May 21, 2002
Endostatin shows no toxicity and some clinical activity in latest report on phase I trial
Paul Eder, MD
An updated report on Phase 1 trials of the angiogenic inhibitor Endostatin says it exhibits virtually no toxicity even at high doses, while shrinking tumors in two of 28 advanced cancer patients and slowing disease progression in four others for more than six months. Researchers from Dana-Farber Cancer Institute presented the latest results at the annual meeting of the American Society for Clinical Oncology (ASCO) in Orlando on May 21. Preliminary results initially were reported at the ASCO meeting in 2001.
"We have seen some preliminary signs of clinical activity and we have set a recommended dose for the Phase 2" trials, which have begun in Boston and elsewhere, said J. Paul Eder, MD, clinical director, Experimental Therapeutics Program at Dana-Farber.
Two of the 28 patients treated in the Phase 1 trial remain on the compound, receiving Endostatin continuously via self-injected shots under the skin. The other patients either were removed from the study because their disease progressed or discontinued therapy for various other reasons.
The Phase 1 trial, conducted to determine the safety of the drug, began in 1999 at Dana-Farber, Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, and Massachusetts General Hospital, all of which are located in Boston.
One intriguing finding in the Phase 1 trial could give researchers a tool for measuring how well drugs like Endostatin are working in a particular patient. Blood analyses showed that endothelial cells, which make up the lining of blood vessels, were circulating in greater numbers in cancer patients than in normal volunteers. The patients might have more circulating endothelial cells because their bodies are creating more vessels to feed the tumors, Eder said. Alternatively, the growing network of blood vessels feeding the cancer might be shedding the endothelial cells, he said.
A more useful finding was that patients whose cancers were shrunk or halted by Endostatin had a dramatic, 10-fold reduction in circulating endothelial cells. "This suggests that measurement of circulating endothelial cells could be an indirect measurement of the body's response to Endostatin," said Eder. "This could become a predictive test that would help us determine who is likely to respond" to Endostatin.
The researchers started Phase II trials of Endostatin last October. Unlike the Phase I trials which included patients with a variety of cancer types, the Phase II trials only will enroll patients with neuroendocrine tumors, an uncommon type of cancer that responded to Endostatin in the initial trials.
Discovered in the Children's Hospital Boston laboratory of Judah Folkman, MD, Endostatin is a natural substance that blocks the formation of new blood vessels around and in tumors, thereby disrupting their ability to survive and grow. The formation of new blood vessels, a process called angiogenesis, can be helpful - in wound healing, for example - or harmful: it is involved not only in cancer but in diseases such as macular degeneration of the eye, arthritis, and heart disease.
One attraction of anti-angiogenic drugs is that they are gentler than conventional chemotherapy drugs, which kill cancer cells but also damage normal cells, often resulting in punishing side effects such as hair loss, nausea and blood cell abnormalities.
EntreMed, Inc., of Rockville, Md., is supporting trials of Endostatin. It is among some 80 anti-angiogenic drugs that are being tested in humans as potential treatments to fight or control cancer. All are in early stages of clinical trials and none has moved close to approval for general use.
The trials in Boston are being coordinated by Dana-Farber/Partners Cancer Care, which includes Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Massachusetts General Hospital, as well as by Beth Israel Deaconess Medical Center.
Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.
