab and lenvatinib/placebo.
• Has had an allogeneic tissue/solid organ transplant.