E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019828 |
E.1.2 | Term | Hepatocellular carcinoma non-resectable |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to compare the overall survival (OS; time from randomization to death) in patients with hepatocellular carcinoma (HCC) who had disease progression during or following sorafenib therapy, or were intolerant to this agent. Patients will receive either ramucirumab (IMC-1121B) drug product (hereafter referred to as ramucirumab DP) plus best supportive care (BSC) or placebo plus BSC. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are to evaluate: Progression-free survival (PFS) Best objective response rate (ORR) Time to radiographic progression Patient-reported outcome (PRO) measures of disease-specific symptoms and health-related quality of life Safety profile of ramucirumab DP Ramucirumab serum concentrations Pharmacodynamics of ramucirumab Immunogenicity of ramucirumab |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
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. 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, all of the following are present (at the time of study entry): a. There are either clinical, laboratory, or radiographic findings consistent with a diagnosis of liver 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, c. The patient has a serum alpha-fetoprotein (AFP) concentration greater than the institutional upper limit of normal (ULN). 7. The patient has 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. 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 level and BSC. 9. The patient has received sorafenib as the most recent systemic therapeutic intervention. 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. The patient has resolution to Grade ≤ 1 by the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.02 (NCI-CTCAE v 4.02) of all clinically significant toxic effects of prior locoregional therapy, surgery, chemoembolization, or other anticancer therapy, including 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 × ULN; b. Serum creatinine ≤ 1.2 × ULN or calculated creatinine clearance > 50 mL/minute; c. Absolute neutrophil count (ANC) ≥ 1.0 × 10 exp3/μL (1.0 × 10 exp9/L), hemoglobin ≥ 9 g/dL (5.58 mmol/L), and platelets ≥ 75 × 10 exp3/μL (75 × 10 exp9/L); d. International Normalized Ratio (INR) ≤ 1.5. 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 sexually active, is postmenopausal, surgically sterile, or using effective contraception (hormonal or barrier methods). 14. Female patients of childbearing potential must have a negative serum pregnancy test within 7 days prior to randomization. |
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E.4 | Principal exclusion criteria |
1. The patient (P) has undergone major surgery within 28 days prior to randomization, or subcutaneous venous access device placement within 7 days prior to randomization. 2. Hepatic locoregional therapy (including radiation, surgery, hepatic arterial embolization, chemoembolization, radiofrequency ablation, cryoablation, or percutaneous ethanol injection) within 28 days prior to randomization 3. Radiation to any nonhepatic site within 14 days prior to randomization 4. Sorafenib within 14 days prior to randomization 5. Any investigational therapy within 28 days prior to randomization 6. Any previous systemic therapy with vascular endothelial growth factor inhibitors or vascular endothelial growth factor receptor inhibitors (including investigational agents) other than sorafenib for treatment of HCC 7. Fibrolamellar carcinoma 8. Any transfusion, blood component preparation, erythropoietin, albumin preparation, or granulocyte colony-stimulating factors within 14 days prior to randomization 9. P 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. P is receiving ongoing therapy with nonsteroidal anti-inflammatory agents (NSAIDs, eg, indomethacin, ibuprofen, naproxen, or similar agents) or other antiplatelet agents (eg, clopidogrel, ticlopidine, dipyridamole, anagrelide). Aspirin at doses of 325 mg/day or below is permitted. 11. Symptomatic congestive heart failure, unstable angina pectoris, or symptomatic or poorly controlled cardiac arrhythmia. 12. Any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to randomization. 13. Uncontrolled arterial hypertension ≥ 150 / ≥ 90 mm Hg despite standard medical management 14. 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. 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. P.s with evidence of portal hypertension (defined as splenomegaly, platelets < 100 × 10 exp3/μL [100 × 10 exp9/L], or any prior history of variceal bleeding) must have had endoscopic evaluation within the 3 months immediately prior to randomization. P.s 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, they 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. CNS metastases or carcinomatous meningitis 17. Serious illness or medical condition(s), including but not limited to the following: a. Known HIV infection or 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. Pregnancy (confirmed by serum β-HCG test) or lactating 19. 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. Prior liver transplant 21. Ascites or encephalopathy refractory to medical management 22. Participation in another interventional clinical trial. Participation in surveys or observational studies is allowed. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint: Overall Survival Overall survival is defined as the time from the date of randomization to the date of death from any cause. If the patient is alive at the end of the follow-up period or is lost to follow-up, OS data will be censored on the last date the patient is known to be alive. Overall survival will be evaluated by the Kaplan-Meier method, and a 95% confidence interval will be provided for the median OS in each treatment arm. The primary analysis will compare the observed OS under the combination therapy ramucirumab DP plus BSC versus placebo plus BSC. The comparison will use the log-rank test, stratified at randomization by geographic region (North America vs Europe vs East Asia), etiology of liver disease (hepatitis B vs hepatitis C vs other etiologies), and Child-Pugh score (Child-Pugh A vs B [B7 or B8]). An additional analysis with an unstratified log-rank test will also be performed. The estimation of the survival curves for the 2 treatment groups will be generated using the Kaplan-Meier methodology. A stratified Cox proportional hazards regression model to compare the treatments within the clusters defined by the stratifying variables will also be performed to generate the hazard ratio (HR). An additional unstratified Cox regression model will be employed to explore the effects of prognostic variables, including the stratification variables and additional factors (eg, Child-Pugh score, presence of macrovascular invasion, extrahepatic spread, BCLC stage, presence vs absence of histologic confirmation of diagnosis, and prior treatment with sorafenib [including duration of treatment and reasons for discontinuation]), on treatment efficacy.
Safety Endpoints The safety and tolerability of ramucirumab DP are determined by reported SAEs, AEs, physical examinations, vital sign measurements, and clinical laboratory evaluations. Patients who receive any quantity of ramucirumab DP or placebo are considered evaluable for safety. Adverse events will be summarized by MedDRA System Organ Class and preferred term, classified from verbatim terms. The incidence and percentage of patients with at least 1 occurrence of a preferred term will be included, according to the most severe NCI-CTCAE v 4.02 grade. Causality (relationship to study therapy), will be separately summarized. Duration of AE will be determined and included in the listings, along with action taken and outcome. Adverse events leading to treatment discontinuation will also be listed. Laboratory results will be classified according to NCI-CTCAE v 4.02. Incidence of laboratory abnormalities will be summarized. Laboratory results not corresponding to an NCI-CTCAE v 4.02 term will not be graded. Pretreatment and posttreatment immunogenicity samples will be assayed using a double antigen radiometric assay. A sample will be considered positive for anti-ramucirumab antibodies if it exhibits a posttreatment antibody level that exceeds the positive upper cut point determined from the anti-ramucirumab level seen in healthy untreated individuals. A patient will be considered to have an anti-ramucirumab response if there are 2 consecutive positive samples or if the final sample tested is positive. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 90 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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This study will be considered complete when 1 or more of the following is met: • All patients have completed an End-of-Study visit. • The IRB/aEC, ImClone, or a regulatory authority discontinues the study due to safety considerations. • The Steering Committee (SC) discontinues the study in response to a recommendation from the IDMC, or because of safety concerns. • The SC defines an administrative or clinical cut-off date. • ImClone defines an administrative or clinical cut-off date. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |