Hepatocellular Cancer
Conditions
Keywords
Hepatocellular Cancer, HCC, Liver Cancer, radiofrequency ablation, RFA, sorafenib, nexavaar, liver directed therapy, interventional radiology
Brief summary
The purpose of this research study is to determine if sorafenib improves the effectiveness of a procedure called radiofrequency ablation (RFA) for the treatment of hepatocellular cancer (HCC). Radiofrequency ablation has been used to treat many types of tumors, including hepatocellular cancers. During RFA a needle is inserted into the tumor tissue and heat is used to kill the tumor cells. Sorafenib has been approved by the FDA for the treatment of hepatocellular cancer that cannot be treated with surgery. Pre-clinical data suggests that sorafenib may improve the efficacy of RFA.
Detailed description
Hepatocellular cancer (HCC) has a poor prognosis with increasing mortality in the United States. Because HCC generally develops in patients with underlying liver disease, resection is often not possible. Liver transplant improves survival for HCC patients but given the national organ donor shortage often patients have to wait a considerable time for transplant. Liver-directed therapies such as radiofrequency ablation (RFA) remain important tools to control tumor growth and to potentially bridge patients to liver transplant. However, liver-directed therapies for HCC tumors greater than 3cm in size are suboptimal, leaving a critical unmet need. Antiangiogenic systemic agents, such as oral sorafenib, reduce tumor blood flow and have been shown to improve RFA efficacy in animal and in computer models.
Interventions
DRUGSorafenib
PROCEDUREradiofrequency ablation
Sponsors
Dana-Farber Cancer Institute
Brigham and Women's Hospital
Bayer
Onyx Therapeutics, Inc.
National Cancer Institute (NCI)
Beth Israel Deaconess Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed hepatocellular cancer (HCC) by pathology or by NCCN imaging guidelines * All HCC stages are allowed. May be a liver transplant candidate. * At least one tumor (index tumor) accurately measured as 3.5-7cm in diameter (long and short axis diameter to be recorded, but only one needs to meet this criteria) on baseline imaging. * No prior therapy for the index tumor * No prior systemic treatment for HCC within 4 weeks and no prior anti-VEGF therapy within 8 weeks of study entry. * Life expectancy \> 8 weeks. * ECOG \>=0 or 1 * RFA clinically indicated for index tumor. * Acceptable overall RFA and anesthesia risk. * Adequate bone marrow, liver and renal function: Hemoglobin \>9.0 g/dl; Absolute neutrophil count (ANC)\>1,500/mm3; Platelet count correctable to \>50,000/mm3; compensated liver function (Child-Turcotte-Pugh A, B7 or B8); Creatinine \<1.5 times ULN; INR correctable to \<1.5. * Ability to take oral medication and no evidence of impaired absorption.
Exclusion criteria
* Urgent treatment of the index tumor anticipated. * Participants who have not recovered from adverse events due to agents administered more than 4 weeks earlier. Participants currently receiving any other study agents. * Known brain metastases * History of allergic reactions attributed to compounds of similar chemical or biologic composition to sorafenib. * Participants receiving medications or substances that are inducers of CYP3A4 (rifampicin, St. John's wort, phenytoin, carbamazepine, phenobarbital and dexamethasone) or that are metabolized/eliminated by predominantly UGT1A1 pathway or by CYP2B6 and CYP2C8. * Decompensated liver disease * Uncontrolled hypertension * Thrombolic or embolic events within the past 6 months. * Hemorrhage/bleeding event within 4 weeks * Serious non-healing wound, ulcer, or bone fracture. * Evidence of severe or uncorrectable bleeding diathesis or coagulopathy * Major surgery, open biopsy or significant traumatic injury within 4 weeks of study entry. * Contraindication to or inability to undergo the RFA procedure, * Contraindication to or inability to undergo imaging with MRI * Uncontrolled intercurrent illness * Individuals with a history of a different malignancy unless disease-free for at least 5 years and are deemed by the Investigator to be at low risk for recurrence. Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin. * HIV-positive individuals on combination antiretroviral therapy For additional inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Coagulation Zone Diameter-Short Axis | Up to day 50 from study enrollment (target 30 days after RFA) | The size of the coagulation zone was determined on CT imaging obtained after RFA for the single index tumor. |
| Coagulation Zone Diameter-Long Axis | Up to day 50 from study enrollment (target 30 days after RFA) | The size of the coagulation zone was determined on CT imaging obtained after RFA for the single index tumor. |
| Coagulation Zone Volume | Up to day 50 from study enrollment (target 30 days after RFA) | The size of the coagulation zone was determined on CT imaging obtained after RFA for the single index tumor. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Feasibility Rate | Up to day 14 since enrollment | Feasibility rate is defined as the percentage of participants completing radiofrequency ablation following 9 days of sorafenib or placebo therapy. |
| Number of Treatment-Related Grade 1-4 Adverse Events (AEs) One Month After Radiofrequency Ablation (RFA) | Up to day 40 post RFA (target 30 days) | AEs were assessed based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v3.0). The number of Grade 1-4 AEs with treatment attribution possibly, probably or definitely related one month after RFA treatment were counted for this outcome. Worst grade by patient within AE type was calculated. Participants could have multiple AE types within a grade. |
| Number of Treatment-Related Grade 1-4 Adverse Events (AEs) by Day 9 | Day 9 | AEs were assessed based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v3.0). The number of Grade 1-4 AEs with treatment attribution possibly, probably or definitely related up to day 9 of study drug treatment were counted for this outcome. Worst grade by patient within AE type was calculated. Participants could have multiple different AE types within a grade. |
| Number of Treatment-Related Grade 1-4 Adverse Events (AEs) on Day of Radiofrequency Ablation (RFA) | Up to day 14 (target day 10 RFA) | AEs were assessed based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v3.0). The number of Grade 1-4 AEs with treatment attribution possibly, probably or definitely related on day of RFA treatment were counted for this outcome. Worst grade by patient within AE type was calculated. Participants could have multiple AE types within a grade. |
Countries
United States
Participant flow
Recruitment details
Participants enrolled from June 2009 through August 2013.
Participants by arm
| Arm | Count |
|---|---|
| Sorafenib Participants received a nine-day course of oral sorafenib 400 mg twice a day and radiofrequency ablation (RFA) on Day 10. Tumors in each group underwent RFA using a standard regimen (1 cm tip, 70 ± 2º C, 5 min). | 10 |
| Placebo Participants received a nine-day course of placebo pills twice a day and radiofrequency ablation (RFA) on Day 10. Tumors in each group underwent RFA using a standard regimen (1 cm tip, 70 ± 2º C, 5 min). | 10 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Intercurrent illness | 1 | 0 |
Baseline characteristics
| Characteristic | Sorafenib | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 69 years STANDARD_DEVIATION 10 | 66 years STANDARD_DEVIATION 11 | 68 years STANDARD_DEVIATION 10 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 7 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 4 Participants |
| Present Liver Cirrhosis | 10 Participants | 10 Participants | 20 Participants |
| Present Portal Vein Thrombosis | 1 Participants | 5 Participants | 6 Participants |
| Region of Enrollment United States | 10 participants | 10 participants | 20 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 16 Participants |
| Tumor Size - Long Axis | 4.9 centimeters STANDARD_DEVIATION 1.7 | 5.3 centimeters STANDARD_DEVIATION 1.3 | 5.1 centimeters STANDARD_DEVIATION 1.5 |
| Tumor Size - Short Axis | 4.4 centimeters STANDARD_DEVIATION 1.3 | 4.4 centimeters STANDARD_DEVIATION 1.4 | 4.4 centimeters STANDARD_DEVIATION 1.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 10 |
| other Total, other adverse events | 9 / 9 | 10 / 10 |
| serious Total, serious adverse events | 1 / 9 | 1 / 10 |
Outcome results
Primary
Coagulation Zone Diameter-Long Axis
The size of the coagulation zone was determined on CT imaging obtained after RFA for the single index tumor.
Time frame: Up to day 50 from study enrollment (target 30 days after RFA)
Population: The analysis population is comprised of all participants who completed treatment ending with RFA.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sorafenib | Coagulation Zone Diameter-Long Axis | 42.4 millimeters | Standard Deviation 9.2 |
| Placebo | Coagulation Zone Diameter-Long Axis | 44.1 millimeters | Standard Deviation 7.8 |
Primary
Coagulation Zone Diameter-Short Axis
The size of the coagulation zone was determined on CT imaging obtained after RFA for the single index tumor.
Time frame: Up to day 50 from study enrollment (target 30 days after RFA)
Population: The analysis population is comprised of all participants who completed treatment ending with day 10 RFA.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sorafenib | Coagulation Zone Diameter-Short Axis | 36.0 millimeters | Standard Deviation 7.8 |
| Placebo | Coagulation Zone Diameter-Short Axis | 35.1 millimeters | Standard Deviation 8.8 |
Primary
Coagulation Zone Volume
The size of the coagulation zone was determined on CT imaging obtained after RFA for the single index tumor.
Time frame: Up to day 50 from study enrollment (target 30 days after RFA)
Population: The analysis population is comprised of all participants who completed treatment ending with RFA.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sorafenib | Coagulation Zone Volume | 30.7 centimeters^3 | Standard Deviation 24.6 |
| Placebo | Coagulation Zone Volume | 30.5 centimeters^3 | Standard Deviation 21.5 |
Comparison: Assuming the two trial arms were independent, the standard deviation was 0.5cm for both arms and a sample size of 16 evaluable patients (8 per arm), the study had an 84% power at a 5% (two-sided) significance level to detect 0.8cm difference in ablation zone size. In order to allow a 20% drop-out rate, a total of 20 subjects were accrued.p-value: 0.794Wilcoxon (Mann-Whitney)
Secondary
Feasibility Rate
Feasibility rate is defined as the percentage of participants completing radiofrequency ablation following 9 days of sorafenib or placebo therapy.
Time frame: Up to day 14 since enrollment
Population: The analysis population is comprised of all enrolled participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib | Feasibility Rate | 90 percentage of particpants |
| Placebo | Feasibility Rate | 90 percentage of particpants |
Secondary
Number of Treatment-Related Grade 1-4 Adverse Events (AEs) by Day 9
AEs were assessed based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v3.0). The number of Grade 1-4 AEs with treatment attribution possibly, probably or definitely related up to day 9 of study drug treatment were counted for this outcome. Worst grade by patient within AE type was calculated. Participants could have multiple different AE types within a grade.
Time frame: Day 9
Population: The analysis population is comprised of all treated participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib | Number of Treatment-Related Grade 1-4 Adverse Events (AEs) by Day 9 | 8 adverse events |
| Placebo | Number of Treatment-Related Grade 1-4 Adverse Events (AEs) by Day 9 | 4 adverse events |
Secondary
Number of Treatment-Related Grade 1-4 Adverse Events (AEs) on Day of Radiofrequency Ablation (RFA)
AEs were assessed based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v3.0). The number of Grade 1-4 AEs with treatment attribution possibly, probably or definitely related on day of RFA treatment were counted for this outcome. Worst grade by patient within AE type was calculated. Participants could have multiple AE types within a grade.
Time frame: Up to day 14 (target day 10 RFA)
Population: The analysis population is comprised of all participants who completed treatment ending with RFA.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib | Number of Treatment-Related Grade 1-4 Adverse Events (AEs) on Day of Radiofrequency Ablation (RFA) | 5 adverse events |
| Placebo | Number of Treatment-Related Grade 1-4 Adverse Events (AEs) on Day of Radiofrequency Ablation (RFA) | 4 adverse events |
Secondary
Number of Treatment-Related Grade 1-4 Adverse Events (AEs) One Month After Radiofrequency Ablation (RFA)
AEs were assessed based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v3.0). The number of Grade 1-4 AEs with treatment attribution possibly, probably or definitely related one month after RFA treatment were counted for this outcome. Worst grade by patient within AE type was calculated. Participants could have multiple AE types within a grade.
Time frame: Up to day 40 post RFA (target 30 days)
Population: The analysis population is comprised of all treated participants who were evaluable for AEs at day40.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib | Number of Treatment-Related Grade 1-4 Adverse Events (AEs) One Month After Radiofrequency Ablation (RFA) | 8 adverse events |
| Placebo | Number of Treatment-Related Grade 1-4 Adverse Events (AEs) One Month After Radiofrequency Ablation (RFA) | 4 adverse events |