Pharmacokinetic (PK) analysis of a phase I study of continuous oral treatment with the angiokinase inhibitor BIBF 1120, in combination with carboplatin and paclitaxel in patients with advanced non-small cell lung cancer (NSCLC)

Abstract

3567 Background: BIBF 1120 is a potent, orally available tyrosine kinase inhibitor (VEGFR 1/2/3, PDGFR α/β and FGFR 1/3) that suppresses tumor growth by angiogenesis inhibition. Recently, the combination of a VEGF inhibitor with standard chemotherapy improved the therapeutic outcome of first line NSCLC patients. Methods: The primary objectives of this Phase I trial were to determine the safety, tolerability, the maximum tolerated dose (MTD) and the PK of BIBF 1120 in combination with paclitaxel and carboplatin in previously untreated NSCLC patients. The BIBF 1120 dose was increased by 50 mg per cohort until the MTD was determined. BIBF 1120 was taken on Days 2–21 with carboplatin (AUC= 6 min·mg/mL) and paclitaxel (200 mg/m2) administered on Day 1 of each 21-day cycle. PK samples were taken on Days 1 and 2 of treatment cycle (TC) 1 and 2. PK parameters were analysed by non-compartmental techniques. Results: Twenty-five patients with stage IIIB/IV NSCLC, performance score 0–1, were enrolled and treated at doses of 50 mg/day (n=3), 100 mg/day (n=3), 150 mg/day (n=3), 200 mg/day (n=13) and 250 mg/day (n=3). The MTD of BIBF 1120 was 200 mg bid. BIBF 1120 steady state was reached after 7 days of bid dosing. No systematic change in trough plasma concentrations or deviation from dose linearity of BIBF 1120 was observed in combination with carboplatin and paclitaxel. PK parameters of carboplatin and paclitaxel are displayed in the table. Conclusions: 200 mg of BIBF 1120 bid in combination with standard doses of carboplatin and paclitaxel is considered the recommended dose for continuous daily treatment for patients with advanced or metastatic NSCLC. There were no clinically relevant changes to the PK parameters of paclitaxel or carboplatin after 20 days administration of 200 mg BIBF 1120 bid, showing that this may be a viable combination in future studies. TC1 (before BIBF 1120 dosing) TC2 (after 20 days of BIBF 1120 dosing) N gMean gCV[%] N gMean gCV[%] Paclitaxel AUC0-∞ ng·h/mL 8 18,800 21.6 7 21,900 27.9 Cmax ng/mL 8 6,020 29.2 8 7,260 25.9 Carboplatin AUC0- ∞ ng·h/mL 6 66,300 21.8 5 78,300 32.9 Cmax ng/mL 6 16,900 19.5 6 18,300 37.1 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Boehringer Ingelheim Pharma GmbH & Co. KG, Boehringer Ingelheim Pharmaceuticals Inc. US Oncology Boehringer Ingelheim