Cambridge, UK, 26th May 2009. Astex Therapeutics announced today that it has successfully completed an initial Phase I trial of AT9283 in patients with refractory solid tumours and will be reporting key data from the study at the American Society for Clinical Oncology (ASCO) Annual Meeting, May 29-June 2nd in Orlando, Florida.
Treatment with AT9283, a multi-targeted kinase inhibitor, was found to be generally well tolerated in highly-refractory patients with solid tumours when administered as a 72 hour continuous intravenous infusion repeated every three weeks. Over 30% of patients derived clinical benefit from single agent treatment with AT9283. One patient with pre-treated non small cell lung cancer achieved a durable partial response and more than 13 patients experienced a best response of stable disease according to the RECIST criteria. Amongst these 13 patients three achieved prolonged disease stabilisation of at least six months duration. The study was conducted under the supervision of Professor Hilary Calvert at the Northern Institute for Cancer Research, Newcastle Upon Tyne, UK and Professor Ian Judson at the Cancer Research UK Centre for Cancer Therapeutics at the Royal Marsden Hospital, Sutton, UK. Results from the study will be presented in a poster session (Abstract #2566).
In addition to intravenous infusion, the oral bioavailability of AT9283 in human subjects was also confirmed when the compound was administered orally to a number of patients.
Biomarker data of biochemical and biological markers, such as p53, phospho-histone H3, PCNA and Ki67 from skin samples support the biological activity of AT9283 in this trial. Clinical pharmacokinetic data also support exposures consistent with this biological activity. “We were delighted to see target modulation in samples from patients at generally well tolerated doses supporting the potential utility of AT9283 in the treatment of patients with solid tumours,” said John Lyons, Ph.D., VP of Translational R&D.
Additional Phase I trials are testing alternative dosing schedules of AT9283 in patients with solid tumours and haematological malignancies. Combination trials are planned as a result of the positive outcome of this Phase I trial.
About AT9283
AT9283 is a small molecule inhibitor of Aurora kinases A and B, with potent activity also against c-ABL and JAK2. Aurora kinases have been demonstrated to be over-expressed in several high risk cancers. Exposure of cancer cell lines to AT9283 resulted in endoreplication leading to a polyploidy state and cell death by apoptosis. Preclinical activity has been demonstrated in xenografts of colorectal (HCT116), ovarian (A2780) carcinoma and leukaemia (HL60). Tumour growth delay and regressions were observed with an intermittent dosing schedule. Histone H3 phosphorylation has been demonstrated as an effective biomarker of AT9283 Aurora kinase B activity. Preclinical toxicity studies confirmed myelosuppresion as the main dose limiting toxicity.
Inhibitors of Aurora kinases, such as AT9283, represent attractive novel anti-cancer agents for the treatment of a broad range of solid tumours and haematological malignancies as evidenced by anticancer activity in tumour models and emerging early clinical data in adults. AT9283 has been found to be well tolerated in adult patients with haematological malignancies using an intravenous 72 hour infusion on a 21 day schedule. Furthermore, in an ongoing Phase I clinical trial, AT9283 has demonstrated early signals of efficacy in approximately one third of adult patients with relapsed/refractory acute myeloid leukemia.
