Combining Angiogenesis-Targeted Treatments for Liver Cancer
Name of the Trial
Phase I/II Study of TRC105 in Combination with Sorafenib in Hepatocellular Carcinoma (NCI-11-C-0102). See the protocol summary.
Dr. Tim Greten, NCI Center for Cancer Research
Why This Trial Is Important
Hepatocellular carcinoma is the most common form of primary liver cancer in adults. Surgery to remove the tumor (resection) is the preferred treatment for patients with limited disease, but many patients are ineligible for resection because of the location of the tumor within the liver, coexisting medical conditions, or both. Options to treat people with unresectable, localized liver cancer include radiofrequency ablation, transarterial chemoembolization, or liver transplantation, but, again, not all patients are eligible for these procedures.
In 2008, the results of a phase III clinical trial established the drug sorafenib as the first systemic agent to improve the survival of patients with unresectable hepatocellular carcinoma. In that study, patients treated with sorafenib lived almost 3 months longer than those who received a placebo. Sorafenib is a targeted drug that interferes with several molecular pathways important for tumor growth and metastasis, including pathways involved in the development of new blood vessels needed to nourish the tumor (tumor angiogenesis). Doctors are eager to see if combining sorafenib with other agents will enhance the benefits seen with sorafenib alone.
An experimental biological agent called TRC105 may also be effective against hepatocellular carcinoma. It too interferes with the development and recruitment of new blood vessels to a tumor, but it does so by blocking a pathway that is different from the ones affected by sorafenib. Rather, TRC105 blocks the activity of a protein called endoglin (CD105), which is overexpressed by the endothelial cells of tumor blood vessels. TRC105 is being tested in a phase II study as a single agent for patients with unresectable hepatocellular carcinoma that progressed despite treatment with sorafenib.
In this trial, patients with unresectable hepatocellular carcinoma who are ineligible for a liver transplant or other local therapies will be given oral sorafenib at the standard approved dose and intravenous TRC105. In the first, or phase I, part of the trial, successive groups of patients will be given escalating doses of TRC105 to determine its maximum tolerated dose when combined with standard-dose sorafenib. In the second, or phase II, part of the trial, doctors will treat patients who have not had prior systemic therapy with standard-dose sorafenib and TRC105 at the previously determined maximum tolerated dose. Patients will receive this combined treatment as long as there is no tumor growth and the side effects remain tolerable. Doctors will measure the time it takes for the patients’ tumors to begin growing again, that is, until disease progression.
“TRC105 is an antibody that recognizes and binds to endoglin, which is expressed on the proliferating endothelial cells of the tumor vasculature,” said Dr. Greten. “The reason we believe that angiogenesis is a valid target in hepatocellular carcinoma is that these tumors are highly vascularized, so much so that radiologists can diagnose hepatocellular carcinoma by recognizing the imaging pattern in the blood vessels of the liver.
“We know from our preclinical studies that endoglin is upregulated by treatment with sorafenib, meaning there is more of that protein expressed, so there is a strong rationale for combining the endoglin-targeting agent with sorafenib and blocking angiogenesis through two independent pathways,” he explained.