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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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