A phase I study of BIBF 1120, an orally active triple angiokinase inhibitor (VEGFR, PDGFR, FGFR) in patients with advanced solid malignancies

Abstract

3054 Background: BIBF 1120 is a potent orally available inhibitor of VEGF, PDGF and FGF receptor kinases. It also inhibits members of the Src family of tyrosine kinases (Src, Lck, Lyn). Methods: Pts with a variety of advanced solid malignancies were enrolled. BIBF 1120 as a continuous once daily dosing was started at 100mg/day and doubled in successive cohorts until the observation of ≥CTC grade (gr) 2 drug-related toxicities. Thereafter, escalation steps by no more than 50% were allowed. All pts underwent pharmacokinetic (PK) sampling. Dynamic contrast-enhanced MRI (DCE-MRI) studies were performed at baseline, days 2, 28 and 56 to assess functional tumour change following treatment. Results: To date, 39 pts (18M/21F) with a wide range of malignancies have been enrolled. Median age: 57 yrs (range: 22–77). ECOG PS 0/1: 17/22. 37 pts who had ≥21 days treatment were evaluable for toxicity. Median duration of treatment: 2 months (range: 8 days - 13 months). Pts were treated at 5 dose levels: 100mg/d (n=6), 200mg/d (n=6), 300mg/d (n=6), 400mg/d (n=14), 450mg/d (n=5). The most common toxicities were nausea, vomiting, diarrhoea, abdominal pain, fatigue (all ≤gr 2) and asymptomatic, reversible elevation in liver enzymes (gr 3 in 10 pts) seen at ≥200mg/d. MTD was identified as 400mg/d, with 2 pts experiencing dose-limiting liver enzyme elevation at 450mg/d which returned to baseline within 2 weeks of stopping treatment. 29 pts who had ≥8 weeks’ treatment were assessable for response: 10 pts had SD for 4, 5, 6, 7, 8.5, 11 months (ovarian, cervical, colon, prostate, renal cancer, GIST, NSCLC and leiomyomatosis). One pt with prostate cancer had significant prolongation of his PSA doubling time from 2 months to 10 months, and a pt with renal cancer had SD for 11 months. PK analysis showed in general increasing mean Cmax and AUC values with the dose, displaying moderate to high interpatient variability. Cmax values were reached ∼3 hrs after dosing. Mean t1/2ranged from 7.5–14.0 hrs. 28 pts underwent DCE-MRI studies (analysis on-going). Conclusions: BIBF 1120 was well-tolerated in pts with advanced malignancy and 400mg/d was defined as MTD. Study is on-going with further pts being treated at twice daily dosing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Boehringer Ingelheim Ltd. AstraZeneca, Boehringer Ingelheim, Celgene, Novartis, Topotargets Chroma, GlaxoSmithKline, Oncolytics Biotech, Roche Chiron, Human Genome Sciences, Pfizer