| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Advanced Hepatocellular Carcinoma
///
Carcinoma Hepatocelular avanzado |
|
| 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 | 10019829 |
| E.1.2 | Term | Hepatocellular carcinoma recurrent |
|
| 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 |
|
| 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 of subjects with advanced HCC who have progressed
on/after or are intolerant to sorafenib and receive brivanib plus best supportive care
(BSC) to those receiving placebo plus BSC. |
|
| E.2.2 | Secondary objectives of the trial |
? To compare the time to progression (TTP) (investigator assessed using modified
WHO criteria).
? To compare the investigator assessed objective response rate (ORR) and disease
control rate (DCR) using modified WHO criteria
? To assess duration of response, duration of disease control and time to response
? To assess the safety profile of brivanib. |
|
| 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.
b) Advanced disease defined as:
i) disease not eligible for surgical or loco-regional therapy or
ii) disease progressive after surgical or loco-regional therapy
c) Patient has failed ? 14 days of sorafenib treatment:
i) Documented radiographic progression
ii) Documented symptomatic progression
iii) Documented intolerance to sorafenib
d) Cirrhotic status of Child-Pugh Class A or B with a score of 7.
e) ECOG performance status 0, 1, 2.
f) Subjects who have a life expectancy of at least 8 weeks.
g) Accessible for treatment and follow-up.
h) Locoregional therapy must be completed at least 3 weeks prior to the baseline
scan; previously treated lesions are not selected as index lesions.
i) At lease one measurable untreated lesion. All subjects must have at least one
previously un-irradiated, bi-dimensionally measurable lesion by CT or MRI scan
? 20mm. Index lesions that are previously un-irradiated and are bi-dimensionally
measurable by spiral CT scan to be ? 10mm will be permitted.
i) The lesion can be accurately measured bidimensionally according to WHO criteria.
ii) The lesion has not been previously treated with surgery, radiation therapy,
radiofrequency ablation, percutaneous ethanol or acetic acid injection, or cryoablation.
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.
4) Age and Sex
a) Male or female subjects ? 18 years of age.
b) 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 potential.
WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of investigational product. |
|
| 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) Brain metastasis or evidence of leptomeningeal disease.
b) Known fibrolamellar HCC or mixed cholangiocarcinoma and HCC.
c) Any encephalopathy.
d) Any ascites.
e) Bleeding esophageal or gastric varices within 2 months prior to inclusion.
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 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.
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) Any other hemorrhage/bleeding event > CTC AE Grade 3 within 4 weeks except
for esophageal or gastric varices (see 4.2.2 Target disease Exceptions).
f) Active infection, less than 7 days after completing systemic antibiotic therapy.
g) Psychiatric illness/social situations that would limit compliance with study requirements.
h) History of non-healing wounds or ulcers, or bone fractures within 3 months of
fracture.
i) 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.
j) History of organ allograft or on an allograft waiting list.
k) Vena cava thrombosis or occlusion.
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.
r) Active, untreated hepatitis B.
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 or targeted agents for HCC
except for sorafenib (prior loco-regional treatment including TACE is allowed).
b) Prior immunotherapy for HCC.
c) Concomitant treatment with rifampin (and its analogues), and St John?s Wort.
d) Prior use of systemic investigational agents for HCC (except for sorafenib).
e) Radiotherapy within 4 weeks prior to start of study drug.
f) Required anticoagulation therapy with an agent such as warfarin or heparin.
g) 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 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. |
|
| 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 | 22 |
| 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 |
|
| 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
| |
| 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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