MK-0457, a Novel Aurora Kinase and BCR-ABL Inhibitor, Is Active Against BCR-ABL T315I Mutant Chronic Myelogenous Leukemia (CML). (2006)

Abstract Background. MK-0457 (VX-680) is a small-molecule inhibitor of aurora kinases A, B, and C, and wildtype and mutant BCR-ABL, including the T315I variant. The T315I BCR-ABL mutation mediates high level resistance to imatinib, dasatinib and nilotinib. MK-0457 has in vitro activity against cells expressing wild-type or mutated BCR-ABL, including the T315I BCR-ABL mutation, at a concentration of ~1μM. A Phase I study of MK-0457 is being conducted in patients with refractory hematologic malignancies, including CML. Methods. After IRB approval, 15 consenting patients with refractory CML (median 5 prior regimens), ECOG performance status ≤2, and adequate organ function were enrolled using a standard dose escalation scheme with 3 patients/dose level until dose-limiting toxicity (DLT), followed by 6 patients/level. MK-0457 was administered by continuous 5-day intravenous infusion every 2 to 3 weeks. DLT was defined as grade 3 or higher non-hematologic toxicity during cycle 1. Pharmacokinetics (PKs) were collected pre-dose through 168 h and analyzed for MK-0457 by HPLC/mass spec. Steady state volume of distribution (Vdss), clearance (CL), maximal concentration (Cmax) and terminal half-life (t1/2) were determined by WinNonLin. Results. Fifteen CML patients received MK-0457 dosed at 8, 12, 16, 20, 24, 28, and 32 mg/m2/hr. All but three of these patients had a history of accelerated phase or blast crisis. Eleven of these patients carried the BCR-ABL T315I mutation. All eleven BCR-ABL T315I mutant CML patients demonstrated clinical signals of anti-leukemic activity. By conventional criteria, there was one major hematological response, four minor hematological responses, one complete cytogenetic response, two partial cytogenetic responses, and one minimal cytogenetic response. Some degree of molecular response, as measured by BCR-ABL:ABL transcript ratio, was detected in five of six patients for whom such data were available. The longest a patient was treated was for 15 cycles, and is still ongoing. The patients with the best clinical response had the largest magnitude inhibition of BCR-ABL in leukemia cells as measured by levels of phosphoCRKL, a substrate of the BCR-ABL fusion kinase. None of the patients without the BCR-ABL T315I mutation showed objective responses. Remarkably, no drug-related non-hematological toxicity was observed. Some patients had apparent myelosuppression, which is an expected mechanism-based side effect of Aurora kinase inhibition. Plasma concentrations reached steady state rapidly (i.e., within 24 h) and declined biexponentially after the end of infusion; after a rapid initial decay, a slower decaying terminal phase demonstrated a t1/2 ~15 h. Steady state plasma concentrations are ≥ 1μM at a dose level of ≥ 20 mg/m2/hr. Conclusion. MK-0457 is very well tolerated and achieves plasma levels similar to those causing efficacy in preclinical models of CML. MK-0457 is the first T315I BCR-ABL inhibitor to show activity against this highly refractory, poor prognostic subpopulation of CML. Further evaluation of MK-0457 alone and in combination with other BCR-ABL inhibitors in CML is warranted.