Radiation Therapy With Sorafenib for TACE-Resistant Hepatocellular Carcinoma

This study has been withdrawn prior to enrollment.
(Closed due to poor accrual.)
Sponsor:
Information provided by (Responsible Party):
Medical College of Wisconsin
ClinicalTrials.gov Identifier:
NCT01618253
First received: June 4, 2012
Last updated: September 4, 2013
Last verified: September 2013
  Purpose

To determine the maximum tolerated radiation dose with concurrent sorafenib for unresectable hepatocellular carcinoma that has not responded to transarterial chemoembolization.


Condition Intervention Phase
Hepatocellular Carcinoma
Hepatocellular Cancer
Hepatoma
Liver Cancer
Drug: Sorafenib
Radiation: Conventional fractionation (2 Gy per day) external beam radiation therapy
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Study of Radiation Therapy With Concurrent Sorafenib for Hepatocellular Carcinoma Not Responding to Transarterial Chemoembolization

Resource links provided by NLM:


Further study details as provided by Medical College of Wisconsin:

Primary Outcome Measures:
  • Maximum Tolerated Dose [ Time Frame: From date of enrollment until 3 months after completion of treatment. ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: 1 & 3 months post-treatment. ] [ Designated as safety issue: No ]
    Evaluated by either contrast enhanced MRI (preferred) or CT.

  • Patterns of Failure [ 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. ] [ Designated as safety issue: No ]
    Classified as local (in-field), regional (intrahepatic out-of-field), or distant (extrahepatic, which includes porta hepatic lymph nodes).

  • Progression Free Survival [ 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. ] [ Designated as safety issue: No ]
    From date of enrollment until first local, regional, or distant failure following RT, last follow-up, or death from any cause.

  • Overall Survival [ 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. ] [ Designated as safety issue: No ]
    From date of enrollment until last follow-up or death.

  • Health Related Quality of Life [ Time Frame: 1, 2, & 3 months post-treatment. ] [ Designated as safety issue: No ]
    FACT-Hep survey will be utilized to establish pre-treatment baseline and then compared to post-treatment evaluations at months 1, 2, and 3.


Enrollment: 0
Study Start Date: June 2012
Estimated Study Completion Date: June 2016
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Radiation therapy with concurrent sorafenib Drug: Sorafenib
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.
Other Names:
  • Sorafenib Tosylate
  • Nexavar
Radiation: Conventional fractionation (2 Gy per day) external beam radiation therapy

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.

Other Names:
  • External Beam Radiation Therapy
  • Radiation Therapy
  • Radiotherapy

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.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01618253

Locations
United States, Wisconsin
Froedtert Memorial Lutheran Hospital
Milwaukee, Wisconsin, United States, 53226
Sponsors and Collaborators
Medical College of Wisconsin
Investigators
Principal Investigator: Beth A. Erickson-Wittmann, M.D. Medical College of Wisconsin
  More Information

Publications:
Responsible Party: Medical College of Wisconsin
ClinicalTrials.gov Identifier: NCT01618253     History of Changes
Other Study ID Numbers: PRO00017344
Study First Received: June 4, 2012
Last Updated: September 4, 2013
Health Authority: United States: Data and Safety Monitoring Board
United States: Institutional Review Board

Keywords provided by Medical College of Wisconsin:
Transarterial Chemoembolization
TACE
Sorafenib Tosylate
Sorafenib
Nexavar
External Beam Radiation Therapy
Radiation Therapy
Radiotherapy
Radiation

Additional relevant MeSH terms:
Carcinoma
Liver Neoplasms
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Adenocarcinoma
Sorafenib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on April 14, 2014