A Phase 3 Multicenter, Randomized, Double-blinded, Active-controlled, Clinical Study to Evaluate the Safety and Efficacy of Lenvatinib (E7080/MK-7902) in Combination With Pembrolizumab (MK-3475) Versus Lenvatinib in First-line Therapy of Participants With Advanced Hepatocellular Carcinoma (LEAP-002)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 794
- 试验地点
- 278
- 主要终点
- Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
研究概览
简要总结
The purpose of this study is to evaluate the safety and efficacy of lenvatinib (E7080/MK-7902) in combination with pembrolizumab (MK-3745) versus lenvatinib in combination with placebo as first-line therapy for the treatment of advanced hepatocellular carcinoma in adult participants.
The primary hypotheses of this study are that lenvatinib plus pembrolizumab is superior to lenvatinib plus placebo with respect to progression-free survival (PFS) and overall survival (OS).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Is male or female and ≥18 years of age at the time of signing the informed consent
- •Has a diagnosis of hepatocellular carcinoma confirmed by radiology, histology, or cytology
- •Has Barcelona Clinic Liver Cancer (BCLC) Stage C disease, or BCLC Stage B disease not amenable to locoregional therapy or refractory to locoregional therapy, and not amenable to a curative treatment approach
- •Has a Child-Pugh class A liver score
- •Has a predicted life expectancy of >3 months
- •Has at least one measurable hepatocellular carcinoma (HCC) lesion based on RECIST 1.1 as confirmed by BICR
- •Has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1
- •Participants with hepatitis B will be eligible as long as their virus is well controlled
排除标准
- •Has had esophageal or gastric variceal bleeding within the last 6 months
- •Has gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib
- •Has a preexisting Grade ≥3 gastrointestinal or non-gastrointestinal fistula
- •Has clinically significant hemoptysis from any source or tumor bleeding within 2 weeks prior to the first dose of study intervention
- •Has significant cardiovascular impairment within 12 months of the first dose of study intervention such as history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or cerebrovascular accident stroke, or cardiac arrhythmia associated with hemodynamic instability
- •Has had major surgery to the liver within 4 weeks prior to the first dose of study intervention
- •Has had a minor surgery (ie, simple excision) within 7 days prior to the first dose of study intervention
- •Has serious non-healing wound, ulcer, or bone fracture
- •Has received any systemic chemotherapy for HCC or chemotherapy for any malignancy in the past 3 years
- •Has received prior therapy with an anti-programmed cell death 1 (ant-PD-1), anti-programmed cell death ligand 1 (anti-PD-L1), or anti- programmed cell death ligand 2 (anti-PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX-40, or CD137)
- •Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention
- •Has a known additional malignancy that is progressing or has required active treatment within the past 3 years with the exceptions of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that has undergone potentially curative therapy
- •Has a known history of, or any evidence of, central nervous system (CNS) metastases and/or carcinomatous meningitis as assessed by local site investigator
- •Has severe hypersensitivity (≥Grade 3) to study intervention and/or any of their excipients
- •Has an active autoimmune disease that has required systemic treatment in past 2 years
- •Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
- •Has urine protein ≥1 grams/24 hours
- •Prolongation of corrected QT (QTc) interval to >480 milliseconds (corrected by Fridericia Formula)
- •Has left ventricular ejection fraction (LVEF) below the institutional normal range as determined by multigated acquisition scan (MUGA) or echocardiogram (ECHO)
- •Has an active infection requiring systemic therapy with the exceptions of hepatitis B virus (HBV) or hepatitis C virus (HCV)
- •Has a known history of human immunodeficiency virus (HIV) infection
- •Has known active tuberculosis (Bacillus tuberculosis)
- •Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
- •Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study
- •Is 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 study intervention
- •Has had an allogenic tissue/solid organ transplant
研究组 & 干预措施
lenvatinib plus pembrolizumab
Participants receive lenvatinib 12 mg (for participants with screening body weight ≥60 kg) or 8 mg (for participants with screening body weight <60 kg) orally once a day (QD) plus pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W). Pembrolizumab will be administered for up to 35 cycles (approximately 24 months). Lenvatinib will be administered until progressive disease or unacceptable toxicity.
干预措施: lenvatinib (Drug)
lenvatinib plus pembrolizumab
Participants receive lenvatinib 12 mg (for participants with screening body weight ≥60 kg) or 8 mg (for participants with screening body weight <60 kg) orally once a day (QD) plus pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W). Pembrolizumab will be administered for up to 35 cycles (approximately 24 months). Lenvatinib will be administered until progressive disease or unacceptable toxicity.
干预措施: pembrolizumab (Biological)
lenvatinib plus placebo
Participants receive lenvatinib 12 mg (for participants with screening body weight ≥60 kg) or 8 mg (for participants with screening body weight <60 kg) orally QD plus saline placebo by IV infusion on Day 1 Q3W. Saline placebo will be administered for up to 35 cycles (approximately 24 months). Lenvatinib will be administered until progressive disease or unacceptable toxicity.
干预措施: lenvatinib (Drug)
lenvatinib plus placebo
Participants receive lenvatinib 12 mg (for participants with screening body weight ≥60 kg) or 8 mg (for participants with screening body weight <60 kg) orally QD plus saline placebo by IV infusion on Day 1 Q3W. Saline placebo will be administered for up to 35 cycles (approximately 24 months). Lenvatinib will be administered until progressive disease or unacceptable toxicity.
干预措施: saline placebo (Drug)
结局指标
主要结局
Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
时间窗: Up to approximately 41 months
PFS was defined as the time from the date of the first documentation of disease progression, as determined by blinded independent central review (BICR) per RECIST 1.1 or death due to any cause (whichever occurred first). Disease progression was defined as at least 20 percent (%) increase (including an absolute increase of at least 5 millimeter \[mm\]) in the sum of diameter of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. PFS was estimated and analyzed using Kaplan-Meier method.
Overall Survival (OS)
时间窗: Up to approximately 41 months
OS was defined as the time from randomization until death from any cause
次要结局
- Objective Response Rate (ORR) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST)(Up to approximately 41 months)
- Duration of Response (DOR) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST)(Up to approximately 41 months)
- Disease Control Rate (DCR) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST)(Up to approximately 41 months)
- Time to Disease Progression (TTP) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST)(Up to approximately 41 months)
- Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)(Up to approximately 41 months)
- Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)(Up to approximately 41 months)
- Time to Disease Progression (TTP) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)(Up to approximately 41 months)
- Number of Participants Who Experienced an Hepatic Event of Clinical Interest (HECI)(Up to approximately 68 months)
- Progression-free Survival (PFS) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST)(Up to approximately 41 months)
- Number of Participants Who Experienced an Serious Adverse Event (SAE)(Up to approximately 68 months)
- Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)(Up to approximately 41 months)
- Number of Participants Who Experienced an Adverse Event (AE)(Up to approximately 68 months)
- Number of Participants Who Discontinued Study Drug Due to an Adverse Event(Up to approximately 68 months)
- Number of Participants Who Experienced an Immune-related Adverse Event (irAE) of Clinical Interest(Up to approximately 41 months)