Danusertib, a Multi-Kinase Aurora Inhibitor, Promising for Treatment of CML Refractory to First- and Second-generation Kinase In

The details of this study were presented at the 2009 meeting of the American Society of Hematology (ASH) in New Orleans in early December.[1]

Danusertib is a small-molecule pan-aurora kinase inhibitor that has been in Phase I clinical trials for the treatment of patients with solid tumors. One recent study from the Netherlands evaluated danusertib in 50 patients with advanced or metastatic solid tumors.[2] Disease stabilization was observed in 24% of patients, with five lasting more than six months. The main side effect was transient neutropenia. Another Phase I study was carried out by researchers from Fox Chase Cancer Center in 56 patients with advanced solid tumors.[3] This study was carried out with and without Neupogen® (filgrastim) support. They found that dose-limiting toxicity was febrile neutropenia without the use of Neupogen. Objective responses were seen in one patient with small cell lung cancer and one patient with ovarian cancer.

Patients with CML and Ph+ ALL who fail therapy with second-generation tyrosine kinase inhibitors have few non-transplant therapeutic options, especially those with the BCR-abl T3151 mutation. This mutation is a major cause of resistance to current tyrosine kinase inhibitors. The current study involved patients with accelerated or blast phase of CML and PH+ALL who had failed previous therapy with first and second generation tyrosine kinase inhibitiors. This study included 23 patients, of whom 14 had the BCR-Abl T3151 mutation. Responses to initial therapy were observed in six of 14 evaluable patients. These responses included one complete cytogenetic remission, one partial cytogenetic remission, one minimal cytogenetic response, five hematologic responses, and one clinical improvement of an extramedullary mass. A complete hematological response was seen in one patient with Ph+ ALL with the T3151 mutation. Further responses were observed with continued cycles of therapy.

Comments: This is an ongoing study, but early data would suggest that danusertib may become a useful agent for the treatment of CML and Ph+ALL and possibly solid tumors.

References:

[1] Cortes-Franco J, Dombret H, Schafhausen P, et al. Danusertib hydrochloride (PHA-739358), a multi-kinase aurora inhibitior, elicits clinical benefit in advanced chronic myeloid leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia. Blood. 2009;114:356, abstract number 864.

[2] Steeghs N, Eskens FA, Gelderblom H, et al. Phase I pharmacokinetic and pharmacodynamic study of the aurora kinase inhibitor danusertib in patients with advanced or metastatic solid tumors. Journal of Clinical Oncology. 2009;27:5094-5101.

[3] Cohen RB, Jones SF, Aggarwal C, et al. A phase I dose-escalation study of danusertib (PHA-739358) administered as a 24-hour infusion with and without granulocyte colony-stimulating factor in a 14-day cycle in patients with advanced solid tumors. Clinical Cancer Research. 2009;15:6694-6701.

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