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)-China Extension Study

Nonsquamous Non-small Cell Lung Cancer Clinical Trial

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 Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04716933
• Other study ID #: 7902-006 China Extension
• Secondary ID: MK-7902-006E7080
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: November 5, 2019
• Est. completion date: August 30, 2024

Study information

• Verified date: June 2024
• Source: Merck Sharp & Dohme LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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 from mainland China 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.

Description:

The China extension study will include participants previously enrolled in mainland China for the global study for MK-7902-006 (NCT03829319) plus those enrolled in mainland China as part of the China extension enrollment period.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 201
• Est. completion date: August 30, 2024
• Est. primary completion date: August 11, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Nonsquamous Non-small Cell Lung Cancer

Intervention

Biological:
• Pembrolizumab
IV infusion Q3W

Drug:
• Carboplatin
IV infusion Q3W
• Cisplatin
IV infusion Q3W
• Pemetrexed
IV infusion Q3W
• Lenvatinib
Oral capsule once daily
• Placebo matching lenvatinib
Oral capsule once daily

Locations

Country	Name	City	State
China	Beijing Cancer Hospital ( Site 0120)	Beijing	Beijing
China	Cancer Hospital Chinese Academy of Medical Science ( Site 0117)	Beijing	Beijing
China	Peking Union Medical College Hospital ( Site 0108)	Beijing	Beijing
China	Jilin Cancer Hospital ( Site 0115)	Changchun	Jilin
China	First Affiliated Hospital of The Third Military Medical University ( Site 0118)	Chongqing	Chongqing
China	The Second Hospital Affiliated to AMU ( Site 0119)	Chongqing	Chongqing
China	Fujian Provincial Cancer Hospital ( Site 0102)	Fuzhou	Fujian
China	Southern Medical University Nanfang Hospital ( Site 0121)	Guangzhou	Guangdong
China	The First Affiliated Hospital Zhejiang University ( Site 0109)	Hangzhou	Zhejiang
China	Zhejiang Cancer Hospital ( Site 0113)	Hangzhou	Zhejiang
China	The Third Affiliated Hospital of Harbin Medical University ( Site 0100)	Harbin	Heilongjiang
China	Shanghai Pulmonary Hospital ( Site 0101)	Shanghai	Shanghai
China	Zhongshan Hospital Fudan University ( Site 0103)	Shanghai	Hunan
China	Tianjin Medical University Cancer Institute & Hospital ( Site 0111)	Tianjin	Tianjin
China	Cancer Hospital Affiliated to Xinjiang Medical University ( Site 0110)	Urumuqi	Xinjiang
China	The First Affiliated Hospital of Wenzhou Medical University ( Site 0124)	Wen Zhou	Zhejiang
China	Hubei Cancer Hospital ( Site 0122)	Wuhan	Hubei
China	Wuhan Union Hospital ( Site 0123)	Wuhan	Hubei
China	Henan Cancer Hospital ( Site 0112)	Zhengzhou	Henan

Sponsors (2)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC	Eisai Inc.

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1: Number of Participants with a Dose-limiting Toxicity	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.	Cycle 1; each cycle is 21 days (up to 21 days)
Primary	Part 1: Number of Participants with One or More Adverse Events	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 1 of this study will be presented.	Through 90 days post last dose of study treatment (Up to approximately 27 months)
Primary	Part 2: Progression-free Survival (PFS) 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	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 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, 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. PFS as assessed per modified RECIST 1.1 will be presented.	Up to approximately 24 months
Primary	Part 2: Overall Survival (OS)	OS is defined as the time from randomization to the time of death from any cause. OS will be presented.	Up to approximately 45 months
Secondary	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	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.	Up to approximately 24 months
Secondary	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	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.	Up to approximately 24 months
Secondary	Part 2: Number of Participants with One or More Adverse Events	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.	Up to approximately 24 months
Secondary	Part 2: Number of Participants Who Discontinue Study Treatment Due to an Adverse Event	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.	Up to approximately 24 months
Secondary	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	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.	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)
Secondary	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	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.	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)

External Links

•   Merck Clinical Trials Information