Clinical Trials /

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)

NCT04662710

Description:

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.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Esophageal Adenocarcinoma
  • Gastric Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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)
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: 7902-015
  • SECONDARY ID: 2020-001990-53
  • SECONDARY ID: MK-7902-015
  • SECONDARY ID: E7080-G000-321
  • SECONDARY ID: jRCT2051200127
  • NCT ID: NCT04662710

Conditions

  • Advanced/Metastatic Gastroesophageal Adenocarcinoma

Interventions

DrugSynonymsArms
PembrolizumabMK-3475, Keytruda®Lenvatinib + Pembrolizumab + Chemotherapy
LenvatinibMK-7902, E7080Lenvatinib + Pembrolizumab + Chemotherapy
OxaliplatinChemotherapy
CapecitabineChemotherapy
Leucovorin (or Levoleucovorin)Chemotherapy
5-FUChemotherapy

Purpose

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.

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 778 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.
    

Trial Arms

NameTypeDescriptionInterventions
Lenvatinib + Pembrolizumab + ChemotherapyExperimentalParticipants 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).
  • Pembrolizumab
  • Lenvatinib
  • Oxaliplatin
  • Capecitabine
  • Leucovorin (or Levoleucovorin)
  • 5-FU
ChemotherapyExperimentalParticipants receive chemotherapy with either CAPOX Q3W or mFOLFOX6 Q2W. A cycle is 6 weeks (42 days).
  • Oxaliplatin
  • Capecitabine
  • Leucovorin (or Levoleucovorin)
  • 5-FU

Eligibility 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, 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part 1: Number of Participants with Dose Limiting Toxicities (DLTs)
Time Frame:Up to ~21 days
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure: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 ~22 months
Safety Issue:
Description: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.
Measure:Part 2: ORR Per RECIST 1.1 as Assessed by BICR in All Participants
Time Frame:Up to ~22 months
Safety Issue:
Description: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.
Measure: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 ~22 months
Safety Issue:
Description: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.
Measure:Part 2: DOR Per RECIST 1.1 as Assessed by BICR in All Participants
Time Frame:Up to ~22 months
Safety Issue:
Description: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.
Measure:Part 2: Number of Participants with AEs
Time Frame:Up to ~25 months
Safety Issue:
Description: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.
Measure:Part 2: Number of Participants who Discontinued Study Treatment Due to an AE
Time Frame:Up to ~22 months
Safety Issue:
Description: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.

Details

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

Trial Keywords

  • Programmed Cell Death-1 (PD1, PD-1)
  • Programmed Death-Ligand 1 (PDL1, PD-L1)

Last Updated

June 17, 2021