A multicentre, open-label, phase-I/randomised phase-II study to evaluate safety, pharmacokinetics, and efficacy of nintedanib vs. sorafenib in European patients with advanced hepatocellular carcinoma.

BACKGROUND: This multicentre, open-label, phase-I/randomised phase-II trial evaluated safety, pharmacokinetics, maximum-tolerated-dose (MTD) per dose-limiting toxicities (DLTs), and efficacy of nintedanib vs. sorafenib in European patients with unresectable advanced hepatocellular carcinoma (aHCC). METHODS: Phase I: Patients were stratified into two groups per baseline aminotransferase/alanine aminotransferase and Child-Pugh score; MTD was determined. Phase II: Patients were randomised 2:1 to nintedanib (MTD) or sorafenib (400-mg bid) in 28-day cycles until intolerance or disease progression. Time-to-progression (TTP, primary endpoint), overall survival (OS) and progression-free survival (PFS) were determined. RESULTS: Phase-I: no DLTs observed; nintedanib MTD in both groups was 200 mg bid. Phase-II: patients (N = 93) were randomised to nintedanib (n = 62) or sorafenib (n = 31); TTP was 5.5 vs. 4.6 months (HR = 1.44 [95% CI, 0.81-2.57]), OS was 11.9 vs. 11.4 months (HR = 0.88 [95% CI, 0.52-1.47]), PFS was 5.3 vs. 3.9 months (HR = 1.35 [95% CI, 0.78-2.34]), respectively (all medians). Dose intensity and tolerability favoured nintedanib. Fewer patients on nintedanib (87.1%) vs. sorafenib (96.8%) had drug-related adverse events (AEs) or grade ≥ 3 AEs (67.7% vs. 90.3%), but more patients on nintedanib (28 [45.2%]) had AEs leading to drug discontinuation than did those on sorafenib (7 [22.6%]). CONCLUSIONS: Nintedanib may have similar efficacy to sorafenib in aHCC.

Gel-immobilized heparin-binding lectin as sensitive sensor for certain groups of charge-bearing carbohydrates.

The specificity of lectins to carbohydrate moieties in principle enables them to serve as sensors for sugars with ligand properties. However, experimental systems and parameters to measure this interaction need to be defined. On the basis of knowledge about temperature-sensitive volume changes of gels, composed of acrylamide derivatives, and about the influence of presence of charge-bearing groups within the gel on this behavior, we covalently immobilized a human heparin-binding lectin into a gel matrix. Besides the lectin-carrying derivative N-isopropylacrylamide and N,N'-methylenebisacrylamide are the monomeric constituents of the polymer. The lectin has been attached to divinyl sulfone-activated N-hydroxymethylacrylamide. Several anionic sugar moieties are added to the solution, covering the gel pieces, and the mechanical response of the individual gel slices in dependence to stepwise temperature increases is automatically recorded with an electronic transducer at a sensitivity of 5 mV/microns. Only carboxyl group-containing sugar moieties like glucuronic acid notably reduce the extent of the temperature-dependent gel shrinking as indicator for a protein-carbohydrate interaction. The individual slices are reuseable, emphasizing practical applications. This sensitive and automated assay concept with the covalently immobilized heparin-binding protein is supposed to be adaptable to other groups of lectins with specificity to anionic sugars like sialic acid-binding proteins.