MK-0457, a Novel Multikinase Inhibitor, Is Active in Patients with Chronic Myeloid Leukemia (CML) and Acute Lymphocytic Leukemia (ALL) with the T315I BCR-ABL Resistance Mutation and Patients with Refractory JAK-2 Positive Myeloproliferative Diseases (MPD).

Abstract

MK-0457 (VX-680) is a small molecule inhibitor of aurora kinases A, B, and C, FLT3, and JAK-2 with nanomolar level broad spectrum pre-clinical anti-tumor activity. 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. A Phase I study of MK-0457 is being conducted in patients with refractory hematologic malignancies. The study regime is a 5-day continuous IV regimen given every 2 to 3 weeks. To date, dose levels of 8 (N=4), 12 (N=5), 16 (N=3), 20 (N=4), 24 (N=15), 28 (N=6), and 32 (N=3) mg/m2/hr have been investigated. No MK-0457-attributable extramedullary Grade 3 adverse events (AEs) have been observed to date, and thus, the maximum-tolerated dose (MTD) has not yet been reached. Grade 1 nausea was observed in 1 patient each at the 12 and 24 mg/m2/hr levels, and there have been 4 patients with Grade 1 alopecia. Dose-proportional PK has been observed across dose levels. Myelosuppression is consistently seen with MK-0457 at all dose levels studied to date and appears dose-related. Of 40 patients on study to date, 15 had CML, 2 had ALL, 13 had acute myeloid leukemia (AML), and 10 had rapidly progressive or transforming MPD. A nested PCR strategy followed by direct DNA sequencing using the dideoxy chain termination method was used to detect and monitor mutations in codons 221 to 500 of the BCR-ABL kinase domain in CML and ALL patients. Of 15 patients with CML, 11 had a T315I BCR-ABL mutation as had 1 of 2 ALL patients. Of 14 currently evaluable patients with CML, 11 had an objective (hematologic, cytogenetic, and/or molecular) response, including all 11 patients with the T315I mutation. The patient with T315I-mutant ALL also had an objective response. Six of 8 currently evaluable patients with JAK-2 positive refractory MPD have achieved an objective response. Downregulation of BCR-ABL and CrkL phosphorylation in leukemia cells from CML and ALL patients treated on study has been documented – the possible role of aurora kinase inhibition in these clinical responses requires further investigation. Accrual to the study is ongoing at the 36 mg/m2/hr dose level. The currently reported cases are the first observed clinical activity of a kinase inhibitor against the T315I positive CML/ALL and JAK-2 positive MPD. The observation of responses in these patients to doses of MK-0457 associated with no significant toxicity warrants further study.