Study of Sorafenib and Transarterial Chemoembolization (TACE) to Treat Hepatocellular Carcinoma

Phase II Trial of Sorafenib Combined With Doxorubicin Eluting Bead-Transarterial Chemoembolization (LC Bead-TACE) for Patients With Hepatocellular Carcinoma

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.

Study Overview

• Status: Completed
• Conditions: Hepatocellular Carcinoma; Hepatoma
• Intervention / Treatment: Drug: sorafenib; Procedure: LC Bead-TACE

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • The Johns Hopkins Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: sorafenib and drug eluting beads; single arm	Drug: sorafenib; sorafenib: given 400 mg twice per day for as long as it is beneficial; Other Names: sorafenib (Nexavar); Procedure: 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; Other Names: LC Beads manufactured by Biocompatibles

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	6 weeks (Cycle 1)
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.	2 years (Cycles 2-5+)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	6 months
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	6 months
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.	3 years
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.	3 years
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.	3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Estimated Percentage of Participants Surviving After One Year	Percentage of study patients surviving after one year from initial treatment analyzed with Kaplan-Meier curve.	1 year
Estimated Percentage of Participants Surviving After Three Year	Percentage of study patients surviving after three years from initial treatment analyzed with Kaplan-Meier curve.	3 years
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.	up to 4 years

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: Bayer; Biocompatibles UK Ltd

Study record dates

Study Major Dates

• Study Start: February 1, 2009
• Primary Completion (ACTUAL): March 1, 2015
• Study Completion (ACTUAL): March 1, 2015

Study Registration Dates

• First Submitted: February 4, 2009
• First Submitted That Met QC Criteria: February 13, 2009
• First Posted (ESTIMATE): February 16, 2009

Study Record Updates

• Last Update Posted (ACTUAL): November 11, 2021
• Last Update Submitted That Met QC Criteria: October 15, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Nexavar; doxorubicin; sorafenib; transarterial chemoembolization; primary liver cancer; drug eluting beads
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Sorafenib
• Other Study ID Numbers: J08110