Hepatocellular Carcinoma, Hepatoma
Conditions
Keywords
primary liver cancer, sorafenib, Nexavar, doxorubicin, drug eluting beads, transarterial chemoembolization
Brief summary
This study will combine two therapies to treat patients with unresectable hepatocellular carcinoma; sorafenib, and drug eluting beads delivered intra-arterially. The purpose of the study is to establish the safety and the effectiveness of the combination therapy. The investigators hypothesize that the combination of the two therapies will not result in greater toxicities to patients than that expected for either therapy given alone.
Interventions
DRUGsorafenib
sorafenib: given 400 mg twice per day for as long as it is beneficial
PROCEDURELC Bead-TACE
LC Beads loaded with doxorubicin Doxorubicin loaded LC Beads: given intra-arterially into the liver, up to fours times in a 6 month period
Sponsors
Bayer
Biocompatibles UK Ltd
Yale University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Unresectable hepatocellular carcinoma (HCC) patients with liver-predominant disease as described in section 5.1, or patients with hepatocellular carcinoma who refuse surgery. No more than 30% of the cohort should have macrovascular invasion and/or asymptomatic extrahepatic disease. Multifocal HCC is acceptable, no diffuse HCC. 2. Age \> 18 years old 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 4. Childs class of A or B (up to 7) (see Table 5.0) 5. Adequate end-organ function as manifested by: * Absolute neutrophil count of \> 1500/mm3 and platelets \> 50,000/mm3 * Creatinine ≤ 2.0 * Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) \< 5 x upper limit of normal (ULN) * Total bilirubin of ≤ 3 * Albumin \> 2.0 * International normalized ratio (INR) \< 2.0 * Leukocyte count \>3000 cells/mm3 6. Amylase and lipase ≤ 1.5 the upper limit of normal 7. Patients who have received previous hepatic surgery , radiofrequency ablation (RFA), percutaneous ethanol injection (PEI), or cryoablation are eligible if target lesion(s) have not been treated and local therapy completed \> 6 weeks prior to entry. 8. Left ventricular ejection fraction ≥ 45% 9. Patients with asymptomatic HIV infection are not eligible 10. Willingness of male and female subjects, who are not surgically sterile or post menopausal, to use reliable methods of birth control for the duration of the study and for 30 days after the last dose of study medication. 11. Patient must have signed informed consent prior to registration on study. 12. Resolution of all acute toxic effects of any prior local treatment to Common Terminology Criteria for Adverse Events (CTCEA) Grade 1 or 0. 13. At least one tumor lesion can be accurately measured in at least one dimension according to RECIST. The lesion has not been previously treated with local therapy (such as surgery, radiation therapy, RFA, PEI, or cryoablation) unless it has shown progression in the interim.
Exclusion criteria
1. Patients unable to swallow oral medications 2. Prior embolization, systemic or radiation therapy for HCC (liver) 3. Tumor burden in the liver exceeding 70%. 4. Complete occlusion of the entire portal venous system 5. Ascites refractory to diuretic therapy (minimal or trace on imaging is acceptable) 6. 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, and T1). Any cancer curatively treated \> 3 years prior is permitted. 7. Patients with clinically significant gastrointestinal bleeding within 30 days prior to study entry 8. History of bleeding within the past 4 weeks (unless deemed by PI as clinically insignificant, for ex., a brief episode of epistaxis) 9. Any contraindication to doxorubicin administration 10. Evidence of severe or uncontrolled systemic diseases, 11. Congestive cardiac failure \> New York Heart Association (NYHA) class 2, myocardial ischemia within 6 months, active coronary artery disease, cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin, unstable angina, or laboratory finding that in the view of the investigator makes it undesirable for the patient to participate in the trial 12. Any prior history of hypertensive crisis or hypertensive encephalopathy 13. History of stroke or transient ischemic attack within 6 months prior to study enrollment 14. Inadequately controlled hypertension (defined as systolic blood pressure of 150/100 mmHg on antihypertensive medications) (patients with treated hypertension are eligible) 15. Significant vascular disease (e.g., aortic aneurysm, aortic dissection, peripheral vascular disease) 16. History of organ allograft 17. Presence of grade \> 2 hepatic encephalopathy (see Appendix D) 18. Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an additional experimental drug 19. Evidence of bleeding diathesis or coagulopathy or on warfarin. Note: If a patient has been on coumadin for a period of 1 month and has been stable, they may be accepted into the protocol. 20. Presence of clinically evident central nervous system or brain metastases 21. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1, anticipation of need for major surgical procedure during the course of the study 22. Vascular anatomy that precludes catheter placement or injection of LC Bead microspheres 23. Presence of collateral vessel pathways potentially endangering normal territories during embolization 24. Pregnant (positive pregnancy test) or lactating 25. Inability to comply with study and/or follow-up procedures 26. Life expectancy of less than 12 weeks 27. Child B8, B9 and C 28. ECOG ≥ 2 29. Patients with concomitant HIV infection or AIDS-related or serious acute or chronic illness 30. Presence of porto-systemic shunt 31. Severe atheromatosis 32. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of study results 33. Active clinically serious infections (\>grade 2) 34. Patients receiving therapy for hepatitis A, B, or C. 35. Patients with obvious and/or symptomatic extrahepatic disease. Findings of uncertain significance, such as lung lesions less than 10 mm in diameter or enlarged periportal lymph nodes will not exclude patients, however, findings highly suspicious for metastatic HCC will exclude patients from this study. 36. Any contraindication for an arterial procedure such as impaired clotting tests (platelet count \< 50.000/mm3 or prothrombin activity \< 50 percent) 37. Any contraindication for systemic chemotherapy administration (serum bilirubin \> 3mg/dL, leukocyte count \< 3.000 cells/mm3) 38. Any contraindication for sorafenib administration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | 6 weeks (Cycle 1) | Treatment toxicities assessed by CTCAE v3.0 were stratified by cycle - patients on Cycle 1, and patients on Cycles 2-5 or more. 50 patients were reviewed for toxicities for Cycle 1, and all 50 patients experienced at least one adverse event during this time period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy - Factors Associated With Overall Survival (OS) After Combination Treatment With Sorafenib and TACE | 3 years | Overall survival was assessed with Kaplan-Meier estimates of survival, and the Mantel-Cox log-rank test was used to determine differences in survival. |
| Efficacy Assessed by European Association for the Study of the Liver (EASL) Criteria to Determine Response and Disease Control Rate | 6 months | Efficacy as assessed by radiographic tumor response using the EASL criteria at baseline and at 6 months post the initiation of treatment. Complete response (CR): 100% tumor necrosis Partial Response (PR): more than 50% tumor necrosis Progressive Disease (PD): increase in tumor enhancement by more than 25% Stable Disease (SD): Cases that do not qualify for one of the above criteria |
| Efficacy - Median TTP After Combination Treatment With Sorafenib and TACE | 3 years | Time to progression (TTP) - defined as the time from initiation of therapy to disease progression (radiological). Median TTP calculated for all subjects and stratified by Barcelona Clinic Liver Cancer (BCLC) staging. 46 patients out of 50 were reviewed for this outcome. 3 patients were excluded because they underwent liver transplantation and 1 patient was excluded for hepatic resection. |
| Efficacy - Overall Survival (OS) After Combination Treatment With Sorafenib and TACE | 3 years | Overall survival was assessed with Kaplan-Meier estimates of survival, and the Mantel-Cox log-rank test was used to determine differences in survival. All 50 patients were included in survival analyses as all 50 received at least one dose of sorafenib. |
| Efficacy Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) to Determine Response and Disease Control Rate | 6 months | Efficacy as assessed by radiographic tumor response using the RECIST criteria at baseline and at 6 months post the initiation of treatment. 33 out of the original 50 patients were evaluable at this time point, with 17 out of the 50 exiting prior to 6 months or were not assessable by RECIST criteria. Complete response (CR): Disappearance of all lesions targeted with therapy Partial Response (PR): at least 30% decrease in sum of longest diameter (LD) of targeted lesions Progressive Disease (PD): at least 20% increase in the sum of LD of targeted lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR or sufficient increase to qualify for PD |
Other
| Measure | Time frame | Description |
|---|---|---|
| Estimated Percentage of Participants Surviving After Three Year | 3 years | Percentage of study patients surviving after three years from initial treatment analyzed with Kaplan-Meier curve. |
| Median Overall Survival OS Stratified by BCLC Criteria | up to 4 years | Median overall survival stratified by Barcelona Clinic Liver Cancer (BCLC) staging as assessed by Kaplan-Meier estimator. Patients are grouped to stages A (early), B (intermediate), and C (advanced) according to stage of disease. |
| Estimated Percentage of Participants Surviving After One Year | 1 year | Percentage of study patients surviving after one year from initial treatment analyzed with Kaplan-Meier curve. |
Countries
United States
Participant flow
Recruitment details
This study enrolled patients diagnosed with unresectable hepatocellular carcinoma who were eligible to receive a combination therapy of sorafenib and transarterial chemoembolization. Enrollment took place from 3/2009 to 12/2011 at Johns Hopkins Hospital.
Pre-assignment details
90 patients consented and screened for study. 38 were ineligible and 2 later declined participation.
Participants by arm
| Arm | Count |
|---|---|
| Sorafenib and Drug Eluting Beads single arm
sorafenib: sorafenib: given 400 mg twice per day for as long as it is beneficial
LC Bead-TACE: LC Beads loaded with doxorubicin
Doxorubicin loaded LC Beads: given intra-arterially into the liver, up to fours times in a 6 month period | 50 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Bridged to liver transplant | 3 |
| Overall Study | Bridged to resection | 1 |
Baseline characteristics
| Characteristic | Sorafenib and Drug Eluting Beads |
|---|---|
| Age, Continuous | 60 years |
| Region of Enrollment United States | 50 Participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 50 |
| other Total, other adverse events | 50 / 50 |
| serious Total, serious adverse events | 8 / 50 |
Outcome results
Primary
Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment.
Treatment toxicities assessed by CTCAE v3.0 were stratified by cycle - patients on Cycle 1, and patients on Cycles 2-5 or more.
Time frame: 2 years (Cycles 2-5+)
Population: 39 patients were reviewed for toxicities for Cycle 2-5+. 11 patients out of the original 50 exited the study prior to Cycle 2.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Acute renal failure | 1 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Anemia | 14 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Lymphopenia | 19 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Pancytopenia | 1 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Thrombocytopenia | 11 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Arrhythmia | 2 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Chest pain | 1 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Hypertension | 4 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Lower extremity edema | 3 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Fatigue | 30 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Fever | 4 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Hand-foot skin reaction | 20 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Mucositis | 6 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Rash | 12 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Skin pain | 3 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Ascites | 2 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Anorexia | 14 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Diarrhea | 15 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Nausea or vomiting | 13 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Epistaxis or hemoptysis | 1 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Cholangitis | 1 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Elevated ALT level | 9 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Elevated AST level | 10 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Elevated AP level | 15 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Elevated amylase level | 7 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Elevated lipase level | 9 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Elevated INR level | 8 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Hyperbilirubinemia | 11 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Hypoalbuminemia | 14 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Infection | 8 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Liver abscess | 1 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Dizziness | 1 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Headache | 6 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Encephalopathy | 3 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Nonspecific abdominal pain | 22 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Musculoskeletal pain | 17 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Right upper quadrant pain | 10 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Pain - other | 4 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Death (disease progression) | 2 # of participants with adverse events |
Primary
Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment.
Treatment toxicities assessed by CTCAE v3.0 were stratified by cycle - patients on Cycle 1, and patients on Cycles 2-5 or more. 50 patients were reviewed for toxicities for Cycle 1, and all 50 patients experienced at least one adverse event during this time period.
Time frame: 6 weeks (Cycle 1)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Hematoma | 3 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Tumor rupture | 1 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Anemia | 13 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Lymphopenia | 24 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Thrombocytopenia | 8 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Arrhythmia | 4 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Chest pain | 2 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Dissection | 1 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Embolus or coagulopathy | 1 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Hypertension | 7 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Lower extremity edema | 12 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Fatigue | 42 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Fever | 15 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Hand-foot skin reaction | 23 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Mucositis | 11 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Rash | 26 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Skin pain | 4 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Ascites | 3 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Anorexia | 28 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Diarrhea | 19 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Nausea or vomiting | 24 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Epistaxis or hemoptysis | 1 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Hematochezia | 2 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Elevated ALT level | 25 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Elevated AST level | 24 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Elevated AP level | 17 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Elevated amylase level | 10 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Elevated lipase level | 15 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Elevated INR level | 16 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Hyperbilirubinemia | 30 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Hypoalbuminemia | 27 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Infection | 6 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Dizziness | 4 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Headache | 9 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Encephalopathy | 3 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Nonspecific abdominal pain | 24 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Musculoskeletal pain | 24 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Right upper quadrant pain | 24 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Pain - other | 12 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Acute renal failure | 3 # of participants with adverse events |
| Sorafenib and Drug Eluting Beads | Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Death (disease progression) | 1 # of participants with adverse events |
Secondary
Efficacy Assessed by European Association for the Study of the Liver (EASL) Criteria to Determine Response and Disease Control Rate
Efficacy as assessed by radiographic tumor response using the EASL criteria at baseline and at 6 months post the initiation of treatment. Complete response (CR): 100% tumor necrosis Partial Response (PR): more than 50% tumor necrosis Progressive Disease (PD): increase in tumor enhancement by more than 25% Stable Disease (SD): Cases that do not qualify for one of the above criteria
Time frame: 6 months
Population: 32 out of the 50 patients had imaging assessable by EASL criteria at 6 months - 18 out of the original 50 had exited prior to this time point or did not have applicable imaging.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sorafenib and Drug Eluting Beads | Efficacy Assessed by European Association for the Study of the Liver (EASL) Criteria to Determine Response and Disease Control Rate | Complete Response | 7 Participants |
| Sorafenib and Drug Eluting Beads | Efficacy Assessed by European Association for the Study of the Liver (EASL) Criteria to Determine Response and Disease Control Rate | Partial Response | 15 Participants |
| Sorafenib and Drug Eluting Beads | Efficacy Assessed by European Association for the Study of the Liver (EASL) Criteria to Determine Response and Disease Control Rate | Stable Disease | 8 Participants |
| Sorafenib and Drug Eluting Beads | Efficacy Assessed by European Association for the Study of the Liver (EASL) Criteria to Determine Response and Disease Control Rate | Progressive Disease | 2 Participants |
| Sorafenib and Drug Eluting Beads | Efficacy Assessed by European Association for the Study of the Liver (EASL) Criteria to Determine Response and Disease Control Rate | Disease control rate (CR + PR + SD) | 30 Participants |
Secondary
Efficacy Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) to Determine Response and Disease Control Rate
Efficacy as assessed by radiographic tumor response using the RECIST criteria at baseline and at 6 months post the initiation of treatment. 33 out of the original 50 patients were evaluable at this time point, with 17 out of the 50 exiting prior to 6 months or were not assessable by RECIST criteria. Complete response (CR): Disappearance of all lesions targeted with therapy Partial Response (PR): at least 30% decrease in sum of longest diameter (LD) of targeted lesions Progressive Disease (PD): at least 20% increase in the sum of LD of targeted lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR or sufficient increase to qualify for PD
Time frame: 6 months
Population: 33 out of the original 50 patients were evaluable for this outcome, with 17 out of the original 50 exiting prior to 6 months or were not assessable by RECIST criteria.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sorafenib and Drug Eluting Beads | Efficacy Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) to Determine Response and Disease Control Rate | Complete Response | 1 Participants |
| Sorafenib and Drug Eluting Beads | Efficacy Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) to Determine Response and Disease Control Rate | Partial Response or Stable Disease | 30 Participants |
| Sorafenib and Drug Eluting Beads | Efficacy Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) to Determine Response and Disease Control Rate | Progressive Disease | 2 Participants |
| Sorafenib and Drug Eluting Beads | Efficacy Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) to Determine Response and Disease Control Rate | Disease control rate (CR + PR + SD) | 31 Participants |
Secondary
Efficacy - Factors Associated With Overall Survival (OS) After Combination Treatment With Sorafenib and TACE
Overall survival was assessed with Kaplan-Meier estimates of survival, and the Mantel-Cox log-rank test was used to determine differences in survival.
Time frame: 3 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sorafenib and Drug Eluting Beads | Efficacy - Factors Associated With Overall Survival (OS) After Combination Treatment With Sorafenib and TACE | Median liver tumor burden >10% | 2.60 Hazard ratio |
| Sorafenib and Drug Eluting Beads | Efficacy - Factors Associated With Overall Survival (OS) After Combination Treatment With Sorafenib and TACE | Median tumor size > 10cm | 2.12 Hazard ratio |
| Sorafenib and Drug Eluting Beads | Efficacy - Factors Associated With Overall Survival (OS) After Combination Treatment With Sorafenib and TACE | ECOG performance status | 2.45 Hazard ratio |
| Sorafenib and Drug Eluting Beads | Efficacy - Factors Associated With Overall Survival (OS) After Combination Treatment With Sorafenib and TACE | BCLC stage | 2.49 Hazard ratio |
Secondary
Efficacy - Median TTP After Combination Treatment With Sorafenib and TACE
Time to progression (TTP) - defined as the time from initiation of therapy to disease progression (radiological). Median TTP calculated for all subjects and stratified by Barcelona Clinic Liver Cancer (BCLC) staging. 46 patients out of 50 were reviewed for this outcome. 3 patients were excluded because they underwent liver transplantation and 1 patient was excluded for hepatic resection.
Time frame: 3 years
Population: Median TTP stratified by BCLC staging; 3 patients had BCLC stage A disease, 14 with stage B, and 29 with stage C.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sorafenib and Drug Eluting Beads | Efficacy - Median TTP After Combination Treatment With Sorafenib and TACE | Median TTP | 13.9 months |
| Sorafenib and Drug Eluting Beads | Efficacy - Median TTP After Combination Treatment With Sorafenib and TACE | Median TTP for BCLC stage A | 27.6 months |
| Sorafenib and Drug Eluting Beads | Efficacy - Median TTP After Combination Treatment With Sorafenib and TACE | Median TTP for BCLC stage B | 24.7 months |
| Sorafenib and Drug Eluting Beads | Efficacy - Median TTP After Combination Treatment With Sorafenib and TACE | Median TTP for BCLC stage C | 9.5 months |
Secondary
Efficacy - Overall Survival (OS) After Combination Treatment With Sorafenib and TACE
Overall survival was assessed with Kaplan-Meier estimates of survival, and the Mantel-Cox log-rank test was used to determine differences in survival. All 50 patients were included in survival analyses as all 50 received at least one dose of sorafenib.
Time frame: 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib and Drug Eluting Beads | Efficacy - Overall Survival (OS) After Combination Treatment With Sorafenib and TACE | 20.4 months |
Other Pre-specified
Estimated Percentage of Participants Surviving After One Year
Percentage of study patients surviving after one year from initial treatment analyzed with Kaplan-Meier curve.
Time frame: 1 year
Population: All 50 patients were included in survival analyses as all 50 received at least one dose of sorafenib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib and Drug Eluting Beads | Estimated Percentage of Participants Surviving After One Year | 64 percentage of participants |
Other Pre-specified
Estimated Percentage of Participants Surviving After Three Year
Percentage of study patients surviving after three years from initial treatment analyzed with Kaplan-Meier curve.
Time frame: 3 years
Population: All 50 patients were included in survival analyses as all 50 received at least one dose of sorafenib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib and Drug Eluting Beads | Estimated Percentage of Participants Surviving After Three Year | 19.6 percentage of participants |
Other Pre-specified
Median Overall Survival OS Stratified by BCLC Criteria
Median overall survival stratified by Barcelona Clinic Liver Cancer (BCLC) staging as assessed by Kaplan-Meier estimator. Patients are grouped to stages A (early), B (intermediate), and C (advanced) according to stage of disease.
Time frame: up to 4 years
Population: 50 total participants received sorafenib on trial. 3 were classified as BCLC A, 16 as BCLC B, and 31 as BCLC C.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sorafenib and Drug Eluting Beads | Median Overall Survival OS Stratified by BCLC Criteria | BCLC A | 45.6 months |
| Sorafenib and Drug Eluting Beads | Median Overall Survival OS Stratified by BCLC Criteria | BCLC B | 29.7 months |
| Sorafenib and Drug Eluting Beads | Median Overall Survival OS Stratified by BCLC Criteria | BCLC C | 8.0 months |