A 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 (LEAP-011)

1. Have a histologically or cytologically confirmed diagnosis of
advanced/unresectable or metastatic urothelial carcinoma of the renal pelvis,
ureter, bladder, or urethra. Both transitional cell and mixed
transitional/nontransitional cell histology are allowed, but transitional cell
carcinoma must be the predominant histology, 2. Have at least 1 measurable
target lesion per RECIST 1.1 as assessed by the local site
investigator/radiologist, per the criteria defined in the protocol, 3. Have
provided an archival tumor tissue sample or newly obtained core or excisional
biopsy of a tumor lesion not previously irradiated and adequate for PD-L1
evaluation. , 4. Have received no prior systemic chemotherapy for advanced or
metastatic UC with the following exceptions:, - Neoadjuvant platinum-based
chemotherapy for treatment of muscle-invasive bladder cancer with recurrence
>12 months from completion of the therapy is permitted, - Adjuvant
platinum-based chemotherapy following radical cystectomy, with recurrence >12
months from completion of the therapy, is permitted, 5. Meet criteria for
either option a or option b:, a. Have a tumor(s) with PD-L1 CPS >=10 and be
considered ineligible to receive cisplatin-based combination therapy, based on
1 of the following:, - ECOG PS 2 within 7 days prior to randomization, - CrCl
(calculated or measured using the institutional standard) >=30 to <=60 mL/min, -
NCI CTCAE Version 4.0 Grade >=2 audiometric hearing loss, - NCI CTCAE Version
4.0 Grade >=2 peripheral neuropathy, OR, b. In the opinion of the investigator,
be considered ineligible to receive any platinum-based chemotherapy (ie,
ineligible for cisplatin and carboplatin) based on:, - ECOG PS 2 within 7 days
prior to randomization, and at least 1 of the following:, - Documented visceral
metastatic disease, - CrCl >=30 to <=60 mL/min, - NCI CTCAE Version 4.0 Grade >=2
audiometric hearing loss, - NCI CTCAE Version 4.0 Grade >=2 peripheral
neuropathy, - Other reason, identified on the case report form, for the
participant being unable to receive both cisplatin and carboplatin safely.
Additional criteria for platinum ineligibility will be considered and allowed
on a case-by-case basis, following consultation with the Sponsor, 6. Be male or
female and >=18 years of age and considered an adult per local regulations on
the day of signing the informed consent, 7. Have ECOG PS 0, 1, or 2 within 7
days prior to randomization and a life expectancy of >=3 months, 8. Male
participants are eligible to participate if they agree to the following during
the intervention period and for at least 30 days after the last dose of
pembrolizumab or lenvatinib/placebo:, - Be abstinent from heterosexual
intercourse as their preferred and usual lifestyle and agree to remain
abstinent, OR, - Must agree to use contraception unless confirmed to be
azoospermic as detailed below:, - Agree to use a male condom plus partner use
of an additional contraceptive method when having penile-vaginal intercourse
with a WOCBP who is not currently pregnant, 9. A female participant is eligible
to participate if she is not pregnant or breastfeeding and at least one of the
following conditions applies:, - Is not a WOCBP, OR, - Is a WOCBP and using a
contraceptive method that is highly effective with low user dependency, or be
abstinent from heterosexual intercourse as her preferred and usual lifestyle,
during the intervention period and for at least 120 days post pembrolizumab or
30 days post lenvatinib/placebo, - A WOCBP must have a negative highly
sensitive pregnancy test within 72 hours before the first dose of study
intervention, - If a urine test cannot be confirmed as negative, a serum
pregnancy test is required. In such cases, the participant must be excluded
from participation if the serum pregnancy result is positive, - The
investigator is responsible for review of medical history, menstrual history,
and recent sexual activity to decrease the risk of including a woman with an
early undetected pregnancy, 10. The participant (or legally acceptable
representative if applicable) provides written informed consent for the study,
11. Have adequately controlled BP with or without antihypertensive medications,
defined as BP <=150/90 mm Hg at screening and no change in antihypertensive
medications within 1 week prior to randomization, 12. Have adequate organ
function

1. Has disease that is suitable for local therapy administered with curative
intent (eg, chemotherapy and radiation for Stage 3 disease). , 2. Has tumor
with any neuroendocrine or small cell component., 3. Has a history of a
gastrointestinal condition or procedure (eg, gastric bypass, malabsorption)
that, in the opinion of the investigator, may affect oral drug absorption., 4.
Has had major surgery within 3 weeks prior to the first dose of study
intervention., 5. Has a pre-existing Grade >=3 gastrointestinal or
non-gastrointestinal fistula., 6. Has radiographic evidence of major blood
vessel invasion/infiltration, or has had clinically significant hemoptysis (at
least 0.5 teaspoon of bright red blood) or tumor bleeding within 2 weeks prior
to the first dose of study intervention. The degree of tumor
invasion/infiltration of major blood vessels should be considered because of
the potential risk of severe hemorrhage associated with tumor
shrinkage/necrosis following lenvatinib therapy., 7. Has had significant
cardiovascular impairment within 12 months of the first dose of study
intervention, such as history of 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., 8. Has known intolerance or severe
hypersensitivity (Grade >=3) to pembrolizumab or lenvatinib or any of their
excipients , 9. Has received lenvatinib as monotherapy or in combination with a
PD-1/PD-L1 inhibitor or has previously been enrolled in a clinical study
evaluating lenvatinib for bladder cancer, regardless of the treatment
received., 10. Is a WOCBP who has a positive urine pregnancy test within 24
hours before randomization , 11. 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 (eg, CTLA-4, OX 40, CD137), or any other antibody or drug targeting
T-cell costimulatory pathways in the adjuvant or advanced/metastatic setting.,
12. Has received prior radiotherapy to a metastatic site without the use of
chemotherapy radiosensitization within 3 weeks of the first dose of study
intervention, with the exception of palliative radiotherapy to bone lesions,
which is allowed if completed 2 weeks before the start of study intervention.
Participants must have recovered from all radiation-related toxicities, and
must not require corticosteroids. , 13. Has received a live vaccine within 30
days prior to the first dose of study intervention, 14. In the investigator*s
judgment, has not recovered from toxicity or other complications from any major
surgery prior to starting study intervention., 15. Is currently participating
in or has participated in a trial of an investigational agent or has used an
investigational device within 4 weeks prior to the first dose of study
intervention., 16. Has an LVEF below the institutional normal range, as
determined by MUGA or ECHO, 17. Has history or presence of an abnormal ECG
that, in the investigator*s opinion, is clinically meaningful. , 18. 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, 19. Has had an
active malignancy (except locally advanced or metastatic UC) within the past 36
months, 20. Has central nervous system (CNS) metastases, unless the participant
has completed local therapy and has discontinued use of corticosteroids for
this indication for at least 4 weeks before starting treatment in this study.
Any signs or symptoms of CNS metastases must be stable for at least 4 weeks
before starting study intervention, 21. Has an active autoimmune disease that
has required systemic treatment in the past 2 years., 22. Has a history of
(non-infectious) pneumonitis that required systemic steroids, or current
pneumonitis, 23. Has an active infection requiring systemic therapy, 24. Has a
known history of human immunodeficiency virus (HIV) infection, 25. Has a known
history of or is positive for active hepatitis B or has active hepatitis C, 26.
Has active tuberculosis, 27. Has a history or current evidence of any
condition, therapy, or laboratory abnormality that might confound the results
of the study, interfere with the
participant*s participation for the full duration of the study, or is not in
the best interest of the participant to participate, in the opinion of the
treating investigator., 28. Has a known psychiatric or substance abuse disorder
that would interfere with the participant*s ability to cooperate with the
requirements of the study., 29. Is receiving hemodialysis., 30. A participant
with >1+ proteinuria on urinalysis at screening will undergo 24-hour urine
collection for quantitative assessment of proteinuria. A participant with urine
protein >=1 g/24 h will be excluded. , 31. 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, 32. Has had an allogeneic tissue/solid
organ transplantation