A Study of Ramucirumab (IMC-1121B) Drug Product (DP) and Best Supportive Care (BSC) Versus Placebo and BSC as 2nd-Line Treatment in Participants With Hepatocellular Carcinoma After 1st-Line Therapy With Sorafenib
NCT ID: NCT01140347
Last Updated: 2015-12-28
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
565 participants
INTERVENTIONAL
2010-10-31
2015-03-31
Brief Summary
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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.
Detailed Description
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Conditions
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Keywords
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
DOUBLE
Study Groups
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Ramucirumab DP and BSC
Ramucirumab DP (IMC-1121B)
8 milligrams/kilogram (mg/kg) intravenous (IV) every 2 weeks
BSC
Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.
Placebo and BSC
Placebo
8 mg/kg IV every 2 weeks
BSC
Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.
Interventions
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Placebo
8 mg/kg IV every 2 weeks
Ramucirumab DP (IMC-1121B)
8 milligrams/kilogram (mg/kg) intravenous (IV) every 2 weeks
BSC
Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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
Exclusion Criteria
* 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
18 Years
ALL
No
Sponsors
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Eli Lilly and Company
INDUSTRY
Responsible Party
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Principal Investigators
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Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)
Role: STUDY_DIRECTOR
Eli Lilly and Company
Locations
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ImClone Investigational Site
Orange, California, United States
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San Francisco, California, United States
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New Haven, Connecticut, United States
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Jacksonville, Florida, United States
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New Orleans, Louisiana, United States
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Boston, Massachusetts, United States
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Worcester, Massachusetts, United States
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Ann Arbor, Michigan, United States
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St Louis, Missouri, United States
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Newark, New Jersey, United States
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New York, New York, United States
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Winston-Salem, North Carolina, United States
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Dayton, Ohio, United States
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Philadelphia, Pennsylvania, United States
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Charleston, South Carolina, United States
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Lubbock, Texas, United States
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Seattle, Washington, United States
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Milwaukee, Wisconsin, United States
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Bankstown, New South Wales, Australia
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Kogarah, New South Wales, Australia
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Liverpool Bc, New South Wales, Australia
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Kurralta Park, South Australia, Australia
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Prahran, Victoria, Australia
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Linz, , Austria
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Salzburg, , Austria
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Steyr, , Austria
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Vienna, , Austria
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Bonheiden, , Belgium
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Brussels, , Belgium
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Charleroi, , Belgium
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Edegem, , Belgium
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Leuven, , Belgium
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Liège, , Belgium
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Ottignies, , Belgium
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Belo Horizonte, , Brazil
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Botucatu, , Brazil
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Brasília, , Brazil
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Campinas, , Brazil
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Ijuí, , Brazil
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Ribeirão Preto, , Brazil
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Rio de Janeiro, , Brazil
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Salvador, , Brazil
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Sao Jose Rio Preto, , Brazil
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São Paulo, , Brazil
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Plovdiv, , Bulgaria
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Sofia, , Bulgaria
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Varna, , Bulgaria
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Ottawa, Ontario, Canada
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Brib, , Czechia
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Hradec Králové, , Czechia
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Olomouc, , Czechia
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Prague, , Czechia
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Helsinki, , Finland
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Amiens, , France
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Angers, , France
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Avignon, , France
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Besançon, , France
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Bordeaux, , France
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Clermont-Ferrand, , France
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La Roche-sur-Yon, , France
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Limoges, , France
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Marseille, , France
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Nice, , France
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Paris, , France
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Poitiers, , France
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Reims, , France
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Saint-Etienne, , France
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Berlin, , Germany
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Bielefeld, , Germany
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Bonn, , Germany
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Düsseldorf, , Germany
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Essen, , Germany
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Frankfurt, , Germany
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Freiburg im Breisgau, , Germany
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Hamburg, , Germany
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Hanover, , Germany
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Homburg, , Germany
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Leipzig, , Germany
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Magdeburg, , Germany
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Munich, , Germany
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Münster, , Germany
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Tübingen, , Germany
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Ulm, , Germany
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Weiden, , Germany
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Kowloon, , Hong Kong
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Pokfulam, , Hong Kong
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Shatin, , Hong Kong
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Budapest, , Hungary
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Beersheba, , Israel
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Petah Tikva, , Israel
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Tel Aviv, , Israel
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Bari, , Italy
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Benevento, , Italy
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Bologna, , Italy
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Genova, , Italy
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Lecce, , Italy
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Milan, , Italy
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Modena, , Italy
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Padua, , Italy
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Palermo, , Italy
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Pavia, , Italy
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Rome, , Italy
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Udine, , Italy
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Chiba, , Japan
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Fukuoka, , Japan
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Hyōgo, , Japan
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Ishikawa, , Japan
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Kanagawa, , Japan
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Kochi, , Japan
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Kyoto, , Japan
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Miyagi, , Japan
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Osaka, , Japan
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Osaka-Pref, , Japan
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Saga, , Japan
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Tochigi, , Japan
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Tokushima, , Japan
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Tokyo, , Japan
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Amsterdam, , Netherlands
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Rotterdam, , Netherlands
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Oslo, , Norway
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Quezon City, , Philippines
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Lisbon, , Portugal
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Santa Maria da Feira, , Portugal
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Bucharest, , Romania
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Cluj-Napoca, , Romania
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Craiova, , Romania
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Anyang, , South Korea
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Incheon, , South Korea
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Seodaemun-Gu, , South Korea
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Seoul, , South Korea
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Ávila, , Spain
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Girona, , Spain
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Madrid, , Spain
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Ourense, , Spain
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Valencia, , Spain
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Stockholm, , Sweden
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Bern, , Switzerland
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Changhua, , Taiwan
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Kuei Shan Hsiang, , Taiwan
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Liouying/Tainan, , Taiwan
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Niaosung, , Taiwan
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Taichung, , Taiwan
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Tainan City, , Taiwan
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Taipei, , Taiwan
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Bangkok, , Thailand
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Hat Yai, , Thailand
Countries
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References
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Llovet JM, Singal AG, Villanueva A, Finn RS, Kudo M, Galle PR, Ikeda M, Callies S, McGrath LM, Wang C, Abada P, Widau RC, Gonzalez-Gugel E, Zhu AX. Prognostic and Predictive Factors in Patients with Advanced HCC and Elevated Alpha-Fetoprotein Treated with Ramucirumab in Two Randomized Phase III Trials. Clin Cancer Res. 2022 Jun 1;28(11):2297-2305. doi: 10.1158/1078-0432.CCR-21-4000.
Mitani S, Chen Y, Inoue K, Mori J, Gao L, Long A, Wakabayashi S. Clinical Impact of a Shortened Infusion Duration of Ramucirumab in Japanese Patients -A Model-Based Approach. Gan To Kagaku Ryoho. 2021 Nov;48(11):1381-1387.
Zhu AX, Finn RS, Kang YK, Yen CJ, Galle PR, Llovet JM, Assenat E, Brandi G, Motomura K, Ohno I, Daniele B, Vogel A, Yamashita T, Hsu CH, Gerken G, Bilbruck J, Hsu Y, Liang K, Widau RC, Wang C, Abada P, Kudo M. Serum alpha-fetoprotein and clinical outcomes in patients with advanced hepatocellular carcinoma treated with ramucirumab. Br J Cancer. 2021 Apr;124(8):1388-1397. doi: 10.1038/s41416-021-01260-w. Epub 2021 Feb 3.
Reig M, Galle PR, Kudo M, Finn R, Llovet JM, Metti AL, Schelman WR, Liang K, Wang C, Widau RC, Abada P, Zhu AX. Pattern of progression in advanced hepatocellular carcinoma treated with ramucirumab. Liver Int. 2021 Mar;41(3):598-607. doi: 10.1111/liv.14731. Epub 2020 Dec 5.
Zhu AX, Nipp RD, Finn RS, Galle PR, Llovet JM, Blanc JF, Okusaka T, Chau I, Cella D, Girvan A, Gable J, Bowman L, Wang C, Hsu Y, Abada PB, Kudo M. Ramucirumab in the second-line for patients with hepatocellular carcinoma and elevated alpha-fetoprotein: patient-reported outcomes across two randomised clinical trials. ESMO Open. 2020 Aug;5(4):e000797. doi: 10.1136/esmoopen-2020-000797.
Kudo M, Okusaka T, Motomura K, Ohno I, Morimoto M, Seo S, Wada Y, Sato S, Yamashita T, Furukawa M, Aramaki T, Nadano S, Ohkawa K, Fujii H, Kudo T, Furuse J, Takai H, Homma G, Yoshikawa R, Zhu AX. Ramucirumab after prior sorafenib in patients with advanced hepatocellular carcinoma and elevated alpha-fetoprotein: Japanese subgroup analysis of the REACH-2 trial. J Gastroenterol. 2020 Jun;55(6):627-639. doi: 10.1007/s00535-020-01668-w. Epub 2020 Feb 27.
Arnold D, Fuchs CS, Tabernero J, Ohtsu A, Zhu AX, Garon EB, Mackey JR, Paz-Ares L, Baron AD, Okusaka T, Yoshino T, Yoon HH, Das M, Ferry D, Zhang Y, Lin Y, Binder P, Sashegyi A, Chau I. Meta-analysis of individual patient safety data from six randomized, placebo-controlled trials with the antiangiogenic VEGFR2-binding monoclonal antibody ramucirumab. Ann Oncol. 2017 Dec 1;28(12):2932-2942. doi: 10.1093/annonc/mdx514.
Chau I, Peck-Radosavljevic M, Borg C, Malfertheiner P, Seitz JF, Park JO, Ryoo BY, Yen CJ, Kudo M, Poon R, Pastorelli D, Blanc JF, Chung HC, Baron AD, Okusaka T, Bowman L, Cui ZL, Girvan AC, Abada PB, Yang L, Zhu AX. Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib: Patient-focused outcome results from the randomised phase III REACH study. Eur J Cancer. 2017 Aug;81:17-25. doi: 10.1016/j.ejca.2017.05.001. Epub 2017 Jun 4.
Zhu AX, Baron AD, Malfertheiner P, Kudo M, Kawazoe S, Pezet D, Weissinger F, Brandi G, Barone CA, Okusaka T, Wada Y, Park JO, Ryoo BY, Cho JY, Chung HC, Li CP, Yen CJ, Lee KD, Chang SC, Yang L, Abada PB, Chau I. Ramucirumab as Second-Line Treatment in Patients With Advanced Hepatocellular Carcinoma: Analysis of REACH Trial Results by Child-Pugh Score. JAMA Oncol. 2017 Feb 1;3(2):235-243. doi: 10.1001/jamaoncol.2016.4115.
Kudo M, Hatano E, Ohkawa S, Fujii H, Masumoto A, Furuse J, Wada Y, Ishii H, Obi S, Kaneko S, Kawazoe S, Yokosuka O, Ikeda M, Ukai K, Morita S, Tsuji A, Kudo T, Shimada M, Osaki Y, Tateishi R, Sugiyama G, Abada PB, Yang L, Okusaka T, Zhu AX. Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma: Japanese subgroup analysis of the REACH trial. J Gastroenterol. 2017 Apr;52(4):494-503. doi: 10.1007/s00535-016-1247-4. Epub 2016 Aug 22.
Zhu AX, Park JO, Ryoo BY, Yen CJ, Poon R, Pastorelli D, Blanc JF, Chung HC, Baron AD, Pfiffer TE, Okusaka T, Kubackova K, Trojan J, Sastre J, Chau I, Chang SC, Abada PB, Yang L, Schwartz JD, Kudo M; REACH Trial Investigators. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2015 Jul;16(7):859-70. doi: 10.1016/S1470-2045(15)00050-9. Epub 2015 Jun 18.
Other Identifiers
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CP12-0919
Identifier Type: OTHER
Identifier Source: secondary_id
I4T-IE-JVBF
Identifier Type: OTHER
Identifier Source: secondary_id
2010-019318-26
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
13895
Identifier Type: -
Identifier Source: org_study_id