A Randomized, Double-blind, Multi-center Phase III Study of Brivanib plus Best Supportive Care (BSC) versus Placebo plus BSC in Subjects with Advanced Hepatocellular Carcinoma (HCC) who have Failed or are Intolerant to Sorafenib

• Register: REBEC
• Last refreshed on: 29 April 2013
• Main ID: RBR-28gdtz
• Date of registration: 27/06/2011
• Primary sponsor: Bristol-Myers Squibb - Brazil
• Public title: A Randomized, Double-blind, Multi-center Phase III Study of Brivanib plus Best Supportive Care (BSC) versus Placebo plus BSC in Subjects with Advanced Hepatocellular Carcinoma (HCC) who have Failed or are Intolerant to Sorafenib
• Scientific title: A Randomized, Double-blind, Multi-center Phase III Study of Brivanib plus Best Supportive Care (BSC) versus Placebo plus BSC in Subjects with Advanced Hepatocellular Carcinoma (HCC) who have Failed or are Intolerant to Sorafenib
• Date of first enrolment: 01/02/2010
• Target sample size: 339
• Recruitment status: recruitment completed
• URL: http://www.ensaiosclinicos.gov.br/rg/RBR-28gdtz/
• Study design: Therapeutic, multicenter, double-blind, randomized, parallel with 2 arms and phase 3 Clinical Trial.

Countries of recruitment

Belgium, Brazil, Canada, China, France, Germany, Greece, Hong Kong, India, Italy, Japan, Korea, Democratic People's Republic of, Russian Federation, Sweden, Taiwan, Province of China, United States

Contacts

• Name: Juliana Castro
• Affiliation: Bristol-Myers Squibb

• Name: Juliana Castro
• Affiliation: Bristol-Myers Squibb

Key inclusion & exclusion criteria

Inclusion criteria: 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.
Histologic or cytologic confirmed diagnosis of hepatocellular carcinoma.
Advanced disease defined as:
Disease not eligible for surgical or loco-regional therapy or
Disease progressive after surgical or loco-regional therapy
Patient has failed >= 14 days of sorafenib treatment:
Documented radiographic progression Documented symptomatic progression
Documented intolerance to sorafenib Cirrhotic status of Child-Pugh Class A or B with a score of 7).
Eastern Cooperative Oncology Group performance status 0, 1, 2
Subjects who have a life expectancy of at least 8 weeks.
Accessible for treatment and follow-up.
Locoregional therapy must be completed at least 3 weeks prior to the baseline
scan; previously treated lesions are not selected as index lesions.
At lease one measurable untreated lesion. All subjects must have at least one
previously un-irradiated, bi-dimensionally measurable lesion by computerized tomography or magnetic resonance imaging scan >= 20mm. Index lesions that are previously un-irradiated and are bi-dimensionally measurable by spiral CT scan to be >= 10mm will be permitted.
The lesion can be accurately measured bidimensionally according to WHO
criteria.
The lesion has not been previously treated with surgery, radiation therapy,
radiofrequency ablation, percutaneous ethanol or acetic acid injection, or
cryoablation.
Bone metastases are not considered measurable lesions.
Adequate hematologic function with absolute neutrophil counts >= 1,500/mm3,
platelet count >= 60 x 109/L, and hemoglobin >= 8.5 g/dl.
Adequate hepatic function with serum total bilirubin <= 3 mg/dl, serum albumin
>= 2.8 g/dL and alanine aminotransferase and aspartate aminotransferase <= 5 times the institutional upper limits of normal.
Amylase and lipase < 1.5 times the institutional upper limit of normal.
Adequate renal function with serum creatinine <= 2.0 mg/dl.
International normalized ratio (INR) <= 2.3 or Prothrombin Time (PT) <= 6
seconds above control.
Left ventricular ejection fraction (LVEF) >= 50% as measured by 2-D
Echocardiogram.
Male or female subjects >= 18 years of age.
Women of childbearing potential (WOCBP) must be using an adequate method
of contraception to avoid pregnancy throughout the study and up to 12 weeks
after the last dose of investigational product in such a manner that the risk of
pregnancy is minimized.
WOCBP include any female who has experienced menarche and who has not
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation,or bilateral oophorectomy) or is not postmenopausal. Post menopause is defined as:
Amenorrhea >= 12 consecutive months without another cause or
For women with irregular menstrual periods and on hormone replacement
therapy (HRT), a documented serum follicle stimulating hormone (FSH) level
>= 35 mIU/mL.
Women who are using oral contraceptives, other hormonal contraceptives
(vaginal products, skin patches, or implanted or injectable products), or
mechanical products such as an intrauterine device or barrier methods
(diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing
abstinence or where their partner is sterile (eg, vasectomy) should be considered to be of childbearing pot
Exclusion criteria: 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.
Women who are pregnant or breastfeeding.
Women with a positive pregnancy test on enrollment or prior to investigational
product administration.
Sexually active fertile men not using effective birth control if their partners are WOCBP.
Brain metastasis or evidence of leptomeningeal disease.
Known fibrolamellar HCC or mixed cholangiocarcinoma and HCC.
Any encephalopathy.
Any ascites.
Bleeding esophageal or gastric varices within 2 months prior to inclusion.
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.
History of active cardiac disease:
Uncontrolled hypertension which is defined as systolic blood pressure greater
than 150 mmHg or diastolic pressure greater than 90 mmHg despite optimal
medical management. Subjects with a history of persistent hypertension who
are receiving treatment with calcium channel blockers that are CYP3A4
substrates should be changed to an alternative antihypertensive medication.
Congestive heart failure NYHA (New York Heart Association) class III and
IV
Active coronary artery disease, unstable or newly diagnosed angina or
myocardial infarction less than 12 months prior to study entry.
Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta
blockers or digoxin.
Valvular heart disease >= Common Terminology Criteria for Adverse Events Grade 2.
QTc (Fridericia) > 450 msec on two consecutive electrocardiograms. (baseline electrocardiogram should be
repeated if QTc is found to be > 450 msec).
Thrombotic or embolic events within the past 6 months, such as a
cerebrovascular accident (including transient ischemic attacks), pulmonary
embolism.
Any other hemorrhage/bleeding event > CTC AE Grade 3 within 4 weeks except
for esophageal or gastric varices
Active infection, less than 7 days after completing systemic antibiotic therapy.
Psychiatric illness/social situations that would limit compliance with study
requirements.
History of non-healing wounds or ulcers, or bone fractures within 3 months of fracture.
Major surgical procedure, open biopsy, or significant traumatic injury less than 3
weeks or those who receive minor surgical procedures (eg core biopsy or fine
needle aspiration) within 1 week.
History of organ allograft or on an allograft waiting list.
Vena cava thrombosis or occlusion.
Portal-caval shunts.
Inability to swallow tablets or untreated malabsorption syndrome.
Pre-existing thyroid abnormality with thyroid function that cannot be maintained
in the normal range with medication.
History of human immunodeficiency virus (HIV) infection.
Substance abuse, medical, psychological or social conditions that may interfere
with the patient’s participation in the study or evaluation of the study results.
Any medical condition that is unstable or which could jeopardize the safety of
the patient and his/her compliance in the study.
Active, untreated hepatitis B.
Positive pregnancy test.
Hyponatremia with sodium < 130 mmol/L.
Baseline serum potassium < 3.5 mmol/L (potassium supplementation may be
given to restore the serum potassium above this level prior to stu

Age minimum: 18Y
Age maximum: 0
Gender: -

Health Condition(s) or Problem(s) studied

Advanced Hepatocellular Carcinoma
C22.0
C04.588.274.623

C00-D48

Intervention(s)

Comparison group: 226 patients will receive brivanib orally in a dose of 800 mg once daily. Control group: 113 patients given placebo once a day. All study drugs could be administered with or without food. In the absence of intolerable toxic manifestations , patients will continue receiving treatment daily until unacceptable toxicity occurs or disease progression. If the investigators find that the patient is benefiting from the drug-blind study, you can keep them until the radiographic progression of disease

Primary Outcome(s)

Primary endpoint of this study is overall survival in the intent-to-treat population. Subjects will be evaluated for tumor response every six weeks. Documentation of disease state will be performed by either computerized tomography (CT) or magnetic resonance imaging (MRI). Progression will be determined based on modified World Health Organization (WHO) criteria. All
randomized subjects will be followed for survival.

Secondary Outcome(s)

Time to progression (TTP): Time from randomization to disease progression. Subjects who never progress will be censored at their last tumor assessment date. For subjects with no tumor measurements, TTP will be censored at the date of randomization.
Objective response rate (ORR): Proportion of randomized subjects in each treatment
arm, whose best response is CR or PR using modified WHO criteria as assessed by the
investigators.
Disease control rate: Proportion of randomized subjects in each treatment arm, whose best response is CR, PR or SD using modified WHO criteria as assessed by the
investigators.
Time to response: Time from randomization to the time when response criteria are met
for CR or PR, whichever occurs first. Time to response is computed only for subjects
whose best response is CR or PR.
Duration of response: Time from randomization to disease progression or death for randomized subjects whose best response is PR or CR. Subjects who neither progress nor die will be censored on the date of their last tumor assessment.
Duration of disease control: Time for randomization to disease progression or death from randomized subjects whose best response is PR, CR or SD. Subjects who neither progress nor die will be censored on the date of their last tumor assessment.

Secondary ID(s)

ANVISA

CONEP

NCT00825955

Source(s) of Monetary Support

Bristol-Myers Squibb - Brazil