Anticancer agent - danusertib
Patients with chronic myeloid leukaemia can live with the disease for some years with few symptoms, but eventually they will experience a blast crisis when leukaemic progenitor cells in the bone marrow start to divide rapidly without differentiating into granulocytes and macrophages.
Patients with chronic myeloid leukaemia can live with the disease for some years with few symptoms, but eventually they will experience a blast crisis when leukaemic progenitor cells in the bone marrow start to divide rapidly without differentiating into granulocytes and macrophages.
The leukaemic cells usually have a genetic translocation between chromosomes 9 and 22, leaving chromosome 9 too long and chromosome 22 too short. The c-ABL kinase inhibitor imatinib (Glivec) has a dramatic effect on the prognosis of patients with CML, but resistance to the drug can develop leaving patients in need of alternative therapeutic options.
Nerviano is one of several companies that are investigating a drug that works in a different way – an aurora kinase inhibitor. These kinases are vital for the cell division process, and if the activity is deregulated abnormalities can creep in, leading to genetic instability. Aurora kinases are upregulated in terms of expression level and activity in numerous cancers, including CML. Their investigational drug, danusertib, inhibits several forms of aurora kinase and also c-ABL that has become resistant to imatinib.1
Several clinical trials have already been carried out. These include a multi-centre Phase II trial in seven patients with CML who had relapsed on imatinib or a related drug.2 Subjects were given danusertib as a once weekly six hour infusion of 250 or 350 mg/m2/day for three consecutive weeks, every four weeks. Two of the patients achieved a complete haematological response, and one of these achieved a complete cytogenic and molecular response after three months on the higher dose. One patient developed uncomplicated grade 4 neutropoenia.
The drug is also being investigated in solid tumours. In one trial, 56 patients with advanced solid tumours were given 14 day cycles of 24 hour intravenous infusions of danusertib in doses of 45 to 1,000mg/m2, either with or without granulocyte colony stimulating factor.3 The drug was well tolerated, and the dose limiting toxicity of brief grade 4 neutropoeinia, which coadministration with GCSF prevented. A partial response was achieved by one patient with small cell lung cancer, and clinically relevant disease stabilisation lasting for more than three months in a further nine patients. Further trials are under way.