Back to resultsRadiation Therapy With Sorafenib for TACE-Resistant Hepatocellular Carcinoma
Primary Purpose
Hepatocellular Carcinoma, Hepatocellular Cancer, Hepatoma
Status
Withdrawn
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Sorafenib
Conventional fractionation (2 Gy per day) external beam radiation therapy
Sponsored by
About this trial
This is an interventional treatment trial for Hepatocellular Carcinoma focused on measuring Transarterial Chemoembolization, TACE, Sorafenib Tosylate, Sorafenib, Nexavar, External Beam Radiation Therapy, Radiation Therapy, Radiotherapy, Radiation
Eligibility Criteria
Inclusion Criteria:
- Radiographic or histologic diagnosis of hepatocellular carcinoma (HCC).
- Maximum of 3 HCC lesions within the liver.
- No evidence of lymphadenopathy or metastatic disease per either CT or PET.
- Prior transarterial chemo-embolization (TACE) at least 28 days prior to initiation of protocol therapy.
- Evidence of either progressive disease or stable disease following TACE.
- Child Pugh Class A (score 5-6) or B (score 7).
- Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1 (or Karnofsky ≥70%).
- Normal organ and marrow function (platelets >60,000/mc; hemoglobin ≥8.5 g/dL; international normalized ratio (INR) ≤2.3; albumin ≥2.8 g/dL; total bilirubin ≤3 mg/dL; aspartate aminotransferase (AST) / alanine aminotransferase (ALT) <5x upper limit of normal; creatinine ≤1.5x upper limit of normal).
- Negative human immunodeficiency virus serology.
- Negative pregnancy test for women of child bearing age.
- Ability to understand and willingness to sign a written informed consent document.
Exclusion Criteria:
- Less than 800 cc of normal liver.
- Child Pugh Class B (score 8-9) or C (score 10-15).
- Acute/active hepatitis B infection.
- Prior systemic chemotherapy or abdominal radiation therapy.
- Portal venous (main, primary right, or primary left trunks) or inferior vena cava thrombosis.
- Prior malignancy within 5 years of enrollment except for non-melanoma skin cancer.
- Prior history of myocardial infarction, cerebrovascular accident, or esophageal variceal bleed in the last 6 months.
- Pre-existing heart failure with either a clinical classification of New York Heart Association Class III or IV or cardiac ejection fraction of <45%.
- Systolic blood pressure > 160 mmHg or diastolic pressure > 100 mmHg despite optimal medical management.
- Pulmonary hemorrhage or other serious bleeding event (grade 2+) within 4 weeks initiation of protocol therapy.
- Prior history of scleroderma or active systemic lupus erythematosus.
Sites / Locations
- Froedtert Memorial Lutheran Hospital
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Radiation therapy with concurrent sorafenib
Arm Description
Outcomes
Primary Outcome Measures
Maximum Tolerated Dose
Maximum tolerated dose (MTD) will be determined by dose limiting toxicity (DLT) that is observed in either the acute (during treatment) or subacute (up to 3 months after treatment) setting. Acute DLT will be defined by grade 3-5 hepatic, gastrointestinal, dermatologic, hematologic, or pulmonary toxicity per Common Toxicity Criteria for Adverse Effects (CTCAE), v4.0. Subacute DLT will be defined by radiation induced liver disease (RILD) or grade 3-5 gastrointestinal, hematologic, or pulmonary toxicity per CTCAE, v4.0.
Secondary Outcome Measures
Radiographic Response
Evaluated by either contrast enhanced MRI (preferred) or CT.
Patterns of Failure
Classified as local (in-field), regional (intrahepatic out-of-field), or distant (extrahepatic, which includes porta hepatic lymph nodes).
Progression Free Survival
From date of enrollment until first local, regional, or distant failure following RT, last follow-up, or death from any cause.
Overall Survival
From date of enrollment until last follow-up or death.
Health Related Quality of Life
FACT-Hep survey will be utilized to establish pre-treatment baseline and then compared to post-treatment evaluations at months 1, 2, and 3.
Full Information
NCT ID
NCT01618253
First Posted
June 4, 2012
Last Updated
September 4, 2013
Sponsor
Medical College of Wisconsin
1. Study Identification
Unique Protocol Identification Number
NCT01618253
Brief Title
Radiation Therapy With Sorafenib for TACE-Resistant Hepatocellular Carcinoma
Official Title
Phase I Study of Radiation Therapy With Concurrent Sorafenib for Hepatocellular Carcinoma Not Responding to Transarterial Chemoembolization
Study Type
Interventional
2. Study Status
Record Verification Date
September 2013
Overall Recruitment Status
Withdrawn
Why Stopped
Closed due to poor accrual.
Study Start Date
June 2012 (undefined)
Primary Completion Date
June 2015 (Anticipated)
Study Completion Date
June 2016 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Medical College of Wisconsin
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
To determine the maximum tolerated radiation dose with concurrent sorafenib for unresectable hepatocellular carcinoma that has not responded to transarterial chemoembolization.
Detailed Description
In patients with unresectable hepatocellular carcinoma (HCC), transarterial chemoembolization (TACE) is first line therapy. Non-responders to TACE (i.e. stable or progressive disease) represent a poor prognosis population with limited options. Sorafenib is indicated for first line salvage therapy, however it only improves survival 2-3 months and just has a 2-3% response rate. Thus, sorafenib is merely a cytostatic agent that delays progression and does not cytoreduce disease.
Radiation therapy (RT) is a non-invasive treatment that can cytoreduce HCC with minimal morbidity using modern techniques. A meta-analysis and multiple retrospective series suggest TACE + RT improve survival when compared to TACE alone. Higher RT doses are similarly associated with increased survival due to improved local control. Paradoxically, some series suggest that RT can induce vascular endothelial growth factor (VEGF) expression which may stimulate HCC.
Pre-clinical data suggest that combining RT with concurrent sorafenib (a VEGF inhibitor) improves tumor control. However, clinical data is limited to case reports and safety has not been well characterized. Prior to determining if this combination can improve control of HCC in this poor prognosis population, the optimal radiation dose with concurrent sorafenib must be determined by a phase I dose escalation trial.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatocellular Carcinoma, Hepatocellular Cancer, Hepatoma, Liver Cancer
Keywords
Transarterial Chemoembolization, TACE, Sorafenib Tosylate, Sorafenib, Nexavar, External Beam Radiation Therapy, Radiation Therapy, Radiotherapy, Radiation
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Radiation therapy with concurrent sorafenib
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Sorafenib
Other Intervention Name(s)
Sorafenib Tosylate, Nexavar
Intervention Description
Sorafenib 400 mg PO bid will be started two weeks prior to initiation of radiation therapy (RT) and continue until the end of protocol specified radiation dose.
Intervention Type
Radiation
Intervention Name(s)
Conventional fractionation (2 Gy per day) external beam radiation therapy
Other Intervention Name(s)
External Beam Radiation Therapy, Radiation Therapy, Radiotherapy
Intervention Description
Patients will be stratified by the maximum diameter of HCC in any plane (≤10 cm or >10 cm) based on post-TACE, contrast enhanced MRI or CT. If only 1 lesion is present, the maximum diameter of that lesion in any plane determines stratification. If >1 but ≤3 lesions are present, the sum of the maximum diameter in any plane of all the lesions determines stratification.
The MTD will be determined utilizing a standard 3 + 3 dose escalation scheme (4 Gy increase per bin). For lesions ≤10 cm, the starting RT dose bin will be 42 Gy and escalate to a pre-determined maximum of 62 Gy if no DLT's are experienced. For lesions >10 cm, the starting RT dose bin will be 40 Gy and escalate to a pre-determined maximum of 52 Gy if no DLT's are experienced.
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose
Description
Maximum tolerated dose (MTD) will be determined by dose limiting toxicity (DLT) that is observed in either the acute (during treatment) or subacute (up to 3 months after treatment) setting. Acute DLT will be defined by grade 3-5 hepatic, gastrointestinal, dermatologic, hematologic, or pulmonary toxicity per Common Toxicity Criteria for Adverse Effects (CTCAE), v4.0. Subacute DLT will be defined by radiation induced liver disease (RILD) or grade 3-5 gastrointestinal, hematologic, or pulmonary toxicity per CTCAE, v4.0.
Time Frame
From date of enrollment until 3 months after completion of treatment.
Secondary Outcome Measure Information:
Title
Radiographic Response
Description
Evaluated by either contrast enhanced MRI (preferred) or CT.
Time Frame
1 & 3 months post-treatment.
Title
Patterns of Failure
Description
Classified as local (in-field), regional (intrahepatic out-of-field), or distant (extrahepatic, which includes porta hepatic lymph nodes).
Time Frame
From date of enrollment until the date of first documented progression, last known folow-up, or date of death from any cause, whichever came first, assessed up to 10 years.
Title
Progression Free Survival
Description
From date of enrollment until first local, regional, or distant failure following RT, last follow-up, or death from any cause.
Time Frame
From date of enrollment until the date of first documented progression, last known folow-up, or date of death from any cause, whichever came first, assessed up to 10 years.
Title
Overall Survival
Description
From date of enrollment until last follow-up or death.
Time Frame
From date of enrollment until the date of last known folow-up or date of death from any cause, whichever came first, assessed up to 10 years.
Title
Health Related Quality of Life
Description
FACT-Hep survey will be utilized to establish pre-treatment baseline and then compared to post-treatment evaluations at months 1, 2, and 3.
Time Frame
1, 2, & 3 months post-treatment.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Radiographic or histologic diagnosis of hepatocellular carcinoma (HCC).
Maximum of 3 HCC lesions within the liver.
No evidence of lymphadenopathy or metastatic disease per either CT or PET.
Prior transarterial chemo-embolization (TACE) at least 28 days prior to initiation of protocol therapy.
Evidence of either progressive disease or stable disease following TACE.
Child Pugh Class A (score 5-6) or B (score 7).
Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1 (or Karnofsky ≥70%).
Normal organ and marrow function (platelets >60,000/mc; hemoglobin ≥8.5 g/dL; international normalized ratio (INR) ≤2.3; albumin ≥2.8 g/dL; total bilirubin ≤3 mg/dL; aspartate aminotransferase (AST) / alanine aminotransferase (ALT) <5x upper limit of normal; creatinine ≤1.5x upper limit of normal).
Negative human immunodeficiency virus serology.
Negative pregnancy test for women of child bearing age.
Ability to understand and willingness to sign a written informed consent document.
Exclusion Criteria:
Less than 800 cc of normal liver.
Child Pugh Class B (score 8-9) or C (score 10-15).
Acute/active hepatitis B infection.
Prior systemic chemotherapy or abdominal radiation therapy.
Portal venous (main, primary right, or primary left trunks) or inferior vena cava thrombosis.
Prior malignancy within 5 years of enrollment except for non-melanoma skin cancer.
Prior history of myocardial infarction, cerebrovascular accident, or esophageal variceal bleed in the last 6 months.
Pre-existing heart failure with either a clinical classification of New York Heart Association Class III or IV or cardiac ejection fraction of <45%.
Systolic blood pressure > 160 mmHg or diastolic pressure > 100 mmHg despite optimal medical management.
Pulmonary hemorrhage or other serious bleeding event (grade 2+) within 4 weeks initiation of protocol therapy.
Prior history of scleroderma or active systemic lupus erythematosus.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Beth A. Erickson-Wittmann, M.D.
Organizational Affiliation
Medical College of Wisconsin
Official's Role
Principal Investigator
Facility Information:
Facility Name
Froedtert Memorial Lutheran Hospital
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
16675562
Citation
Chung YL, Jian JJ, Cheng SH, Tsai SY, Chuang VP, Soong T, Lin YM, Horng CF. Sublethal irradiation induces vascular endothelial growth factor and promotes growth of hepatoma cells: implications for radiotherapy of hepatocellular carcinoma. Clin Cancer Res. 2006 May 1;12(9):2706-15. doi: 10.1158/1078-0432.CCR-05-2721.
Results Reference
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PubMed Identifier
17909054
Citation
Plastaras JP, Kim SH, Liu YY, Dicker DT, Dorsey JF, McDonough J, Cerniglia G, Rajendran RR, Gupta A, Rustgi AK, Diehl JA, Smith CD, Flaherty KT, El-Deiry WS. Cell cycle dependent and schedule-dependent antitumor effects of sorafenib combined with radiation. Cancer Res. 2007 Oct 1;67(19):9443-54. doi: 10.1158/0008-5472.CAN-07-1473.
Results Reference
background
PubMed Identifier
20421145
Citation
Ren ZG, Zhao JD, Gu K, Chen Z, Lin JH, Xu ZY, Hu WG, Zhou ZH, Liu LM, Jiang GL. Three-dimensional conformal radiation therapy and intensity-modulated radiation therapy combined with transcatheter arterial chemoembolization for locally advanced hepatocellular carcinoma: an irradiation dose escalation study. Int J Radiat Oncol Biol Phys. 2011 Feb 1;79(2):496-502. doi: 10.1016/j.ijrobp.2009.10.070. Epub 2010 Apr 24.
Results Reference
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Radiation Therapy With Sorafenib for TACE-Resistant Hepatocellular Carcinoma
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