Sunday, Feb. 28 2010
For the melanoma patients who signed on to try a drug known as PLX4032, the
clinical trial was a last resort. Their bodies were riddled with tumors,
leaving them almost certainly just months to live.
But a few weeks after taking their first dose, nearly all of them began to
Lee Reyes, 30, of Fresno, Calif., who had begun using a feeding tube because of
a growth pressing against his throat, bit into a cinnamon roll.
Nothing, he told his mother, had ever tasted as good.
Rita Quigley, who had been grateful just to find herself breathing each morning
since learning she had the virulent skin cancer, went shopping for new clothes
with her daughters at a mall in Huntsville, Ala.
Randy Williams, 46, who drove 600 miles from his home in Jonesboro, Ark., to
the M.D. Anderson Cancer Center in Houston, the nearest place he could get the
experimental drug, rolled out of bed. "Something's working," he thought,
"because nothing's hurting."
It was a sweet moment, in autumn 2008, for Dr. Keith Flaherty, the University
of Pennsylvania oncologist leading the drug's first clinical trial. A new kind
of cancer therapy, it was tailored to a particular genetic mutation that was
driving the disease, and after six years of disappointments, his faith in the
promise of such a "targeted" approach finally seemed borne out. His
collaborators at five other major cancer centers, melanoma clinicians who had
tested dozens of potential therapies for their patients with no success, were
In a kind of "pinch me" exercise, the six doctors sent each other "before and
after" CT scans of their patients.
One was of Mark Bunting, 52, an airline pilot in Sandy, Utah. His initial scan
in early October showed the cancer in his bones, an incursion considered
virtually impossible to reverse. After two months on the drug, it had all but
"Holy Cow!" Flaherty typed in reply to the slide from Dr. Toni Ribas at the
University of California-Los Angeles, that Dec. 17.
"Are you sure it is the same patient??" added Dr. Jeffrey A. Sosman at the
Vanderbilt-Ingram Cancer Center in Nashville.
From New York, Dr. Paul B. Chapman of Memorial Sloan-Kettering Cancer Center,
perhaps the most determined skeptic of the group, acknowledged, "This looks
The trial of PLX4032 offers a glimpse at how doctors, patients and drug
developers navigate a medical frontier at a time when more drugs tailored to
the genetic profile of a cancer are being widely tested on humans for the first
Throughout the fall, the only two patients on the trial whose tumors continued
to grow were the ones who did not have the particular gene mutation for which
the drug had been designed. They were removed from the trial. By late December,
tumors in the 11 patients who did have the mutation had shrunk. Those involved
in the trial held their collective breath waiting to see how long the
remissions would last.
It was a far cry from where they had been a year earlier, when a previous
incarnation of the drug had no effect. Urged on by Flaherty and Chapman, the
companies that owned it had spent months devising a new formulation that could
be absorbed at higher doses.
But the new drug, still in the earliest phase of testing, had to pass several
more hurdles before federal regulators would determine whether it was safe and
effective enough for widespread use.
In December, as the doctors added more patients to the Phase 1 trial, looking
for the highest dose they could give without intolerable side effects, they
scrambled to prepare slides with graphs and statistics to convince the Food and
Drug Administration that the drug should be tested in a larger Phase 2 trial.
The agency required a summary of any and all side effects — there had been only
a few — and any deaths of patients on the study; thankfully, there had been
none since the drug was reformulated. In a matter of days they needed to submit
their findings for a prestigious meeting of clinical oncologists in June.
The side effects struck at the 1,120-milligram dose.
Many patients had been taking the reformulated drug for five months with no
signs of relapsing. The doctors had hoped that by pushing up the dose they
could shut down the cancer more effectively. Some patients were taking as many
as 28 pills a day.
Kerri Adams, in Oklahoma City, woke up one morning covered in a rash.
Frightened that she would be dropped from the trial, she tried to ignore it.
But at work, her boss was horrified and insisted that she call the doctor.
Another woman's hand swelled up, and she could not make a fist. A Philadelphia
patient had horrible nausea and diarrhea, and Bunting's joints grew so stiff
that he had to hand jars to his wife to remove the lids, even when they had
already been opened.
Maybe the drug, designed to turn off only the defective B-RAF protein, was, at
high doses, also affecting its role in healthy cells. Or perhaps it was
interfering with other proteins the body needed to function properly.
On their next conference call, the doctors agreed that they had to dial back
As the side effects began to subside, many of the patients began to believe
they had beaten their cancer.
One evening, Bunting performed what had become his pill-taking ritual as his
wife puttered around the kitchen.
He liked the water to be room temperature, so he heated it in the microwave and
added cold from the tap. He burped, and some powder from the pills came out of
his mouth just as she turned to look.
They both laughed.
ONE STEP FORWARD ...
When Christopher Nelson strolled into the University of Pennsylvania for a
scheduled day of blood work and monitoring in mid-March, he was greeted as if
he had risen from the dead.
Gazing out the window of the clinic room, he spied a hot dog stand.
"Dirty water dogs," he exclaimed.
"Can you get me one?" he asked his wife's sister. "Actually, two?"
"Chris is feeling better," the nurse told Flaherty casually when she saw him.
"What do you mean?" he pressed.
"Well, he's off pain meds," she said.
Flaherty was not scheduled to see Nelson until three weeks later. But between
appointments that day, the doctor found time to visit his patient. In Nelson's
room, Flaherty broke into a wide smile, a tension he had not realized he was
holding seeping out of him.
He had never seen a melanoma patient who had been that sick improve that much.
He was not sure he had ever seen a melanoma patient that sick who improved at
Sharlene Nelson hugged him. In the weeks that followed, Christopher Nelson
gained 17 pounds. One morning a friend drove him to Atlantic City, where for a
$35 buy-in, they played his favorite game, Texas hold 'em, all day. The drug
had made him sensitive to the sun, and he burned his skin cleaning the pool one
afternoon, even with strong sunblock. Sharlene Nelson bought an umbrella, and
he spent much of the spring sitting underneath it.
"Today's a nice day," he said over the phone to a friend one day in early May.
"There's a cloud, and the sun is behind it."
NOT TOTAL SUCCESS
In mid-May, right before he was to fly to Orlando, Fla., to present the trial's
data, Flaherty received a message on his BlackBerry as he was walking on
The first patient to respond in the trial, Elmer Bucksbaum, had been admitted
to the hospital. The cancer had spread to his brain.
Flaherty stopped walking.
The drug, Flaherty knew, was powerless in the brain. But had the drug held off
the cancer elsewhere in Bucksbaum's body? Or would other patients, too, begin
Bucksbaum died a few days later.
Flaherty called his family and offered his condolences. It had been not quite