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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT03898180




Registration number
NCT03898180
Ethics application status
Date submitted
29/03/2019
Date registered
1/04/2019
Date last updated
6/02/2024

Titles & IDs
Public title
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)
Scientific title
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)
Secondary ID [1] 0 0
MK-7902-011
Secondary ID [2] 0 0
7902-011
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Urothelial Carcinoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Non melanoma skin cancer
Cancer 0 0 0 0
Kidney
Cancer 0 0 0 0
Bladder - transitional cell cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Other interventions - Pembrolizumab
Treatment: Drugs - Lenvatinib
Treatment: Drugs - Placebo for lenvatinib

Experimental: Pembrolizumab + Lenvatinib - 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]).

Active Comparator: Pembrolizumab + Placebo - 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]).


Other interventions: Pembrolizumab
IV infusion

Treatment: Drugs: Lenvatinib
oral capsule

Treatment: Drugs: Placebo for lenvatinib
oral capsule
Intervention code [1] 0 0
Other interventions
Intervention code [2] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Progression-free Survival (PFS)
Timepoint [1] 0 0
Up to ~25 months
Primary outcome [2] 0 0
Overall Survival (OS)
Timepoint [2] 0 0
Up to ~25 months
Secondary outcome [1] 0 0
Objective Response Rate (ORR)
Timepoint [1] 0 0
Up to ~25 months
Secondary outcome [2] 0 0
Duration of Response (DOR)
Timepoint [2] 0 0
Up to ~25 months
Secondary outcome [3] 0 0
Disease Control Rate (DCR)
Timepoint [3] 0 0
Up to ~25 months
Secondary outcome [4] 0 0
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
Timepoint [4] 0 0
Baseline and Up to ~60 months
Secondary outcome [5] 0 0
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
Timepoint [5] 0 0
Up to ~60 months
Secondary outcome [6] 0 0
Number of Participants Who Experience an Adverse Event (AE)
Timepoint [6] 0 0
Up to ~25 months
Secondary outcome [7] 0 0
Number of Participants Who Discontinue Study Treatment Due to an AE
Timepoint [7] 0 0
Up to ~25 months

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
6/05/2019
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/07/2024
Actual
Sample size
Target
Accrual to date
Final
487
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC
Recruitment hospital [1] 0 0
Macquarie University ( Site 0151) - North Ryde
Recruitment hospital [2] 0 0
Mater Misericordiae Ltd ( Site 0158) - South Brisbane
Recruitment hospital [3] 0 0
Monash Health ( Site 0160) - Clayton
Recruitment hospital [4] 0 0
Peninsula Health Frankston Hospital ( Site 0153) - Frankston
Recruitment hospital [5] 0 0
Austin Health-Austin Hospital ( Site 0154) - Heidelberg
Recruitment postcode(s) [1] 0 0
2109 - North Ryde
Recruitment postcode(s) [2] 0 0
4101 - South Brisbane
Recruitment postcode(s) [3] 0 0
3168 - Clayton
Recruitment postcode(s) [4] 0 0
3199 - Frankston
Recruitment postcode(s) [5] 0 0
3084 - Heidelberg
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
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Georgia
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United States of America
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Illinois
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United States of America
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Maine
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United States of America
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Michigan
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United States of America
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Missouri
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Nevada
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New York
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Oklahoma
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Pennsylvania
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South Carolina
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Texas
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United States of America
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Virginia
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United States of America
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Washington
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Argentina
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Buenos Aires
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Argentina
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Caba
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Argentina
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Rio Negro
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Argentina
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Santa Fe
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Argentina
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Cordoba
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Argentina
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Mendoza
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Canada
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Ontario
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Canada
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Quebec
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China
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Beijing
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China
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Chongqing
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Fujian
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Guangdong
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Heilongjiang
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Hubei
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Hunan
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China
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Shanxi
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China
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Xinjiang
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China
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Zhejiang
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Denmark
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Hovedstaden
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Denmark
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Midtjylland
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Denmark
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Syddanmark
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Ain
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Alsace
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France
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Bouches-du-Rhone
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Finistere
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Gironde
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Maine-et-Loire
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Meurthe-et-Moselle
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Rhone
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Val-de-Marne
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France
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Vendee
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Paris
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Baden-Wurttemberg
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Germany
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Hessen
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Germany
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Mecklenburg-Vorpommern
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Germany
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Niedersachsen
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Germany
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Nordrhein-Westfalen
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Germany
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Schleswig-Holstein
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Germany
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Hamburg
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Hungary
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Bacs-Kiskun
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Hungary
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Borsod-Abauj-Zemplen
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Hungary
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Jasz-Nagykun-Szolnok
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Hungary
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Vas
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Hungary
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Budapest
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Hungary
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Kaposvar
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Afula
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Israel
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Ashdod
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Israel
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Haifa
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Israel
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Jerusalem
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Israel
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Kfar Saba
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Israel
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Petach-Tikwa
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Israel
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Ramat Gan
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Israel
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Tel Aviv
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Israel
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Zerifin
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Italy
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Lombardia
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Italy
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Pordenone
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Italy
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Bari
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Italy
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Bologna
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Italy
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Catania
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Italy
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Milano
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Italy
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Terni
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Italy
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Verona
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Japan
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Aomori
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Japan
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Chiba
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Japan
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Ehime
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Japan
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Hokkaido
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Japan
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Ibaraki
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Japan
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Kanagawa
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Japan
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Nara
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Japan
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Saitama
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Japan
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Yamaguchi
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Japan
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Akita
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Japan
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Nagasaki
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Japan
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Osaka
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Japan
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Tokushima
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Japan
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Tokyo
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Korea, Republic of
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Jeonranamdo
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Korea, Republic of
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Kyonggi-do
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Korea, Republic of
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Taejon-Kwangyokshi
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Korea, Republic of
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Seoul
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Netherlands
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Gelderland
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Netherlands
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Limburg
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Netherlands
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Noord-Brabant
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Netherlands
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Overijssel
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Netherlands
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Zuid-Holland
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Netherlands
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Utrecht
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Poland
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Dolnoslaskie
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Malopolskie
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Mazowieckie
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Poland
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Slaskie
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Russian Federation
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Leningradskaya Oblast
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Russian Federation
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Moskva
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Russian Federation
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Murmanskaya Oblast
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Russian Federation
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Nizhegorodskaya Oblast
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Russian Federation
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Omskaya Oblast
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Russian Federation
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Sankt-Peterburg
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Russian Federation
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Yaroslavskaya Oblast
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Spain
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Barcelona
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Spain
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La Coruna
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Spain
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Madrid, Comunidad De
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Spain
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Badajoz
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Spain
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Madrid
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Taiwan
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Kaohsiung
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Taiwan
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Taichung
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Taiwan
State/province [127] 0 0
Tainan
Country [128] 0 0
Taiwan
State/province [128] 0 0
Taipei
Country [129] 0 0
Turkey
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Adana
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Turkey
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Ankara
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Turkey
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Antalya
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Turkey
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Istanbul
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Turkey
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Izmir
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Turkey
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Konya
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Turkey
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Sakarya
Country [136] 0 0
United Kingdom
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Derbyshire
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United Kingdom
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Essex
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United Kingdom
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Hertfordshire
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United Kingdom
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Kent
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United Kingdom
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Lancashire
Country [141] 0 0
United Kingdom
State/province [141] 0 0
London, City Of
Country [142] 0 0
United Kingdom
State/province [142] 0 0
Nottingham
Country [143] 0 0
United Kingdom
State/province [143] 0 0
Plymouth
Country [144] 0 0
United Kingdom
State/province [144] 0 0
Stoke-on-Trent

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Merck Sharp & Dohme LLC
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Eisai Inc.
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief 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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT03898180
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Merck Sharp & Dohme LLC
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries