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Safety and Efficacy Study of Pembrolizumab (MK-3475) Combined With Lenvatinib (MK-7902/E7080) as First-line Intervention in Adults With Advance Melanoma (MK-7902-003/E7080-G000-312/LEAP-003)

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ClinicalTrials.gov Identifier: NCT03820986
Recruitment Status : Recruiting
First Posted : January 29, 2019
Last Update Posted : November 21, 2019
Sponsor:
Collaborator:
Eisai Inc.
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Brief Summary:

The purpose of this study is to assess the safety and efficacy of pembrolizumab (MK-3475) combined with lenvatinib (MK-7902/E7080) compared to pembrolizumab alone (with placebo for lenvatinib) as first-line treatment in adults with no prior systemic therapy for their advance melanoma.

The primary study hypotheses are that: 1) The combination of pembrolizumab and lenvatinib is superior to pembrolizumab and placebo as assessed by Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), and 2) The combination of pembrolizumab and lenvatinib is superior to pembrolizumab and placebo as assessed by Overall Survival (OS). For this study, RECIST 1.1 has been modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.


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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 660 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 3 Randomized, Placebo-controlled Trial to Evaluate the Safety and Efficacy of Pembrolizumab (MK-3475) and Lenvatinib (E7080/MK-7902) Versus Pembrolizumab Alone as First-line Intervention in Participants With Advanced Melanoma (LEAP-003)
Actual Study Start Date : March 12, 2019
Estimated Primary Completion Date : April 6, 2024
Estimated Study Completion Date : April 6, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: Pembrolizumab+Lenvatinib
Participants receive pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 administrations (up to approximately 2 years) PLUS lenvatinib 20 mg via oral capsule daily for up to at least 2 years.
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 3-week cycle for up to 35 administrations (up to approximately 2 years) PLUS placebo for lenvatinib via oral capsule daily for up to at least 2 years.
Biological: Pembrolizumab
IV infusion
Other Names:
  • MK-3475
  • KEYTRUDA®

Drug: Placebo for lenvatinib
Oral capsule




Primary Outcome Measures :
  1. Progression-free Survival (PFS) as Assessed by Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to approximately 2 years ]
    PFS is defined as the time from date of randomization to the date of the first documentation of 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 one or more new lesions is also considered PD. For this study, RECIST 1.1 has been modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. PFS as assessed by modified RECIST 1.1 will be presented.

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


Secondary Outcome Measures :
  1. Objective Response Rate (ORR) as Assessed by Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to approximately 2 years ]
    ORR is defined as the percentage of participants in the analysis population who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. For this study, RECIST 1.1 has been modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. ORR as assessed by modified RECIST 1.1 will be presented.

  2. Duration of Response (DOR) as Assessed by Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to approximately 2 years ]
    For participants who demonstrated CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions), DOR is defined as the date of the first documented evidence of CR or PR until 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 one or more new lesions is also considered PD. For this study, RECIST 1.1 has been modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. DOR as assessed by modified RECIST 1.1 will be presented.

  3. Number of Participants with Adverse Events (AEs) [ Time Frame: Up to approximately 28 months ]
    An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experience an AE will be presented.

  4. Number of Participants Who Discontinue Study Treatment Due to Adverse Events (AEs) [ Time Frame: Up to approximately 2 years ]
    The number of participants who discontinue study treatment due to an AE will be presented.

  5. Change from Baseline in European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire-Core 30 [QLQ-C30] Global Health Status (GHS) Score [ Time Frame: Baseline (Cycle 1 Day 1: Predose) and at designated time points: Predose; each cycle is 21 days (Up to approximately 2 years) ]
    The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. The GHS Score consists of participant responses to questions regarding GHS (How would you rate your overall health during the past week?). For GHS, responses range in score from 0 to 100, with a higher score indicating a better outcome. The change from Baseline in GHS Score will be presented.

  6. Change from Baseline in European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire-Core 30 [QLQ-C30] Physical Function (PF) Score [ Time Frame: Baseline (Cycle 1 Day 1: Predose) and at designated time points: Predose; each cycle is 21 days (Up to approximately 2 years) ]
    The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. The PF Score consists of participant responses to questions regarding PF (5 questions about daily activities [strenuous activities, long walks, short walks, bed/chair rest and needing help with eating, dressing, washing themselves or using the toilet]. For PF, responses range in score from 0 to 100, with a higher score indicating a better outcome. The change from Baseline in PF Score will be presented.

  7. Time to True Deterioration (TTD) Based on Change from Baseline in European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire-Core 30 [QLQ-C30] in Global Health Status (GHS) Score [ Time Frame: Up to approximately 2 years ]
    TTD is defined as the time from Baseline to 1st onset of a ≥10-point negative change (decrease) in EORTC-QLQ-C30 GHS Score. The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. The GHS Score consists of participant responses to questions regarding GHS (How would you rate your overall health during the past week?). For GHS, responses range in score from 0 to 100, with a higher score indicating a better outcome. TTD, based on a ≥10-point negative change (decrease) from Baseline in GHS Score will be presented.

  8. Time to True Deterioration (TTD) Based on Change from Baseline in European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire-Core 30 [QLQ-C30] in Physical Function (PF) Score [ Time Frame: Up to approximately 2 years ]
    TTD is defined as the time from Baseline to 1st onset of a ≥10-point negative change (decrease) in EORTC-QLQ-C30 PF Score. The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. The PF Score consists of participant responses to questions regarding PF (5 questions about daily activities [strenuous activities, long walks, short walks, bed/chair rest & needing help with eating, dressing, washing themselves or using the toilet]. For PF, responses range in score from 0 to 100, with a higher score indicating a better outcome. TTD, based on a ≥10-point negative change (decrease) from Baseline in PF Score will be presented.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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 histologically or cytologically confirmed melanoma
  • Has unresectable Stage III or Stage IV melanoma, as per American Joint Committee on Cancer guidelines, not amenable to local therapy
  • Has been untreated for advanced or metastatic disease except as follows: a. proto-oncogene B-Raf (BRAF) V600 mutation-positive melanoma may have received standard of care targeted therapy as first-line therapy for advanced or metastatic disease. b. Prior adjuvant or neoadjuvant therapy, with targeted therapy or immunotherapy (such as anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], anti-programmed cell death 1 [anti-PD-1] therapy or Interferon) will only be permitted if relapse did not occur during active treatment or within 6 months of treatment discontinuation.
  • Has an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1
  • Has the presence of ≥1 measurable lesion by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1
  • Provides a tumor biopsy. Participants must submit tumor sample during Screening for confirmation of adequacy of tumor tissue at a central pathology laboratory. Participants who do not submit a tumor tissue sample will not be randomized. The tumor biopsy may not be obtained from a lone target lesion. Confirmation of presence of tumor tissue is not required prior to randomization.
  • Has resolution of toxic effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia). If participant received major surgery or radiation therapy of >30 Gray (Gy), they must have recovered from the toxicity and/or complications from the intervention.
  • Male participants must agree to use contraception during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period
  • Female participants must not be pregnant, not breastfeeding, and ≥1 of the following conditions applies: a. Not a woman of childbearing potential (WOCBP) OR b. A WOCBP who agrees to use study-approved contraception during the treatment period and for at least 120 days after the last dose of study treatment
  • Has adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤150/90 mmHg at screening and no change in antihypertensive medications within 1 week before Cycle 1 Day 1
  • Has adequate organ function

Exclusion Criteria:

  • Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days before the first dose of study treatment.
  • Has a known additional malignancy that is progressing or requires active treatment. Exceptions include early stage cancers (carcinoma in situ or Stage 1, non-ulcerated primary melanoma <1 mm in depth with no nodal involvement) treated with curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, or in situ breast cancer that has undergone potentially curative therapy.
  • Has known active central nervous system metastases and/or carcinomatous meningitis
  • Has ocular melanoma
  • Has known hypersensitivity to active substances or any of their excipients including previous clinically significant hypersensitivity reaction to treatment with another monoclonal antibody
  • Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease-modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  • Has an active infection requiring systemic therapy
  • Has known history of human immunodeficiency virus (HIV) infection
  • Has known history of or is positive for hepatitis B virus or hepatitis C virus infection
  • Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
  • Has a history of active tuberculosis (Bacillus tuberculosis)
  • Has presence of gastrointestinal condition including malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib
  • Has had a major surgery within 4 weeks prior to Cycle 1 Day 1. Adequate wound healing after major surgery must be assessed clinically and have resolved completely prior to Cycle 1 Day 1.
  • Has a pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula
  • Has radiographic evidence of major blood vessel invasion/infiltration
  • Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study treatment
  • Has clinically significant cardiovascular disease within 12 months of the first dose of study treatment including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability
  • Has received prior systemic treatment for unresectable or metastatic melanoma other than targeted therapy as noted in Inclusion Criteria above
  • Has received prior therapy with a monoclonal antibody, chemotherapy, or an investigational agent or device within 4 weeks or 5 half-lives (whichever is longer) before administration of study treatment or not recovered (≤Grade 1 or at Baseline) from adverse events due to previously administered agents.

Exception to this rule would be use of denosumab, which is not excluded. Note: Participants with alopecia and ≤Grade 2 neuropathy are an exception and may enroll.

  • Has received prior radiotherapy within 2 weeks of first dose of study treatment (Cycle 1 Day 1) with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks prior to Cycle 1 Day 1. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.
  • Has received live vaccine within 30 days before the first dose of 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
  • 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): NCT03820986


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

  Show 85 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: NCT03820986     History of Changes
Other Study ID Numbers: 7902-003
2018-002520-16 ( EudraCT Number )
MK-7902-003 ( Other Identifier: Merck Protocol Number )
E7080-G000-312 ( Other Identifier: Eisai Protocol Number )
LEAP-003 ( Other Identifier: Merck )
First Posted: January 29, 2019    Key Record Dates
Last Update Posted: November 21, 2019
Last Verified: November 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.:
programmed cell death 1 (PD-1, PD1)
programmed cell death-ligand 1 (PD-L1, PDL1)
programmed cell death-ligand 2 (PD-L2, PDL2)
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Pembrolizumab
Lenvatinib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action