Aurora kinases play a role in the regulation of mitosis, and the consequent formation of daughter cells, and a failure of this regulatory system can lead to the formation of tumours. Several aurora kinase inhibitors are in development for the treatment of cancers, including Millennium’s MLN8237, which selectively inhibits aurora kinase A.1
It is still in the early stages of development, but several initial clinical trials have been carried out, including a dose escalation Phase I trial in 65 patients with solid tumours.2 Subjects were given oral doses of 5 to 150mg once a day for seven days, or 25–70mg once a day for 14 or 21 days. A durable partial response was seen in one patient with platinum refractory ovarian cancer, which was maintained with treatment tolerance for more than 1.5 years, and eight patients with different tumours achieved stable disease for at least six cycles. The most common side-effects included nausea, diarrhoea, fatigue and hair loss. They recommended a dose of 50mg twice a day for seven days, in 21-day cycles.
A Phase I trial has also been carried out in children with refractory solid tumours.3 The drug was given either once a day or in divided doses twice a day for seven days, every 21 days. The single doses investigated were 45, 60, 80 and 100mg/m2/day, and the twice daily regimen 60 and 80mg/m2/day.
Of the 37 patients enrolled in the study, 32 were fully evaluable for toxicity. Three of the four patients given the highest single dose developed dose limiting neutropoenia or thrombocytopoenia, and two of the six in the 80mg twice a day group developed dose limiting myelosuppression. Hand-foot-skin syndrome was a much more prevalent problem in the divided dose group – five of 11 patients were affected, compared with one of 21. They determined that the recommended dosing schedule for paediatric patients should be 80mg/m2/day as a single daily dose.
references
1. M.G. Manfredi et al. Proc. Natl Acad. Sci. USA 2007, 104, 4106
2. E.C. Dees et al. J. Clin. Oncol. 2010, 28 (15, suppl.) Abst 3010
3. Y.P. Mosse et al. J. Clin. Oncol. 2010, 28 (15, suppl.) Abst 9529
