Pharmacokinetic Results from a Phase 1 Study of a Multi-Targeted Tyrosine Kinase Inhibitor, ABT-869, in Patients with Refractory or Relapsed Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndrome (MDS)

ABT-869 is an orally bioavailable, potent and specific inhibitor of multiple receptor tyrosine kinases (RTKs) including vascular endothelial and platelet growth factor, FLT3, STAT5, and ERK receptors. Since multiple RTKs, particularly FLT3, are commonly expressed and activated in AML/MDS, ABT-869 may prove to be an attractive therapeutic option. The current multi-center, two arm, dose-escalation study was designed

1. to assess the safety, pharmacodynamics, pharmacokinetics (PK) and preliminary anti-tumor activity of ABT-869 as monotherapy in arm A, and

2. to determine the PK, safety profile and potential of a PK or PD mediated drug interaction in patients with AML or MDS treated with ABT-869 plus Cytosine arabinoside (Ara-C) in arm B.

No dose was administered on D7 (arm A) and D12 (arm B). In single-agent Arm A enrollment is complete (N=29) with 9, 4, 12 and 4 patients enrolled in each of the 10, 12.5, 15, and 20 mg cohorts, respectively. Dosing began with the 10 mg/day cohort and escalated to the 20 mg/day cohort to define a recommended phase 2 dose (RP2D) of 15 mg. During dose escalation, in the 10 mg cohort, 2 patients experienced DLTs of fatigue while in the 20 mg cohort, 3 patients experienced DLTs of fatigue and 1 patient experienced a DLT of proteinuria. In currently enrolling arm B (N=17), ABT-869 was administered in combination with Ara-C. ABT-869 was initiated on day 6 following administration of Ara-C at 1.5 mg/m² on days 1–3 (patients ≥64 years old) or days 1–4 (patients <64 years old); dosing began at 10 mg and escalated to 12.5 mg. In arm B, 2 patients on the 12.5 mg cohort experienced DLTs, one of gr 3 fatigue and one of gr 3 proteinuria, leading to selection of an RP2D of 10 mg. In arm A, the average effective half-life for ABT-869 ranged from 11.7–13.5 h, and the average CL ranged from 4.9–6.6 L/h. The dose-normalized (DN) Cmax were similar between arm A (N=27) and arm B (N=9) at 0.016 ± 0.007 (mean ± SD) and 0.014 ± 0.004 (μg/mL/mg), respectively. The DN Cmax geometric mean ratio of arm B vs. A was 0.938 (90% confidence interval 0.71 – 1.24). DN AUC24 was different between arm A and arm B (0.21 ± 0.10 vs. 0.10 ± 0.04 μg*hr/mL/mg, respectively). The DN AUC24 geometric mean ratio of arm B vs. A was 0.494 (90% confidence interval 0.36–0.68). The DLTs observed in this study were consistent with VEGF receptor tyrosine kinase inhibition including fatigue and proteinuria as seen in both arms A and B. The most common adverse events across all grades (majority being grade 1/2) as reported from the available arm A data were diarrhea, fatigue, dry mouth, nausea, vomiting, asthenia, anorexia, and decreased appetite. In addition, grade 3 events observed were; asthenia (12%), fatigue (6%), febrile neutropenia (6%) and pancytopenia (6%). The latter two events are reflective of the pancytopenia present at the time of study enrollment. ABT-869 has an acceptable safety profile. Preliminary results from this ongoing phase 1 study demonstrate that in arm A the PK of ABT-869 are dose proportional over the 10–20 mg dose range. Differences in ABT- 869 AUC between arm A and arm B are being further investigated and will be correlated with pharmacodynamic endpoints.