Phase I Study of Radiation Therapy With Concurrent Sorafenib for Hepatocellular Carcinoma Not Responding to Transarterial Chemoembolization
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
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.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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 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.
From date of enrollment until 3 months after completion of treatment.
Beth A. Erickson-Wittmann, M.D.
Medical College of Wisconsin
United States: Data and Safety Monitoring Board
|Froedtert Memorial Lutheran Hospital||Milwaukee, Wisconsin 53226|