The first tests in humans with endostatin began two years ago. What are the results so far?

The rules of clinical trials for endostatin are the same that the FDA sets for any other cancer drug. In the phase one of the trial you are only allowed to start with very few patients, for which any other option has failed, slowly increasing the dose in order to test the drug¿s safety. All phase I studied have shown that both endostatin and angiostatin are very well tolerated and have virtually no side effects. This is the most exciting thing about these drugs. On average a patient cannot stay on chemotherapy for more than six weeks, because either there are too many side effects or the tumor escapes [becomes resistant to the treatment]. So far, no patient has been reported to [have to] stop endostatin because of adverse reactions. Furthermore, there were some patients whose disease became stable, and they regained their energy and weight. In few patients, there was also a slow tumor regression. [Results were reported in May at the meeting of American Society of Clinical Oncology and in the Journal of Clinical Oncology, September 2002 ]. Last spring endostatin moved to phase II to test its efficacy in rare neuro-endocrine tumors of the pancreas. [Other phase II trials started in May (endostatin for metastatic melanoma) and July (angiostatin and chemotherapy for non-small cell lung cancer).]

Still, these results are very far from the dramatic improvements that you observed in mice. Why is it so difficult to replicate the experiments in humans?

Well, first of all these [Phase I] experiments are primarily designed to test a drug¿s safety, not its efficacy. Then, when you experiment with mice you can increase the dose, give different drugs in combination, and choose on which tumors and at what stage you want to try them. With humans, of course, the rules are strict: you can only give a single drug to patients with very advanced tumors, starting at very low doses. For example, we found the most dramatic effects in mice when endostatin and angiostatin were used in combination, but the FDA will not allow to use both drugs together before the end of phase II, maybe early phase III [large-scale, with many human patients] of the trials. Moreover, we have evidence that the drugs would work better if given at an early stage of the tumor. Another complication is that each tumor puts out different amounts of angiogenic stimulators. Some breast cancers, for instance, make only one angiogenic factor while others make six. That means that you have to balance the dose against a specific tumor, as much as you would adjust the dose of insulin according to your blood sugar levels for diabetes. But this is not the way you do clinical trials. You can¿t start with the dose you think is effective for each patient: everyone has to stay on a fixed schedule. But we are beginning to learn that when the drugs are approved--I don¿t know how many years that will be--a physician won¿t just stay on the same dose no more than you do with penicillin.

After endostatin and angiostatin were first hailed as the miracle cure, now many say that they are not meeting the expectations. How do you feel about all the ups and downs of your work in the press?

I feel that these drugs are not much different than any drugs going through clinical trials. Expectations are not the same for everyone. For example, researchers may have different expectation than the public or the press. Suppose that you read the abstract of phase I endostatin trial saying that the drug has shown "linear pharmacokinetics." It is a very good finding for an early trial, because it means that blood levels of the drug directly correlated with increasing doses, as predicted. But the same report can be deceiving for the public. It¿s very hard for reporters to explain the many hurdles of clinical testing of any new drug and it¿s hard for the public to understand that, on average, most drugs take seven to 10 years to be approved. Expectations are also biased by decades of experience with classic chemotherapy. With chemotherapy you expect to see a fast tumor regression, because the drugs directly kill the cancer cells; but it doesn¿t work this way for angiogenesis inhibitors, which are designed to turn off the blood supply, so that the tumor gradually slows down and, eventually, stops growing.

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