A Randomized, Multi-Center, Blinded, Placebo-Controlled Study Of Mapatumumab ([HGS1012], A Fully Monoclonal Antibody To TRAIL-R1) In Combination With Sorafenib As A First-Line Therapy In Subjects With Advanced Hepatocellular Carcinoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 101
- 试验地点
- 1
- 主要终点
- Time to Progression-Blinded Independent Central Review (BICR) Assessment
研究概览
简要总结
Mapatumumab is a fully human, agonist monoclonal antibody that activates the cell death pathway in tumor cells by specifically binding to TRAIL-R1 with high affinity. Sorafenib, a multikinase inhibitor, is the standard of care for treatment of patients with advanced hepatocellular carcinoma (HCC). The mechanisms of sorafenib and mapatumumab action suggest that these agents could interact synergistically. This is a Phase 2, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of mapatumumab in combination with sorafenib in subjects with advanced hepatocellular carcinoma.
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
- •Child-Pugh Class A.
- •Barcelona Clinic Liver Cancer (BCLC) advanced stage (C) hepatocellular carcinoma, or BCLC intermediate stage (B) hepatocellular carcinoma if treatment with transarterial chemoembolization is not considered appropriate
- •Measurable disease demonstrating intratumoral arterial enhancement by contrast enhanced computerized tomography (CT), with use of multislice scanners, or contrast enhanced dynamic magnetic resonance imaging (MRI), with at least 1 tumor lesion that meets the following criteria: located in the liver; can be accurately measured in at least 1 dimension; well delineated area of viable, hypervascular (contrast enhancement in the arterial phase) tumor that is >2 centimeter (cm) in the axial plane; suitable for repeat measurement; OR not previously treated with locoregional or systemic treatment unless the lesion shows a well-delineated area of viable (contrast enhancement in the arterial phase) tumor that is >2 cm in the axial plane. (If the lesion is poorly demarcated or exhibits atypical enhancement as a result of the previous intervention, then it cannot be selected as a target lesion)
- •Radiologic eligibility (measurable disease) must be must be confirmed by the BICR prior to randomization.
- •Adequate bone marrow, renal and liver function as defined in the protocol.
- •Performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) Scale
- •Age 18 years or older
- •Have the ability to understand the requirements of the study, provide written informed consent (including consent for the use and disclosure of research-related health information), and comply with the study and follow-up procedures.
排除标准
- •Any co-morbid condition that in the judgment of the investigator renders the subject at high risk of treatment complications or reduces the possibility of assessing clinical effect.
- •Received prior investigational or non-investigational cytotoxic chemotherapy, hormonal therapy, biological therapy (including but not limited to monoclonal antibodies, small molecules or other immunotherapy) to treat hepatocellular carcinoma.
- •History of organ allograft.
- •Previously received mapatumumab or sorafenib.
- •Underwent resection, radiofrequency ablation, radiation or chemoembolization within 4 weeks before enrollment or not recovered from such treatments.
- •Need for concomitant anticancer therapy (surgery, radiation therapy, chemotherapy, immunotherapy, radiofrequency ablation) or other investigational agents during the study treatment period.
- •Major surgery (i.e., the opening of a major body cavity, requiring the use of general anesthesia) within 4 weeks before enrollment; minor surgery (except for insertion of vascular access device) within 2 weeks before enrollment; or not yet recovered from the effects of the surgery.
- •Systemic steroids within 1 week before enrollment except steroids used as part of an antiemetic regimen or maintenance-dose steroids for non-cancerous disease.
- •Hepatic encephalopathy, per the investigator's evaluation.
- •History of clinically significant gastrointestinal bleeding requiring procedural intervention (e.g., variceal banding, transjugular intrahepatic portosystemic shunt procedure, arterial embolization, topical coagulation therapy) within 4 weeks before enrollment.
- •Gastrointestinal disease resulting in an inability to take oral medication or a requirement for intravenous hyperalimentation.
- •History of any infection requiring hospitalization or intravenous antibiotics within 2 weeks before enrollment.
- •Known brain or spinal cord metastases unless adequately treated (surgery or radiotherapy) with no evidence of progression and neurologically stable off anticonvulsants and steroids.
- •Known human immunodeficiency virus infection.
- •Unstable angina, myocardial infarction, cerebrovascular accident, >= Class II congestive heart failure according to the New York Heart Association Classification for Congestive Heart Failure within 6 months before enrollment.
- •Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin.
- •Uncontrolled hypertension (systolic blood pressure >150 millimeters of mercury [mmHg] or diastolic pressure >90 mmHg despite optimal medical management).
- •Using and unable to discontinue use of concomitant strong CYP3A4 inducers (e.g., including but not limited to St. John's Wort, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital)
- •Pregnant female or nursing mother. All females with an intact uterus (unless amenorrheic for the 24 months before enrollment) must have a negative serum pregnancy test at screening. All non-sterile or non-postmenopausal females must practice a medically accepted method of contraception over the course of the study and for 60 days after the last dose of study agent.
- •Males who do not agree to use effective contraception during the study and for a period of 60 days following the final dose of study agent.
- •Subject is currently enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study(s) or subject is receiving other investigational agents.
- •Acute or chronic severe renal insufficiency (glomoerular filtration rate <30 milliliters [mL]/minute/1.73 square meters) or acute renal insufficiency of any severity due to the hepato-renal syndrome.
- •Hepatitis B virus deoxyribonucleic acid (DNA) levels >2,000 international units/mL.
研究组 & 干预措施
Sorafenib plus mapatumumab
Mapatumumab 30 milligrams (mg)/kilogram (kg) intravenously on Day 1 of each cycle (i.e. every 21 days) plus sorafenib 400 mg orally twice daily continuously in each cycle until radiologic disease progression or unacceptable toxicity
干预措施: Mapatumumab (Drug)
Sorafenib plus mapatumumab
Mapatumumab 30 milligrams (mg)/kilogram (kg) intravenously on Day 1 of each cycle (i.e. every 21 days) plus sorafenib 400 mg orally twice daily continuously in each cycle until radiologic disease progression or unacceptable toxicity
干预措施: Sorafenib (Drug)
Sorafenib plus Placebo
Placebo intravenously on Day 1 of each cycle (i.e. every 21 days) plus sorafenib 400 mg orally twice daily continuously in each cycle until radiologic disease progression or unacceptable toxicity
干预措施: Placebo (Drug)
Sorafenib plus Placebo
Placebo intravenously on Day 1 of each cycle (i.e. every 21 days) plus sorafenib 400 mg orally twice daily continuously in each cycle until radiologic disease progression or unacceptable toxicity
干预措施: Sorafenib (Drug)
结局指标
主要结局
Time to Progression-Blinded Independent Central Review (BICR) Assessment
时间窗: Randomization to maximum of 24.1 months
Time to progression is defined as the time from randomization to radiologic disease progression based on blinded independent review (BICR) of imaging scans using modified Response Evaluation Criteria in Solid Tumors assessment (mRECIST) for hepatocellular carcinoma. The primary analysis was performed using Kaplan Meier methods. The median time to progression is reported with one-sided 90% confidence interval. Analysis was performed on the modified Intent to Treat (mITT) Population which comprised of all randomized participants who received at least part of 1 dose of study agent (mapatumumab/placebo and/or sorafenib) with participants analyzed according to the groups to which they were randomized. NA indicates upper limit was not measurable as one-sided confidence interval is presented.
次要结局
- Time to Progression-Investigator Assessment(Randomization to maximum of 52.9 months)
- Median Overall Survival(Randomization to maximum of 52.9 months)
- Progression Free Survival-BICR Assessment(Randomization to maximum of 24.1 months)
- Progression Free Survival-Investigator Assessment(Randomization to maximum of 52.9 months)
- Percentage of Participants With Objective Response-BICR Assessment(Randomization to maximum of 24.1 months)
- Percentage of Participants With Objective Response-Investigator Assessment(Randomization to maximum of 52.9 months)
- Number of Participants With Worst Toxicity Grade-chemistry Parameters(Enrolment to maximum of 52.9 months)
- Percentage of Participants With Disease Control-BICR Assessment(Randomization to maximum of 24.1 months)
- Percentage of Participants With Disease Control-Investigator Assessment(Randomization to maximum of 52.9 months)
- Time to Response-BICR Assessment(Randomization to maximum of 24.1 months)
- Duration of Response-BICR Assessment(Randomization to maximum of 24.1 months)
- Number of Participants With Treatment-emergent Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs)(Start of study treatment to maximum of 52.9 months)
- Number of Participants With Severe AEs(Start of study treatment to maximum of 52.9 months)
- Number of Participants With Worst Toxicity Grade-hematology Parameters(Enrolment to maximum of 52.9 months)
- Number of Participants With Anti-mapatumumab Antibodies(Randomization to maximum of 24.1 months)
- Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)(Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days))
- Change From Baseline in Heart Rate(Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days))
- Change From Baseline in Temperature(Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days))
- Change From Baseline in Respiratory Rate(Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days))
- Change From Baseline in Weight(Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days))
- Serum Concentration of Mapatumumab(Day1 pre-dose(Cycle 1,2,4,5,6,8,9,10,12,14,16,17,18,20,22,24,26,28,30,32,34);end of infusion (Cycle 1);Day8 pre-dose(Cycle 1);Day15 pre-dose (Cycle 1,2);Day21(Cycle 2,4,6,8,9,12,14,16,18,20,22,24,26,28,30,32,34);Cycle 99(end of treatment) (21-day cycles))