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)

Study Overview
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Brief Summary
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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: 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 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.

Official Title
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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)

Conditions
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Urothelial Carcinoma

Intervention / Treatment
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* Biological: Pembrolizumab
* Drug: Lenvatinib
* Drug: Placebo for lenvatinib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab + Lenvatinib<br>Participants receive pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to  2 years) PLUS lenvatinib 20 mg via oral capsule once daily (QD) until progressive disease or discontinuation. With protocol amendment 3 (effective: Sep-24-2021), participants discontinue lenvatinib and participants who remain on treatment will receive open label pembrolizumab only, at the same dose and schedule (IV 200 mg on Day 1 of each 21-Day cycle for up to 35 cycles [up to  2 years]). | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;Drug: Lenvatinib<br>* oral capsule<br>* Other names: LENVIMA®;|
| Active Comparator: Pembrolizumab + Placebo<br>Participants receive pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to  2 years) PLUS placebo for lenvatinib via oral capsule QD until progressive disease or discontinuation. With protocol amendment 3 (effective: Sep-24-2021), participants discontinue placebo and participants who remain on treatment will receive open label pembrolizumab only, at the same dose and schedule (IV 200 mg on Day 1 of each 21-Day cycle for up to 35 cycles [up to  2 years]). | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;Drug: Placebo for lenvatinib<br>* oral capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS was defined as the time from randomization to the first documented progressive disease (PD) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) by blinded independent central review (BICR), or death due to any cause, whichever occurs first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. PFS as assessed by BICR per RECIST 1.1 is presented. Protocol-specified final analysis for this primary outcome measure was performed with an analysis data cut-off date of July-26-2021. | Up to  25 months | 
| Overall Survival (OS) | OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were to be censored at the date of the last follow-up. Protocol-specified final analysis for this primary outcome measure was performed with an analysis data cut-off date of July-26-2021. | Up to  25 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR was defined as the percentage of participants who had a confirmed complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by BICR. The percentage of participants who experienced a CR or PR is presented. Protocol-specified final analysis for this secondary outcome measure was performed with an analysis data cut-off date of July-26-2021. | Up to  25 months | 
| Duration of Response (DOR) | For participants who demonstrated a confirmed complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by BICR, DOR was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. DOR for participants who had not progressed or died at the time of analysis was to be censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions as well as an absolute increase of ≥5 mm in the sum of diameters. The appearance of one or more new lesions was also considered PD. The DOR as assessed by BICR per RECIST 1.1 for participants who experienced a confirmed CR or PR is presented. Protocol-specified final analysis for this secondary outcome measure was performed with an analysis data cut-off date of July-26-2021. | Up to  25 months | 
| Disease Control Rate (DCR) | DCR was defined at the percentage of participants who have a complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions) or stable disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease [PD: ≥20% increase in the sum of diameters of target lesions and an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD]. DCR for participants who had not progressed or died at the time of analysis was to be censored at the date of their last tumor assessment. The DCR as assessed by BICR per RECIST 1.1 is presented. Protocol-specified final analysis for this secondary outcome measure was performed with an analysis data cut-off date of July-26-2021. | Up to  25 months | 
| Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score | The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the questions regarding Global Health Status (GHS; How would you rate your overall health during the past week?) and Quality of Life (QoL; How would you rate your overall quality of life during the past week?) are scored on a 7-point scale (1= Very poor to 7=Excellent). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The change from baseline in GHS (EORTC QLQ-C30 Item 29) and QoL (EORTC QLQ-C30 Item 30) combined score will be presented. A higher score indicates a better outcome. | Baseline and Up to  60 months | 
| Time to Deterioration (TTD) in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score | The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the questions regarding Global Health Status (GHS; How would you rate your overall health during the past week?) and Quality of Life (QoL; How would you rate your overall quality of life during the past week?) are scored on a 7-point scale (1= Very poor to 7=Excellent). TTD is defined as the time from baseline to the first onset of a ≥10-point negative change (decrease) from baseline in GHS (EORTC QLQ-C30 Item 29) & QoL (EORTC QLQ-C30 Item 30) combined score. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The TTD, as assessed based on a ≥10-point negative change (decrease) from baseline in GHS and QoL combined score, will be presented. A longer TTD indicates a better outcome. | Up to  60 months | 
| Number of Participants Who Experience an Adverse Event (AE) | An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who experienced an AE is presented. Protocol-specified final analysis for this secondary outcome measure was performed with an analysis data cut-off date of July-26-2021. | Up to  25 months | 
| Number of Participants Who Discontinue Study Treatment Due to an AE | An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinued study treatment due to an AE is presented. Protocol-specified final analysis for this secondary outcome measure was performed with an analysis data cut-off date of July-26-2021. | Up to  25 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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)