Phase I study of the Aurora B kinase inhibitor barasertib (AZD1152) to assess the pharmacokinetics, metabolism and excretion in patients with acute myeloid leukemia

Between November 2009 and June 2010, six patients were enrolled in this study. One patient died before receiving any study treatment; the remaining five completed Cycle 1 and were therefore included in the PK and safety analysis sets. Three of these five patients completed at least one further treatment cycle. One patient started Cycle 2 on Day 36 after a 7-day delay due to logistical reasons; this patient also started Cycle 3 on Day 78 but discontinued treatment on the same day due to worsening of the disease. The second patient also started Cycle 2 on Day 36 after a 7-day delay in order to allow for hematological recovery and subsequently received Cycle 3, starting on Day 64. The third patient started Cycle 2 on Day 57 for logistical reasons. The baseline demographic and disease characteristics were representative of the intended patient population for this study (Table 1). At the time of data cutoff (August 20, 2010), and for those patients who had received barasertib, one patient was still on treatment, two patients had progressed, one patient had withdrawn due to lack of response, and one patient had died due to an AE.

Maximal plasma concentrations of barasertib and barasertib-hQPA were achieved by the first scheduled sample, taken 24 h from the SOI (Fig. 1a). During the infusion period, the geometric mean plasma concentration of barasertib-hQPA was approximately threefold higher than that of barasertib (Table 2); this is consistent with previous studies [15, 16]. Following the EOI, plasma concentrations of barasertib fell rapidly, reaching the LLOQ by 6 h after EOI; it was therefore not possible to determine the terminal elimination half-life (t_½), total clearance (CL) or volume of distribution (V) of barasertib. In contrast, barasertib-hQPA plasma levels declined in a triphasic manner, with a rapid initial phase (with plasma concentrations decreased to one-third of the plasma steady-state concentration within 2 h post-EOI) followed by a slower decline thereafter. Low concentrations (~4 ng/mL) of barasertib-hQPA were still detectable at the final sampling point of 408 h (Day 18; Fig. 1a); the terminal elimination phase had a mean t_½ of 66.3 h (Table 2). Barasertib-hQPA was extensively distributed to the tissues, with a relatively slow rate of total clearance (Table 2). For four patients, maximum plasma radioactivity concentration was achieved 5 min prior to [¹⁴C]-EOI; for the remaining patient, this was achieved 1 h prior to [¹⁴C]-EOI. The concentrations of radioactivity in whole blood were lower than in plasma (with a ratio approximating 0.7) at all time points examined (Fig. 1a). Urine concentrations of barasertib were below LLOQ at all time points; during the infusion period, the geometric mean urine concentrations of barasertib-hQPA were approximately 4–5 μg/mL, declining rapidly following EOI. The renal clearance values for barasertib-hQPA represent approximately 10 % of the total clearance of barasertib-hQPA from plasma (Table 2).

The target dose of [¹⁴C]-barasertib was 250 μCi; the actual dose received ranged from 231 to 268 μCi. Overall, 72–82 % of total radioactivity was recovered, with approximately double the amount recovered in feces (mean ± SD, 51 ± 6.6 %) compared with urine (mean ± SD, 27 ± 5.5 %; Fig. 1B). There was large inter-patient variability in the rate of recovery of radioactivity in feces: the majority (>40 %) of radioactivity was recovered by 120 h in three patients, while in the remaining two patients, the majority (>44 %) was recovered during the last two time points (144–192 h) and it was evident that radioactivity was still being eliminated in feces after the end of the sample collection period. In contrast, the excretion of radioactivity in urine occurred predominantly within 72 h and was almost complete by 96 h from the [¹⁴C]-SOI.

Representative chromatographs for HPLC-RAD analyses of plasma, urine and feces samples are presented in Fig. 2. In plasma, the main metabolite was barasertib-hQPA; a large proportion of unmetabolized barasertib was also detected in plasma samples. Overall, the main excreta metabolites identified were the following: barasertib-hQPA (range, 13.2–33.7 %); barasertib-hQPA N-acetic acid (range, 7.8–10.5 %); barasertib-hQPA desfluoroaniline N-acetic acid (range, 5.1–9.5 %); N-formyl or ethoxy barasertib-hQPA (range, 3.5–9.2 %); and barasertib-hQPA desfluoroaniline (range, 1.6–4.5 %). Unlike plasma, desfluoroaniline metabolites made up a significantly larger proportion of the metabolites in excreta (~15 % compared with ~2 % in plasma) (Table 3). No glutathione or epoxide metabolites were detected in any samples. The main pathways identified in human metabolism of barasertib were (1) cleavage of the phosphate group to form barasertib-hQPA, followed by oxidation; and (2) loss of the fluoroaniline moiety to form barasertib-hQPA desfluoroaniline, followed by oxidation.

There were no dose interruptions or dose reductions during the study. The most common AEs (any grade; any cause) were nausea and stomatitis (n = 4 each); stomatitis and febrile neutropenia were the only grade ≥3 AEs reported in more than one patient (Table 4). Grade ≥3 AEs were experienced by three patients. One patient experienced febrile neutropenia and stomatitis (both grade 3); a second patient reported febrile neutropenia, stomatitis, anemia, abdominal distension, gingival bleeding, neutropenic sepsis, hypocalcemia, hypomagnesemia and lethargy (all grade 3). The third patient experienced febrile neutropenia and thrombocytopenia (both grade 4); this patient subsequently experienced grade 5 multi-organ failure, which was the only death during the study and was considered unrelated to study treatment (this patient had marrow failure with neutropenia as a consequence of AML; this became complicated by septicemia). Abnormalities in some hematological, clinical chemistry and urinalysis results were observed, which were consistent with the patients’ underlying disease. There were no clinically relevant changes in vital signs or ECG measurements.

Four patients were evaluable for disease response. One patient achieved a complete response (commenced Cycle 3, Day 92; duration ~6 months; a 73-year-old female with a complex abnormal karyotype who had previously failed hypomethylating therapy); the cytogenetic profile of this patient at screening was “adverse complex.” No response was observed in the remaining three patients.