The investigational drug AMN107 produces strong responses in patients whose chronic myeloid leukemia is resistant to imatinib
The investigational drug AMN107 produces
powerful responses in patients whose chronic myeloid leukemia is
resistant to imatinib, according to a presentation at the annual
meeting of the American Association for Cancer Research.
In the latest analysis of a trial with more
than 100 patients, the drug produced increasingly strong benefits
as doses were steadily raised. Over 90 percent of participants with
the earlier stage "chronic" phase of the disease have
had a hematologic response with blood counts returning to normal,
said Francis Giles, MD, a professor of medicine in the Department
of Leukemia at M. D. Anderson.
In addition, more than 70 percent of patients
with the advanced "accelerated" and terminal "blast"
stages of the disease had similar benefits, and the number of complete
molecular remissions in patients also is steadily increasing.
Giles could offer only estimates of response
because the study employs a new model of clinical trial design in
which patients are continuously given higher doses of the drug.
"So the results change daily as patients fare increasingly
better on higher doses," he said. "We are seeing benefit
at lower doses that will only be fully quantifiable when all patients
are on the maximal safe dose - a dose which we have not yet defined."
Clear activity was seen at the very first
dose of 50 milligrams offered to the first patients who enrolled
in May, 2004, Giles said. "This week everyone is being moved
to the latest ceiling, which is 400 milligrams twice a day, and
based on its safety and effectiveness, I believe we will soon move
to 600 milligrams twice a day.
"If I had to guess, I would think the
overall response rate across the whole population will be well over
75 percent," he commented. Only within the last month have
chronic phase patients been allowed into the study, and Giles estimates
response in those patients may reach close to 100 percent because
their cancer has not yet had the chance to form new mutations that
the drug cannot treat. For that same reason, some patients with
more advanced cancer will not respond to the drug, Giles added.
Despite what Giles called very exciting results
with AMN107, he stressed that patients should not think that they
need to switch to this experimental drug. "Gleevec is incredibly
powerful and failures are very rare in early phase chronic myeloid
leukemia. It is very effective in the great majority of patients,"
he said. "We are focused on a minority of patients, less than
10 percent of chronic patients, who more than likely need some other
form of intervention to give them a normal life span."
The disease is caused by creation of the
Philadelphia chromosome, which contains a novel, fused-together
gene, BCR-ABL, which produces an enzyme that switches on uncontrolled
growth in the bone marrow cell. Imatinib binds to the Bcr-Abl enzyme,
shutting down its activity, which often leads to death of the leukemia
cell.
AMN107 is estimated to be up to 30 to 100
times more potent than imatinib because it was designed to more
efficiently bind to Bcr-Abl, including to mutated forms of the enzyme
that can produce imatinib resistance, Giles said.
Because the drugs have not been compared head-to-head, Giles said,
"I can't say that AMN107 is better than Gleevec."
Giles, however, is planning to open a clinical
trial at M. D. Anderson this summer to test AMN107 as a "frontline"
therapy - the first treatment given - in patients with chronic phase
disease. Another six clinical trials testing the drug in all three
separate phases of CML, as well as in other leukemias in which imatinib
has shown some benefit, also are slated to open soon.
Giles suggests that in the future, both imatinib
and AMN107, as well as perhaps other new tailored agents, may all
be used in treating CML, especially if these drugs show a synergistic
effect.
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