E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
intermediate stage hepatocellular carcinoma (HCC)
Carcinoma hepatocelular (CHC) en estadio intermedio |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
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 |
To compare the Overall Survival (OS) of HCC patients who receive brivanib as adjuvant treatments to TACE therapy, with the OS of HCC patients who receive matched placebo with TACE therapy. |
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E.2.2 | Secondary objectives of the trial |
? To compare the Time-To-Disease Progression (TTDP) of patients receiving brivanib with TACE therapy to that of patients receiving placebo with TACE therapy. ? To compare the time to extrahepatic spread or vascular invasion in the brivanib and placebo arms. ? To determine the total number of TACE sessions in the brivanib and placebo arms. ? To compare the rate of TACE sessions in the brivanib and placebo arms. ? To compare the Time-to-Progression (tumor) after the first TACE session in the brivanib and placebo arms. ? To evaluate the safety of brivanib in combination with TACE. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent a) Voluntary signed and dated written informed consent form in accordance with regulatory and institutional guidelines obtained before the performance of any protocol-related procedures not part of normal patient care. 2) Target Population a) Patients with diagnosis of hepatocellular carcinoma (HCC) meeting the criteria below: i) Biopsy-proven HCC (histology or cytology), OR ii) Radiological evidence of HCC showing lesion arterial hypervascularity and venous phase washout by either dynamic (triple-phase), contrast-enhanced computed tomography of the abdomen OR dynamic (triple-phase) contrast (gadolinium)-enhanced MRI, AND (1) Serology positive for hepatitis B or C, AND (2) Alpha fetoprotein > 400 ?g/L at the time of diagnosis b) One lesion that is ? 5 cm, OR multinodular disease with 4 or more lesions (at least one of which has a diameter > 3 cm) c) Cirrhotic status of Child-Pugh Class A or B with a score of 7 d) ECOG performance status of 0 or 1 e) Life expectancy of at least 12 weeks f) Ability to comply with visits/procedures required by protocol 3) Physical and Laboratory Test Findings a) Adequate hematologic function with absolute neutrophil counts ? 1,500/mm3, platelet count ? 60 x 10E9/L, and hemoglobin ? 8.5 g/dL b) Adequate hepatic function with serum total bilirubin ? 3 mg/dL, serum albumin ? 2.8 g/dL, and ALT and AST ? 5 times the institutional upper limits of normal (ULN) c) Amylase and lipase < 1.5 times the institutional upper limit of normal d) Adequate renal function with serum creatinine ? 2.0 mg/dL e) Prothrombin time (PT): International normalized ratio (INR) < 1.7 or PT < 4 seconds above control f) Left ventricular ejection fraction (LVEF) ? 50% as measured by 2-D Electrocardiogram g) All laboratory test finding should be stable within the range listed in a) - f) without continuous supportive treatment, such as blood transfusion, coagulation factors and/or platelet infusion, red/white blood cell growth factor administration, albumin infusion, ursodeoxycholic acid, or drug treatment for lowering liver enzyme/bilirubin, etc. 4) Age and Sex a) Men and women, ages 18 or older Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 12 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized. |
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E.4 | Principal exclusion criteria |
1) Sex and Reproductive Status a) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 12 weeks after the last dose of investigational product. b) Women who are pregnant or breastfeeding. c) Women with a positive pregnancy test on enrollment or prior to investigational product administration. d) Sexually active fertile men not using effective birth control if their partners are WOCBP. 2) Target Disease Exceptions a) Diffuse pattern of disease on CT/MRI b) Presence of extra-hepatic lesions c) Main portal vein or vena cava thrombosis or occlusion d) Intrahepatic or portal-caval shunts e) Any previous TACE procedure for HCC f) Prior use of systemic treatment for HCC g) Prior history of or current ascites or encephalopathy 3) Medical History and Concurrent Diseases a) Previous or concurrent cancer that is distinct in primary site or histology from HCC, except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis & T1). Any cancer curatively treated > 5 years prior to entry is permitted. b) History of cardiac disease: i) Uncontrolled hypertension which defined as systolic blood pressure greater than 150 mmHg or diastolic pressure greater than 90 mmHg despite optimal medical management. ii) Congestive heart failure NYHA (New York Heart Association) class III and IV iii) Active coronary artery disease, unstable or newly diagnosed angina or myocardial infarction less than 12 months prior to study entry iv) Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin v) Valvular heart disease ? CTCAE Grade 2 c) QTc (Fridericia) > 450 msec on two consecutive ECGs (baseline ECG should be repeated if QTc is found to be > 450 msec) d) Thrombotic or embolic events within the past 6 months, such as a cerebrovascular accident (including transient ischemic attacks), pulmonary embolism e) Hemorrhage/bleeding event ? CTCAE Grade 3 within 4 weeks prior to study entry f) Prior history of gastrointestinal bleeding within the past year or presence of gastro-duodenal ulcers or gastro-esophageal varices documented by gastroscopy g) History of non-healing wounds or ulcers, or bone fractures within 3 months of fracture h) Major surgical procedure, open biopsy, or significant traumatic injury less than 3 weeks or those who receive minor surgical procedures (e.g., core biopsy or fine needle aspiration) within 1 week i) History of organ allograft or on an allograft waiting list j) Inability to swallow tablets or untreated malabsorption syndrome k) Pre-existing thyroid abnormality of thyroid function that cannot be maintained in the normal range with medication l) History of human immunodeficiency virus (HIV) infection m) Active infection, less than 7 days after completing systemic antibiotic therapy n) Active, untreated hepatitis o) Substance abuse, medical, psychological or social conditions that may interfere with the patient?s compliance with study requirements and participation in the study or evaluation of the study results. p) Any medical condition that is unstable or which could jeopardize the safety of the patient and his/her compliance in the study. 4) Physical and Laboratory Test Findings a) Positive pregnancy test b) Hyponatremia with sodium < 130 mmol/L c) Baseline serum potassium < 3.5 mmol/L (potassium supplementation may be given to restore the serum potassium above this level prior to study entry) 5) Allergies and Adverse Drug Reactions a) Known or suspected history of allergy to brivanib or any agents given in association with this trial 6) Prohibited Treatments and/or Therapies a) Prior use of any systemic anti-cancer chemotherapy, immunotherapy, investigational or molecular targeted agents for HCC b) Prior immunotherapy for HCC c) Concomitant treatment with rifampin (and its analogues), or St John?s Wort d) Patients requiring anticoagulation therapy with an agent such as warfarin or heparin e) Patients requiring chronic anti-platelet therapy (aspirin at dose > 300 mg/day, clopidogrel at dose > 75 mg/day) f) Radiotherapy within 4 weeks prior to start of study drug 7) Other Exclusion Criteria a) Prisoners or patients who are involuntarily incarcerated b) Patients who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of the study is Overall Survival (OS). OS will be defined as the time from the date of randomization to the date of death. If the patient is lost to follow-up, survival will be censored on the last date the patient was known to be alive. |
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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 | No |
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 | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 15 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 15 |