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)
概览
- 阶段
- 3 期
- 干预措施
- Pembrolizumab
- 疾病 / 适应症
- Nonsquamous Non-small Cell Lung Cancer
- 发起方
- Merck Sharp & Dohme LLC
- 入组人数
- 761
- 试验地点
- 245
- 主要终点
- Part 1: Number of Participants With a Dose-limiting Toxicity (DLT)
- 状态
- 已完成
- 最后更新
- 2个月前
概览
简要总结
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.
研究者
入排标准
入选标准
- •Histologically or cytologically confirmed diagnosis of Stage IV (American Joint Committee on Cancer \[AJCC\], version 8 or current version), 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.
- •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 archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion (not previously irradiated).
- •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.
- •Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed.
- •Male participants must agree for at least 7 days after the last dose of lenvatinib/matching placebo and up to 180 days after the last dose of chemotherapeutic agents to:
- •Refrain from donating sperm PLUS either:
排除标准
- •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 intratumoral caviations, encasement, or invasion of a major blood vessel. Additionally, the degree of proximity to major blood vessels should be considered for exclusion because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis after lenvatinib-therapy. (In the chest, major blood vessels include the main pulmonary artery, the left and right pulmonary arteries, the 4 major pulmonary veins, the superior or inferior vena cava, and the aorta).
- •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 or active Hepatitis C. 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.
研究组 & 干预措施
Pemetrexed+Platinum Chemotherapy+Pembrolizumab+Placebo
In 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.
干预措施: Pembrolizumab
Pemetrexed+Platinum Chemotherapy+Pembrolizumab+Lenvatinib
Participants 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.
干预措施: Pembrolizumab
Pemetrexed+Platinum Chemotherapy+Pembrolizumab+Lenvatinib
Participants 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.
干预措施: Carboplatin
Pemetrexed+Platinum Chemotherapy+Pembrolizumab+Lenvatinib
Participants 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.
干预措施: Cisplatin
Pemetrexed+Platinum Chemotherapy+Pembrolizumab+Lenvatinib
Participants 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.
干预措施: Pemetrexed
Pemetrexed+Platinum Chemotherapy+Pembrolizumab+Lenvatinib
Participants 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.
干预措施: Lenvatinib
Pemetrexed+Platinum Chemotherapy+Pembrolizumab+Placebo
In 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.
干预措施: Carboplatin
Pemetrexed+Platinum Chemotherapy+Pembrolizumab+Placebo
In 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.
干预措施: Cisplatin
Pemetrexed+Platinum Chemotherapy+Pembrolizumab+Placebo
In 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.
干预措施: Pemetrexed
Pemetrexed+Platinum Chemotherapy+Pembrolizumab+Placebo
In 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.
干预措施: Placebo matching lenvatinib
结局指标
主要结局
Part 1: Number of Participants With a Dose-limiting Toxicity (DLT)
时间窗: Cycle 1; each cycle is 21 days (up to 21 days)
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.
Part 1: Number of Participants Who Experienced an Adverse Event (AE)
时间窗: Up to approximately 48 months
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.
Part 1: Number of Participants Who Discontinued Study Drug Due to an Adverse Event
时间窗: Up to approximately 58 months
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 medication due to and adverse event during Part 1 of this study will be presented.
Part 2: Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
时间窗: Up to approximately 36 months
PFS was 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 occurred first. Per RECIST 1.1, PD was 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 was also considered PD. Data are from the product-limit (Kaplan-Meier) method for censored data. PFS as assessed by blinded independent central review (BICR) per RECIST 1.1 is presented.
Part 2: Overall Survival (OS)
时间窗: Up to approximately 47 months
OS is defined as the time from randomization to the time of death from any cause. OS is presented.
次要结局
- Part 2: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)(Up to approximately 19 months)
- Part 2: Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)(Up to approximately 48 months)
- Part 2: Number of Participants Who Experienced an Adverse Event (AE)(Up to approximately 58 months)
- Part 2: Number of Participants Who Discontinued Study Drug Due to an Adverse Event(Up to approximately 58 months)
- Part 2: Change From Baseline in Global Health Status (GHS) (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 [EORTC QLQ-C30] Items 29 and 30) Score(Baseline and Week 27)
- Part 2: Change From Baseline in Cough (EORTC Quality of Life Questionnaire-Lung Cancer Module 13 [QLQ-LC13] Item 31) Score(Baseline and week 27)
- Part 2: Change From Baseline in Chest Pain (EORTC QLQ-LC13 Item 40) Score(Baseline and Week 27)
- Part 2: Change From Baseline in Dyspnea (EORTC QLQ-C30 Item 8) Score(Baseline and Week 27)
- Part 2: Change From Baseline in Physical Functioning (EORTC QLQ-C30 Items 1-5) Score(Baseline and Week 27)
- Part 2: Time to True Deterioration (TTD) Based on Change From Baseline in Global Health Status (GHS)/Quality of Life (QoL) (EORTC QLQ-C30 Items 29 and 30) Score(Baseline and Week 27)
- Part 2: TTD Based on Change From Baseline in Cough EORTC QLQ-LC13 (Item 31) Score(Baseline And Week 27)
- Part 2: TTD Based on Change From Baseline in Chest Pain EORTC QLQ-LC13 (Item 40) Score(Baseline and Week 27)
- Part 2: TTD Based on Change From Baseline in Dyspnea EORTC QLQ-C30 (Item 8) Score(Baseline and Week 27)
- Part 2: TTD Based on Change From Baseline in Physical Functioning EORTC QLQ-C30 (Items 1 Through 5) Score(Baseline and Week 27)
- Part 2: Time to True Deterioration (TTD) Based on Change From Baseline in the Composite Endpoint of Cough (EORTC QLQ-LC13 Item 31), Chest Pain (EORTC QLQ-LC13 Item 40), or Dyspnea (EORTC QLQ-C30 Item 8)(Baseline and Week 27)