The primary objective of this study is to assess the overall survival (OS) of oral linifanib given as monotherapy daily (QD) compared to sorafenib given twice daily (BID) per standard of care in subjects with advanced or metastatic HCC. The…
ID
Source
Brief title
Condition
- Hepatobiliary neoplasms malignant and unspecified
- Hepatobiliary neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy analysis will be a comparison of overall survival (OS)
distributions between the linifanib and sorafenib treatment groups.
Time to death for a given subject will be defined as the number of days from
the date that the subject was randomized to the date of the subject's death.
All events of death (up to the 667th death for final analysis) will be
included, regardless of whether the event occurred while the subject was still
taking study drug, or after the subject discontinued study drug. If a subject
has not died, then the data will be censored at the date when the subject was
last known to be alive.
Secondary outcome
Secondary efficacy analyses comparing the effects of linifanib versus sorafenib
will also be performed on time to progression (TTP) and objective response rate
(ORR). Time to progression will be defined as the number of days from the date
of randomization to the date of earliest disease progression, per RECIST
(version 1.1). All disease progression will be included regardless of whether
the event occurred while the
subject was taking the study drug or had previously discontinued the study
drug. If the subject does not experience disease progression, then the data
will be censored at the date of last radiographic tumor assessment. If the
subject does not experience disease progression and does not have any
radiographic tumor assessment, then the subject will be censored at the date of
randomization. Objective response rate is defined as the proportion of subjects
with complete or partial response per RECIST (version 1.1); all response
assessments must be confirmed by scans not less than 4 weeks apart.
Background summary
Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and
the third most common cause of mortality. There are approximately 560 000 new
cases diagnosed each year. Additionally, over half a million deaths can be
attributed to liver cancer annually.
Although there is a wide geographic variety in HCC incidence, the majority of
the HCC cases (>80%) occur in sub-Saharan Africa and in eastern Asia. In these
regions, infection with the Hepatitis B virus (HBV) and dietary exposure to
aflatoxin B1 are the primary risk factors. In other areas of the world, such as
the United States and Europe, the Hepatitis C virus (HCV) and alcohol
consumption are the principal risk factors. It is these regions where HCC
incidence is on the rise. Across all geographic regions the incidence of HCC
among men is two to four times higher than that is seen in females. The most
common and unifying condition associated with HCC is cirrhosis, which develops
after long latencies of chronic liver disease.
Patients will have compromised liver function as a result of both cirrhosis
and/or tumor replacement. Many subjects with HCC also have portal hypertension
contributing to hepatic dysfunction. Despite the fact that primary curative
treatment is resection, subjects are often inoperable because of marginal liver
function or unresectable due to portal vein involvement or distant metastases.
For the 80% of patients with unresectable tumors, the median survival is 4
months.
HCC is known to be a highly vascular tumor and overexpresses vascular
endothelial growth factor (VEGF). One multiple tyrosine kinase
inhibitor/anti-angiogenic agent (sorafenib) has been approved for the treatment
of unresectable HCC and other anti-angiogenic agents are under phase 3 clinical
investigation.
Study objective
The primary objective of this study is to assess the overall survival (OS) of
oral linifanib given as monotherapy daily (QD) compared to sorafenib given
twice daily (BID) per standard of care in subjects with advanced or metastatic
HCC. The secondary objectives of this study are to assess time to progression
(TTP) and objective response rate (ORR) in those subjects treated with
linifanib compared with sorafenib. The tertiary objectives are to assess
progression free survival (PFS) and quality of life (QoL).
Study design
This is a Phase 3, randomised, open-label, multinational, multicenter study to
evaluate the efficacy and tolerability of linifanib compared to to sorafenib in
subjects with advanced or metastatic HCC who have not received prior systemic
therapy.
Subjects will be randomized in a 1:1 ratio to 1 of the 2 treatment groups
(linifanib or sorafenib). Approximately 900 subjects will be enrolled at
approximately 200 sites. Two interim analyses are planned.
Intervention
During the study, patients will receive oral linifanib (17.5 mg once a day) or
oral sorafenib (400 mg twice a day).
Patients that are in the linifanib treatment arm will have to take their
medication under fasting conditions. Fasting is described as no food and
beverages for 2 hours before and after treatment dosing.
Study burden and risks
The use of linifanib or sorafenib will cause side effects, which will be
discussed with the patient, and is displayed in the patient information.
Risks of blood samples being drawn include pain, bruising, bleeding,
inflammation, infection, temporary redness of the skin at the injection site
and light-headedness.
The MUGA scan will be done using a radioactive tracer. The amount of radiation
is very low and does not cause radiation sickness. In rare occasions, this can
cause allergic reactions.
Subjects receiving anti-angiogenic therapy like linifanib may be at a higher
risk of bleeding and blood clots. Other drugs in this class have had
complications of wound healing.
As the endpoints of this study are not displayed in time, it is not possible to
predict the amount of times the patient has to return to the hospital for a
visit.
Siriusdreef 51
2132 WT, Hoofddorp
NL
Siriusdreef 51
2132 WT, Hoofddorp
NL
Listed location countries
Age
Inclusion criteria
Each subject must fulfill all of the following criteria within 21 days prior to the first day of therapy.
1) Subject must be >= 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
3) Radiological criteria: two coincident imaging techniques (Four techniques considered: ultrasound, spiral computed tomography (CT), magnetic resonance imaging (MRI) and angiography)
4) Focal lesion > 2 cm with arterial hypervascularization
5) Combined criteria: one imaging technique associated with AFP (alpha fetoprotein) > 400 ng/mL
6) 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.
7) Subjects must show signs of progression (i.e., new lesion per RECIST version 1.1) if prior
liver-directed therapy was received.
8) Subject has an Eastern Cooperative Oncology Group (ECOG) Performance status of 0 to 1.
9) 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
* Creatinine <= 1.5 × ULN
* Serum albumin >= 2.8 g/dL
* PT <= 6 seconds prolonged
10) Women of childbearing potential and men must agree to use adequate contraception 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.
11) 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).
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, 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) The 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) The 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).
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2009-013435-38-NL |
| ClinicalTrials.gov | NCT01009593 |
| CCMO | NL30198.029.09 |