Abstract
AT9283 is a small molecule inhibitor of aurora kinases A and B, JAK2, and JAK3 (IC50 <5nM in each case). AT9283 was administered as a 72-hour continuous intravenous infusion to patients with refractory hematological malignancies at 6 different dose levels: 3, 6, 12, 24 and 48 mg/m2 daily x 3. Inclusion/exclusion criteria, and definitions of DLT and MTD were standard. A 3+3 dose escalation phase I design was implemented. To date, 20 patients have been treated: 3 at 3, 3 at 6, 7 at 12, 3 at 24 and 4 at 48 mg/m2/daily x 3. Seven were females; median age was 58 years (range 22 to 86); 19 patients had previously treated acute myeloid leukemia (AML); 15 were in second or subsequent salvage; abnormal cytogenetics were present in 15. Two patients had undergone prior matched unrelated allografts. The median number of prior chemotherapy regimens was 2 (range 1 to 5). Pharmacokinetic data is available for patients treated at early dose levels only. Median systemic clearance varied up to two-fold between patients with some suggestion of a non-linear increase in exposure at higher dose levels. At the completion of the infusion, the plasma concentration of AT9283 decreased rapidly exhibiting a multiphasic elimination and a terminal half-life of 6 to 13 hours. At doses of 3 to 48 mg/m2/D x 3, no MTD has been defined; 2 patients treated at 12 mg/m2/D x 3 developed tumor lysis syndrome which resolved spontaneously in one case and required hemodialysis in the second. This dose level was expanded to treat 6 patients. Patients received a median of two cycles of treatment (range 1 to 3). So far, 6 of 20 patients (30%) exhibited evidence of anti-leukemia activity, with significant reductions in bone marrow blasts (≥ 50%) observed at all dose levels: In summary, AT9283 shows good early results and continues to accrue patients to define the DLT and MTD with the 72-hour infusion schedule. In vitro studies suggest that prolonging the duration of infusion will increase the drug’s biological effect. This will be explored following the identification of the MTD for a 72-hour infusion.
Reactive intermediates in copanlisib metabolism identified by LC-MS/MS: phase I metabolic profiling