Study of First-line Pembrolizumab (MK-3475) With Lenvatinib (MK-7902/E7080) in Urothelial Carcinoma Cisplatin-ineligible Participants Whose Tumors Express Programmed Cell Death-Ligand 1 and in Participants Ineligible for Platinum-containing Chemotherapy (MK-7902-011/E7080-G000-317/ LEAP-011)
Condition: Urothelial Carcinoma
MeSH terms: Carcinoma; Carcinoma, Transitional Cell
Intervention: Pembrolizumab; Lenvatinib; Placebo for lenvatinib
Intervention description: IV infusion; oral capsule; oral capsule
Intervention MeSH terms: Pembrolizumab; Lenvatinib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking description: The study was unblinded with Amendment 3.
Enrollment: 487.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Advanced or metastatic urothelial cancer; Lenvatinib; Pembrolizumab; Programmed Cell Death-1 (PD1, PD-1); Programmed Cell Death 1 Ligand 1 (PDL1, PD-L1); Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)

Summary:

      The purpose of this study is to evaluate the efficacy and safety of lenvatinib
      (MK-7902/E7080) in combination with pembrolizumab (MK-3475) in the treatment of
      cisplatin-ineligible participants with a Programmed Cell Death-Ligand 1 (PD-L1) Combined
      Positive Score (CPS) ≥10, or in participants ineligible for any platinum-containing
      chemotherapy regardless of CPS, with advanced/unresectable or metastatic urothelial carcinoma
      (UC).

      The primary hypotheses for this study are that:

        1. Pembrolizumab + lenvatinib is superior to pembrolizumab + placebo with respect to
           Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version
           1.1 (RECIST 1.1) by blinded independent central review (BICR), and

        2. Pembrolizumab + lenvatinib is superior to pembrolizumab + placebo with respect to
           Overall Survival (OS).

      With Amendment 3 (effective: September [Sep]-24-2021) participants discontinued lenvatinib
      and placebo; participants who remained on treatment in the study arms received open-label
      pembrolizumab.

      With Amendment 3 the external Data Monitoring Committee was discontinued.

      With Amendment 4 (effective: December-5-2022) Second Course will no longer be offered. Any
      participant receiving Second Course treatment prior to initiation of Amendment 4 will be able
      to complete treatment as planned.

      With Amendment 4 study participation will end after the final administration of
      pembrolizumab. Participants who either complete 35 administrations of pembrolizumab or
      discontinue pembrolizumab will discontinue from the study following the safety follow-up
      visit. AEs and spontaneously reported pregnancies will be reported and followed per protocol.
      All participants in efficacy follow-up prior to initiation of Amendment 4 will stop efficacy
      assessments and be discontinued from the study. All participants in survival follow-up prior
      to initiation of Amendment 4 are considered to have completed the study and should have a
      final survival contact. The overall study ends when the last participant completes the last
      study-related contact or visit, withdraws from the study, or is lost to follow-up.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Has a histologically or cytologically confirmed diagnosis of advanced/unresectable
             (inoperable) or metastatic urothelial carcinoma (UC) of the renal pelvis, ureter
             (upper urinary tract), bladder, or urethra.

          -  Has ≥1 measurable target lesion per RECIST 1.1 as assessed by the local site
             investigator/radiologist.

          -  Has provided an archival tumor tissue sample or newly obtained core or excisional
             biopsy of a tumor lesion not previously irradiated and adequate for Programmed
             Death-Ligand 1 (PD-L1) evaluation.

          -  Has received no prior systemic chemotherapy for advanced or metastatic UC with the
             following exceptions:

          -  Neoadjuvant (prior to surgery) platinum-based chemotherapy for treatment of
             muscle-invasive bladder cancer with recurrence >12 months from completion of the
             therapy is permitted.

          -  Adjuvant (following surgery) platinum-based chemotherapy following radical cystectomy,
             with recurrence >12 months from completion of the therapy, is permitted.

          -  Meets criteria for either option a or option b (below):

          -  a. Has a tumor(s) with PD-L1 combined positive score (CPS) ≥10 and is considered
             ineligible to receive cisplatin-based combination therapy, based on 1 of the
             following:

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 2 within 7
             days prior to randomization

          -  National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (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, is considered ineligible to receive any
             platinum-based chemotherapy (i.e., ineligible for cisplatin and carboplatin) based on:

          -  ECOG PS of 2 within 7 days prior to randomization and ≥1 of the following:

          -  Documented visceral metastatic disease

          -  NCI CTCAE Version 4.0 Grade ≥2 audiometric hearing loss

          -  NCI CTCAE Version 4.0 Grade ≥2 peripheral neuropathy

          -  Other reason for the participant's 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. Note:
             Participants considered ineligible for any platinum-based chemotherapy are eligible
             for this study regardless of their tumor PD-L1 status.

          -  Has ECOG PS 0, 1, or 2 within 7 days prior to randomization and a life expectancy of
             ≥3 months.

          -  Male participants are eligible to participate if they agree to the following during
             the treatment period and for ≥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 (vasectomized or
             secondary to medical cause as detailed below:

          -  Agrees to use a male condom plus partner use of an additional contraceptive method
             when having penile-vaginal intercourse with a woman of childbearing potential (WOCBP)
             who is not currently pregnant. Note: Men with a pregnant or breastfeeding partner must
             agree to remain abstinent from penile-vaginal intercourse or use a male condom during
             each episode of penile-vaginal penetration.

          -  A female participant is eligible to participate if she is not pregnant or
             breastfeeding and if she is not a WOCBP OR is a WOCBP and is using a contraceptive
             method that is highly effective (with a failure rate of <1% per year) with low user
             dependency, or is abstinent from heterosexual intercourse as her preferred and usual
             lifestyle during the intervention period and for ≥120 days post pembrolizumab or ≥30
             days post lenvatinib/placebo.

          -  Has adequately controlled blood pressure (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.

          -  Has adequate organ function.

        Exclusion Criteria:

          -  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.