Efficacy of Localized Concurrent Chemo-radiation Therapy and Sorafenib Sequential Therapy in Advanced Hepatocellular Carcinoma
Primary Purpose
Hepatocellular Carcinoma
Status
Completed
Phase
Phase 2
Locations
Korea, Republic of
Study Type
Interventional
Intervention
CCRT
sorafenib
Sponsored by

About this trial
This is an interventional treatment trial for Hepatocellular Carcinoma
Eligibility Criteria
Inclusion Criteria:
- Subjects must have confirmed diagnosis of unresectable hepatocellular carcinoma (HCC) categorized to stage C based on Barcelona Clinic Liver Cancer (BCLC) staging system with any of following criteria: 1) Lesion limited to a single lobe that is within the radiotherapy field, 2) Lesion not limited to a single lobe, but the lesion that is not within the radiotherapy field can be controlled by transarterial chemoembolization or radiofrequency ablation, 3) Presence of metastatic lesions that measure < 1.0 cm in the long axis, 4) The lesion can be accurately measured in at least one dimension as ≥ 1.0 cm
- Males or females aged at least 20 years and below 76 years
- Eastern Cooperative Oncology Group performance status (ECOG-PS) 0 or 1
- Adequate liver function, defined as: 1) Child-Pugh score ≤ 7, 2) Bilirubin ≤ 3.0 mg/dL
- Adequate bone marrow function, defined as: 1) Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, 2) White blood cell count (WBC) ≥ 4.0 × 109/L, 3) Platelet count ≥ 60 × 109/L
- Adequate renal function, defined as serum creatinine < 2.0 mg/dL
- Subjects with hepatitis B virus (HBV)-related HCC must have adequately controlled HBV replication status
- Adequate blood coagulation factors, defined as international normalized ratio (INR) ≤ 2.3
- Provide written informed consent
- Willing and able to comply with all aspects of the protocol
Exclusion Criteria:
- Significant liver function impairment, defined as bilirubin > 3.0 mg/dL or uncontrolled ascites
- Imaging findings for HCC corresponding to any of the following: 1) Diffuse HCC with > 50% liver occupation, that is not adequate for external radiotherapy, 2) Presence of metastatic lesions that measure ≥ 1.0 cm in the long axis
- Uncontrolled significant active infection
- Presence of active malignancy (except for HCC)
- Females who are lactating or pregnant; females of childbearing potential who have not received pregnancy test or shown positive on pregnancy test
- Any medical or other condition that in the opinion of the investigator would preclude the subject's participation in a clinical study
- Major surgery within 4 weeks prior to enrollment
Sites / Locations
- Department of Internal Medicine, Yonsei University College of Medicine
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
CCRT-sorafenib group
Arm Description
Outcomes
Primary Outcome Measures
Overall survival
Secondary Outcome Measures
PFSL defined as dynamic CT scan
Progression-free survival in the liver(PFSL)
PFSO defined as definitive imaging technique
progression-free survival overall (PFSO)
tumor response defined as modified RECIST
toxicity defined as NCI-CTC(version 4.02)
toxicity defined as National Cancer Institute-Common Toxicity Criteria (version 4.02)
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02425605
Brief Title
Efficacy of Localized Concurrent Chemo-radiation Therapy and Sorafenib Sequential Therapy in Advanced Hepatocellular Carcinoma
Official Title
Efficacy of Localized Concurrent Chemo-radiation Therapy and Sorafenib Sequential Therapy in Advanced Hepatocellular Carcinoma: a Prospective Phase 2 Trial
Study Type
Interventional
2. Study Status
Record Verification Date
February 2019
Overall Recruitment Status
Completed
Study Start Date
December 3, 2014 (undefined)
Primary Completion Date
September 22, 2017 (Actual)
Study Completion Date
September 22, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Yonsei University
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
This is a single-center, single-arm, open-label, prospective phase 2 trial to assess the efficacy of localized concurrent chemoradiation therapy (CCRT) and sorafenib sequential therapy in subjects with advanced HCC. Approximately 47 subjects will be enrolled and will receive CCRT and sorafenib sequentially until all-cause mortality.
Detailed Description
This is a single-center, single-arm, open-label, prospective phase 2 trial to assess the efficacy of localized concurrent chemoradiation therapy (CCRT) and sorafenib sequential therapy in subjects with advanced HCC. Approximately 47 subjects will be enrolled and will receive CCRT and sorafenib sequentially until all-cause mortality.
Sorafenib is the current standard of care for advanced hepatocellular carcinoma (HCC) patients following clinical results from the two pivotal trials in Western and Asian patients. The median overall survival in patients with unresectable hepatocellular carcinoma (HCC) who are treated with sorafenib have shown to be approximately 14 months. However in the presence of portal vein invasion or extrahepatic metastases, the median overall survival is significantly lowered to 5.6 - 8.9 months.
Going forward, improvement in patient-related outcomes would be highly desirable.
A pilot study has been conducted in subjects with advanced HCC with portal vein invasion for which effective therapeutic methods have not been established. This was a single-center, open-label study of localized concurrent chemoradiation therapy (CCRT) for locally advanced HCC patients with portal vein invasion. A total of 40 subjects with advanced HCC with portal vein invasion were enrolled. The subjects were treated with a total of 45 Gy of external beam radiotherapy (1.8 Gy per session, 5 sessions a week, for 5 weeks), with hepatic arterial infusion of 5-flourouracil (5-FU) during the first and last 5 days of radiation therapy (5-FU 500 mg infusion for 5 hours) through the pre-inserted chemoport. Eighteen (45%) subjects had an objective tumor response at 1 month after completion of localized CCRT. The 3-year survival rate was 24.2% and median overall survival was 13.1 months.
Treatment-related serious adverse events (CTCAE grade 3 or higher) were anemia, leukopenia, thrombocytopenia, mucositis and liver decompensation, and their rates were 2.5%, 2.4-5.0%, 17.5%, 10% and 7.3-17.5%, respectively. In addition, 2.4-5.0% of adverse events were chemoport-related adverse events including infection and port obstruction.
Although sorafenib has been shown to increase overall survival in advanced HCC patients as compared to placebo through anti-angiogenesis effect, its tumoricidal effect is not evident. Meanwhile, based on the above analysis from the pilot study, localized CCRT has been regarded as a promising treatment with tumoricidal effect for advanced HCC patients. Therefore, combining sorafenib treatment with CCRT is anticipated to augment anti-tumor effect and improve tumor response and median overall survival.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatocellular Carcinoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
47 (Actual)
8. Arms, Groups, and Interventions
Arm Title
CCRT-sorafenib group
Arm Type
Experimental
Intervention Type
Radiation
Intervention Name(s)
CCRT
Other Intervention Name(s)
Localized concurrent chemoradiation therapy(CCRT)
Intervention Description
The subject is treated with a total of 45 Gy of external beam radiotherapy (1.8 Gy per session, 5 sessions a week, for 5 weeks), with hepatic arterial infusion of 5-flourouracil (5-FU) during the first and last 5 days of radiation therapy (5-FU 500 mg infusion for 5 hours) for radiosensitization through the pre-inserted chemoport.
Intervention Type
Drug
Intervention Name(s)
sorafenib
Other Intervention Name(s)
sorafenib(Nexavar®) sequential therapy
Intervention Description
Four weeks after completion of CCRT, the subject is given daily sorafenib treatment and will be followed for survival.
Primary Outcome Measure Information:
Title
Overall survival
Time Frame
36 months after the enrollment
Secondary Outcome Measure Information:
Title
PFSL defined as dynamic CT scan
Description
Progression-free survival in the liver(PFSL)
Time Frame
36 months after the enrollment
Title
PFSO defined as definitive imaging technique
Description
progression-free survival overall (PFSO)
Time Frame
36 months after the enrollment
Title
tumor response defined as modified RECIST
Time Frame
36 months after the enrollment
Title
toxicity defined as NCI-CTC(version 4.02)
Description
toxicity defined as National Cancer Institute-Common Toxicity Criteria (version 4.02)
Time Frame
36 months after the enrollment
10. Eligibility
Sex
All
Minimum Age & Unit of Time
20 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Subjects must have confirmed diagnosis of unresectable hepatocellular carcinoma (HCC) categorized to stage C based on Barcelona Clinic Liver Cancer (BCLC) staging system with any of following criteria: 1) Lesion limited to a single lobe that is within the radiotherapy field, 2) Lesion not limited to a single lobe, but the lesion that is not within the radiotherapy field can be controlled by transarterial chemoembolization or radiofrequency ablation, 3) Presence of metastatic lesions that measure < 1.0 cm in the long axis, 4) The lesion can be accurately measured in at least one dimension as ≥ 1.0 cm
Males or females aged at least 20 years and below 76 years
Eastern Cooperative Oncology Group performance status (ECOG-PS) 0 or 1
Adequate liver function, defined as: 1) Child-Pugh score ≤ 7, 2) Bilirubin ≤ 3.0 mg/dL
Adequate bone marrow function, defined as: 1) Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, 2) White blood cell count (WBC) ≥ 4.0 × 109/L, 3) Platelet count ≥ 60 × 109/L
Adequate renal function, defined as serum creatinine < 2.0 mg/dL
Subjects with hepatitis B virus (HBV)-related HCC must have adequately controlled HBV replication status
Adequate blood coagulation factors, defined as international normalized ratio (INR) ≤ 2.3
Provide written informed consent
Willing and able to comply with all aspects of the protocol
Exclusion Criteria:
Significant liver function impairment, defined as bilirubin > 3.0 mg/dL or uncontrolled ascites
Imaging findings for HCC corresponding to any of the following: 1) Diffuse HCC with > 50% liver occupation, that is not adequate for external radiotherapy, 2) Presence of metastatic lesions that measure ≥ 1.0 cm in the long axis
Uncontrolled significant active infection
Presence of active malignancy (except for HCC)
Females who are lactating or pregnant; females of childbearing potential who have not received pregnancy test or shown positive on pregnancy test
Any medical or other condition that in the opinion of the investigator would preclude the subject's participation in a clinical study
Major surgery within 4 weeks prior to enrollment
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Beom Kyung Kim, M.D., Ph.D.
Organizational Affiliation
Severance Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Internal Medicine, Yonsei University College of Medicine
City
Seoul
ZIP/Postal Code
120-752
Country
Korea, Republic of
12. IPD Sharing Statement
Learn more about this trial
Efficacy of Localized Concurrent Chemo-radiation Therapy and Sorafenib Sequential Therapy in Advanced Hepatocellular Carcinoma
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