Aurora Kinase Inhibitor Shows Activity in Chronic Myelogenous Leukemia

Allison Gandey

December 12, 2006

December 12, 2006 (Orlando) — A new aurora kinase inhibitor is the first to show clinical activity in a population of treatment-resistant leukemia patients with a poor prognosis. The new Merck and Vertex Pharmaceuticals product, dubbed MK-0457, has been proposed as a targeted approach to address refractory forms of blood cancer.

"We really are focused on disease elimination," lead investigator Francis Giles, MD, from the MD Anderson Cancer Center, in Houston, Texas, told reporters attending the American Society of Hematology 48th Annual Meeting and Exposition. "In regulatory terms, the advantage of the drug is that you are alive. This is an exciting new agent, and there's a great need because there is currently no alternative for these patients."

Patients with refractory chronic myelogenous leukemia often develop resistance to anticancer therapies such as imatinib, dasatinib, and nilotinib. One of the most common mutations that can occur is T3151. The new product is said to address this problem by targeting aurora kinases and BCR-ABL, a gene that when altered promotes uncontrolled cell growth and disease progression in leukemia.

The investigators conducted a phase 1 study in 15 patients with chronic myelogenous leukemia and a history of accelerated or blastic phase disease. Of these, 11 patients carried the T3151 BCR-ABL mutation. Participants received treatment by continuous 5-day intravenous infusions every 2 to 3 weeks for an average of 3 months of therapy to date. The researchers experimented with 8 different doses, ranging from 8 to 40 mg/m 2 per hour. They used a standard dose-escalation scheme, with 3 patients per dose level until dose-limiting toxicity, followed by 6 patients per level. Toxicity was defined as a grade 3 or higher nonhematologic adverse event during cycle 1.

Presenting the findings at the meeting, Jamie Freedman, MD, from Merck in Pittsburgh, Pennsylvania, told attendees that the new aurora kinase inhibitor was "very well tolerated in this phase 1 study." Some patients had apparent myelosuppression, which the researchers say is an expected mechanism-based side effect of aurora kinase inhibition. One patient received 15 cycles of therapy and continues to receive treatment.

Patients with T3151 Mutation Responded to Therapy

All 11 patients with the T315I mutation showed clinical signals of antileukemic activity. There was 1 major hematological response, 4 minor, 1 complete cytogenetic response, 2 partial cytogenetic responses, and 1 minimal cytogenetic response. None of the patients without the T315I mutation showed responses.

Investigators are moving forward on new studies of MK-0457. "There will be a pivotal international study of as many centers around the world as we can manage," Dr. Giles said in a news conference. He told Medscape there will be many challenges ahead. "We are looking to initiate distribution for a product with an unknown clinical benefit in a rare subset of leukemia patients." And questions remain about dosing. "If we find that long term all of the dosing levels are safe, it will be difficult to select which to pursue."

Scientists are also investigating whether the product can be offered as an oral tablet. "This is a really exciting area," vice president of the American Society of Hematology, Kenneth Kaushansky, MD, from the University of California, San Diego, told reporters. "Hematology is moving very rapidly from biochemical and molecular study to clinic, and we have the very privileged opportunity of observing these benefits with developments such as this."

ASH 48th Annual Meeting and Exposition: Abstract 163. Presented December 11, 2006.


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