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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)

NCT03898180

Description:

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).

Related Conditions:
  • Bladder Urothelial Carcinoma
  • Renal Pelvis and Ureter Urothelial Carcinoma
  • Urethral Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief 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)
  • Official 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)

Clinical Trial IDs

  • ORG STUDY ID: 7902-011
  • SECONDARY ID: 2018-003752-21
  • SECONDARY ID: MK-7902-011
  • SECONDARY ID: E7080-G000-317
  • SECONDARY ID: LEAP-011
  • NCT ID: NCT03898180

Conditions

  • Urothelial Carcinoma

Interventions

DrugSynonymsArms
PembrolizumabMK-3475, KEYTRUDA®Pembrolizumab+Lenvatinib
LenvatinibMK-7902, E7080, LENVIMA®Pembrolizumab+Lenvatinib
Placebo for lenvatinibPembrolizumab+Placebo

Purpose

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).

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab+LenvatinibExperimentalParticipants receive pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 21-day cycle for up to 35 cycles (approximately 2 years) PLUS lenvatinib 20 mg via oral capsule once daily (QD) until progressive disease or discontinuation. Lenvatinib may be continued past 35 cycles until a discontinuation criterion is met.
  • Pembrolizumab
  • Lenvatinib
Pembrolizumab+PlaceboActive ComparatorParticipants receive pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (approximately 2 years) PLUS placebo for lenvatinib via oral capsule QD until progressive disease or discontinuation. Placebo may be continued past 35 cycles until a discontinuation criterion is met.
  • Pembrolizumab
  • Placebo for lenvatinib

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 (25 dB in 2 consecutive frequency
             ranges)

          -  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 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 ≥95 days after the last dose of pembrolizumab or
             lenvatinib/placebo and refrain from donating sperm during this period:

          -  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 after the last dose of
             pembrolizumab or lenvatinib/placebo.

          -  Has adequately controlled blood pressure (BP) with or without antihypertensive
             medications, defined as BP ≤140/90 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 4 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).

          -  Brief (<7 days) use of systemic corticosteroids is allowed when use is considered
             standard of care.

          -  Participants with vitiligo, psoriasis, type 1 diabetes mellitus, hypothyroidism, or
             resolved childhood asthma/atopy will be an exception to this rule.

          -  Participants requiring intermittent use of bronchodilators, inhaled steroids, or local
             steroid injections will not be excluded.

          -  Participants with hypothyroidism that is stable with hormone replacement or Sjøgren's
             syndrome will not be excluded.

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
Time Frame:Up to approximately 40 months
Safety Issue:
Description:PFS is defined as the time from randomization to the first documented progressive disease (PD) or death from any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of ≥1 new lesions is also considered PD.

Secondary Outcome Measures

Measure:Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR)
Time Frame:Up to approximately 40 months
Safety Issue:
Description:ORR is defined as the percentage of participants who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1.
Measure:Duration of Response (DOR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR)
Time Frame:Up to approximately 40 months
Safety Issue:
Description:DOR is defined as the time from the first documented evidence of Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) to the earliest date of progressive disease (PD; per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of ≥1 new lesions is also considered PD) or death due to any cause, whichever comes first, for participants with a confirmed CR or PR.
Measure:Disease Control Rate (DCR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR)
Time Frame:Up to approximately 40 months
Safety Issue:
Description:DCR is defined as the percentage of participants who have a Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: ≥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. Note: The appearance of ≥1 new lesions is also considered PD.])
Measure: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
Time Frame:Baseline and up to approximately 40 months
Safety Issue:
Description: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.
Measure: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
Time Frame:Up to approximately 40 months
Safety Issue:
Description:TTD is defined as the time from baseline to the first onset of a ≥10-point negative change (decrease) from baseline in Global Health Status (GHS; EORTC QLQ-C30 Item 29) & Quality of Life (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.
Measure:Number of Participants Who Experience an Adverse Event (AE)
Time Frame:Up to approximately 40 months
Safety Issue:
Description:An AE is defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment.
Measure:Number of Participants Who Discontinue Study Treatment Due to an AE
Time Frame:Up to approximately 40 months
Safety Issue:
Description:The number of participants who discontinue study treatment due to an AE will be presented.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Merck Sharp & Dohme Corp.

Trial Keywords

  • Advanced or metastatic urothelial cancer
  • Lenvatinib
  • Pembrolizumab
  • Programmed Cell Death-1 (PD1, PD-1)
  • Programmed Death-Ligand 1 (PDL1, PD-L1)

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