E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hepatocellular carcinoma non-resectable |
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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 |
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 and to compare the rate of TACE sessions 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 μg/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 echocardiogram 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, or albumin infusion. 4) Age and Sex a) Men and women, ages 18 or older Women of childbearing potential (WOCBP), WOCBP whose male partners receive study drug, and male patients 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. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity must be 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of investigational product. In the case of urine pregnancy testing, a serum sample for pregnancy testing must also be obtained within 72 hours prior to start of investigational product to confirm the urine results. Investigational product may be initiated prior to the confirmatory serum pregnancy test results being available. |
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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 up to 12 weeks after their last dose of study drug if their partners are WOCBP. 2) Target Disease Exceptions a) Diffuse pattern of disease on CT/MRI b) Presence of extra-hepatic lesions c) Any macroscopic vascular invasion of the portal system/vena cava or any evidence of vascular invasion on imaging d) Surgically created shunts (e.g. portal-caval shunts) e) Any previous TACE or TAE (transarterial embolization without instillation of chemotherapy agent) procedure for HCC f) Prior use of systemic treatment for HCC g) Prior history of or current encephalopathy h) Any ascites that is considered clinically significant, defined as: i) Current ascites requiring medical treatment ii) Prior history of ascites requiring treatment, even if the ascites have since resolved. 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 is defined as systolic blood pressure greater than 150 mmHg or diastolic blood 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 lower gastrointestinal bleeding within the past 6 months g) History of unstable and/or active gastro-duodenal ulcers OR upper gastrointestinal bleeding within the past 6 months. h) Any variceal bleed in the past 6 months i) History of non-healing wounds or ulcers, or bone fractures within 3 months of fracture j) Major surgical procedure, open biopsy, or significant traumatic injury less than 3 weeks prior to the start of investigational product administration, or those who receive minor surgical procedures (e.g., core biopsy or fine needle aspiration) within 1 week prior to the start of investigational product administration k) History of organ allograft or on an allograft waiting list l) Inability to swallow tablets or untreated malabsorption syndrome m) Pre-existing thyroid abnormality of thyroid function that cannot be maintained in the normal range with medication n) History of human immunodeficiency virus (HIV) infection FOR COMPLETE LIST, REFER TO PROTOCOL |
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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 | 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 | 2 |
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 | |
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 |