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Designing Clinical Trials
by Robert Cooke
High expectations are hard to live up to, especially if they're someone else's.
Judah Folkman found himself in that position as his two big antiangiogenesis
drugs, endostatin and angiostatin, finally headed toward clinical trials near
the end of 1999. Folkman was expected to cure cancer—it said so in The
New York Times. Now all he needed was for the drugs to work in people as
unequivocally as they had in mice. But it was not so simple, of course, and the
results would not be known quickly.
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Doctors previewing a candidate for a clinical trial of
endostatin.
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The first phase of the trials, as in tests of all drugs overseen by the Food
and Drug Administration, was designed to test for safety, not efficacy. So
those receiving the first test doses would be the patients with the most
advanced cancers, patients for whom everything else had failed, and they would
receive very small doses to start with. Moreover, the experience with mice as
well as with patients like Jennifer LaChance and Tonya Kalesnik, who had been
treated with interferon, indicated that antiangiogenesis drugs have a slow,
cumulative effect, taking up to a year to eliminate tumors. It stretched the
limits of reasonable expectation to think that the critically ill patients in
the first trials would take a few injections of low-dosage, slow-acting drugs
and waltz out of their hospital wards, cancer-free.
Obviously, such waltzing wasn't likely. A study that had recently been done at
the Johns Hopkins Medical Institutions, in Baltimore, showed starkly that very
little about a drug's potential is discernible from the results of Phase I
trials. Because the patients admitted to such trials are desperately ill, and
because the doses of drugs given are so small, half of the patients fail—they drop out within 1.8 months, even if the drug being tested ultimately turns
out to be effective. In contrast, in trials of drugs that turn out to be flops—never making it to the market—half of the patients drop out by 1.6
months. Statistically that's almost dead even, and the take-home lesson is that
Phase I toxicity trials generally don't say much about a candidate drug's
ultimate success. Thus, by any measure, the expectations for Folkman's
antiangiogenic agents were far beyond reason.
Michael O'Reilly discovered endostatin and angiostatin.
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Endostatin on trial
Endostatin, the second of the antiangiogenic agents discovered by Michael
O'Reilly less than half a decade earlier, was the first to be put to the test,
in trials involving 15 patients at each of three sites: the Dana-Farber Cancer
Institute in Boston, the M.D. Anderson Cancer Center in Houston, and the
University of Wisconsin Medical Center in Madison. The clinical researchers
would start with very small doses—only 15 milligrams per kilogram of body
weight daily, measures so insignificant that they were unlikely to have any
effect—and then gradually escalate them to see if there came a point when
the drugs became toxic and should be stopped. The idea was to see if, and how
much, endostatin could be given safely. If the drug passed that test, proving
itself nontoxic, then the dosages would be increased to levels where they could
begin to be tested for efficacy—to see if they actually worked against
tumors.
Even then, it could be yet another year before the results were in. Because
antiangiogenesis works by shutting down the growth and migration of
blood-vessel cells, it's a far slower process than poisoning or blasting tumor
cells with radiation or chemotherapy. The tests in mice had made it clear that
the antiangiogenic drugs had to be continued for a very long time, and that
stopping too early would allow the blood vessels to regrow, reigniting tumor
growth. Slow and steady was the rule. So the first patients selected for the
trials had to wonder how lucky they were: The protocols of the studies made it
unlikely any of the first patients would be saved by the new drugs.
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Studies in mice have shown that, to be effective, antiangiogenic
drugs must be administered for an extended period.
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Still patients lined up, brave and desperate people who knew their chances were
worse if they didn't try at all. The first endostatin trials were scheduled for
October 1999 at Dana-Farber, and as news of that first opportunity got around,
thousands of patients called, wrote, and e-mailed, frantically hoping to
qualify for one of the 30 slots in the small toxicity test. The same rush
happened a few months later in Wisconsin, and again in Texas, when the two
other Phase I endostatin trials were opened under auspices of the National
Cancer Institute. Most of the applicants were disappointed. Some patients
arrived with complications beyond cancer, such as high blood pressure or
diabetes, or even the wrong kind of cancer. People with brain tumors, for
example, were excluded because the doctors could not know whether endostatin
might weaken the blood vessels feeding the brain tumor so much that
hemorrhaging into the brain might occur.
Unlike most clinical trials, in which all the treatment centers do exactly the
same things, the doctors running the three endostatin trials were allowed to
set some of their own rules, select the kinds of tumors they would treat, and
decide how to enroll their patients. This was because antiangiogenesis was so
new and untested that no one really knew how to use endostatin. "Since no one
knows," explained Dr. Mark Kieran, director of pediatric neurooncology at
Dana-Farber, "having one person write the protocol would be very
arbitrary."
Patients chosen for the endostatin trial
had to have tumors that defied all other treatments, including
surgery.
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In Boston, patients were selected almost on a first-come, first-served basis,
while in Houston and Madison they were chosen from among patients who were
already under care at the hospitals. There were only two things patients in all
three trials had to have in common: Their malignancies had to have defied all
previous treatments, and the patients couldn't be so near death that they might
succumb in just a week or two, before they could be evaluated for signs of drug
toxicity. Such an immediate death would be seen as a waste of the precious drug
while raising serious questions about why the patient died. Was it the cancer
or the drug?
Continue: Watching and Waiting
Dr. Folkman Speaks |
Cancer Caught on Video
Designing Clinical Trials |
Accidental Discoveries |
How Cancer Grows
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