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Stereotactic Body Radiation Therapy and Transarterial Chemoembolization in Treating Patients With Liver Cancer That Cannot Be Removed by Surgery

Primary Purpose

Child-Pugh Class A, Child-Pugh Class B, Stage IIIA Hepatocellular Carcinoma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Laboratory Biomarker Analysis
Stereotactic Body Radiation Therapy
Transarterial Chemoembolization
Sponsored by
Ohio State University Comprehensive Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Child-Pugh Class A focused on measuring SBRT

Eligibility Criteria

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

Inclusion Criteria:

  • Patients must have a diagnosis of hepatocellular carcinoma by at least one criterion listed below:

    • Histologically confirmed
    • Magnetic resonance imaging (MRI) or computerized tomography (CT) findings consistent with hepatocellular carcinoma
    • Alpha fetoprotein (AFP) > 400 ng/mL AND evidence of at least one solid liver lesion > 2 cm regardless of specific imaging characteristics on CT or MRI
  • Patients must be non-transplantable, unresectable, or medically inoperable and eligible for TACE as determined by a multi-disciplinary team
  • Absolute neutrophil count >= 1.5 × 10^9/L
  • Hemoglobin >= 9 g/dl
  • Platelets >= 50,000/mm^3
  • Prothrombin time (PT)/international normalized ratio (INR) and activated partial thromboplastin time (PTTa) =< 1.5
  • Albumin >= 2.5 g/dL
  • Alkaline phosphatase < 5 x upper limit of normal (ULN)
  • Total bilirubin =< 2.0 mg/dL
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 5 x ULN
  • Creatinine =< 1.5 mg/dL and calculated creatinine clearance >= 60 mL/min or 24-hour urine creatinine clearance >= 60 mL/min
  • Must have Childs-Pugh A or B liver disease
  • Patients must have no clinical signs of heart failure and meet New York Heart Association functional classification I or II defined as:

    • Class I - patients with no limitation of activities; they suffer no symptoms from ordinary activities
    • Class II - patients with slight, mild limitation of activity; they are comfortable with rest or with mild exertion
  • Must have 1-3 liver lesions amenable to SBRT with tumor size < 15 cm (single lesion or sum)
  • Must be able to undergo two MRI scans, one before study treatment begins and another shortly after SBRT
  • Patients with extrahepatic disease, portal hypertension, or bilobar disease are allowed
  • Normal renal function (creatinine < 1.5 mg/dL)
  • Within 2 weeks of registration: patients must have vital signs, history/physical examination, laboratory studies (complete blood count [CBC] with differential, chemistries including liver function tests, AFP, creatinine clearance [CrCl] assessment, pregnancy test if needed)
  • Life expectancy of at least 12 weeks in the opinion of investigator
  • Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
  • Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed
  • Women of child-bearing potential (WOCBP) must have a negative pregnancy test within 14 days of the first administration of study treatment; urine human chorionic gonadotropin (HCG) is an acceptable pregnancy assessment
  • Women/men of reproductive potential must be counseled on contraception/abstinence while receiving the study treatment

Exclusion Criteria:

  • Childs-Pugh C liver function
  • Major liver vascular invasion
  • Prior radiation to the liver or other upper abdominal regions
  • Must not have any evidence of bleeding diathesis or active gastrointestinal bleeding
  • Any concurrent malignancy other than non-melanoma skin cancer, non-invasive bladder cancer, or carcinoma in situ of the cervix; patients with a previous malignancy without evidence of disease for >= 3 years will be allowed to enter the trial
  • History of active connective tissue disease (scleroderma)
  • Subjects who are breast-feeding, or have a positive pregnancy test will be excluded from the study; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
  • Medical contraindication to MR imaging (e.g. pacemakers, metallic implants, aneurysm clips, known contrast allergy to gadolinium contrast, pregnancy, nursing mothers, weight greater than 350 pounds)
  • Any serious and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures, in the opinion of the investigator; this could include severe, active co-morbidities such as:

    • Uncontrolled cardiac disease (hypertension, unstable angina, myocardial infarction within last 6 months, uncontrolled congestive heart failure, cardiomyopathy with decreased ejection fraction)
    • Acute bacterial or fungal infection requiring intravenous antibiotics at time of registration
    • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days of registration
    • Hepatic insufficiency resulting in jaundice and/or coagulation defects

Sites / Locations

  • Ohio State University Comprehensive Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (SBRT, TACE)

Arm Description

Patients undergo SBRT on day 1 and TACE on day 2.

Outcomes

Primary Outcome Measures

Feasibility of SBRT in combination with TACE, measured by the number of patients able to tolerate all study procedures
Determined on the intent-to-treat principle. Any treatment delivery difficulties that arise that could impede successful delivery of this therapy sequence will be evaluated. The capability of the Ohio State University (OSU) system and communication between departments will be analyzed and deemed effective if it facilitates the successful treatment completion of all patients.

Secondary Outcome Measures

Change in diffusion
Tested by comparing mean values pre- and post-SBRT using a paired t-test. Should there be concern for outliers, the median for each metric will be determined and compared using a corresponding non-parametric procedure.
Change in hypoxia measurements
Tested by comparing mean values pre- and post-SBRT using a paired t-test. Should there be concern for outliers, the median for each metric will be determined and compared using a corresponding non-parametric procedure.
Change in perfusion
Tested by comparing mean values pre- and post-SBRT using a paired t-test. Should there be concern for outliers, the median for each metric will be determined and compared using a corresponding non-parametric procedure.
Incidence of toxicities
Includes measurement of grade 2-5 gastrointestinal symptoms, such as nausea, abdominal pain, hepatitis, enteritis, gastritis, bowel perforation, and fistula, as defined by Common Terminology Criteria for Adverse Events version 4.03.
Local control
Calculated using standard clinical follow-up with MRI imaging and labs.
Objective response rate (CR + PR) as measured by modified RECIST criteria version 1
Overall survival
Calculated using standard clinical follow-up with MRI imaging and labs. Estimated using Kaplan-Meier analysis.
Progression-free survival
Calculated using standard clinical follow-up with MRI imaging and labs. Estimated using Kaplan-Meier analysis.

Full Information

First Posted
July 23, 2015
Last Updated
October 5, 2021
Sponsor
Ohio State University Comprehensive Cancer Center
Collaborators
Varian Medical Systems
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1. Study Identification

Unique Protocol Identification Number
NCT02507765
Brief Title
Stereotactic Body Radiation Therapy and Transarterial Chemoembolization in Treating Patients With Liver Cancer That Cannot Be Removed by Surgery
Official Title
A Pilot Trial of Stereotactic Body Radiation Therapy (SBRT) to Induce Tumor Hyperemia in Combination With Transarterial Chemoembolization (TACE) for Unresectable Hepatocellular Carcinoma
Study Type
Interventional

2. Study Status

Record Verification Date
October 2021
Overall Recruitment Status
Completed
Study Start Date
July 2015 (Actual)
Primary Completion Date
January 18, 2019 (Actual)
Study Completion Date
January 5, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ohio State University Comprehensive Cancer Center
Collaborators
Varian Medical Systems

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This pilot clinical trial studies stereotactic body radiation therapy (SBRT) and transarterial chemoembolization (TACE) in treating patients with liver cancer that cannot be removed by surgery. SBRT is a specialized radiation therapy that delivers a high dose of radiation directly to the tumor and may kill more tumor cells and cause less damage to normal tissue. Chemoembolization kills tumor cells by carrying drugs directly into blood vessels near the tumors and then blocking the blood flow to allow a higher concentration of the drug to reach the tumor for a longer period of time. SBRT may make TACE more beneficial by increasing blood flow to the tumor, which may allow more of the TACE chemotherapy to enter the tumor. Giving SBRT with TACE may work better in treating patients with liver cancer that cannot be removed by surgery.
Detailed Description
PRIMARY OBJECTIVES: I. To establish the feasibility of completing SBRT followed by TACE in a 2 day time period. SECONDARY OBJECTIVES: I. To determine acute tumor perfusion changes after SBRT using functional magnetic resonance imaging (MRI) (magnetic resonance [MR]-dynamic contrast enhanced [DCE]/perfusion weighted imaging [PWI], MR-diffusion, blood oxygen level dependent [BOLD] sequences). II. To establish safety and tolerability of this regimen. III. To determine overall response rates (using modified Response Evaluation Criteria in Solid Tumors [RECIST] criteria), including objective response rate (partial response [PR] + complete response [CR]) and clinical benefit rate (stable disease [SD] + PR + CR) at 1, 3, and 6 months after TACE. IV. To evaluate local control, progression-free survival, and overall survival at 1, 3, 6, 9, and 12 months after a single-dose of SBRT followed by TACE. V. To correlate micro ribonucleic acid (miRNA) biomarkers with response and toxicity. OUTLINE: This is a dose-escalation study of SBRT. Patients undergo SBRT on day 1 and TACE on day 2. After completion of study treatment, patients are followed up at 1-2 weeks and at 1, 3, 6, 9, 12, 18, and 24 months.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Child-Pugh Class A, Child-Pugh Class B, Stage IIIA Hepatocellular Carcinoma, Stage IIIB Hepatocellular Carcinoma, Stage IIIC Hepatocellular Carcinoma, Stage IVA Hepatocellular Carcinoma, Stage IVB Hepatocellular Carcinoma
Keywords
SBRT

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
16 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (SBRT, TACE)
Arm Type
Experimental
Arm Description
Patients undergo SBRT on day 1 and TACE on day 2.
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Radiation
Intervention Name(s)
Stereotactic Body Radiation Therapy
Other Intervention Name(s)
SBRT
Intervention Description
Undergo SBRT
Intervention Type
Procedure
Intervention Name(s)
Transarterial Chemoembolization
Other Intervention Name(s)
TACE
Intervention Description
Undergo TACE
Primary Outcome Measure Information:
Title
Feasibility of SBRT in combination with TACE, measured by the number of patients able to tolerate all study procedures
Description
Determined on the intent-to-treat principle. Any treatment delivery difficulties that arise that could impede successful delivery of this therapy sequence will be evaluated. The capability of the Ohio State University (OSU) system and communication between departments will be analyzed and deemed effective if it facilitates the successful treatment completion of all patients.
Time Frame
2 days
Secondary Outcome Measure Information:
Title
Change in diffusion
Description
Tested by comparing mean values pre- and post-SBRT using a paired t-test. Should there be concern for outliers, the median for each metric will be determined and compared using a corresponding non-parametric procedure.
Time Frame
Baseline to day 1 post-SBRT
Title
Change in hypoxia measurements
Description
Tested by comparing mean values pre- and post-SBRT using a paired t-test. Should there be concern for outliers, the median for each metric will be determined and compared using a corresponding non-parametric procedure.
Time Frame
Baseline to day 1 post-SBRT
Title
Change in perfusion
Description
Tested by comparing mean values pre- and post-SBRT using a paired t-test. Should there be concern for outliers, the median for each metric will be determined and compared using a corresponding non-parametric procedure.
Time Frame
Baseline to day 1 post-SBRT
Title
Incidence of toxicities
Description
Includes measurement of grade 2-5 gastrointestinal symptoms, such as nausea, abdominal pain, hepatitis, enteritis, gastritis, bowel perforation, and fistula, as defined by Common Terminology Criteria for Adverse Events version 4.03.
Time Frame
Up to 30 days
Title
Local control
Description
Calculated using standard clinical follow-up with MRI imaging and labs.
Time Frame
Up to 12 months
Title
Objective response rate (CR + PR) as measured by modified RECIST criteria version 1
Time Frame
Up to 6 months
Title
Overall survival
Description
Calculated using standard clinical follow-up with MRI imaging and labs. Estimated using Kaplan-Meier analysis.
Time Frame
Up to 12 months
Title
Progression-free survival
Description
Calculated using standard clinical follow-up with MRI imaging and labs. Estimated using Kaplan-Meier analysis.
Time Frame
Up to 12 months
Other Pre-specified Outcome Measures:
Title
Change in BOLD response to oxygen breathing based on T2 contrast induced by deoxyhemoglobin serving as an endogenous contrast agent
Time Frame
Baseline to day 1 post-SBRT
Title
Change in Kel (washout phase constant) values calculated from the DCE curve
Time Frame
Baseline to day 1 post-SBRT
Title
Change in mean apparent diffusion coefficient generated from diffusion weighted images by using the b values
Time Frame
Baseline to day 1 post-SBRT
Title
Change in miRNA expression
Time Frame
Baseline to up to 3 months
Title
Change in plateau signal intensity calculated from the DCE curve
Time Frame
Baseline to day 1 post-SBRT

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must have a diagnosis of hepatocellular carcinoma by at least one criterion listed below: Histologically confirmed Magnetic resonance imaging (MRI) or computerized tomography (CT) findings consistent with hepatocellular carcinoma Alpha fetoprotein (AFP) > 400 ng/mL AND evidence of at least one solid liver lesion > 2 cm regardless of specific imaging characteristics on CT or MRI Patients must be non-transplantable, unresectable, or medically inoperable and eligible for TACE as determined by a multi-disciplinary team Absolute neutrophil count >= 1.5 × 10^9/L Hemoglobin >= 9 g/dl Platelets >= 50,000/mm^3 Prothrombin time (PT)/international normalized ratio (INR) and activated partial thromboplastin time (PTTa) =< 1.5 Albumin >= 2.5 g/dL Alkaline phosphatase < 5 x upper limit of normal (ULN) Total bilirubin =< 2.0 mg/dL Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 5 x ULN Creatinine =< 1.5 mg/dL and calculated creatinine clearance >= 60 mL/min or 24-hour urine creatinine clearance >= 60 mL/min Must have Childs-Pugh A or B liver disease Patients must have no clinical signs of heart failure and meet New York Heart Association functional classification I or II defined as: Class I - patients with no limitation of activities; they suffer no symptoms from ordinary activities Class II - patients with slight, mild limitation of activity; they are comfortable with rest or with mild exertion Must have 1-3 liver lesions amenable to SBRT with tumor size < 15 cm (single lesion or sum) Must be able to undergo two MRI scans, one before study treatment begins and another shortly after SBRT Patients with extrahepatic disease, portal hypertension, or bilobar disease are allowed Normal renal function (creatinine < 1.5 mg/dL) Within 2 weeks of registration: patients must have vital signs, history/physical examination, laboratory studies (complete blood count [CBC] with differential, chemistries including liver function tests, AFP, creatinine clearance [CrCl] assessment, pregnancy test if needed) Life expectancy of at least 12 weeks in the opinion of investigator Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed Women of child-bearing potential (WOCBP) must have a negative pregnancy test within 14 days of the first administration of study treatment; urine human chorionic gonadotropin (HCG) is an acceptable pregnancy assessment Women/men of reproductive potential must be counseled on contraception/abstinence while receiving the study treatment Exclusion Criteria: Childs-Pugh C liver function Major liver vascular invasion Prior radiation to the liver or other upper abdominal regions Must not have any evidence of bleeding diathesis or active gastrointestinal bleeding Any concurrent malignancy other than non-melanoma skin cancer, non-invasive bladder cancer, or carcinoma in situ of the cervix; patients with a previous malignancy without evidence of disease for >= 3 years will be allowed to enter the trial History of active connective tissue disease (scleroderma) Subjects who are breast-feeding, or have a positive pregnancy test will be excluded from the study; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Medical contraindication to MR imaging (e.g. pacemakers, metallic implants, aneurysm clips, known contrast allergy to gadolinium contrast, pregnancy, nursing mothers, weight greater than 350 pounds) Any serious and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures, in the opinion of the investigator; this could include severe, active co-morbidities such as: Uncontrolled cardiac disease (hypertension, unstable angina, myocardial infarction within last 6 months, uncontrolled congestive heart failure, cardiomyopathy with decreased ejection fraction) Acute bacterial or fungal infection requiring intravenous antibiotics at time of registration Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days of registration Hepatic insufficiency resulting in jaundice and/or coagulation defects
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Terence Williams, MD, PhD
Organizational Affiliation
Ohio State University Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ohio State University Comprehensive Cancer Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
32712254
Citation
Sebastian NT, Miller ED, Yang X, Diaz DA, Tan Y, Dowell J, Spain J, Rikabi A, Elliott E, Knopp M, Williams TM. A Pilot Trial Evaluating Stereotactic Body Radiation Therapy to Induce Hyperemia in Combination With Transarterial Chemoembolization for Hepatocellular Carcinoma. Int J Radiat Oncol Biol Phys. 2020 Dec 1;108(5):1276-1283. doi: 10.1016/j.ijrobp.2020.07.033. Epub 2020 Jul 23.
Results Reference
result
Links:
URL
http://cancer.osu.edu
Description
The Jamesline

Learn more about this trial

Stereotactic Body Radiation Therapy and Transarterial Chemoembolization in Treating Patients With Liver Cancer That Cannot Be Removed by Surgery

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