Phase I and pharmacodynamic trial of AT9283, an aurora kinase inhibitor, in patients with refractory leukemia

A phase I dose-escalation study of MSC1992371A, an oral inhibitor of aurora and other kinases, in advanced hematologic malignancies

“…This has warranted further investigation of barasertib in AML. AT9283, an inhibitor of aurora kinases A and B and other kinases related to myeloid cell proliferation, has also demonstrated early evidence of activity in refractory AML and CML [7]. A fourth AKI, MK-0457, has achieved clinical responses in 3 patients with T315I-phenotype-refractory CML or Ph+ ALL at doses not associated with AEs [8].…”

Aurora kinase inhibitors: novel small molecules with promising activity in acute myeloid and Philadelphia-positive leukemias

“…The maximum tolerated dose of AT9283 as a 72-h intravenous infusion was 108 mg/m 2 /day. 22 Although the ABL mutation status of the two CML patients was not reported, murine xenograft studies using BCR-ABL (T315I and E255K) transfected BaF3 cells and primary patient samples (E255K mutated) have demonstrated the in vivo efficacy of AT9283 against ABL mutants. 25 Danusertib (PHA-739358), a pan-Aurora and ABL inhibitor, is currently being evaluated in a phase I study of patients with advanced stage CML (CML BC or CML AP ) or Ph þ ALL resistant or intolerant of imatinib or second-generation TKI therapy.…”

“…22 Pharmacodynamic studies demonstrated a reduction in phosphorylation of histone H3, CrkL and STAT5, suggesting multi-kinase inhibition. 22 It should be noted that as STAT5 phosphorylation is downstream of ABL, FLT3 and JAK2 signalling, 15,23,24 it is unclear which kinase target was primarily responsible for STAT5 inhibition by AT9283. Doselimiting toxicities included elevated transaminases, non-cardiac creatine kinase and lactate dehydrogenase rises, tumor lysis syndrome, myelosuppression and alopecia.…”

“…22 Two patients with CML AP refractory to imatinib and dasatinib experienced hematological responses, one of which also had a partial cytogenetic response. 22 Pharmacodynamic studies demonstrated a reduction in phosphorylation of histone H3, CrkL and STAT5, suggesting multi-kinase inhibition.…”

“…22 Two patients with CML AP refractory to imatinib and dasatinib experienced hematological responses, one of which also had a partial cytogenetic response. 22 Pharmacodynamic studies demonstrated a reduction in phosphorylation of histone H3, CrkL and STAT5, suggesting multi-kinase inhibition. 22 It should be noted that as STAT5 phosphorylation is downstream of ABL, FLT3 and JAK2 signalling, 15,23,24 it is unclear which kinase target was primarily responsible for STAT5 inhibition by AT9283.…”