A Clinical Phase I, Pharmacakinetic (Pk), And Pharmacodynamic Study Of Twice Daily Bibf 1120 In Advanced Cancer Patients.

3031 Background: BIBF 1120 is a potent, orally available triple angiokinase inhibitor (VEGFRs, PDGFRs, FGFRs) that suppresses tumor growth by angiogenesis inhibition. After an initial study with once daily dosing in advanced cancer patients, twice daily (bid) dosing was performed in order to increase drug exposure without increasing toxicity. Methods: Treatment cycles consisted of 28 days continuous administration of BIBF 1120 bid followed by 7 days off. The dose was escalated until dose limiting toxicity (DLT) was observed. Further treatment cycles were allowed in the absence of progressive disease and persistent toxicity. PK profiles were obtained at the beginning and at end of the 1st cycle. Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) was performed at baseline, day 3, day 30, and after each further cycle. Results: 36 patients (5 female, 31 male) were included, 33 completed treatment cycle 1, and 3 patients were excluded due to unrelated adverse events (AE) or DLT. The dose was escalated according to the following scheme: 150 mg bid, 150+200 mg, 200 mg bid, 250 mg bid and 300 mg bid. Main drug-related AEs (mostly ≤CTC°2) were nausea, vomiting, and diarrhoea. Elevations of hepatic enzymes (LFT) were dose limiting (≥CTC°3) in 2/5 patients at 300 mg bid. 23/36 patients (64%) were treated for more than two cycles. 3 patients showed a partial tumor response at ≥200 mg bid (RECIST). In DCE-MRI, blood flow and permeability (IAUC60) in target lesions were reduced by ≥40% in 10/34 evaluable patients. BIBF 1120 exposure (AUC) displayed moderate to high variability. Maximum plasma concentrations were reached ∼3 hours after drug intake. BIBF 1120 was extensively distributed out of the blood and showed a high clearance with a mean terminal half-life of ∼15 h. Conclusions: As compared to once daily dosing, bid administration of BIBF 1120 allowed increased drug exposure to cancer patients without additional toxicity. AEs largely consisted of mild/moderate gastrointestinal toxicity. Reversible LFT elevations constituted DLT at 300 mg bid. Based on these results, 250 mg bid is considered the maximum tolerated dose of BIBF 1120. Encouraging signs of anti-tumor activity have been observed. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Boehringer Ingelheim Boehringer Ingelheim Boehringer-Ingelheim