By Lynda Williams, Senior medwireNews Reporter
Phase I/II clinical trial data support the use of bosutinib as second- or third-line tyrosine kinase inhibitor (TKI) therapy in Japanese patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukaemia (CML).
The initial dose-escalation part of the open-label study was carried out in 17 patients with chronic phase CML who were resistant or intolerant to full-dose imatinib. No maximum tolerated dose was determined; however, the researchers drew on earlier dosing data to set the bosutinib dose at 500 mg/day.
Over 24 weeks of treatment, three of the patients given bosutinib 400 mg/day, four given 500 mg/day and one patient given 600 mg/day had a cumulative major cytogenetic response (MCyR).
The second-part of the study consisted of bosutinib 500 mg/day treatment given to a further 28 patients with chronic phase CML and seven patients with advanced phase CML who were all intolerant or resistant to full-dose imatinib. A third group of 11 patients with chronic or advanced phase CML who were resistant or intolerant to both imatinib and second-line TKI therapy with dasatinib or nilotinib were also included.
The 24-week cumulative MCyR rate was 36% for the chronic phase patients, with complete and partial cytogenetic responses occurring in 29% and 7%, respectively. Median time to MCyR was 12.3 weeks.
The 24-week rates for the advanced and third-line TKI patients were 43% and 18%, with complete responses achieved by 14% and 9%, respectively. Median time to MCyR was 5.0 and 18.1 weeks, respectively.
The cumulative complete haematological response (CHR) was confirmed in 79% of the chronic phase patients with a median duration of 5.3 weeks, and the major molecular response (MMR) rate was 43%, lasting a median of 36.1 weeks.
None of the advanced CML patients achieved a CHR or MMR over the first 24 weeks. Among the third-line TKI patients, the cumulative CHR and MMR rates were 70% and 18%, respectively.
Overall, 20 (32%) patients experienced serious adverse events while using bosutinib, with gastroenteritis the only event reported for more than two patients. Sixteen (25%) patients discontinued treatment following adverse events and 67% reduced their dose.
One patient had serious diarrhoea and 13% grade 3 diarrhoea but no patient discontinued treatment as results of this side effect. Liver-related side effects were reported for 62% of patients, with serious, grade 3 and grade 4 events in 5%, 46% and 3%, respectively. A fifth (21%) of patients discontinued treatment due to liver events.
Writing in the International Journal of Haematology, the researchers observe the range of different side effects associated with bosutinib, nilotinib and dasatinib.
“Taken together with the efficacy data for each TKI, this information may be useful in determining which TKI may be most appropriate for individual patients”, say Chiaki Nakaseko, from Chiba University Hospital in Japan, and study co-authors.
The team concludes: “The safety and [pharmacokinetic] profiles of bosutinib up to 600 mg/day were confirmed in Japanese patients with Ph+ CML resistant/intolerant to imatinib.
“Bosutinib 500 mg/day demonstrated clinical activity and an acceptable safety profile in this population.”
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