Experimental Drug for Relapsed or Resistant Ovarian Cancer
Name of the Trial
Phase II Study of Birinapant for Advanced Ovarian, Fallopian Tube, and Peritoneal Cancer (NCI-12-C-0191). See the protocol summary.
Dr. Christina Annunziata, NCI Center for Cancer Research
Why This Trial Is Important
Epithelial ovarian cancer is the most common and most deadly type of gynecologic cancer. In 2012, more than 22,000 women were expected to receive a diagnosis of ovarian cancer, and approximately 15,500 were expected to die from the disease.
Most cases of ovarian cancer, along with the biologically similar fallopian tube and primary peritoneal cancers, initially respond to treatment with debulking surgery and combination chemotherapy. Some women cannot undergo surgery, however, and not all respond to chemotherapy. Furthermore, about 80 percent of those who do respond to initial treatment will eventually experience a relapse.
Although subsequent chemotherapy may help, the disease almost always returns and develops drug resistance. New treatments are desperately needed to help improve survival for women with these cancers.
An experimental drug called birinapant (TL32711) may be a new option for women with recurrent or treatment-resistant ovarian cancer. Birinapant acts as an antagonist of a family of proteins called inhibitors of apoptosis (IAPs). These proteins get their name from the role they play in regulating apoptosis, which is a type of programmed cell death that is normally initiated when cells become damaged or are no longer needed.
IAPs are an essential part of a cellular signaling pathway that is often activated in ovarian and related cancers. Preclinical studies by researchers at NCI suggest that birinapant may disrupt this signaling pathway, which ultimately causes ovarian cancer cells to undergo apoptosis.
In this phase II trial, women with metastatic or otherwise unresectable epithelial ovarian, fallopian tube, or primary peritoneal cancer that has recurred after, or has not responded to, previous therapies will receive birinapant intravenously once a week for the first 3 weeks of each 4-week cycle. Treatment will continue until disease progression or unacceptable toxicity occurs.
"Birinapant has shown very good activity in preclinical in vitro studies and mouse models of ovarian cancer cells," Dr. Annunziata said. "We've conducted in vitro studies in our lab of this drug both with and without TNF [tumor necrosis factor], and it looks like TNF increases the ability of birinapant to kill cancer cells that express the TNF receptor. Tumor necrosis factor levels have been found to be very high in some women with ovarian cancer, especially in ascites fluid. Birinapant seems to reprogram the TNF response from a cell stimulatory pathway to a cell death pathway."
Doctors want to determine the efficacy of birinapant in these cancers, as measured by overall response rate or stable disease lasting at least 6 months. They will also look at overall survival, toxicity, and the effect of birinapant on molecular markers, such as TNF, as secondary endpoints.