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Designing Clinical Trials
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Watching and waiting

Folkman was delighted that clinical trials had finally begun for the antiangiogenesis drugs, and he was optimistic about their long-term promise. But he knew exactly what to worry about. Most central was the simple possibility that the human body might metabolize the drug differently than the mouse body, rendering it impotent. That's what he'd had in mind when he'd quipped to Times reporter Gina Kolata that if you were a mouse with cancer, he could take good care of you.

The clinical trials, meanwhile, were out of his control. He was just an intensely interested observer. So he worried about how they were being run and how they were being perceived. Someone might give the wrong doses and derail the trials. Or people wouldn't truly understand the process, especially with a new kind of drug like endostatin, which needed time and patience. Some of these drugs—whether those developed by his lab or by others—might fail, he thought, perhaps leading some people to doubt his entire premise. "It's the same as the Challenger space shuttle," he told people. "Challenger crashed because of a frozen O-ring. But that does not overturn Newton's principles. Some drug failures are the result of bad O-rings."

The clinical trials were run by others; all Dr. Folkman could do was await the results.

The clinical researchers worked hard to learn all they could from the first patients. In all three centers, the patients were tested almost incessantly with MRI scans, blood tests, positron-emission topography (PET) scans, and a battery of other diagnostic measures meant to watch for signs of damage to their vital organs. It seemed to evoke the experience of astronauts setting out on a dangerous test flight.

For some of the patients who found their way up Binney Street in Boston to get their daily endostatin infusions, the hardest part was the loneliness. Some patients had come from as far across the country as Alaska, leaving family and friends—all their support—behind. And when they realized that the low doses were unlikely to cure them, some gradually began to lose hope and concluded that the isolation wasn't worth it. A man from Alaska gave up and went home to be with his eight children, and face the dire consequences of his cancer. Another patient missed her young children so much that she, too, went home.

Meanwhile, the drug was showing zero toxicity in all the Phase I trials. The doctors caring for these patients were amazed that they saw none of the typical episodes of vomiting, diarrhea, nausea, and loss of hair normally experienced by patients in cancer drug trials. In fact, the oncologists, who usually spent much of their time trying to get their patients through the dreadful side effects of chemotherapy, had very little to do. Their patients felt fine, even wanting to put their clothes on and go home. Some went on shopping trips, and a few even began talking about taking vacations abroad. But some impatient cancer researchers outside the trials took the seeming lack of toxicity as a bad sign, an indication that the drug wasn't working. "Toxicity is equal to efficacy in most oncologists' minds," Roy Herbst, the oncologist who was leading the endostatin trial in Houston, said in the early going. "That's cancer. That's the way our drugs work." But this drug was different. It wasn't chemotherapy. It wasn't poison.

Drugs used in chemotherapy are toxic, but antiangiogenic drugs work in a completely different way.

Signs of improvement

Little by little, as the doses of endostatin were increased during the winter, a few reports began to leak out of the three medical centers that a few patients were doing better. In addition to the complete lack of toxicity, the doctors were saying quietly to each other that in some patients the tumors seemed to have stopped growing. The nurses knew it, too, and the word had it in Boston that one man's tumors—both his primary tumor and its metastases—had begun to shrink. Even at tiny doses of endostatin—in relative terms only one seventh the doses that had been effective in mice—his metastases were down 50 percent. Word from the clinic was that he was feeling so good, despite being an end-stage cancer patient, that he would come in for his daily injection and then head off to work.

And he was not alone in showing progress. Another patient in the Boston trial, described only as a 60-year-old woman from Chicago fighting metastatic breast cancer, was also showing signs of tumor shrinkage. Tests indicated that the interior of her tumor was deteriorating, as if it were liquefying and dying. She, too, was feeling far better than when she arrived in Boston months earlier. But in July 2000 she shocked the doctors by deciding to go home to Chicago, needing to take care of pressing personal business. Daily doses of endostatin were needed, but her doctors found no way to arrange for her injections while she was out of town. So there was real fear that an interruption in endostatin treatments would free her tumor to regrow explosively. But eleven days later, when she reported in again for treatments at Dana-Farber, the relieved doctors found that her cancer had not regrown. While visiting home, she had stopped in her office to see fellow workers, who were amazed at how good she looked and by her energy level and high spirits. She obviously felt good, as did several other patients in the trial, who reported much-improved quality of life.

Endostatin appeared to help some patients in the drug's first clinical trial.

Such hints of success were not officially announced, however, for fear of setting off a massive rush of patients seeking a drug that was unproven, and in any event unavailable. In April 2000, doctors and the Food and Drug Administration decided it was better to wait and be sure, allowing time for the drug-manufacturing process to be scaled up before breaking any news. There wouldn't be much solid evidence until the trial ended, and even bigger, more convincing trials could begin.

It was at that point, in mid-March 2000, that the FDA asked doctors at Dana-Farber to stop increasing doses until the two other centers could catch up. The agency wanted everyone to keep treating at 240 milligrams per kilogram of body weight per day for a while to let the patient numbers build up, while the debate continued over whether to escalate higher, to 300, 400, or 500 milligrams per day. An intense argument also erupted over whether—and what—to report. Half of the experimenters wanted to present the data on toxicity at the upcoming American Society of Clinical Oncology meeting in mid-May, in New Orleans. Others in the research group argued that even the data showing early signs of efficacy in a few patients should be included. It was evidence, albeit preliminary, that small, regular doses of endostatin were associated with improvements, especially in patients with the slowest-growing types of tumors. This seemed to support Folkman's prediction that less-aggressive cancers would be most sensitive to the drug.

In the spring of 2000, clinical trials began for angiostatin, the other antiangiogenesis drug developed in Dr. Folkman's lab at Children's Hospital in Boston.

Next up: angiostatin

As this was occurring, in spring 2000, trials began at Thomas Jefferson University in Philadelphia for angiostatin, the other antiangiogenesis drug developed in Folkman's lab. The early results offered a surprise that had nothing to do with cancer—a surprise to everyone but Folkman. One of the first patients enrolled in the trial saw her decades-long struggle with the skin disorder called psoriasis suddenly resolve. Psoriasis is caused by abnormal blood vessel growth in the skin, and it was one of the ailments that Folkman had suggested might yield to antiangiogenesis treatment. Although the results were serendipitous—and seen only in one patient—the discovery set off immediate interest in testing angiostatin as a potential treatment for the very bothersome skin condition. And it offered unexpected but welcome evidence that antiangiogenesis treatment was offering value in medical settings.

Excerpted with permission from Dr. Folkman's War: Angiogenesis and the Struggle to Defeat Cancer, by Robert Cooke (Random House, 2001). Newsday journalist Robert Cooke has been a science writer for 35 years. For more information on clinical trials—how they are designed, where they are currently taking place, and more—see the National Cancer Institute's Cancer Trials Web page at http://www.cancer.gov/clinical_trials/.

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