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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)

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ClinicalTrials.gov Identifier: NCT03898180
Recruitment Status : Recruiting
First Posted : April 1, 2019
Last Update Posted : June 19, 2019
Sponsor:
Collaborator:
Eisai Inc.
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

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).

Condition or disease Intervention/treatment Phase
Urothelial Carcinoma Biological: Pembrolizumab Drug: Lenvatinib Drug: Placebo for lenvatinib Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 694 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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)
Actual Study Start Date : May 6, 2019
Estimated Primary Completion Date : December 30, 2022
Estimated Study Completion Date : December 30, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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 (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.
Biological: Pembrolizumab
IV infusion
Other Names:
  • MK-3475
  • KEYTRUDA®

Drug: Lenvatinib
oral capsule
Other Names:
  • MK-7902
  • E7080
  • LENVIMA®

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 (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.
Biological: Pembrolizumab
IV infusion
Other Names:
  • MK-3475
  • KEYTRUDA®

Drug: Placebo for lenvatinib
oral capsule




Primary Outcome Measures :
  1. 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 ]
    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.

  2. Overall Survival (OS) [ Time Frame: Up to approximately 40 months ]
    OS is defined as the time from randomization to the date of death from any cause.


Secondary Outcome Measures :
  1. 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 ]
    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.

  2. 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 ]
    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.

  3. 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 ]
    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.])

  4. 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 ]
    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.

  5. 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 ]
    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.

  6. Number of Participants Who Experience an Adverse Event (AE) [ Time Frame: Up to approximately 40 months ]
    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.

  7. Number of Participants Who Discontinue Study Treatment Due to an AE [ Time Frame: Up to approximately 40 months ]
    The number of participants who discontinue study treatment due to an AE will be presented.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03898180


Contacts
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Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com

  Show 31 Study Locations
Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Eisai Inc.
Investigators
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Study Director: Medical Director Merck Sharp & Dohme Corp.

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Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT03898180     History of Changes
Other Study ID Numbers: 7902-011
2018-003752-21 ( EudraCT Number )
MK-7902-011 ( Other Identifier: Merck Protocol Number )
E7080-G000-317 ( Other Identifier: Eisai Protocol Number )
LEAP-011 ( Other Identifier: Merck )
First Posted: April 1, 2019    Key Record Dates
Last Update Posted: June 19, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Merck Sharp & Dohme Corp.:
Advanced or metastatic urothelial cancer
Lenvatinib
Pembrolizumab
Programmed Cell Death-1 (PD1, PD-1)
Programmed Death-Ligand 1 (PDL1, PD-L1)

Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Transitional Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Cisplatin
Pembrolizumab
Lenvatinib
Antineoplastic Agents
Antineoplastic Agents, Immunological
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action