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First Clinical Trials of Endostatin Yield Lukewarm Results

Renee Twombly

By the strictest criteria, the antiangiogenesis drug endostatin has passed muster in its first two phase I clinical trials in cancer patients, which were formally published last month. Those trials proved that endostatin is a very safe drug, even at a variety of doses—a masterful jump over the first testing hurdle.

But now that these first human tests have been reported, the issue of whether the agent—known as recombinant human endostatin (rh-Endo) and once heralded as a likely cure for cancer—has any beneficial effect looms larger than ever. In fact, researchers at the two institutions that conducted the trials, the Dana Farber Cancer Institute and the University of Texas M. D. Anderson Cancer Center, say their studies have raised more questions than have provided answers.

"In the last 3 years, we’ve been able to show that you can give endostatin safely, but not much more than that," said J. Paul Eder, M.D., clinical director of the Experimental Therapeutics Program at Dana Farber. "We don’t know if the drug is inactive or if it has been tested in the right clinical setting."



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Dr. J. Paul Eder

 
The problem is that unlike cytotoxic treatments, which offer measurable effects on tumor kill and associated side effects, biologic drugs like endostatin may have organic properties that could impact cancer but in ways that are hard to determine in patients with aggressive, advanced cancers, who are the most frequent candidates for phase I studies. This may make it hard to show that endostatin and other antiangiogenesis drugs are best used in early disease, as many researchers believe, perhaps as long-term maintenance therapy or even to prevent cancer development.

In the two studies reported in the September 15 issue of the Journal of Clinical Oncology, novel biomarker tests showed hints of activity, but not enough to base a spate of phase II trials on, researchers say.

Although there were no "objective" responses in any of the 15 patients at Dana Farber who received a 20-minute daily bolus infusion of endostatin until their cancer progressed, there was evidence of "therapeutic benefit" in three patients, said Eder. One patient with a pancreatic neuroendocrine tumor had a minor tumor reduction, and disease in two other patients briefly stabilized. An additional 12 patients who received continuous infusion of the drug showed similar results in a study that has not yet been published, according to Eder.

Based on these results, Dana Farber is now conducting a phase II study of endostatin only in patients with neuroendocrine tumors, and a similar phase II trial has also started at the University of California at San Francisco.

At the M. D. Anderson Cancer Center, a phase II trial using the agent in patients with sarcoma and melanoma has begun, based on its phase I results. In that trial, only two of 25 patients (one with sarcoma, one with melanoma) demonstrated minor and short-lived antitumor activity, according to Roy Herbst, M.D. , Ph.D., an associate professor of medicine in the Department of Thoracic/Head and Neck Medical Oncology.

Still, some anticancer activity is occurring in some patients, contends Herbst. Extensive PET scanning as well as multiple biopsies of tumor tissue suggested that both blood flow and tumor activity generally decreased with increasing doses of endostatin, although there was not a consistent dose effect, he said. "This study is the first to suggest that endostatin can induce endothelial cell apoptosis and changes in tumor flow in some patients with advanced cancer," he said. "We saw enough hints to continue testing, and we need a full court press approach to understand that biologic activity."

But researchers disagree about what those tests should include, especially if it means collecting invasive tumor biopsies. Mark Ratain, M.D., professor of medicine at the University of Chicago, questions the ethics of collecting numerous biopsies on patients and says he doesn’t think "these extra costly studies add anything to our knowledge." In an editorial he co-authored that accompanied the studies, he said that without relevant antitumor activity, "one may seriously question the usefulness" of developing antiangiogenesis compounds as either single agents or in combination therapy. "There is a huge disconnect between the hype and the data," he said in an interview.

That may be because researchers do not yet know how to correlate biologic activity of antiangiogenesis drugs with clinical benefit, or even how to select patients that have the best hope of responding, says King Li, M.D., of the National Institutes of Health. Li heads the new Imaging Sciences Program that is designed to help researchers determine how to measure efficacy in these drugs. "We need a fundamental change of thinking because these new agents work at the molecular level to inhibit pathways, and so we may not see morphological changes," he said.

Li believes image-guided tumor biopsies can be used to determine if endostatin or similar agents are working within specific receptors and pathways, which will reveal which patients—and even the parts of tumors—are responding. "There is no rational approach right now; no one knows what the results mean. We are in the dark," said Li. "We need to be smarter in our design, and provide personalized treatment."

Endostatin may be the best known antiagiogenesis agent, but "it is still at an early stage of development," compared with other such drugs, said William Li, M.D., president of the Angiogenesis Foundation, a Cambridge, Mass., information clearing house and think tank for angiogenesis research. Li said that there are more than 60 different antiangiogenesis compounds in human testing around the world that are all targeting one or more of 30 endogenous angiogenesis inhibitors. "The field is no longer about one or two drugs," he said. There is an "entire fleet, an armada," of agents being tested, he said.

Eder is more cautious than Li. "No one has yet proved angiogenesis is a valid target in cancer treatment with any existing single agent therapy," he said. Still, it is too early to give up on endostatin and the field of angiogenesis," Eder said. "Angiogenic treatment may still offer hope of benefit to patients, but it’s going to be one step at a time."


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