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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00844883
First Posted: February 16, 2009
Last Update Posted: August 28, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
Bayer
Biocompatibles UK Ltd
Information provided by (Responsible Party):
Jeff Geschwind, Yale University
  Purpose
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.

Condition Intervention Phase
Hepatocellular Carcinoma Hepatoma Drug: sorafenib Procedure: LC Bead-TACE Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Trial of Sorafenib Combined With Doxorubicin Eluting Bead-Transarterial Chemoembolization (LC Bead-TACE) for Patients With Hepatocellular Carcinoma

Resource links provided by NLM:


Further study details as provided by Jeff Geschwind, Yale University:

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. [ Time Frame: 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.

  • 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. [ Time Frame: 2 years (Cycles 2-5+) ]
    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 [ Time Frame: 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


  • Efficacy Assessed by European Association for the Study of the Liver (EASL) Criteria to Determine Response and Disease Control Rate [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 - Factors Associated With Overall Survival (OS) After Combination Treatment With Sorafenib and TACE [ Time Frame: 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.


Enrollment: 50
Study Start Date: February 2009
Study Completion Date: March 2015
Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: LC Beads manufactured by Biocompatibles

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00844883


Locations
United States, Maryland
The Johns Hopkins Hospital
Baltimore, Maryland, United States, 21287
Sponsors and Collaborators
Yale University
Bayer
Biocompatibles UK Ltd
  More Information

Responsible Party: Jeff Geschwind, Professor of Radiology and Oncology, Yale University
ClinicalTrials.gov Identifier: NCT00844883     History of Changes
Other Study ID Numbers: J08110
First Submitted: February 4, 2009
First Posted: February 16, 2009
Results First Submitted: April 19, 2017
Results First Posted: August 28, 2017
Last Update Posted: August 28, 2017
Last Verified: July 2017

Keywords provided by Jeff Geschwind, Yale University:
primary liver cancer
sorafenib
Nexavar
doxorubicin
drug eluting beads
transarterial chemoembolization

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Doxorubicin
Liposomal doxorubicin
Sorafenib
Niacinamide
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Protein Kinase Inhibitors
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs