A Study of Ramucirumab (IMC-1121B) Drug Product (DP) and Best Supportive Care (BSC) Versus Placebo and BSC as 2nd-Line Treatment in Patients With Hepatocellular Carcinoma After 1st-Line Therapy With Sorafenib (REACH)

• Progression-free survival (PFS) [ Time Frame: Approximately 43 months ] [ Designated as safety issue: No ]
• Objective response rate (ORR) [ Time Frame: Approximately 43 months ] [ Designated as safety issue: No ]
• Time to radiographic progression [ Time Frame: Approximately 43 months ] [ Designated as safety issue: No ]
• Change in the Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8) [ Time Frame: Approximately 43 months ] [ Designated as safety issue: No ]
• Change in EuroQol EQ-5D, change from baseline in the patient reported outcomes measured at the end of therapy visit [ Time Frame: Approximately 43 months ] [ Designated as safety issue: No ]
• Number of Participants with Adverse Events (AEs) [ Time Frame: Approximately 43 months ] [ Designated as safety issue: Yes ]
• Maximum concentration (Cmax) cycle 1 [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
• Maximum concentration (Cmax) cycle 4 [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
• Maximum concentration (Cmax) cycle 7 [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
• Circulating levels of Vascular Endothelial Growth Factor (VEGF) [ Time Frame: Approximately 43 months ] [ Designated as safety issue: No ]
• Circulating levels of Vascular Endothelial Growth Factor Receptor-1 (VEGFR-1) [ Time Frame: Approximately 43 months ] [ Designated as safety issue: No ]
• Circulating levels of Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) [ Time Frame: Approximately 43 months ] [ Designated as safety issue: No ]
• Serum Anti-ramucirumab Antibody Assessment (Immunogenicity) [ Time Frame: Approximately 43 months ] [ Designated as safety issue: Yes ]

• Measure Progression-free survival (PFS) [ Time Frame: 27 months ] [ Designated as safety issue: No ]
• Best objective response rate (ORR) [ Time Frame: 27 months ] [ Designated as safety issue: No ]
• Time to radiographic progression [ Time Frame: 27 months ] [ Designated as safety issue: No ]
• Patient-reported outcome (PRO) measures of disease-specific symptoms and health-related quality of life [ Time Frame: 27 months ] [ Designated as safety issue: No ]
• Safety profile of ramucirumab DP determined by the incidence and percentage of patients with at least 1 occurrence of an adverse event during the trial as summarized by MedDRA System Organ Class and preferred terms. [ Time Frame: 27 months ] [ Designated as safety issue: Yes ]
  Patients who receive any quantity of ramucirumab DP are considered evaluable for safety.
• Ramucirumab serum concentrations [ Time Frame: 27 months ] [ Designated as safety issue: No ]
  Prior to and approx 1 hr after 1st infusion at Cycle 1, prior to and approx 1 hr after infusion at Cycle 4 (approx 6 wks after 1st infusion at Cycle 1) and prior to and approx 1 hr after infusion at Cycle 7 (approx 12 wks after 1st infusion at Cycle 1)
• Pharmacodynamics of ramucirumab to determine circulating serum levels of markers [ Time Frame: 27 months ] [ Designated as safety issue: No ]
  Markers may include but not limited to VEGF, soluble VEGFR-1, and soluble VEGFR-21
• Assessment of antibodies against ramucirumab for all patients [ Time Frame: 27 months ] [ Designated as safety issue: Yes ]

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 patients, at least 18 years of age, with Child-Pugh score < 7 and diagnosed with hepatocellular carcinoma will be randomized. Patients must have received sorafenib as first-line systemic treatment for HCC, and must have discontinued sorafenib prior to entering the study.

Hypothesis: This sample size will allow differentiation of the expected increase in median OS, from 8 months in the placebo arm to 10.67 months in the ramucirumab arm.

Upon registration and completion of screening procedures, eligible patients 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 patient, or investigator decision.

• Biological: Placebo
  8 mg/kg I.V. infusion every 2 weeks
• Biological: Ramucirumab DP (IMC-1121B)
  8 mg/kg I.V. every 2 weeks
  Other Names:

  • IMC-1121B
  • LY3009806

• Experimental: Ramucirumab DP
  Ramucirumab DP (IMC-1121B)
  Intervention: Biological: Ramucirumab DP (IMC-1121B)
• Placebo Comparator: Placebo
  Placebo
  Intervention: Biological: Placebo

Inclusion criteria:

• Eastern Cooperative Oncology Group Performance Status 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 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 (ie, 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. patients 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 patient 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 (eg, bone) following sorafenib therapy is permitted.
• Resolution of clinically significant toxicity of any anti cancer therapy to grade ≤ 1 by the NCI-CTCAE v. 4.0

Adequate Organ Function defined as:

• Total bilirubin < 3.0 mg/dL (51.3 µmol/L), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 × ULN
• Serum creatinine ≤ 1.2 × ULN or calculated creatinine clearance > 50 mL/minute
• Absolute neutrophil count (ANC) ≥ 1.0 × 10^3/μL (1.0 × 10^9/L), hemoglobin ≥ 9 g/dL (5.58 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. Patients receiving prophylactic low-dose anticoagulant therapy are eligible provided that INR ≤ 1.5 and PTT ≤ 5 seconds above the upper limit of normal (ULN)
• The patient'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 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 (eg, 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. Patients 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 upper limit of normal [ULN]) are met
• Receiving ongoing therapy with nonsteroidal anti-inflammatory agents (NSAIDs, eg, indomethacin, ibuprofen, naproxen, nimesulide, celecoxib, etoricoxib, or similar agents) or other antiplatelet agents (eg, clopidogrel, ticlopidine, prasugrel, dipyridamole, picotamide, indobufen, anagrelide, triflusal).Aspirin (ASA) at doses up to 100 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 ≥ 150 / ≥ 90 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 (patients 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 (eg, banding, sclerotherapy) or represent a high bleeding risk. Patients 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. Patients 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 patients must receive supportive therapy (eg, 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