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 (REACH)

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)

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.

Study Overview

• Status: Completed
• Conditions: Hepatocellular Carcinoma
• Intervention / Treatment: Biological: Ramucirumab DP (IMC-1121B); Other: BSC; Biological: Placebo

• Study Type: Interventional
• Enrollment (Actual): 565
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Bankstown, New South Wales, Australia, 2200
      • ImClone Investigational Site
    • Kogarah, New South Wales, Australia, 2217
      • ImClone Investigational Site
    • Liverpool Bc, New South Wales, Australia, 1871
      • ImClone Investigational Site
  • South Australia
    • Kurralta Park, South Australia, Australia, 5037
      • ImClone Investigational Site
  • Victoria
    • Prahran, Victoria, Australia, 3181
      • ImClone Investigational Site
• Austria
  • Linz, Austria, 4021
    • ImClone Investigational Site
  • Salzburg, Austria, 5020
    • ImClone Investigational Site
  • Steyr, Austria, 4400
    • ImClone Investigational Site
  • Vienna, Austria, A1090
    • ImClone Investigational Site
• Belgium
  • Bonheiden, Belgium, 2820
    • ImClone Investigational Site
  • Brussels, Belgium, 01200
    • ImClone Investigational Site
  • Charleroi, Belgium, 6000
    • ImClone Investigational Site
  • Edegem, Belgium, 2650
    • ImClone Investigational Site
  • Leuven, Belgium, 03000
    • ImClone Investigational Site
  • Liège, Belgium, 4000
    • ImClone Investigational Site
  • Ottignies, Belgium, 1340
    • ImClone Investigational Site
• Brazil
  • Belo Horizonte, Brazil, 30110090
    • ImClone Investigational Site
  • Botucatu, Brazil, 18618-970
    • ImClone Investigational Site
  • Brasilia, Brazil, 72115-700
    • ImClone Investigational Site
  • Campinas, Brazil, 13083-970
    • ImClone Investigational Site
  • Ijui, Brazil, 98700 000
    • ImClone Investigational Site
  • Ribeirao Preto, Brazil, 14049-900
    • ImClone Investigational Site
  • Rio De Janeiro, Brazil, 21941-31
    • ImClone Investigational Site
  • Salvador, Brazil, 41825-010
    • ImClone Investigational Site
  • Sao Jose Rio Preto, Brazil, 15090-000
    • ImClone Investigational Site
  • São Paulo, Brazil, 04039-901
    • ImClone Investigational Site
• Bulgaria
  • Plovdiv, Bulgaria, 4004
    • ImClone Investigational Site
  • Sofia, Bulgaria, 1527
    • ImClone Investigational Site
  • Varna, Bulgaria, 9010
    • ImClone Investigational Site
• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • ImClone Investigational Site
• Czech Republic
  • Brib, Czech Republic, 656 53
    • ImClone Investigational Site
  • Hradec Kralove, Czech Republic, 500 05
    • ImClone Investigational Site
  • Olomouc, Czech Republic, 775 20
    • ImClone Investigational Site
  • Prague, Czech Republic, 150 06
    • ImClone Investigational Site
• Finland
  • Helsinki, Finland, 180
    • ImClone Investigational Site
• France
  • Amiens, France, 80054
    • ImClone Investigational Site
  • Angers, France, 49933
    • ImClone Investigational Site
  • Avignon, France, 84000
    • ImClone Investigational Site
  • Besancon, France, 25020
    • ImClone Investigational Site
  • Bordeaux, France, 33000
    • ImClone Investigational Site
  • Clermont-Ferrand, France, 63003
    • ImClone Investigational Site
  • La Roche Sur Yon, France, 85925
    • ImClone Investigational Site
  • Limoges, France, 87042
    • ImClone Investigational Site
  • Marseille, France, 13385
    • ImClone Investigational Site
  • Nice, France, 06200
    • ImClone Investigational Site
  • Paris, France, 75674
    • ImClone Investigational Site
  • Poitiers, France, 86021
    • ImClone Investigational Site
  • Reims, France, 51092
    • ImClone Investigational Site
  • Saint-Etienne, France, 42055
    • ImClone Investigational Site
• Germany
  • Berlin, Germany, 12203
    • ImClone Investigational Site
  • Bielefeld, Germany, 33611
    • ImClone Investigational Site
  • Bonn, Germany, 53105
    • ImClone Investigational Site
  • Düsseldorf, Germany, 40225
    • ImClone Investigational Site
  • Essen, Germany, 45122
    • ImClone Investigational Site
  • Frankfurt, Germany, 60596
    • ImClone Investigational Site
  • Freiburg, Germany, 79106
    • ImClone Investigational Site
  • Hamburg, Germany, 20246
    • ImClone Investigational Site
  • Hannover, Germany, 30625
    • ImClone Investigational Site
  • Homburg, Germany, 66421
    • ImClone Investigational Site
  • Leipzig, Germany, 04103
    • ImClone Investigational Site
  • Magdeburg, Germany, 39120
    • ImClone Investigational Site
  • Munich, Germany, 81377
    • ImClone Investigational Site
  • Münster, Germany, 48149
    • ImClone Investigational Site
  • Tübingen, Germany, 72076
    • ImClone Investigational Site
  • Ulm, Germany, 89081
    • ImClone Investigational Site
  • Weiden, Germany, 92637
    • ImClone Investigational Site
• Hong Kong
  • Kowloon, Hong Kong
    • ImClone Investigational Site
  • Pokfulam, Hong Kong
    • ImClone Investigational Site
  • Shatin, Hong Kong
    • ImClone Investigational Site
• Hungary
  • Budapest, Hungary, 1122
    • ImClone Investigational Site
• Israel
  • Beer Sheva, Israel, 84101
    • ImClone Investigational Site
  • Petah Tiqva, Israel, 49100
    • ImClone Investigational Site
  • Tel Aviv, Israel, 64239
    • ImClone Investigational Site
• Italy
  • Bari, Italy, 70124
    • ImClone Investigational Site
  • Benevento, Italy, 82100
    • ImClone Investigational Site
  • Bologna, Italy, 40100
    • ImClone Investigational Site
  • Genova, Italy, 16132
    • ImClone Investigational Site
  • Lecce, Italy, 73100
    • ImClone Investigational Site
  • Milano, Italy, 20122
    • ImClone Investigational Site
  • Modena, Italy, 41100
    • ImClone Investigational Site
  • Padova, Italy, 35128
    • ImClone Investigational Site
  • Palermo, Italy, 90127
    • ImClone Investigational Site
  • Pavia, Italy, 27100
    • ImClone Investigational Site
  • Rome, Italy, 00168
    • ImClone Investigational Site
  • Udine, Italy, 33100
    • ImClone Investigational Site
• Japan
  • Chiba, Japan, 260-8677
    • ImClone Investigational Site
  • Fukuoka, Japan, 810-8563
    • ImClone Investigational Site
  • Hyogo, Japan, 650-0046
    • ImClone Investigational Site
  • Ishikawa, Japan, 920-8641
    • ImClone Investigational Site
  • Kanagawa, Japan, 241-0815
    • ImClone Investigational Site
  • Kochi, Japan, 781-8555
    • ImClone Investigational Site
  • Kyoto, Japan, 606-8397
    • ImClone Investigational Site
  • Miyagi, Japan, 983-8520
    • ImClone Investigational Site
  • Osaka, Japan, 565-0871
    • ImClone Investigational Site
  • Osaka-Pref, Japan, 589
    • ImClone Investigational Site
  • Saga, Japan, 840
    • ImClone Investigational Site
  • Tochigi, Japan, 329-0498
    • ImClone Investigational Site
  • Tokushima, Japan, 770-8503
    • ImClone Investigational Site
  • Tokyo, Japan, 181-8611
    • ImClone Investigational Site
• Korea, Republic of
  • Anyang, Korea, Republic of, 431-070
    • ImClone Investigational Site
  • Incheon, Korea, Republic of, 405-760
    • ImClone Investigational Site
  • Seodaemun-Gu, Korea, Republic of, 120-752
    • ImClone Investigational Site
  • Seoul, Korea, Republic of, 135-710
    • ImClone Investigational Site
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • ImClone Investigational Site
  • Rotterdam, Netherlands, 3000 CA
    • ImClone Investigational Site
• Norway
  • Oslo, Norway, 0407
    • ImClone Investigational Site
• Philippines
  • Quezon City, Philippines, 1102
    • ImClone Investigational Site
• Portugal
  • Lisbon, Portugal, 1649-035
    • ImClone Investigational Site
  • Santa Maria Da Feira, Portugal, 4520-211
    • ImClone Investigational Site
• Romania
  • Bucharest, Romania, 022328
    • ImClone Investigational Site
  • Cluj-Napoca, Romania, 3400
    • ImClone Investigational Site
  • Craiova, Romania, 200535
    • ImClone Investigational Site
• Spain
  • Avila, Spain, 05004
    • ImClone Investigational Site
  • Girona, Spain, 17007
    • ImClone Investigational Site
  • Madrid, Spain, 28041
    • ImClone Investigational Site
  • Ourense, Spain, 320004
    • ImClone Investigational Site
  • Valencia, Spain, 46014
    • ImClone Investigational Site
• Sweden
  • Stockholm, Sweden, 14186
    • ImClone Investigational Site
• Switzerland
  • Bern, Switzerland, CH-3010
    • ImClone Investigational Site
• Taiwan
  • Changhua, Taiwan, 500
    • ImClone Investigational Site
  • Kuei Shan Hsiang, Taiwan, 33305
    • ImClone Investigational Site
  • Liouying/Tainan, Taiwan, 736
    • ImClone Investigational Site
  • Niaosung, Taiwan, 883
    • ImClone Investigational Site
  • Taichung, Taiwan, 404
    • ImClone Investigational Site
  • Tainan, Taiwan, 70403
    • ImClone Investigational Site
  • Taipei, Taiwan, 112
    • ImClone Investigational Site
• Thailand
  • Bangkok, Thailand, 10700
    • ImClone Investigational Site
  • Hat Yai, Thailand, 90110
    • ImClone Investigational Site
• United States
  • California
    • Orange, California, United States, 92868
      • ImClone Investigational Site
    • San Francisco, California, United States, 94115
      • ImClone Investigational Site
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • ImClone Investigational Site
  • Florida
    • Jacksonville, Florida, United States, 32207
      • ImClone Investigational Site
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • ImClone Investigational Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • ImClone Investigational Site
    • Worcester, Massachusetts, United States, 01655
      • ImClone Investigational Site
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • ImClone Investigational Site
  • Missouri
    • St Louis, Missouri, United States, 63110
      • ImClone Investigational Site
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • ImClone Investigational Site
  • New York
    • New York, New York, United States, 10029
      • ImClone Investigational Site
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • ImClone Investigational Site
  • Ohio
    • Dayton, Ohio, United States, 45420
      • ImClone Investigational Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19141
      • ImClone Investigational Site
  • South Carolina
    • Charleston, South Carolina, United States, 29414
      • ImClone Investigational Site
  • Texas
    • Lubbock, Texas, United States, 79415
      • ImClone Investigational Site
  • Washington
    • Seattle, Washington, United States, 98109
      • ImClone Investigational Site
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • ImClone Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• 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

Exclusion criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ramucirumab DP and BSC	Biological: Ramucirumab DP (IMC-1121B); 8 milligrams/kilogram (mg/kg) intravenous (IV) every 2 weeks; Other Names: LY3009806; IMC-1121B; Other: 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 Comparator: Placebo and BSC	Other: 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.; Biological: Placebo; 8 mg/kg IV every 2 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	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.	Randomization to death from any cause (up to 37 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	PFS was defined as time from date of randomization until date of objectively determined progressive disease (PD) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 or death from any cause. PD was defined as ≥20% increase in sum of diameters (SOD) of target lesions, taking as reference smallest sum on study (including baseline sum if it was smallest). Sum must show a ≥5 millimeter (mm) increase. Appearance of ≥1 new lesions and unequivocal progression of existing non-target lesions were considered progression. In primary analysis, participants alive and without PD were censored at day of last adequate tumor assessment; progression or deaths without progression occurring immediately after ≥2 missed tumor assessments, were censored at day of the last adequate tumor assessment prior to missing assessments; participants who began new anticancer therapy were censored at day of the last adequate tumor assessment prior to start of new anticancer therapy.	Randomization to PD (up to 36 months)
Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)]	ORR was defined, using RECIST v1.1 criteria, as the percentage of participants who achieved a best overall response of CR or PR. CR was defined as the disappearance of all lesions and any intratumor arterial enhancement in target lesions, the normalization of the tumor marker level and all lymph nodes short axis reduced to <10 mm. PR was defined as ≥30% decrease in the SOD of target lesions, including the short axes of any target lymph nodes, taking as reference the baseline SOD of target lesions, no new lesions and stable nontarget lesions. Percentage of participants was calculated as: (number of participants with CR or PR / number of participants randomized) * 100.	Baseline to the date of first evidence of confirmed CR or PR (up to 37 months)
Time to Radiographic Progression (TTP)	TTP was defined as the time from randomization to the first radiographically documented PD. PD was defined, using RECIST v1.1 criteria, as ≥20% increase in SOD of target lesions, taking as reference smallest sum on study (including baseline sum if it was the smallest). Sum must show an absolute increase of ≥5 mm. Appearance of ≥1 new lesions and unequivocal progression of existing non-target lesions were considered progression. Participants without PD were censored at the day of the last adequate tumor assessment. Progression occurred immediately after ≥2 missed tumor assessments and were censored at the day of the last adequate tumor assessment prior to the missing assessments. Participants who began new anticancer therapy were censored at the day of their last adequate tumor assessment prior to start of new anticancer therapy.	Randomization to PD (up to 36 months)
Change From Baseline in the Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8)	The FHSI-8 is a self-administered 8-item questionnaire that measures a participant's symptoms in the domains of jaundice, stomach pain/discomfort weight loss, and fatigue. Participants rated each item on a 5-point scale from 0 (not at all) to 4 (very much). Item scores were calculated as outlined in the FACIT manual. FHSI-8 total score was the sum of each item's score with a total score ranging from 0 (highly symptomatic) to 32 (asymptomatic).	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)
Change From Baseline in European Quality of Life Questionnaire-5 Dimensions (EQ-5D) Health State Score	The EQ-5D is a self-reported, 5-dimension (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) questionnaire related to the participant's current health state. Each question was scored using a 3 level scale (no problems, some problems, or extreme problems). EQ-5D health state was defined by combining responses from each of the 5 dimensions into a weighted health-state index score according to the United Kingdom (UK) population based algorithm where 0 = death and 1 = perfect health.	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)
Number of Participants With Adverse Events (AEs) and the Number of Participants Who Died	The number of participants with serious AEs (SAEs), other non-serious AEs and participants who died. A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.	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
Cmax of Ramucirumab, Cycle 4		1 hour following completion of Cycle 4 (14-day cycles) infusion
Cmax of Ramucirumab, Cycle 7		1 hour following completion of Cycle 7 (14-day cycles) infusion
Number of Participants With Treatment Emergent Positive Anti-Ramucirumab Response [Serum Anti-Ramucirumab Antibody Assessment (Immunogenicity)]	Participants were considered positive for anti-ramucirumab antibodies [anti-drug antibodies (ADA)] if the post-treatment sample had an increase of at least 4-fold in titer from the pretreatment values. If the pretreatment value was not detected or was not present, a 1:20 post-treatment titer was required to indicate treatment emergence of ADA.	Prior to treatment and 1 hour post end of infusion for Cycles 1, 4 and 7 (14-day cycles)

Collaborators and Investigators

• Sponsor: Eli Lilly and Company

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
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Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (Actual): March 1, 2014
• Study Completion (Actual): March 1, 2015

Study Registration Dates

• First Submitted: June 2, 2010
• First Submitted That Met QC Criteria: June 8, 2010
• First Posted (Estimate): June 9, 2010

Study Record Updates

• Last Update Posted (Estimate): December 28, 2015
• Last Update Submitted That Met QC Criteria: November 24, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Keywords: Hepatocellular carcinoma (HCC); recombinant human immunoglobulin G; subclass 1 (IgG1) monoclonal antibody (MAb); Hepatocellular Carcinoma (HCC) following First-Line Therapy With Sorafenib
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Antineoplastic Agents; Ramucirumab
• Other Study ID Numbers: 13895; CP12-0919 (Other Identifier: ImClone Systems); I4T-IE-JVBF (Other Identifier: Eli Lilly and Company); 2010-019318-26 (EudraCT Number)