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Safety and Efficacy Study of Pemetrexed + Platinum Chemotherapy + Pembrolizumab (MK-3475) With or Without Lenvatinib (MK-7902/E7080) as First-line Intervention in Adults With Metastatic Nonsquamous Non-small Cell Lung Cancer (MK-7902-006/E7080-G000-315/LEAP-006)

NCT03829319

Description:

The purpose of this study is to assess the safety and efficacy of pemetrexed + platinum chemotherapy + pembrolizumab (MK-3475) with or without lenvatinib (MK-7902/E7080) as first-line intervention in adults with metastatic nonsquamous non-small cell lung cancer. The primary study hypotheses state that: 1) the combination of lenvatinib + platinum doublet chemotherapy + pembrolizumab prolongs Progression-free Survival (PFS) as assessed by blinded independent central review (BICR) per modified Response Evaluation Criteria in Solid Tumors version 1.1 (RESIST 1.1) compared to matching placebo + platinum doublet chemotherapy + pembrolizumab, and 2) the combination of lenvatinib + platinum doublet chemotherapy + pembrolizumab prolongs Overall Survival (OS) compared to matching placebo + platinum doublet chemotherapy + pembrolizumab.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Safety and Efficacy Study of Pemetrexed + Platinum Chemotherapy + Pembrolizumab (MK-3475) With or Without Lenvatinib (MK-7902/E7080) as First-line Intervention in Adults With Metastatic Nonsquamous Non-small Cell Lung Cancer (MK-7902-006/E7080-G000-315/LEAP-006)
  • Official Title: A Phase 3 Randomized, Placebo-controlled Study to Evaluate the Safety and Efficacy of Pemetrexed + Platinum Chemotherapy + Pembrolizumab (MK-3475) With or Without Lenvatinib (E7080/MK-7902) as First-line Intervention in Participants With Metastatic Nonsquamous Non-small Cell Lung Cancer (LEAP-006)

Clinical Trial IDs

  • ORG STUDY ID: 7902-006
  • SECONDARY ID: 2018-003824-35
  • SECONDARY ID: MK-7902-006
  • SECONDARY ID: E7080-G000-315
  • SECONDARY ID: LEAP-006
  • NCT ID: NCT03829319

Conditions

  • Nonsquamous Non-small Cell Lung Cancer

Interventions

DrugSynonymsArms
PembrolizumabMK-3475Pemetrexed+Platinum Chemotherapy+Pembrolizumab+Lenvatinib
CarboplatinPemetrexed+Platinum Chemotherapy+Pembrolizumab+Lenvatinib
CisplatinPemetrexed+Platinum Chemotherapy+Pembrolizumab+Lenvatinib
PemetrexedPemetrexed+Platinum Chemotherapy+Pembrolizumab+Lenvatinib
LenvatinibMK-7902, E7080Pemetrexed+Platinum Chemotherapy+Pembrolizumab+Lenvatinib
Placebo matching lenvatinibPemetrexed+Platinum Chemotherapy+Pembrolizumab+Placebo

Purpose

The purpose of this study is to assess the safety and efficacy of pemetrexed + platinum chemotherapy + pembrolizumab (MK-3475) with or without lenvatinib (MK-7902/E7080) as first-line intervention in adults with metastatic nonsquamous non-small cell lung cancer. The primary study hypotheses state that: 1) the combination of lenvatinib + platinum doublet chemotherapy + pembrolizumab prolongs Progression-free Survival (PFS) as assessed by blinded independent central review (BICR) per modified Response Evaluation Criteria in Solid Tumors version 1.1 (RESIST 1.1) compared to matching placebo + platinum doublet chemotherapy + pembrolizumab, and 2) the combination of lenvatinib + platinum doublet chemotherapy + pembrolizumab prolongs Overall Survival (OS) compared to matching placebo + platinum doublet chemotherapy + pembrolizumab.

Trial Arms

NameTypeDescriptionInterventions
Pemetrexed+Platinum Chemotherapy+Pembrolizumab+LenvatinibExperimentalParticipants receive carboplatin Area Under Curve 5 mg/mL/min (AUC5) or cisplatin 75 mg/m^2 via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for 4 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W for 4 cycles PLUS pembrolizumab via IV infusion Q3W for up to 35 cycles (up to 2 years) PLUS lenvatinib via oral capsule once daily for up to 2 years.
  • Pembrolizumab
  • Carboplatin
  • Cisplatin
  • Pemetrexed
  • Lenvatinib
Pemetrexed+Platinum Chemotherapy+Pembrolizumab+PlaceboPlacebo ComparatorIn Parts 1 and 2: Participants receive carboplatin AUC5 or cisplatin 75 mg/m^2 via IV infusion Q3W for 4 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W for 4 cycles PLUS pembrolizumab via IV infusion Q3W for up to 35 cycles (up to 2 years) PLUS (Part 2 only) placebo matching lenvatinib via oral capsule once daily for up to 2 years.
  • Pembrolizumab
  • Carboplatin
  • Cisplatin
  • Pemetrexed
  • Placebo matching lenvatinib

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically or cytologically confirmed diagnosis of Stage IV (American Joint
             Committee on Cancer [AJCC], nonsquamous NSCLC.

          -  Confirmation that Epidermal Growth Factor Receptor (EGFR), ALK Receptor Tyrosine
             Kinase (ALK), or ROS1 Receptor Tyrosine Kinase (ROS1)-directed therapy is not
             indicated as primary treatment (documentation of absence of tumor-activating EGFR
             mutations AND absence of ALK and ROS1 gene rearrangements OR presence of a Kirsten Rat
             Sarcoma (KRAS) gene mutation).

          -  Have measurable disease based on RECIST 1.1. Note: Lesions that appear measurable, but
             are situated in a previously irradiated area, can be considered measurable (eligible
             for selection as target lesions) if they have shown documented growth since the
             completion of radiation.

          -  Provided an evaluable archival tumor tissue sample or newly obtained core or
             excisional biopsy of a tumor lesion (that was not previously irradiated) for central
             PD-L1 testing.

          -  Life expectancy of at least 3 months.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days
             prior to the first dose of study intervention but before randomization.

          -  Male participants must agree to use contraception during the treatment period and for
             at least 120 days after the last dose of pembrolizumab and/or lenvatinib/matching
             placebo and up to 180 days after the last dose of chemotherapeutic agents. A male
             participant must also agree to the following: 1) abstinence from heterosexual
             intercourse as their preferred and usual lifestyle (abstinent on a long term and
             persistent basis) and agree to remain abstinent, OR 2) agree 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, unless confirmed to be azoospermic (vasectomized or secondary to medical
             cause). 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.

          -  Female participant is eligible to participate if she is not pregnant or breastfeeding,
             and at least one of the following conditions applies: 1) not a WOCBP OR 2) a WOCBP and
             using a contraceptive method that is highly effective (with a failure rate of <1% per
             year), with low user dependency, or be abstinent from heterosexual intercourse as
             their preferred and usual lifestyle (abstinent on a long term and persistent basis),
             during the intervention period and for at least 120 days after the last dose of study
             intervention.

          -  Adequate organ function.

          -  Adequately controlled blood pressure (BP) with or without antihypertensive
             medications, defined as BP ≤150/90 mm Hg and no change in antihypertensive medications
             within 1 week prior to randomization. Note: Participants must not have a history of
             uncontrolled or poorly-controlled hypertension, defined as >150/90 mm Hg for >4 weeks
             despite standard medical management.

        Exclusion Criteria:

          -  Known untreated central nervous system (CNS) metastases and/or carcinomatous
             meningitis. Participants with previously treated brain metastases may participate
             provided they are radiologically stable, clinically stable, and have not required
             steroids for at least 14 days prior to the first dose of study intervention.

          -  History of (noninfectious) pneumonitis that required systemic steroids or current
             pneumonitis/interstitial lung disease.

          -  Radiographic evidence of major blood vessel invasion/infiltration.

          -  Known history of an additional malignancy, except if the participant has undergone
             potentially curative therapy with no evidence of that disease recurrence for at least
             3 years since initiation of that therapy. Note: The time requirement also does not
             apply to participants who underwent successful definitive resection of basal cell
             carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the
             skin, in situ cervical cancer, or other in situ cancers.

          -  Active autoimmune disease that has required systemic treatment in the 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 allowed.

          -  Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (doses
             exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive
             therapy within 7 days prior the first dose of study intervention.

          -  Has had allogeneic tissue/solid organ transplant.

          -  Known history of human immunodeficiency virus (HIV) infection. HIV testing is not
             required unless mandated by the local health authority.

          -  Known history of Hepatitis B. No testing for Hepatitis B or Hepatitis C is required
             unless mandated by the local health authority.

          -  History of a gastrointestinal condition or procedure that in the opinion of the
             investigator may affect oral drug absorption.

          -  Active hemoptysis (at least 0.5 teaspoon of bright red blood) within 2 weeks prior to
             the first dose of study intervention.

          -  Significant cardiovascular impairment within 12 months prior to the first dose of
             study intervention, including history of congestive heart failure greater than New
             York Heart Association (NYHA) Class II, unstable angina, myocardial infarction,
             cerebrovascular accident (CVA)/stroke, or cardiac arrhythmia associated with
             hemodynamic instability.

          -  Known history of active tuberculosis.

          -  Active infection requiring systemic therapy.

          -  Has not recovered adequately from any toxicity and/or complication from major surgery
             prior to the first dose of study intervention.

          -  Previously had a severe hypersensitivity reaction to treatment with a monoclonal
             antibody or has a known sensitivity to any component of lenvatinib or pembrolizumab,
             or as applicable, carboplatin, cisplatin, or pemetrexed.

          -  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/or lenvatinib/matching placebo and up to 180
             days after last dose of chemotherapeutic agents.

          -  Received prior systemic chemotherapy or other targeted or biological antineoplastic
             therapy for their metastatic NSCLC. Note: Prior treatment with chemotherapy and/or
             radiation as part of neoadjuvant/adjuvant therapy is allowed as long as therapy was
             completed at least 6 months prior to the diagnosis of metastatic NSCLC.

          -  Received prior treatment with pembrolizumab or any other anti-programmed cell death
             (PD)-1, anti-PD-L1, anti-PD-L2 agent, with lenvatinib or any other receptor tyrosine
             kinase inhibitor (RTKi), or with an agent directed to another stimulatory or
             co-inhibitory T cell receptor.

          -  Received radiotherapy within 14 days prior to the first dose of study intervention or
             received lung radiation therapy of >30 Gy within 6 months prior to the first dose of
             study intervention. Note: Participants must have recovered from all radiation-related
             toxicities to Grade ≤1, not required corticosteroids, and not have had radiation
             pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of
             radiotherapy) to non-CNS disease.

          -  Received systemic steroid therapy (in doses exceeding 10 mg daily of prednisone
             equivalent) within 7 days prior to the first dose of study intervention.

          -  Received a live vaccine within 30 days prior to the first dose of study intervention.

          -  Currently participating and receiving study therapy or has participated in a study of
             an investigational agent and received study therapy or used an investigational device
             within 4 weeks prior to the first dose of study intervention.

          -  History or presence of an abnormal electrocardiogram (ECG) that, in the investigator's
             opinion, is clinically meaningful.

          -  Left ventricular ejection fraction (LVEF) below the institutional (or local
             laboratory) normal range as determined by multigated acquisition scan (MUGA) or
             echocardiogram (ECHO).
      
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 a Dose-limiting Toxicity
Time Frame:Cycle 1; each cycle is 21 days (up to 21 days)
Safety Issue:
Description:Dose-limiting toxicity using Common Terminology Criteria for Adverse Events v4.0 for grading, is defined as any of the following hematologic toxicities: 1) Grade 4 neutropenia, 2) Grade 3 or 4 febrile neutropenia, 3) thrombocytopenia <25,000 cells/mm^3 associated with bleeding and/or which requires platelet transfusion, or any of the following non-hematologic toxicities: 4) any other Grade 4 or 5 toxicity, 5) Grade 3 toxicities lasting >3 days (exclusions apply), 6) Grade 3 hypertension not controlled by medication, 7) Grade 3 or above gastrointestinal perforation, 8) Grade 3 or above wound dehiscence requiring medical or surgical intervention, 9) any grade thromboembolic event, or 10) any Grade 3 nonhematologic laboratory value if medical intervention is required or the abnormality leads to hospitalization.

Secondary Outcome Measures

Measure:Part 2: Objective Response Rate (ORR) as Assessed by BICR according to RECIST 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ
Time Frame:Up to approximately 24 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. ORR as assessed per modified RECIST 1.1 will be presented.
Measure:Part 2; Duration of Response (DOR) as Assessed by BICR according to RECIST 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ
Time Frame:Up to approximately 24 months
Safety Issue:
Description: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 time from the first documented evidence of CR or PR until PD 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, or death from any cause, 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. DOR as assessed per modified RECIST 1.1 will be presented.
Measure:Part 2: Number of Participants with One or More Adverse Events
Time Frame:Up to approximately 24 months
Safety Issue:
Description:An adverse event is defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who experience one of more adverse events during Part 2 of this study will be presented.
Measure:Part 2: Number of Participants Who Discontinue Study Treatment Due to an Adverse Event
Time Frame:Up to approximately 24 months
Safety Issue:
Description:An adverse event is defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who discontinue study treatment during Part 2 of this study will be presented.
Measure:Part 2: Change from Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life; Cough; Chest Pain; Dyspnea; and Physical Functioning Combined Score
Time Frame:Baseline (Cycle 1 Day 1) and at designated timepoints up to 30 days post last dose. Each cycle is 21 days. (Up to approximately 25 months)
Safety Issue:
Description:The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. The EORTC Quality of Life Questionnaire and Lung Cancer Module 13 (QLQ-LC13) is a supplemental lung cancer-specific module used in combination with QLQ-C30. The change from baseline in EORTC QLQ-C30 Global Health Status/Quality of Life (EORTC QLQ-C30 Items 29 and 30); Cough (EORTC QLQ-LC13 Item 31); Chest Pain (EORTC QLQ-LC13 Item 40); Dyspnea (EORTC QLQ-C30 Item 8); and Physical Functioning (EORTC QLQ-C30 Items 1-5) combined score will be presented. An increase in combined score indicates improvement in quality of life.
Measure:Part 2: Time to True Deterioration as Assessed by Change from Baseline in Global Health Status/Quality of Life; Cough; Chest Pain; Dyspnea; and Physical Functioning Combined Score
Time Frame:Baseline (Cycle 1 Day 1) and at designated timepoints up to 30 days post last dose. Each cycle is 21 days. (Up to approximately 25 months)
Safety Issue:
Description:The time to true deterioration will be assessed by change from baseline in EORTC QLQ-C30 Global Health Status/Quality of Life (EORTC QLQ-C30 Items 29 and 30); Cough (EORTC QLQ-LC13 Item 31); Chest Pain (EORTC QLQ-LC13 Item 40); Dyspnea (EORTC QLQ-C30 Item 8); and Physical Functioning (EORTC QLQ-C30 Items 1-5) combined score. True deterioration is defined as the first onset of ≥10-point decrease from baseline.

Details

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

Trial Keywords

  • programmed cell death 1 (PD-1, PD1)
  • programmed cell death-ligand 1 (PD-L1, PDL1)
  • programmed cell death-ligand 2 (PD-L2, PDL2)

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