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

Primary Purpose

Hepatocellular Carcinoma, Hepatoma

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
sorafenib
LC Bead-TACE
Sponsored by
Yale University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hepatocellular Carcinoma focused on measuring primary liver cancer, sorafenib, Nexavar, doxorubicin, drug eluting beads, transarterial chemoembolization

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • The Johns Hopkins Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

sorafenib and drug eluting beads

Arm Description

single arm

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

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
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
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.
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.
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.

Full Information

First Posted
February 4, 2009
Last Updated
October 15, 2021
Sponsor
Yale University
Collaborators
Bayer, Biocompatibles UK Ltd
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1. Study Identification

Unique Protocol Identification Number
NCT00844883
Brief Title
Study of Sorafenib and Transarterial Chemoembolization (TACE) to Treat Hepatocellular Carcinoma
Official Title
Phase II Trial of Sorafenib Combined With Doxorubicin Eluting Bead-Transarterial Chemoembolization (LC Bead-TACE) for Patients With Hepatocellular Carcinoma
Study Type
Interventional

2. Study Status

Record Verification Date
October 2021
Overall Recruitment Status
Completed
Study Start Date
February 2009 (undefined)
Primary Completion Date
March 2015 (Actual)
Study Completion Date
March 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Yale University
Collaborators
Bayer, Biocompatibles UK Ltd

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatocellular Carcinoma, Hepatoma
Keywords
primary liver cancer, sorafenib, Nexavar, doxorubicin, drug eluting beads, transarterial chemoembolization

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
50 (Actual)

8. Arms, Groups, and Interventions

Arm Title
sorafenib and drug eluting beads
Arm Type
Experimental
Arm Description
single arm
Intervention Type
Drug
Intervention Name(s)
sorafenib
Other Intervention Name(s)
sorafenib (Nexavar)
Intervention Description
sorafenib: given 400 mg twice per day for as long as it is beneficial
Intervention Type
Procedure
Intervention Name(s)
LC Bead-TACE
Other Intervention Name(s)
LC Beads manufactured by Biocompatibles
Intervention Description
LC Beads loaded with doxorubicin Doxorubicin loaded LC Beads: given intra-arterially into the liver, up to fours times in a 6 month period
Primary Outcome Measure Information:
Title
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.
Description
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)
Title
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.
Description
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+)
Secondary Outcome Measure Information:
Title
Efficacy Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) to Determine Response and Disease Control Rate
Description
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
Title
Efficacy Assessed by European Association for the Study of the Liver (EASL) Criteria to Determine Response and Disease Control Rate
Description
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
Title
Efficacy - Median TTP After Combination Treatment With Sorafenib and TACE
Description
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
Title
Efficacy - Overall Survival (OS) After Combination Treatment With Sorafenib and TACE
Description
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
Title
Efficacy - Factors Associated With Overall Survival (OS) After Combination Treatment With Sorafenib and TACE
Description
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
Other Pre-specified Outcome Measures:
Title
Estimated Percentage of Participants Surviving After One Year
Description
Percentage of study patients surviving after one year from initial treatment analyzed with Kaplan-Meier curve.
Time Frame
1 year
Title
Estimated Percentage of Participants Surviving After Three Year
Description
Percentage of study patients surviving after three years from initial treatment analyzed with Kaplan-Meier curve.
Time Frame
3 years
Title
Median Overall Survival OS Stratified by BCLC Criteria
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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. Age > 18 years old Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 Childs class of A or B (up to 7) (see Table 5.0) 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 Amylase and lipase ≤ 1.5 the upper limit of normal 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. Left ventricular ejection fraction ≥ 45% Patients with asymptomatic HIV infection are not eligible 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. Patient must have signed informed consent prior to registration on study. Resolution of all acute toxic effects of any prior local treatment to Common Terminology Criteria for Adverse Events (CTCEA) Grade 1 or 0. 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: Patients unable to swallow oral medications Prior embolization, systemic or radiation therapy for HCC (liver) Tumor burden in the liver exceeding 70%. Complete occlusion of the entire portal venous system Ascites refractory to diuretic therapy (minimal or trace on imaging is acceptable) 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. Patients with clinically significant gastrointestinal bleeding within 30 days prior to study entry History of bleeding within the past 4 weeks (unless deemed by PI as clinically insignificant, for ex., a brief episode of epistaxis) Any contraindication to doxorubicin administration Evidence of severe or uncontrolled systemic diseases, 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 Any prior history of hypertensive crisis or hypertensive encephalopathy History of stroke or transient ischemic attack within 6 months prior to study enrollment Inadequately controlled hypertension (defined as systolic blood pressure of 150/100 mmHg on antihypertensive medications) (patients with treated hypertension are eligible) Significant vascular disease (e.g., aortic aneurysm, aortic dissection, peripheral vascular disease) History of organ allograft Presence of grade > 2 hepatic encephalopathy (see Appendix D) Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an additional experimental drug 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. Presence of clinically evident central nervous system or brain metastases 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 Vascular anatomy that precludes catheter placement or injection of LC Bead microspheres Presence of collateral vessel pathways potentially endangering normal territories during embolization Pregnant (positive pregnancy test) or lactating Inability to comply with study and/or follow-up procedures Life expectancy of less than 12 weeks Child B8, B9 and C ECOG ≥ 2 Patients with concomitant HIV infection or AIDS-related or serious acute or chronic illness Presence of porto-systemic shunt Severe atheromatosis Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of study results Active clinically serious infections (>grade 2) Patients receiving therapy for hepatitis A, B, or C. 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. Any contraindication for an arterial procedure such as impaired clotting tests (platelet count < 50.000/mm3 or prothrombin activity < 50 percent) Any contraindication for systemic chemotherapy administration (serum bilirubin > 3mg/dL, leukocyte count < 3.000 cells/mm3) Any contraindication for sorafenib administration
Facility Information:
Facility Name
The Johns Hopkins Hospital
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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