NCT01140347已完成3 期
A Multicenter, Randomized, Double-Blind, Phase 3 Study of Ramucirumab (IMC-1121B) Drug Product and Best Supportive Care (BSC) Versus Placebo and BSC as Second-Line Treatment in Patients With Hepatocellular Carcinoma Following First-Line Therapy With Sorafenib (REACH)
适应症
干预措施
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 565
- 试验地点
- 146
- 主要终点
- Overall Survival (OS)
研究概览
简要总结
This is a Phase 3 multicenter, randomized study evaluating the safety and efficacy of ramucirumab DP plus BSC as a double-blind, placebo-controlled (placebo plus BSC) comparison.
Approximately 544 participants, at least 18 years of age, with Child-Pugh score < 7 and diagnosed with hepatocellular carcinoma will be randomized. Participants must have received sorafenib as first-line systemic treatment for hepatocellular carcinoma (HCC), and must have discontinued sorafenib prior to entering the study.
Hypothesis: This sample size will allow differentiation of the expected increase in median overall survival (OS), from 8 months in the placebo arm to 10.67 months in the ramucirumab arm.
Upon registration and completion of screening procedures, eligible participants with HCC who have disease progression during or following first-line therapy with sorafenib, or were intolerant to this agent, will be randomized to receive either ramucirumab DP or placebo.
The treatment regimen will be continued until radiographic or symptomatic progression, the development of unacceptable toxicity, noncompliance or withdrawal of consent by the participant, or investigator decision.
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
- •Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1
- •Child-Pugh score of <7 (Child-Pugh Class A only)
- •Barcelona Clinic Liver Cancer (BCLC) Stage C or BCLC stage B not amenable to locoregional therapy or refractory to locoregional therapy
- •Diagnosis of HCC (excluding fibrolamellar carcinoma) in the absence of histologic or cytologic confirmation
- •There are either clinical, laboratory, or radiographic findings consistent with a diagnosis of liver cirrhosis
- •Has a liver mass measuring at least 2 centimeters (cm) with characteristic vascularization seen on either triphasic computed tomography (CT) scan or magnetic resonance imaging (MRI) with gadolinium
- •At least 1 measurable or evaluable lesion that is viable [that is (i.e.), is vascularized], and has not been previously treated with locoregional therapy. A lesion that has been previously treated will qualify as a measurable or evaluable lesion if there was demonstrable progression following locoregional therapy
- •Previously treated with sorafenib and has discontinued sorafenib treatment at least 14 days prior to randomization. Participants may have experienced:
- •Radiographically documented disease progression during sorafenib therapy or after discontinuation of sorafenib therapy, or
- •Discontinuation of sorafenib due to an adverse drug reaction, despite dose reduction by 1 level and BSC
- •The participant has received sorafenib as the only systemic therapeutic intervention. Any hepatic locoregional therapy that has been administered prior to sorafenib is allowed, but not following sorafenib. Radiation to metastatic sites [for example (e.g.), bone] following sorafenib therapy is permitted.
- •Resolution of clinically significant toxicity of any anti-cancer therapy to Grade ≤1 by the National Cancer Institute Common Terminology Criteria for Adverse Events volume 4.0 (NCI-CTCAE v. 4.0).
- •Adequate Organ Function defined as:
- •Total bilirubin <3.0 milligrams/deciliter (mg/dL) [51.3 micromole/liter (µmol/L)], aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5 × upper limit of normal (ULN)
- •Serum creatinine ≤1.2 × ULN or calculated creatinine clearance >50 milliliters/minute (mL/min)
- •Absolute neutrophil count (ANC) ≥1.0 × 10^3/microliter (μL) (1.0 × 10^9/liter (L)]), hemoglobin ≥9 grams/deciliter (g/dL) [5.58 millimoles/liter (mmol/L)], and platelets ≥75 × 10^3/µL (75 × 10^9/L)
- •International Normalized Ratio (INR) ≤1.5 and partial thromboplastin time (PTT) ≤5 seconds above ULN. Participants receiving prophylactic low-dose anticoagulant therapy are eligible provided that INR ≤1.5 and PTT ≤5 seconds above the ULN
- •The participant's urinary protein is ≤1+ on dipstick or routine urinalysis. If urine dipstick or routine analysis indicates ≥2+ proteinuria, then a 24-hour urine must be collected and must demonstrate <1000 milligrams (mg) of protein in 24 hours to allow participation in the study
排除标准
- •Major surgery within 28 days prior to randomization, or central venous access device placement within 7 days prior to randomization
- •Hepatic locoregional therapy within 28 days prior to randomization
- •Radiation to any nonhepatic (e.g., bone) site within 14 days prior to randomization
- •Sorafenib within 14 days prior to randomization
- •Received any investigational therapy or non-approved drug within 28 days prior to randomization
- •Received any previous systemic therapy with vascular endothelial growth factor (VEGF) inhibitors or vascular endothelial growth factor receptor (VEGFR) inhibitors (including investigational agents) other than sorafenib for treatment of HCC
- •Fibrolamellar carcinoma
- •Received any transfusion, blood component preparation, erythropoietin, albumin preparation, or granulocyte colony-stimulating factors (G-CSF) within 14 days prior to randomization
- •Therapeutic anticoagulation with warfarin, low-molecular-weight heparin, or similar agents. Participants receiving prophylactic, low-dose anticoagulation therapy are eligible provided that the coagulation parameters defined in the inclusion criteria (INR ≤1.5 and PTT ≤5 seconds above the ULN) are met
- •Receiving ongoing therapy with nonsteroidal anti-inflammatory agents (NSAIDs, e.g., indomethacin, ibuprofen, naproxen, nimesulide, celecoxib, etoricoxib, or similar agents) or other antiplatelet agents (e.g., clopidogrel, ticlopidine, prasugrel, dipyridamole, picotamide, indobufen, anagrelide, triflusal). Aspirin (ASA) at doses up to 100 milligrams/day (mg/day) is permitted
- •Symptomatic congestive heart failure, unstable angina pectoris, or symptomatic or poorly controlled cardiac arrhythmia
- •Any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to randomization
- •Uncontrolled arterial hypertension systolic ≥150 / diastolic ≥90 millimeters of mercury (mm Hg) despite standard medical management
- •Grade 3-4 gastrointestinal bleeding or any variceal bleeding episode in the 3 months prior to randomization requiring transfusion, endoscopic or operative intervention (participants with any bleeding episode considered life-threatening during the 3 months prior to randomization are excluded, regardless of transfusion or intervention status)
- •Esophageal or gastric varices that require immediate intervention (e.g., banding, sclerotherapy) or represent a high bleeding risk. Participants with evidence of portal hypertension (including splenomegaly) or any prior history of variceal bleeding must have had endoscopic evaluation within the 3 months immediately prior to randomization. Participants with evidence of portal hypertension are eligible for study participation if endoscopic evaluation does not indicate esophageal or gastric varices that require immediate intervention or represent a high bleeding risk; however, these eligible participants must receive supportive therapy (e.g., beta blocker therapy) according to institutional standards and clinical guidelines during study participation
- •Central nervous system (CNS) metastases or carcinomatous meningitis
- •History of or current hepatic encephalopathy or current clinically meaningful ascites
研究组 & 干预措施
Placebo and BSC
Placebo Comparator
干预措施: Placebo (Biological)
Placebo and BSC
Placebo Comparator
干预措施: BSC (Other)
Ramucirumab DP and BSC
Experimental
干预措施: Ramucirumab DP (IMC-1121B) (Biological)
Ramucirumab DP and BSC
Experimental
干预措施: BSC (Other)
结局指标
主要结局
Overall Survival (OS)
时间窗: Randomization to death from any cause (up to 37 months)
OS was defined as the time from the date of randomization to the date of death from any cause. Participants who were alive at the end of the follow-up period or were lost to follow-up were censored on the last date the participant was known to be alive.
次要结局
- Cmax of Ramucirumab, Cycle 7(1 hour following completion of Cycle 7 (14-day cycles) infusion)
- Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)](Baseline to the date of first evidence of confirmed CR or PR (up to 37 months))
- Cmax of Ramucirumab, Cycle 4(1 hour following completion of Cycle 4 (14-day cycles) infusion)
- Number of Participants With Adverse Events (AEs) and the Number of Participants Who Died(Baseline to study completion (up to 37 months))
- Maximum Concentration (Cmax) of Ramucirumab, Cycle 1(1 hour following the completion of Cycle 1 (14-day cycle) infusion)
- Time to Radiographic Progression (TTP)(Randomization to PD (up to 36 months))
- Change From Baseline in the Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8)(Baseline, Prior to infusion on Day 1 of Cycle 4, Cycle 10, and Cycle 16 (14-day cycles), and end of treatment (up to 34 months))
- Number of Participants With Treatment Emergent Positive Anti-Ramucirumab Response [Serum Anti-Ramucirumab Antibody Assessment (Immunogenicity)](Prior to treatment and 1 hour post end of infusion for Cycles 1, 4 and 7 (14-day cycles))
- Progression-Free Survival (PFS)(Randomization to PD (up to 36 months))
- Change From Baseline in European Quality of Life Questionnaire-5 Dimensions (EQ-5D) Health State Score(Baseline, Prior to infusion on Day 1 of Cycle 4, Cycle 10, and Cycle 16 (14-day cycles), end of treatment (up to 34 months))
研究者
研究点 (146)
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