Phase I and biomarker study of ABT869, a multiple receptor tyrosine kinase inhibitor, in patients with refractory solid malignancies

Abstract

3519 Background: ABT869 is an orally administered, potent and specific inhibitor of all VEGF and PDGF family tyrosine kinases, including FLT-3, and c-kit receptors. Methods: A phase I study of ABT869 in patients with refractory solid malignancies was initiated to determine the maximum tolerable dose (MTD) of ABT869 given by continuous once-daily oral dosing; evaluate ABT869 pharmacokinetics; assess pharmacodynamic effects on plasma VEGF and circulating endothelial cells (CECs); evaluate tumor response, including an assessment of microcirculatory parameters DCE-MRI. Dose escalation was planned in dose cohorts of 3 patients each. Treatment periods (TP) were defined as 21 days and tumor assessments were performed using CT scans every 6 weeks. DCE-MRI was done at baseline, day 3 and 14 of the first cycle. Cohort expansion to 6 patients was planned if dose limiting toxicity (DLT) occurred in the first cycle of treatment, and MTD was defined as the dose at which ≥ 2/6 patients experienced DLT. Results: 21 evaluable patients (11 male, 10 female patients median age 58 range 29–76) were treated; 6 at 10mg per day, 12 at 0.25mg/kg/day and 3 at 0.3mg/kg/day. Cycle 1 DLTs included fatigue (grade(G) 3 DLT in 1 patient at 10mg), G3 foot rash, proteinuria and hypertension in 1 patient each at 0.25mg/kg/day (RPTD) and 2 patients with G3 hypertension, including G3 proteinuria in one of these patients, at 0.3mg/kg/day (MTD). Other common treatment-related adverse events at RPTD included asthenia, myalgia, mouth irritation, pneumothorax related to cavitating lung nodule in 2 patients. Pharmacokinetics of ABT869 demonstrated oral clearance of 2.8 ± 1.2 L/h, (mean ± SD, N=16) and half-life of 16.9 ± 5.0 h, with minimal drug accumulation at day 15. 2 PRs were seen in NSCLC patients and stable disease > 4 TPs was observed in 12 patients, with CT scan evidence of cavitation of pulmonary disease and reduced DCE-MRI derived parameters. Mean peak plasma VEGF levels were increased significantly from baseline (p=0.031). CEPs and CECs were reduced in most patients by day 15. Conclusions: 0.25mg/kg/day is the RPTD of ABT869. Modulation of plasma VEGF, CECs and DCE MRI show drug activity consistent with antiangiogenic activity. Promising clinical activity is seen, particularly in NSCLC. No significant financial relationships to disclose.