| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Hepatocellular Carcinoma (HCC) |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019828 |
| E.1.2 | Term | Hepatocellular carcinoma non-resectable |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019829 |
| E.1.2 | Term | Hepatocellular carcinoma recurrent |
|
| 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 evaluate the overall survival of oral linifanib given as monotherapy daily compared to sorafenib given twice daily as standard of care in subjects with advanced or metastatic HCC. |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate time to progression and objective response rate in those subjects treated with linifanib compared with sorafenib. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Subjects will have the option to participate in the folllowing substudies:
a) Tissue sample collection: Subjects may consent to providing archived tissue samples taken from a biopsy that was performed at the time of their hepatocellular carcinoma diagnosis. These tissue samples may be used to develop a diagnostic test to identify patients most likely to respond to the drug.
b) Genetic sub-study: Subjects may consent to an additional blood draw that will be used for genetic testing to help determine why some hepatocellular carcinoma patients may benefit from taking ABT-869 more than others do.
c) ECG Collection: At approximately 1 to 4 study sites, triplicate ECGs (defined as first ECG after 5 minutes supine, second ECG approximately 60 seconds after the first ECG and third ECG approximately 60 seconds after the second ECG) will be obtained for a cohort of approximately 30 evaluable subjects (who consent) randomized to receive linifanib. An exposure-response analysis will be explored to characterize the effect of linifanib on QTcF intervals. |
|
| E.3 | Principal inclusion criteria |
1. Subject must be an adult ≥ 18 years of age.
2. Subject must be diagnosed with unresectable or metastatic HCC defined by:
● Histologic or cytologic diagnosis OR
● European Association for the Study of Liver Criteria
o Radiological criteria: two coincident imaging techniques (Four techniques
considered: ultrasound, spiral computed tomography (CT), magnetic
resonance imaging (MRI) and angiography)
o Focal lesion > 2 cm with arterial hypervascularization
o Combined criteria: one imaging technique associated with AFP (alpha
fetoprotein) > 400 ng/mL
3. Subjects must have a measurable lesion by RECIST (version 1.1) on CT scan in at
least one site which has not received prior radiotherapy.
4. Subjects must show signs of progression (i.e., new lesion per RECIST version 1.1)
if prior liver-directed therapy was received.
5. Subject has an Eastern Cooperative Oncology Group (ECOG) Performance status
of 0 to 1.
6. Subject must have the following laboratory values:
● Total Bilirubin ≤ 3.0 mg/dL or equivalent
● AST/ALT ≤ 5 × ULN
● PTT ≤ 1.5 × ULN and INR < 1.5
● ANC ≥ 1.0 × 109/L
● Platelet count ≥ 50 × 109/L if splenomegaly; if splenomegaly is not present,
platelet count ≥ 75 × 109/L
● Serum Creatinine ≤ 1.5 × ULN
● Serum Albumin ≥ 2.8 g/dL
● PT ≤ 6 seconds prolonged
7. Women of childbearing potential and men must agree to use adequate
contraception (one of the following listed below) prior to study entry, for the
duration of study participation and for 90 days following completion of therapy.
Women of childbearing potential must have a negative urine pregnancy test within
7 days prior to initiation of treatment and/or post-menopausal women must be
amenorrheic for at least 12 months to be considered of non-childbearing potential.
● Total abstinence from sexual intercourse (for minimum of one complete
menstrual cycle prior to study drug administration),
● Vasectomized male subjects or vasectomized partner of female subjects,
● Hormonal contraceptives (oral, parenteral or transdermal) for at least
3 months prior to study drug administration,
● Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal
ring with spermicidal jellies or cream),
● Intra-Uterine Device,
● Additionally, male subjects (including those who are vasectomized) whose
partners are pregnant or might be pregnant must agree to use condoms for the
duration of the study and for 90 days following completion of therapy.
8. Subject is capable of understanding and complying with parameters as outlined in
the protocol and able to sign informed consent, approved by an Independent Ethic
Committee (IEC)/Institutional Review Board (IRB) prior to the initiation of any
screening or study-specific procedures, and in the opinion of the Study
Investigator with agreement by the subject, currently no other treatment options
exist that will provide benefit to the subject and/or the subject is willing to receive
(e.g., transcatheter arterial chemoembolization). |
|
| E.4 | Principal exclusion criteria |
1. Subject has received prior systemic (administered intravenously or orally rather
than locoregionally) treatment for HCC.
2. Subject has Child-Pugh grade Class B or C hepatic impairment.
3. Subject has received prior local therapy (including liver-directed therapy) within
4 weeks prior to study drug administration. Local therapies include but are not
limited to: surgery, radiation therapy, hepatic arterial embolization, hepatic
intra-arterial chemotherapy, chemoembolization, radiofrequency ablation,
percutaneous ethanol injection or cryoablation. In addition, subject has not
recovered to ≤ Grade 1 clinically significant adverse effects/toxicities of previous
therapy.
4. Subject has untreated brain or meningeal metastases. CT scans are not required to
rule out brain or meningeal metastases unless there is a clinical suspicion of central
nervous system disease. Subjects with treated brain metastases that are
radiographically or clinically stable (for at least 4 weeks after therapy) and have no
evidence of cavitation or hemorrhage in the brain lesion, are eligible provided that
they are asymptomatic and do not require corticosteroids (must have discontinued
steroids at least 1 week prior to Study Day 1).
5. Subject has previous or concurrent cancer that is distinct in primary site or
histology from HCC except cervical carcinoma in situ, non-melanoma carcinoma
of the skin or in situ carcinoma of the bladder. Any cancer curatively treated
greater than 3 years prior to entry is permitted.
6. Subject has proteinuria defined by the National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI CTCAE) grade > 1 at baseline as
measured by a urine dipstick (2+ or greater) and confirmed by a 24 hour urine collection (> 1 g/24 hrs). Subjects may be re-screened if proteinuria is shown to
be controlled with or without intervention.
7. Subject currently exhibits symptomatic or persistent, uncontrolled hypertension
defined as diastolic blood pressure > 90 mmHg or systolic blood pressure
> 140 mmHg. Subjects may be re-screened if blood pressure is shown to be
controlled with or without intervention.
8. Subject has a documented Left Ventricular Ejection Fraction < 50%.
9. Subject is receiving therapeutic anticoagulation therapy. Low dose
anti-coagulation (e.g., low dose warfarin) for catheter prophylaxis only will be
permitted. No low molecular weight heparin (LMW) is allowed.
10. Subject is receiving anti-retroviral therapy for Human Immunodeficiency Virus
(HIV). Prophylactic antiviral therapy to prevent Hepatitis B virus (HBV)
reactivation is allowed.
11. Female subjects who are pregnant or breast feeding.
12. Presence of > grade 2 encephalopathy by NCI CTCAE criteria.
13. Presence of ≥ grade 2 ascites by NCI CTCAE criteria.
14. Clinically significant uncontrolled condition(s) including but not limited to:
● Active uncontrolled infection
● Class III or IV heart failure as defined by the New York Heart Association
functional classification system
● Unstable angina pectoris or cardiac arrhythmia
● Myocardial infarction within last 6 months
● History of adrenal insufficiency
● History of cerebral vascular accident within last 6 months
● Active ulcerative colitis, Crohn's disease, celiac disease or any other
conditions that interfere with absorption
● History of autoimmune disease with kidney involvement
● History of overt bleeding (> 30 mL bleeding/episode) within 3 months of
study drug administration
● Psychiatric illness/social situation that would limit compliance with study
requirements
● Any medical condition, which in the opinion of the study investigator places
the subject at an unacceptably high risk for toxicities. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| 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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Quality of life, health economics and outcomes research |
|
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 55 |
| 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
|
| The end of study is defined as the date of the last subject's last visit or date of last follow-up contact, whichever is later. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 29 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 29 |
Print
