Hepatocellular Carcinoma

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 will be randomized and will be at least 18 years of age with HCC. Patients must have received sorafenib as first-line systemic treatment for HCC, and must have discontinued sorafenib prior to entering the study.

Ramucirumab (IMC-1121B)

Ramucirumab (IMC-1121B)

I.V. infusion 8 mg/kg

500mg/50ml

Efficacy Assessments:
Efficacy: Overall survival, PFS, ORR, time to radiographic progression, and PRO assessments.
Tumor measurements: By CT scan or equivalent and assessed according to Response Evaluation
Criteria in Solid Tumors, Version 1.1 (RECIST v 1.1). Despite any treatment delays, the imaging studies must be collected approximately every 6 weeks (± 3 days) after first dose for the first 6 months, and every 9 weeks (± 3 days) thereafter.
Survival follow-up: After discontinuation of study therapy, every 2 months ± 7 days for as long as the patient is alive. (Survival follow-up will not be conducted for patients on the extension phase of the study.)
Safety Assessments:
Safety will be evaluated using the NCI-CTCAE v 4.0.
Safety: Adverse events (AEs), serious adverse events (SAEs), physical examinations, vital sign measurements, clinical laboratory evaluations, and treatment discontinuation due to toxicity.

Inclusion and Exclusion Criteria:
Each patient must meet the following criteria to be enrolled in this study:
1. The patient has provided signed informed consent and is amenable to compliance with protocol schedules and testing.
2. The patient is at least 18 years of age or of an acceptable age according to local regulations,whichever is older.
3. The patient has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of
0 or 1.
4. The patient has a Child-Pugh score of < 9 (Child-Pugh A or B [B7 or B8]).
5. The patient has a Barcelona Clinic Liver Cancer (BCLC) stage C at randomization. A patient with BCLC stage B may be eligible if he/she has disease that is not amenable to locoregional therapy or is refractory to locoregional therapy (examples include very large or diffusely infiltrative tumors and intrahepatic tumors that are refractory to transarterial chemoembolization [TACE] or not amenable to TACE).
6. The patient has a diagnosis of HCC (excluding fibrolamellar carcinoma) based on
histopathologic or cytologic findings; or in the absence of histologic confirmation, each of the following is present (at the time of study entry):
a. There are any clinical, laboratory, or radiographic findings consistent with a diagnosis ofliver cirrhosis.
b. The patient has a liver mass measuring at least 2 cm with characteristic vascularization
(intense inhomogeneous enhancement seen in the hepatic arterial-dominant phase and
contrast washout in the late portal venous phase) seen on either triphasic computed
tomography (CT) scan or magnetic resonance imaging (MRI) with gadolinium.
7. The patient has at least one 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.
8. The patient has previously been treated with sorafenib and has discontinued sorafenib
treatment at least 14 days prior to randomization. This will include patients who have
experienced:
a. Radiographically documented disease progression during sorafenib therapy or after
discontinuation of sorafenib therapy, or
b. Discontinuation of sorafenib due to an adverse drug reaction (fatigue, hand-foot
syndrome, desquamation/rash, diarrhea, reversible liver dysfunction, abdominal pain,
anorexia, or leukopenia), despite dose reduction by 1 to 2 levels and BSC.
9. The patient has received sorafenib as the only systemic therapeutic intervention for advanced
HCC as defined in inclusion criterion #5. Any hepatic locoregional therapy (including
radiation, surgery, hepatic arterial embolization, chemoembolization, radiofrequency ablation, cryoablation, percutaneous ethanol injection) that has been administered prior to sorafenib is allowed, but not following sorafenib. Radiation to metastatic sites (eg, bone) following sorafenib therapy is permitted.
10. Except where otherwise noted in the eligibility criteria, the patient has resolution to Grade ≤ 1 by the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI-CTCAE v 4.0) of all clinically significant toxic effects of prior locoregional therapy, surgery, chemoembolization, or sorafenib.
11. The patient has adequate organ function defined as:
a. Total bilirubin < 3.0 mg/dL (51.3 μmol/L), aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) ≤ 5 × the institutional upper limit of normal (ULN);
b. Serum creatinine ≤ 1.2 × ULN or calculated creatinine clearance > 50 mL/minute;
c. Absolute neutrophil count (ANC) ≥ 1.0 × 103/μL (1.0 × 109/L), hemoglobin ≥ 9 g/dL
(5.58 mmol/L; packed red blood cell transfusions are not permitted within one week prior
to baseline hematology profile), and platelets ≥ 75 × 103/μL (75 × 109/L);
d. 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.
12. 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.
13. The patient, if female, is surgically sterile, postmenopausal, or compliant with a highly effective contraceptive method (failure rate < 1%) during and for 12 weeks after the treatment period (oral hormonal contraception alone is not considered highly effective and must be used in combination with a barrier method). If male, the patient is surgically sterile or compliant with a highly effective contraceptive regimen during and for 12 weeks after the treatment period. (The requirements with regard to the methods and duration of contraception during and after treatment may differ between countries. Country-specific requirements will apply only if they are more stringent than those already stipulated in the protocol).
14. Female patients of childbearing potential must have a negative serum pregnancy test within 7 days prior to randomization. Patients who meet any of the following criteria will be excluded from the study:
1. The patient has undergone major surgery within 28 days prior to randomization, or has
undergone central venous access device placement within 7 days prior to randomization.
2. The patient has undergone hepatic locoregional therapy (including radiation, surgery, hepatic arterial embolization, chemoembolization, radiofrequency ablation, cryoablation, or
percutaneous ethanol injection) within 28 days prior to randomization.
3. The patient has undergone radiation to any nonhepatic (eg, bone) site within 14 days prior to
randomization.
4. The patient has received sorafenib within 14 days prior to randomization.
5. The patient has received any investigational therapy or non-approved drug within 28 days
prior to randomization or is concurrently enrolled in any other type of medical research judged
not to be scientifically or medically compatible with this study.
6. The patient has 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.
7. The patient has fibrolamellar carcinoma.
8. The patient has received any transfusion, blood component preparation, erythropoietin,
albumin preparation, or granulocyte colony-stimulating factors (G-CSF) within 14 days prior
to randomization.
9. The patient is receiving 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) are met.
10. The patient is 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.
11. The patient has symptomatic congestive heart failure, unstable angina pectoris, or
symptomatic or poorly controlled cardiac arrhythmia.
12. The patient has experienced any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to randomization.
13. The patient has uncontrolled arterial hypertension ≥ 150 / ≥ 90 mm Hg despite standard
medical management.
14. The patient has experienced any 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).
15. The patient has esophageal or gastric varices that require immediate intervention (eg, banding, sclerotherapy) or represent a high bleeding risk in the opinion of the investigator or consulting gastroenterologist or hepatologist. 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 (as defined in previous sentence) 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. Additional endoscopic assessments during study participation should be performed at the discretion of the consulting gastroenterologist or hepatologist, as clinically indicated.
16. The patient has central nervous system (CNS) metastases or carcinomatous meningitis.
17. The patient has a serious illness or medical condition(s), including but not limited to the
following:
a. Known human immunodeficiency virus (HIV) infection or acquired immunodeficiency
syndrome (AIDS)-related illness;
b. Active or uncontrolled clinically serious infection (patients with chronic viral hepatitis are
eligible);
c. Clinical signs of acute hepatitis;
d Other acute or chronic medical or psychiatric condition or laboratory abnormality that
may increase the risk associated with study participation or study therapy administration,
or may interfere with the interpretation of study results, and in the judgment of the
investigator would make the patient ineligible for entry into this study;
e. Uncontrolled thrombotic or hemorrhagic disorder;
f. Elective or planned major surgery to be performed during the course of the clinical trial;
g. Serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to
randomization;
h. Known allergy or hypersensitivity to MAb treatment or any components used in the
ramucirumab DP preparation;
i. Any other serious uncontrolled medical disorders in the opinion of the investigator.
18. The patient is pregnant (confirmed by serum beta human chorionic gonadotropin [β-HCG]
test) or lactating.
19. The patient has a previous or concurrent malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumors treated curatively, and is with evidence of recurrence for at least 2 years prior to randomization.
20. The patient has had a prior liver transplant.
21. The patient has ascites or encephalopathy refractory to medical management.
22. The patient is participating in another interventional clinical trial. Patients participating in surveys or observational studies are eligible to participate in this study.