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
Condition: Hepatocellular Carcinoma
MeSH terms: Carcinoma; Carcinoma, Hepatocellular
Intervention: Placebo; Ramucirumab DP (IMC-1121B); BSC
Intervention description: 8 mg/kg IV every 2 weeks; 8 milligrams/kilogram (mg/kg) intravenous (IV) every 2 weeks; 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.
Intervention MeSH terms: Ramucirumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 565.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Hepatocellular carcinoma (HCC); recombinant human immunoglobulin G; subclass 1 (IgG1) monoclonal antibody (MAb); Hepatocellular Carcinoma (HCC) following First-Line Therapy With Sorafenib

Summary:

      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.
    

Eligibility criteria:

        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