Testing Vascular Disruption Combined with Chemotherapy for Advanced Solid Tumors
Name of the Trial
Phase I/II Trial of Crolibulin (EPC2407) Plus Cisplatin in Adults with Solid Tumors with a Focus on Anaplastic Thyroid Cancer (NCI-11-C-0027). See the protocol summary.
Dr. Ann W. Gramza, NCI Center for Cancer Research
Why This Trial Is Important
Malignant solid tumors must establish a constant supply of blood in order to grow beyond 1 to 2 mm in diameter. They accomplish this by secreting proteins and chemicals that signal nearby blood vessels to grow offshoots into the tumor in a process called tumor angiogenesis. But these new blood vessels differ from normal blood vessels. They tend to be immature, with poorly developed vessel walls that leak readily, and grow in a disorganized, haphazard manner throughout the tumor, in contrast to the strict organization of normal vasculature.
Numerous drugs and biological agents have been developed to interfere with tumor angiogenesis. These angiogenesis inhibitors typically work by blocking the activity of growth factors secreted by the tumor that spur the formation of new blood vessels or signaling pathways in blood vessel endothelial cells that are targets for the secreted growth factors.
However, a new class of drugs, called vascular disrupting agents, is also being developed to target the tumor blood supply. In contrast to angiogenesis inhibitors, which prevent the formation of new blood vessels to a tumor, vascular disrupting agents attack a tumor’s established blood supply. In animal studies, this approach caused cancer cells within the core of tumors to die rapidly from a lack of nutrients.
These studies also revealed that tumors treated with vascular disrupting agents tended to maintain viable cancer cells around their periphery, where the cells may be able to obtain sufficient nutrients from the surrounding tissue. This observation has led to a strategy of pairing vascular disrupting agents with conventional chemotherapy drugs. Researchers believe that combining these treatments will cause synergistic effects because, although vascular disrupting agents seem to kill cells in the core of a tumor effectively, conventional chemotherapy drugs are much better at killing cancer cells around a tumor’s periphery.
NCI researchers are studying the potential of the vascular disrupting agent crolibulin (EPC2407 and MX-116407) in combination with the chemotherapy drug cisplatin to treat advanced cancers. A previous animal study of the combination showed that crolibulin markedly enhanced the anticancer activity of cisplatin.
In this phase I/II trial, doctors will first assess the safety and tolerability of intravenous crolibulin and cisplatin in patients with advanced solid tumors that have not responded to previous treatment and establish the maximum tolerated dose for the combination. In the second part of the trial, patients with anaplastic thyroid cancer will be randomly assigned to receive crolibulin and cisplatin at the maximum tolerated dose established in the first part of the study or cisplatin alone. Doctors will look for differences in progression-free survival and response rates, as well as assess the effects of treatment on certain molecular markers.
“Anaplastic thyroid cancer is very aggressive and is among the most deadly and rapidly destructive of all solid tumors,” said Dr. Gramza. “Patients with this disease have no effective treatment options and most die within months of their diagnosis. Effective therapies for this uniformly fatal malignancy are urgently needed, and there is evidence that combinations such as crolibulin and cisplatin may potentially benefit these patients.”