Hepatocellular Carcinoma
Conditions
Keywords
Hepatocellular carcinoma, TACE, HepaSphere Microspheres, QuadraSphere Microspheres, Doxorubicin
Brief summary
The purpose of this study is to evaluate overall survival in patients diagnosed with hepatocellular cancer (HCC) treated with HepaSphere/QuadraSphere Microspheres loaded with chemotherapeutic agent doxorubicin compared to conventional transarterial chemoembolization with particle PVA, lipiodol, and doxorubicin.
Detailed description
This phase three, interventional, and prospective study consists of a patient population that has advanced liver cancer (hepatocellular cancer \[HCC\]) that cannot be removed by standard therapies such as surgical removal, liver transplant, and/or ablation. Embolics and drug eluting embolics are being used by interventional radiologists to try and shrink or kill the tumor area. Patients that met eligibility criteria, wanted to participate in the study, and signed the informed consent form (ICF) made up the study subject population. Subjects were randomized on a 1:1 basis (subjects were blinded to arm they were randomized to). Post randomization and within four weeks of the first chemoembolization procedure all subjects had a baseline MRI. Following, the first chemoembolization procedure (hqTACE or cTACE) or 'cycle' was completed. Subjects can (per protocol) receive up to 3 TACE cycles. Within 4 weeks after any TACE cycle, an MRI and labs should be conducted/collected to evaluate disease status (reduction vs progression) and measure treated lesions. Any residual disease that is present after after the first TACE will undergo the next TACE cycle (maximum of three). However, if the liver MRI shows a complete response (absence of HCC) then no additional TACE procedures are performed and the subject is followed for survival.
Interventions
DEVICEHepaSphere/QuadraSphere Microspheres
HepaSphere/QuadraSphere Microspheres loaded with doxorubicin
PROCEDUREPVA, lipiodol, doxorubicin
Conventional TACE procedure using PVA, lipiodol and doxorubicin
Sponsors
Merit Medical Systems, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Masking description
Participants are blinded to the treatment they are randomized to (cTACE or hqTACE). Central Reviewers (two interventional radiologists) will evaluate study participant's liver MRIs to assess the tumor response. The Central Reviewers will be blinded to the treatment the participant received.
Intervention model description
Participants are randomized 1:1 to receive either 1. A Conventional TACE (Trans Arterial Chemoembolization) procedure using PVA, lipiodol and doxorubicin (cTACE), or 2. HepaSphere/QuadraSphere Microspheres loaded with doxorubicin for Trans Arterial Chemoembolization (hqTACE). Participants in both treatment arms will be followed for overall survival, the primary study endpoint.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients must meet all of the following inclusion criteria in order to be entered into the study: 1. Age 18 or older 2. Patient has signed informed consent 3. Patient must have a diagnosis of hepatocellular cancer confirmed by at least one of the following: i. Histological confirmation ii. Magnetic resonance imaging (MRI) result with early enhancement and delayed enhancement washout of at least one solid liver lesion \> 1 cm. Patient must also have evidence of cirrhosis or have chronic hepatitis B. iii. Contrast enhanced computed tomography (CT) with early enhancement and delayed enhancement washout of at least one solid liver lesion \> 1cm. Patient must also have evidence of cirrhosis or have chronic hepatitis B. d. Patient must not be suitable for treatment by resection or percutaneous ablation at time of study entry. Patients not suitable for ablation due to lesion location may be enrolled e. Patient MUST meet at least ONE of the following criteria: i. Stage Child-Pugh B 7 ii. Recurrent HCC iii.Performance status ECOG 1 f. Patient has a life expectancy of at least 6 months g. Absence of occlusive thrombus to the main portal trunk
Exclusion criteria
If patients meet any of the following criteria they may not be entered into the study: 1. Current or previous treatment with chemo- or radiation therapy or sorafenib 2. Previous treatment with any form of transarterial embolization for HCC 3. Patients with current or history of any other cancer except non-melanomatous skin cancer 4. Female patients who are pregnant, breastfeeding, or premenopausal and not using an effective method of contraceptive 5. Performance status ECOG \> 2 6. Child-Pugh scores \>7 7. Active gastrointestinal bleeding 8. Evidence of uncorrectable bleeding diathesis 9. Extra-hepatic spread of the HCC 10. Total Bilirubin \> 3 mg/dL 11. \>50% tumor involvement of the liver 12. Infiltrative or diffuse HCC 13. Encephalopathy not adequately controlled medically 14. Presence of ascites not controlled medically 15. Presence of medically relevant localized or systemic infection, other than hepatitis B, C, D, E or G 16. Any contraindication for MRI (eg. metallic implants) 17. Allergy to contrast media that cannot be managed with prophylaxis 18. Allergy to iodized oil 19. Any contraindication to arteriography 20. Any contraindication for doxorubicin administration, including the following: i. White Blood Cell count (WBC) \<3000 cells/mm₃ ii. Absolute Neutrophil \<1500 cells/mm₃ iii. Cardiac ejection fraction \<50% iv. Other condition deemed exclusionary by physician u. Any contraindication for hepatic embolization, including the following: i. Porto-systemic shunt, or an arteriovenous shunt that cannot be adequately closed prior to chemoembolization ii. Hepatofugal blood flow iii. Serum creatinine \> 2mg/dL iv. Uncorrectable impaired clotting 1. Platelet \<50,000/mm₃ 2. International Normalized Ratio (INR) \> 1.4 3. Activated Prothrombin Time (aPTT) less than 21 or greater than 40 v. AST \> 5X upper limit of normal for lab vi. ALT \> 5X upper limit of normal for lab
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Overall Survival | 2 years | Median overall survival will be calculated using the Intent-to-Treat (ITT) population in each treatment arm when the last subject has completed two years of follow up after their first study TACE procedure. Per protocol, study subjects were followed for survival until death or deemed lost to follow up. All deaths are reported within safety. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rates (ORR) | Study was terminated early so analysis of additional outcome(s) were not possible. | The Objective Response Rate will be calculated for the ITT population by adding the number of participants that were determined to have complete or partial response (utilizing mRECIST criteria) and dividing by the number of ITT participants. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of TACE-Related Adverse Events in Subjects Treated With HepaSphere/QuadraSphere vs Subjects Treated With Conventional TACE. | 30 days | The number of TACE- Related adverse events experienced by subjects treated with HepaSphere/QuadraSphere will be compared to the number of TACE-related adverse events experienced by subjects treated with conventional TACE. Adverse events were recorded for treated subjects from the date of randomization up to and including 30 days post the last study MRI. |
Countries
Belgium, France, Greece, Italy, United States
Participant flow
Recruitment details
Study enrollment began in June 2011 and ended in May 2017.
Pre-assignment details
Of the 235 subjects that were randomized, 224 were treated. Eleven (11) randomized subjects did not receive treatment, 5 of which were not treated at the investigators discretion and 6 that withdrew consent.
Participants by arm
| Arm | Count |
|---|---|
| HepaSphere/QuadraSphere TACE HepaSphere/QuadraSphere TACE
HepaSphere/QuadraSphere Microspheres: HepaSphere/QuadraSphere Microspheres loaded with doxorubicin | 118 |
| Conventional TACE Conventional TACE
PVA, lipiodol, doxorubicin: Conventional TACE procedure using PVA, lipiodol and doxorubicin | 117 |
| Total | 235 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Randomized and Treated | Physician Decision | 3 | 2 |
| Randomized and Treated | Withdrawal by Subject | 4 | 2 |
| Survival Follow-up | Additional treatment excluding liver transplant | 52 | 53 |
| Survival Follow-up | Liver Transplant | 24 | 28 |
| Survival Follow-up | Lost to Follow-up | 6 | 5 |
| Survival Follow-up | Withdrawal by Subject | 2 | 4 |
Baseline characteristics
| Characteristic | HepaSphere/QuadraSphere TACE | Conventional TACE | Total |
|---|---|---|---|
| Age, Continuous | 64.0 years STANDARD_DEVIATION 8.95 | 64.2 years STANDARD_DEVIATION 8.4 | 64.1 years STANDARD_DEVIATION 8.66 |
| Race/Ethnicity, Customized RACE (NIH/OMB) Asian | 8 Participants | 6 Participants | 14 Participants |
| Race/Ethnicity, Customized RACE (NIH/OMB) Black or African American | 8 Participants | 9 Participants | 17 Participants |
| Race/Ethnicity, Customized RACE (NIH/OMB) More than one race | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized RACE (NIH/OMB) Native Hawaiian or Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized RACE (NIH/OMB) Unknown or Not Reported | 5 Participants | 4 Participants | 9 Participants |
| Race/Ethnicity, Customized RACE (NIH/OMB) White | 95 Participants | 96 Participants | 191 Participants |
| Region of Enrollment Belgium | 2 Participants | 2 Participants | 4 Participants |
| Region of Enrollment France | 2 Participants | 4 Participants | 6 Participants |
| Region of Enrollment Greece | 25 Participants | 24 Participants | 49 Participants |
| Region of Enrollment Italy | 4 Participants | 4 Participants | 8 Participants |
| Region of Enrollment United States | 78 Participants | 79 Participants | 157 Participants |
| Sex: Female, Male Female | 24 Participants | 20 Participants | 44 Participants |
| Sex: Female, Male Male | 94 Participants | 97 Participants | 191 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 100 / 111 | 93 / 113 |
| other Total, other adverse events | 86 / 111 | 87 / 113 |
| serious Total, serious adverse events | 23 / 111 | 21 / 113 |
Outcome results
Primary
Median Overall Survival
Median overall survival will be calculated using the Intent-to-Treat (ITT) population in each treatment arm when the last subject has completed two years of follow up after their first study TACE procedure. Per protocol, study subjects were followed for survival until death or deemed lost to follow up. All deaths are reported within safety.
Time frame: 2 years
Population: The analysis populations for both the HepaSphere/QuadraSphere TACE (hqTACE) and conventional TACE (cTACE) arms included all subjects with HCC that received one or more protocol specified TACE procedures.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HepaSphere/QuadraSphere TACE | Median Overall Survival | 9.0 Months |
| Conventional TACE | Median Overall Survival | 7.0 Months |
Secondary
Objective Response Rates (ORR)
The Objective Response Rate will be calculated for the ITT population by adding the number of participants that were determined to have complete or partial response (utilizing mRECIST criteria) and dividing by the number of ITT participants.
Time frame: Study was terminated early so analysis of additional outcome(s) were not possible.
Population: Data was not collected.
Other Pre-specified
Number of TACE-Related Adverse Events in Subjects Treated With HepaSphere/QuadraSphere vs Subjects Treated With Conventional TACE.
The number of TACE- Related adverse events experienced by subjects treated with HepaSphere/QuadraSphere will be compared to the number of TACE-related adverse events experienced by subjects treated with conventional TACE. Adverse events were recorded for treated subjects from the date of randomization up to and including 30 days post the last study MRI.
Time frame: 30 days
Population: Analysis populations were: 1. All subjects treated with HepaSphere/QuadraSphere TACE and 2. All subjects treated with conventional TACE.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HepaSphere/QuadraSphere TACE | Number of TACE-Related Adverse Events in Subjects Treated With HepaSphere/QuadraSphere vs Subjects Treated With Conventional TACE. | 149 A TACE related Adverse Event |
| Conventional TACE | Number of TACE-Related Adverse Events in Subjects Treated With HepaSphere/QuadraSphere vs Subjects Treated With Conventional TACE. | 164 A TACE related Adverse Event |