MK-0457 'Glides Past' Bcr-Abl T315i Mutation

ORLANDO—MK-0457, an investigational small molecule inhibitor of Aurora, JAK-2, and Bcr-Abl kinases, has demonstrated clinical activity in patients with Bcr-Abl T315i mutant chronic myelogenous leukemia (CML), according to results of a phase I trial presented at the 48th Annual Meeting of the American Society of Hematology (abstract 163).

The trial included 44 patients with advanced leukemias and myeloproliferative disorder. Fifteen adult patients with advanced, refractory CML received a 5-day continuous IV infusion of MK-0457 delivered every 2 to 3 weeks at doses ranging from 8 to 40 mg/m²/h. These patients had a median of five prior regimens, including imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna).

"This was a highly refractory CML population," noted Jamie Freedman, MD, PhD, of Merck Research Laboratories, who presented the data on behalf of lead investigator Francis Giles, MD, of M.D. Anderson Cancer Center. All 15 CML patients had a history of accelerated phase or blast crisis, and 9 had the Bcr-Abl T315i mutation.

MK-0457 was extremely well tolerated, Dr. Freedman said. The primary toxicity was myelosuppression in the form of neutropenia, which was dose-dependent. There were no obvious trends in other drug-related hematologic toxicities, such as thrombocytopenia or anemia. Among first-cycle toxicities, one patient had a transient grade 3 lipase elevation at the 40 mg/m²/h dose level but without symptoms or signs of pancreatitis. One other patient had a lipase elevation at a lower dose.

Of the nine refractory CML patients with a Bcr-Abl T315i mutation, eight had a hematologic and/or a cytogenetic response to MK-0457. These included three major and three minor hematologic responses, one complete cytogenetic response, two partial cytogenetic responses, and one minor cytogenetic response.

Dr. Giles commented: "T315i blocks imatinib, nilotinib, and dasatinib from reaching their target. They physically cannot proceed beyond that mutation. But MK 0457, which is a totally different design of drug, can glide past that otherwise fatal obstruction, get in, and inhibit quite effectively," he said. The researchers now plan to see whether adding MK-0457 to nilotinib or dasatinib will delay or prevent progression. "The idea here is if you introduce a little suppression, intermittently, perhaps you can delay or obviate the emergence of this mutation," Dr. Giles said.