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Efficacy and Safety of Lenvatinib (E7080/MK-7902) Plus Pembrolizumab (MK-3475) Plus Chemotherapy in Participants With Advanced/Metastatic Gastroesophageal Adenocarcinoma (MK-7902-015/E7080-G000-321/LEAP-015) (LEAP-015)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04662710
Recruitment Status : Active, not recruiting
First Posted : December 10, 2020
Last Update Posted : March 20, 2023
Sponsor:
Collaborator:
Eisai Inc.
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC

Study Description
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Brief Summary:

The purpose of this study is to assess the efficacy and safety of lenvatinib (E7080/MK-7902) plus pembrolizumab (MK-3475) plus chemotherapy compared with chemotherapy alone in participants with advanced/metastatic gastroesophageal cancer.

The primary study hypotheses are that lenvatinib plus pembrolizumab plus chemotherapy is superior to chemotherapy alone for both overall survival (OS) and 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), in participants with programmed cell death-ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 and in all participants.


Condition or disease Intervention/treatment Phase
Advanced/Metastatic Gastroesophageal Adenocarcinoma Biological: Pembrolizumab Biological: Lenvatinib Drug: Oxaliplatin Drug: Capecitabine Drug: Leucovorin (or Levoleucovorin) Drug: 5-FU Phase 3

Detailed Description:

There will be 2 parts to the study: a Safety Run-in (Part 1) and the Main Study (Part 2). In Part 1 (Safety Run-in), approximately 12 participants will be treated with lenvatinib in combination with pembrolizumab and chemotherapy with either capecitabine and oxaliplatin (CAPOX), or 5-fluorouracil (5-FU), Leucovorin, and oxaliplatin (mFOLFOX6). Participants will be closely followed for dose-limiting toxicities for 21 days after the first dose of study intervention.

In Part 2, up to 878 eligible participants (not including those participating in Part 1) will be randomly assigned in a 1:1 ratio to either lenvatinib plus pembrolizumab plus chemotherapy (CAPOX or mFOLFOX6) or Chemotherapy alone (CAPOX or mFOLFOX6).

Participants can receive up to 18 infusions (up to 2 years) of pembrolizumab in the first course. Participants may be eligible to receive a second course of pembrolizumab (approximately 1 year) at the investigator's discretion.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 890 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 3, Randomized Study to Evaluate the Efficacy and Safety of Lenvatinib (E7080/MK-7902) Plus Pembrolizumab (MK-3475) Plus Chemotherapy Compared With Standard of Care Therapy as First-line Intervention in Participants With Advanced/Metastatic Gastroesophageal Adenocarcinoma (LEAP-015)
Actual Study Start Date : December 30, 2020
Estimated Primary Completion Date : February 2, 2026
Estimated Study Completion Date : February 2, 2026

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Lenvatinib + Pembrolizumab + Chemotherapy
Participants receive lenvatinib administered orally (PO) every day (QD) in combination with pembrolizumab intravenously (IV) every 6 weeks (Q6W) plus chemotherapy with either capecitabine and oxaliplatin (CAPOX) or chemotherapy with 5-FU, leucovorin, and oxaliplatin (mFOLFOX6). Induction with lenvatinib 8 mg QD plus pembrolizumab (400 mg Q6W) plus chemotherapy (CAPOX or mFOLFOX6) will be administered for 2 cycles (approximately 12 weeks), followed by consolidation with lenvatinib 20 mg QD plus pembrolizumab (400 mg Q6W) for 16 cycles. A cycle is 6 weeks (42 days).
 Biological: Pembrolizumab
400 mg Q6W by IV infusion
Other Names:
  • MK-3475
  • Keytruda®

Biological: Lenvatinib
Administered PO QD, 8 mg induction/20 mg consolidation.
Other Names:
  • MK-7902
  • E7080

Drug: Oxaliplatin
130 mg/m^2 administered by IV infusion on Day 1 of Weeks 1 and 4 of each Q6W cycle as part of CAPOX chemotherapy, or 85 mg/m^2 administered by IV infusion on Day 1 and Week 1, 3 and 5 of each Q6W cycle as part of mFOLFOX6 chemotherapy.

Drug: Capecitabine
1000 mg/m^2 administered PO twice daily (BID) on Days 1-14, 22-35 of each Q6W cycle as part of CAPOX chemotherapy.

Drug: Leucovorin (or Levoleucovorin)
Administered by IV infusion at 400 mg/m^2 (leucovorin) or 200 mg/m^2 (levoleucovorin) on Day 1, and Week 1, 3 and 5 of each Q6W cycle as part of mFOLFOX6 chemotherapy.

Drug: 5-FU
400 mg/m^2 bolus IV infusion followed by 2400 mg/m^2 continuous IV infusion administered on Day 1, and Week 1, 3, 5, of each Q2W cycle as part of mFOLFOX6 chemotherapy.
Experimental: Chemotherapy
Participants receive chemotherapy with either CAPOX Q3W or mFOLFOX6 Q2W. A cycle is 6 weeks (42 days).
 Drug: Oxaliplatin
130 mg/m^2 administered by IV infusion on Day 1 of Weeks 1 and 4 of each Q6W cycle as part of CAPOX chemotherapy, or 85 mg/m^2 administered by IV infusion on Day 1 and Week 1, 3 and 5 of each Q6W cycle as part of mFOLFOX6 chemotherapy.

Drug: Capecitabine
1000 mg/m^2 administered PO twice daily (BID) on Days 1-14, 22-35 of each Q6W cycle as part of CAPOX chemotherapy.

Drug: Leucovorin (or Levoleucovorin)
Administered by IV infusion at 400 mg/m^2 (leucovorin) or 200 mg/m^2 (levoleucovorin) on Day 1, and Week 1, 3 and 5 of each Q6W cycle as part of mFOLFOX6 chemotherapy.

Drug: 5-FU
400 mg/m^2 bolus IV infusion followed by 2400 mg/m^2 continuous IV infusion administered on Day 1, and Week 1, 3, 5, of each Q2W cycle as part of mFOLFOX6 chemotherapy.


Outcome Measures
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Primary Outcome Measures :
  1. Part 1: Number of Participants with Dose Limiting Toxicities (DLTs) [ Time Frame: Up to ~21 days ]
    Hematologic DLTs were defined as Grade 4 neutropenia lasting for ≥7 days, Grade 3 or Grade 4 febrile neutropenia, Grade 3 thrombocytopenia with bleeding, Grade 4 thrombocytopenia, or Grade 4 anemia. Other nonhematologic toxicities considered a DLT included any other Grade 4 or Grade 5 toxicity, Grade 3 toxicities lasting >3 days (excluding nausea, vomiting, and diarrhea controlled by medical intervention within 72 hours, and Grade 3 rash in the absence of desquamation with no mucosal involvement), Grade 3 hypertension not able to be controlled by medication, ≥Grade 3 gastrointestinal perforation, ≥Grade 3 wound dehiscence requiring medical or surgical intervention, or any grade thromboembolic event. The number of participants in Part 1 with DLTs will be reported by treatment arm.

  2. Part 1: Number of Participants with Adverse Events (AEs) [ Time Frame: Up to ~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 in Part 1 with AEs will be reported by treatment arm.

  3. Part 1: Number of Participants who Discontinued Study Treatment Due to an AE [ Time Frame: Up to ~25 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 in Part 1 that discontinued study due to an AE will be reported by treatment arm.

  4. Part 2: Overall Survival (OS) in Participants with Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 [ Time Frame: Up to ~44 months ]
    OS is defined as the time from randomization to death due to any cause. OS will be reported by treatment arm for PD-L1 CPS ≥1 participants in Part 2.

  5. Part 2: OS in All Participants [ Time Frame: Up to ~44 months ]
    OS is defined as the time from randomization to death due to any cause. OS will be reported by treatment arm for all participants in Part 2.

  6. Part 2: 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) in Participants with PD-L1 CPS ≥1 [ Time Frame: Up to ~34 months ]
    PFS is defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 by BICR or death from any cause, whichever occurs first. Per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, PD is defined as at least a 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 at least 5 mm. The appearance of one or more new lesions is also considered PD. PFS will be reported by treatment arm for PD-L1 CPS ≥1 participants in Part 2.

  7. Part 2: PFS Per RECIST 1.1 as Assessed by BICR in All Participants [ Time Frame: Up to ~34 months ]
    PFS is defined as the time from randomization to the first documented PD per RECIST 1.1 by BICR or death from any cause, whichever occurs first. Per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, PD is defined as at least a 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 at least 5 mm. The appearance of one or more new lesions is also considered PD. PFS will be reported by treatment arm for all participants in Part 2.


Secondary Outcome Measures :
  1. Part 2: Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by BICR in Participants with PD-L1 CPS ≥1 [ Time Frame: Up to ~25 months ]
    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 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and assessed by BICR. ORR will be reported by treatment arm for PD-L1 CPS ≥1 participants in Part 2.

  2. Part 2: ORR Per RECIST 1.1 as Assessed by BICR in All Participants [ Time Frame: Up to ~25 months ]
    ORR is defined as the percentage of participants in the analysis population who have a CR (disappearance of all target lesions) or a PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and assessed by BICR. ORR will be reported by treatment arm for all participants in Part 2.

  3. Part 2: Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR in Participants with PD-L1 CPS ≥1 [ Time Frame: Up to ~25 months ]
    For participants who demonstrated confirmed CR or PR, DOR is defined as the time from the first CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) to subsequent PD or death due to any cause, whichever occurs first. Per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, PD is defined as at least a 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 at least 5 mm. The appearance of one or more new lesions is also considered PD. DOR will be reported by treatment arm for PD-L1 CPS ≥1 participants in Part 2.

  4. Part 2: DOR Per RECIST 1.1 as Assessed by BICR in All Participants [ Time Frame: Up to ~25 months ]
    For participants who demonstrated confirmed CR or PR, DOR is defined as the time from the first CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) to subsequent PD or death due to any cause, whichever occurs first. Per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, PD is defined as at least a 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 at least 5 mm. The appearance of one or more new lesions is also considered PD. DOR will be reported by treatment arm for all participants in Part 2.

  5. Part 2: Number of Participants with AEs [ Time Frame: Up to ~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 in Part 2 with AEs will be reported by treatment arm.

  6. Part 2: Number of Participants who Discontinued Study Treatment Due to an AE [ Time Frame: Up to ~25 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 in Part 2 that discontinued study due to an AE will be reported by treatment arm.


Eligibility Criteria
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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 and/or cytologically confirmed diagnosis of previously untreated, locally advanced unresectable or metastatic gastroesophageal adenocarcinoma
  • Is not expected to require tumor resection during the treatment course
  • Has gastroesophageal adenocarcinoma that is not HER-2/neu positive
  • Has measurable disease as defined by RECIST 1.1 by scan with IV contrast as determined by the local site investigator
  • Male participants agree to refrain from donating sperm and agree to either remain abstinent from heterosexual intercourse as their preferred and usual lifestyle OR agree to use contraception, during the intervention period and for ≥7 days after last dose of lenvatinib or 90 days after last dose of chemotherapy-whichever comes last
  • Female participants not pregnant or breastfeeding are eligible to participate if not a women of childbearing potential (WOCBP), or if a WOCBP they either use a contraceptive method that is highly effective OR remain abstinent from heterosexual intercourse as their preferred and usual lifestyle, and do not donate eggs (ova, oocytes) to others or freeze/store for their own use, and abstain from breastfeeding during the intervention period through 120 days after last dose of pembrolizumab, 30 days after last dose of lenvatinib, or 180 days after last dose of chemotherapy-whichever occurs last
  • Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale within 3 days prior to the first dose of study treatment
  • Has adequately controlled blood pressure with or without antihypertensive medications
  • Has adequate organ function

Exclusion Criteria:

  • Has had previous therapy for locally advanced unresectable or metastatic gastric/gastroesophageal junction (GEJ) esophageal adenocarcinoma
  • Has had major surgery within 28 days prior to first dose of study interventions
  • Has had radiotherapy within 14 days of randomization
  • Has a known additional malignancy that is progressing or has required active treatment within the past 5 years
  • Has known CNS metastases and/or carcinomatous meningitis
  • Has severe hypersensitivity (≥Grade 3) to treatment with an monoclonal antibody (mAb) or known sensitivity or intolerance to any component of lenvatinib, pembrolizumab, study chemotherapy agents and/or to any excipients, murine proteins, or platinum containing products
  • Has had an allogeneic tissue/solid organ transplant
  • Has perforation risks or significant gastrointestinal (GI) bleeding
  • Has GI obstruction, poor oral intake (CAPOX participants), or difficulty in taking oral medication (CAPOX participants)
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor
  • Has received prior therapy with anti- vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor or anti-VEGF mAb
  • Has received a live or live-attenuated vaccine within 30 days before the first dose of study drug
  • 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)
  • Has radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation
  • Has inadequate cardiac function
  • Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
  • Has poorly controlled diarrhea
  • Has accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks prior to enrollment.
  • Has peripheral neuropathy ≥Grade 2
  • Has a known history of human immunodeficiency virus (HIV) or HIV 1/2 antibodies
  • Has a known history of hepatitis B (defined as HBsAg reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection
  • Has weight loss of >20% within the last 3 months
Contacts and Locations
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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): NCT04662710


Locations
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Sponsors and Collaborators
Merck Sharp & Dohme LLC
Eisai Inc.
Investigators
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Study Director: Medical Director Merck Sharp & Dohme LLC
More Information
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Additional Information:

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Responsible Party: Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier: NCT04662710    
Other Study ID Numbers: 7902-015
MK-7902-015 ( Other Identifier: Merck )
E7080-G000-321 ( Other Identifier: Eisai )
jRCT2051200127 ( Registry Identifier: jRCT )
2020-001990-53 ( EudraCT Number )
First Posted: December 10, 2020    Key Record Dates
Last Update Posted: March 20, 2023
Last Verified: March 2023
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 LLC:
Programmed Cell Death-1 (PD1, PD-1)
Programmed Death-Ligand 1 (PDL1, PD-L1)
Additional relevant MeSH terms:
Layout table for MeSH terms
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Leucovorin
Pembrolizumab
Capecitabine
Oxaliplatin
Lenvatinib
Levoleucovorin
Antineoplastic Agents, Immunological
Antineoplastic Agents
 Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antidotes
Protective Agents
Physiological Effects of Drugs
Vitamin B Complex
Vitamins
Micronutrients
Protein Kinase Inhibitors
Enzyme Inhibitors