| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| advanced hepatocellular carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019828 |
| E.1.2 | Term | Hepatocellular carcinoma non-resectable |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 brivanib versus sorafenib in subjects with
advanced HCC who have not received prior systemic treatment. |
|
| E.2.2 | Secondary objectives of the trial |
• To compare the time to progression (TTP) (investigator assessed using modified
RECIST for HCC)
• To compare the investigator assessed objective response rate (ORR) and disease
control rate (DCR) using modified RECIST for HCC
• To determine duration of response, duration of disease control, and time to response (TTR)
• To assess the safety profile of brivanib and sorafenib
• To explore PK and exposure-response in the study population
• To compare time to symptomatic progression
• To compare health-related quality of life. |
|
| 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) Histologic or cytologic confirmed diagnosis of HCC prior to the start of investigational product administration.
b) Advanced HCC
i) disease not eligible for surgical and / or locoregional therapies
ii) progressive disease after surgical and / or locoregional therapies
c) Child-Pugh Class A
d) ECOG performance status 0-1 Life expectancy of at least 12 weeks
f) Accessible for treatment and follow-up
g) Locoregional therapy must be completed at least 3 weeks prior to the baseline
scan
h) At lease one measurable untreated lesion. All subjects must have at least one
previously un-treated, uni-dimensionally measurable lesion by MRI scan ≥
20mm or by spiral CT scan ≥ 10mm.
i) The lesion can be accurately measured uni-dimensionally according to mRECIST for HCC criteria
ii) The lesion has not been previously treated with surgery, radiotherapy, and /or
locoregional therapy (eg: radiofrequency ablation (RFA), percutaneous ethanol or acetic acid injection (PEI / PAI), transcatheter arterial chemoembolization (TACE) or cryoablation, etc.)
iii) Bone metastases are not considered measurable lesions.
3) Physical and Laboratory Test Finding
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
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) International normalized ratio (INR) ≤ 2.3 or Prothrombin time (PT) ≤ 6 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 3a) - 3f)
without continuous supportive treatment, such as blood transfusion, coagulation
factors and / or platelet infusion, red / white blood cell growth factor administration, or albumin infusion etc.
4) Age and Sex
a) Men and women, ages 18 or older
b) Women of childbearing potential (WOCBP). WOCBP whose male partners receive study drug and male subjects 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.
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. |
|
| 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 the last dose of investigational product if their partners are WOCBP.
2) Target Disease Exceptions
a) Brain metastasis or evidence of leptomeningeal disease
b) Known fibrolamellar HCC or mixed cholangiocarcinoma and HCC
c) History of encephalopathy
d) Any ascites that is considered clinically significant, defined as: i) Any ascites detected by physical exam at screening or ii) Any prior or current ascites that required treatment
e) Evidence of portal hypertension with bleeding esophageal or gastric varices
within the past 6 months
f) Main portal vein or vena cava occlusion caused by HCC.
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 active 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 3 and 4
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 (except HCC tumor thrombus) within the past 6 months, such as a cerebrovascular accident (including transient ischemic attacks), pulmonary embolism
e) Any other hemorrhage/bleeding event ≥ CTCAE Grade 3 within 8 weeks except for esophageal or gastric varices
f) Active infection, less than 7 days after completing systemic antibiotic therapy
g) Active, untreated hepatitis B
h) Psychiatric illness/social situations that would limit compliance with study requirements
i) History of non-healing wounds or ulcers, or bone fractures within 3 months
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 (eg core biopsy or fine needle aspiration) within 1 week
k) History of organ allograft or on an allograft waiting list
l) Portal-caval shunts
m) Inability to swallow tablets or untreated malabsorption syndrome
n) Pre-existing thyroid abnormality with thyroid function that cannot be maintained
in the normal range with medication
o) History of human immunodeficiency virus (HIV) infection
p) Substance abuse, medical, psychological or social conditions that may interfere
with the patient’s participation in the study or evaluation of the study results.
q) 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) Baseline serum 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 sorafenib 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 or molecular
targeted agents for HCC
b) Concomitant treatment with rifampin (and its analogues), or St John’s wort
c) Prior use of systemic investigational agents for HCC
d) Radiotherapy within 4 weeks prior to start of study drug (palliative radiotherapy
for symptomatic control is acceptable)
e) Required anticoagulation therapy with an agent such as coumadin, warfarin or
heparin
f) Required chronic anti-platelet therapy (aspirin at dose ≥ 300 mg/day, clopidogrel
at dose ≥ 75 mg/day).
7) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary endpoint of this study is overall survival. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Survival will be assessed continuously |
|
| E.5.2 | Secondary end point(s) |
- To compare the time to progression (TTP) (investigator assessed using
modified RECIST criteria for HCC
- To compare the investigator assessed objective response rate (ORR)
and disease control rate (DCR) using modified RECIST criteria for HCC
- To determine duration of response, duration of disease control, and
time to response (TTR)
- To assess the safety profile of brivanib and sorafenib
- To explore PK and exposure-response in the study population
- To compare time to symptomatic progression
- To compare health-related quality of life |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Each secondary endpoint will be assessed every 6 weeks |
|
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 46 |
| 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 | No |
| 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 |
| Argentina |
| Australia |
| Belgium |
| Brazil |
| Canada |
| China |
| Czech Republic |
| France |
| Germany |
| Hong Kong |
| India |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Poland |
| Puerto Rico |
| Russian Federation |
| South Africa |
| Spain |
| Sweden |
| Taiwan |
| Thailand |
| Turkey |
| United Kingdom |
| United States |
|
| 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
|
| The study will be closed when the required number of randomized subjects has documented death events. |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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