NCT02435433已完成3 期
Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Ramucirumab and Best Supportive Care (BSC) Versus Placebo and BSC as Second-Line Treatment in Patients With Hepatocellular Carcinoma and Elevated Baseline Alpha-Fetoprotein (AFP) Following First-Line Therapy With Sorafenib
适应症
干预措施
相关药物
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 399
- 试验地点
- 17
- 主要终点
- Overall Survival (OS)
研究概览
简要总结
The purpose of this study is to evaluate the safety and efficacy of ramucirumab in participants with hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein. Participants will be randomized to ramucirumab or placebo in a 2:1 ratio (Main Global Cohort and China Maximized Extended Enrollment [MEE] Cohort). Participants may also receive ramucirumab if eligible to be enrolled in Open-Label Expansion (OLE) Cohort.
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
- •A diagnosis of HCC based on histopathologic findings, or a diagnosis of cirrhosis and a tumor with classical HCC imaging characteristics.
- •Sorafenib was the only systemic therapy for HCC and was discontinued for disease progression or intolerance (Main Global and MEE Cohorts only).
- •The participant received ≤2 prior systemic therapy regimen, excluding prior sorafenib or chemotherapy, for the treatment of HCC (OLE Cohort only).
- •≥1 measurable lesion per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 that has not been previously treated with locoregional therapy. A participant with a lesion(s) that has previously been treated with locoregional therapy is also eligible, if the lesion has documented progression after locoregional treatment and is measureable.
- •Child-Pugh score <7 (Child-Pugh Class A).
- •Barcelona Clinic Liver Cancer (BCLC) Stage C disease or BCLC Stage B disease not amenable to locoregional therapy or refractory to locoregional therapy.
- •Baseline AFP ≥400 nanograms/milliliter.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •Resolution of all clinically significant toxic effects of prior therapy.
- •Total bilirubin ≤1.5 times upper limit of normal value (ULN), aspartate transaminase (AST) and alanine transaminase (ALT) ≤5 × ULN.
- •Creatinine clearance ≥60 milliliters/minute.
- •Urinary protein is ≤1+ on dipstick or routine urinalysis or 24-hour urine demonstrating <1 gram of protein.
- •Absolute neutrophil count ≥1.0 × 10^9/Liter, hemoglobin ≥9 grams/deciliter, and platelets ≥75 × 10^9/Liter.
- •International Normalized Ratio (INR) ≤1.5 and a partial thromboplastin time (PTT) ≤5 seconds above the ULN.
- •Surgically sterile, postmenopausal, or compliant with a highly effective contraceptive method.
- •If a woman of childbearing potential, a negative serum pregnancy test prior to randomization.
- •Willing to provide blood for research. The participant has provided signed informed consent prior to any study specific procedures and is amenable to compliance with protocol schedules and testing.
排除标准
- •Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma.
- •Concurrent malignancy. Participants with carcinoma in situ of any origin and participants with prior malignancies in remission may be eligible with sponsor approval.
- •Previous brain metastases, leptomeningeal disease, or uncontrolled spinal cord compression.
- •History of or current hepatic encephalopathy or clinically meaningful ascites.
- •Ongoing or recent hepatorenal syndrome.
- •Liver transplant (Main Global and MEE cohorts only; Participants with prior liver transplant may be eligible for OLE cohort).
- •Hepatic locoregional therapy following prior systemic therapy or within 28 days prior to randomization.
- •Major surgical procedure, traumatic injury, non-healing wound, or peptic ulcer ≤28 days prior to randomization.
- •Received radiation to any nonhepatic (for example, bone) site within 14 days prior to randomization.
- •Placement of a subcutaneous venous access device within 7 days prior to the first dose of study treatment unless the procedure is judged of low risk of bleeding.
- •Enrolled in a clinical trial involving an investigational product or unapproved use of a drug or in medical research judged not to be scientifically or medically compatible with this study.
- •Discontinued from study treatment from another clinical trial within 28 days prior to randomization.
- •Known allergy to any of the treatment components.
- •Uncontrolled hypertension.
- •Any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, <6 months prior to randomization.
- •Any bleeding episode considered life-threatening, or any Grade 3 or 4 gastrointestinal bleeding episode in the 3 months prior to randomization requiring intervention.
- •Esophageal or gastric varices that require intervention or represent high bleeding risk. Participants with evidence of portal hypertension or prior bleeding must have had endoscopic evaluation within 3 months prior to randomization.
- •Gastrointestinal perforation or fistulae within 6 months prior to randomization.
- •Symptomatic congestive heart failure (New York Heart Association II-IV), unstable angina pectoris, or symptomatic or poorly controlled cardiac arrhythmia.
- •Pregnant or breast-feeding.
- •Any medical or psychiatric condition that may increase the risk associated with study participation or may interfere with the interpretation of study results. Conditions include but are not limited to:
- •Human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness.
- •Active or uncontrolled clinically serious infection. (Participants with chronic viral hepatitis are eligible.)
- •Ongoing or recent history of drug abuse.
- •Uncontrolled hereditary or acquired thrombotic or bleeding disorder.
- •Bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection.
- •Therapeutic dose anticoagulation with warfarin, low molecular-weight heparin, or similar agents.
- •Chronic therapy with nonsteroidal anti-inflammatory agents or other anti-platelet agents. Aspirin at doses up to 100 milligrams/day is permitted.
- •The participant received prior immunotherapy and is experiencing or has experienced any of the following (OLE cohort only):
- •Any clinically significant Grade ≥3 immune-related adverse event (irAE)
- •Any grade neurologic or ocular irAE
- •Any grade immune-related pneumonitis, cardiomyopathy, or hepatitis
- •The participant received prior immunotherapy and at the time of study enrollment, requires steroids or other immunosuppressive agents (OLE cohort only).
研究组 & 干预措施
Ramucirumab + Best Supportive Care (BSC)
Experimental
8 milligrams per kilogram (mg/kg) ramucirumab administered as an intravenous (IV) injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.
干预措施: Ramucirumab (Drug)
Placebo + BSC
Placebo Comparator
Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.
干预措施: Ramucirumab (Drug)
Placebo + BSC
Placebo Comparator
Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.
干预措施: Placebo (Drug)
Open Label Ramucirumab + BSC
Experimental
8 mg/kg ramucirumab administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.
干预措施: Ramucirumab (Drug)
Ramucirumab MEE Cohort + BSC
Experimental
8 mg/kg ramucirumab administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.
干预措施: Ramucirumab (Drug)
Placebo MEE Cohort + BSC
Placebo Comparator
Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.
干预措施: Ramucirumab (Drug)
Placebo MEE Cohort + BSC
Placebo Comparator
Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.
干预措施: Placebo (Drug)
结局指标
主要结局
Overall Survival (OS)
时间窗: From Date of Randomization to Death from Any Cause (Up to 28 Months)
OS time was measured from date of randomization to date of death from any cause. Participants who were not known to have died on or before the date of data cut-off, OS data was censored on the last date (on or before the cut-off date) the participant was known to be alive.
次要结局
- Change From Baseline in EuroQol 5-Dimension 5-Level (EQ-5D-5L) Questionnaire(From Randomization through End of Study (Up to 28 Months))
- Time to Deterioration in Eastern Cooperative Oncology Group Performance Status (ECOG PS)(From Randomization through First Date of Deterioration Observation (ECOG PS≥2) (Up to 28 Months))
- Percentage of Participants With Anti-Ramucirumab Antibodies(Predose Cycle 1: 7 Days prior to First Infusion, Cycle 4: 3 Days Prior to Infusion, Cycle 7 through Follow Up (Up to 28 Months))
- Time to Deterioration of Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8)(From Randomization to the First Date of Deterioration Observation (≥ 3-point decrease) (Up to 28 Months))
- Progression Free Survival (PFS)(From Randomization to Objective Progression or Death from Any Cause (Up to 28 Months))
- Time to Radiographic Progression(From Randomization to Objective Progression (Up to 28 Months))
- Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR)(From Randomization to Objective Progression (Up to 28 Months))
- Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) Before 2nd, 4th, 7th, and 10th Infusion(Predose, Weeks 2, 6, 12 and 18, Day 1; Up to 3 Days Before Infusion (14-Day Cycles))
- PK: Serum Concentration Maximum (Cmax) After 1st, 2nd, 4th, 7th and 10th Ram Infusion(Weeks 0, 2, 6, 12 and 18, Day 1; 1 hour to 1.5 hours Post End of Infusion (14 day-Cycles))
研究者
研究点 (17)
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