Pharmacokinetic (PK) analysis of two dosing schedules of the angiokinase inhibitor BIBF 1120 in patients with hormone- refractory prostate cancer (HRPC) who progressed after docetaxel treatment

Abstract

14578 Background: BIBF 1120 is a novel, oral, potent angiokinase inhibitor blocking the VEGFR 1/2/3, FGFR 1/3, and PDGFR α/β tyrosine kinases at nanomolar concentrations. This randomized, open-label, multicenter Phase II study evaluated the efficacy, safety and PK of two doses of BIBF 1120 in patients with metastatic HRPC that had progressed after docetaxel therapy. Methods: Patients were randomly assigned and treated with BIBF 1120 until disease progression or dose-limiting toxicity. The primary endpoint was response rate defined as a confirmed decline of PSA by ≥20%. PK analysis using high-performance liquid chromatography-mass spectroscopy was performed for PK samples of 36 patients. PK sampling occurred on Days 1 and 29, and every 2 weeks thereafter. Trough plasma concentrations were taken 8–14 hrs after dosing. The distribution of BIBF 1120 plasma concentrations was described using graphs and descriptive statistics. Results: 81 patients were randomly assigned to receive either 250 mg bid (n=41) or 150 mg bid (n= 40) of BIBF 1120 as monotherapy. On Day 1, BIBF 1120 plasma concentrations increased within the first 3 hours after dosing in the 150 mg bid and 250 mg bid groups; maximum values were 66.3 ng/mL and 124 ng/mL, respectively. On Day 29, maximum plasma concentrations were 54.9 ng/mL and 112 ng/mL in the 150 mg bid and 250 mg bid groups, respectively. BIBF 1120 plasma levels had reached steady state by Day 29 in both groups; this may have occurred earlier but there was no PK sampling between Days 1 and 29. Overall, pre-dose plasma concentrations remained stable over the 155-day observation period in both groups; interpatient variability was moderate to high. No systematic change in trough plasma concentrations or deviation from dose proportionality of BIBF 1120 was observed in either group. The gMean pre-dose plasma concentrations of BIBF 1120 were higher in the 250 mg bid group compared with the 150 mg bid group. Conclusions: For both dose groups, BIBF 1120 pre-dose concentrations did not deviate from dose-linearity in this study. For both dose groups, pre-dose concentrations remained stable over the treatment period. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Boehringer Ingelheim, Boehringer Ingelheim France Boehringer Ingelheim, Pharmion, sanofi-aventis AstraZeneca, sanofi-aventis Boehringer Ingelheim