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Abstract: Background: The epidermal growth factor receptor (EGFR) and ERBB2 (HER2) pathways and vascular endothelial growth factor (VEGF)-dependent angiogenesis have a pivotal role in cancer pathogenesis and progression. Robust experimental evidence has shown that these pathways are functionally linked and implicated in acquired resistance to targeted therapies making them attractive candidates for joined targeting. We undertook this phase I trial to assess the safety, the recommended dose for phase II trials (RPTD), pharmacokinetics (PK), pharmacodynamics (PD), and the preliminary antitumour activity of the combination of lapatinib and sorafenib in patients with advanced refractory solid tumours. Methods: Four cohorts of at least three patients each received lapatinib once daily and sorafenib twice daily together on a continuous schedule. Doses of lapatinib and sorafenib were escalated based on dose-limiting toxicities (DLTs) in the first treatment cycle following a traditional 3+3 design until the RPTD was reached. Additional patients were treated at the RPTD to characterise PK profiles of this combination and to investigate the potential interaction between lapatinib and sorafenib. Serum samples were collected at baseline and then prospectively every two cycles to assess changes in PD parameters. This trial is registered with ClinicalTrials.gov, number NCT00984425. Findings: Thirty patients with advanced refractory solid tumours were enroled. DLTs were grade three fatigue and grade 3 atypical skin rash observed at dose levels 3 and 4, respectively. The higher dose level explored (lapatinib 1250mg/day and sorafenib 400mg twice daily) represented the RPTD of the combination. The most common drug-related adverse events were fatigue (68%), hypocalcemia (61%), diarrhoea (57%), lymphopaenia (54%), anorexia (50%), rash (50%), and hypophosphatemia (46%). PK analysis revealed no significant effect of sorafenib on the PK profile of lapatinib. Of the 27 assessable patients for clinical activity, one achieved a confirmed complete response, four (15%) had a partial response, and 12 (44%) achieved disease stabilisation. The disease control rate overall was 63%. Interpretation: Combination treatment with lapatinib and sorafenib was feasible with promising clinical activity and without significant PK interactions. Long term tolerability seems to be challenging. [Copyright &y& Elsevier]

Zn(II)-dinuclear complexes of open-chain polyamino-phenolic ligands are effective tools for the recognition of PMG and AMPA in aqueous media. [Display omitted] • Polyamino-phenolic ligands strongly bind glyphosate and ampa in aqueous solution. • Zn(II)-complexes of polyamino-phenolic ligands afford selective anion recognition/sensing. • Metal coordination requirements and ligand structural features modulate the binding properties. We report on the binding abilities towards the popular herbicide N-(phosphonomethyl)glycine (glyphosate or PMG) and its primary metabolite aminomethylphosphonic acid (AMPA), of the two polyamino-phenolic compounds 3,3′-bis N,N - bis (2- aminoethyl) aminomethyl ]-2,2′-dihydroxybiphenyl (L1) and 2,6-bis{[bis-(2-aminoethyl)amino]methyl}phenol (L2). The presence of peculiar biphenol (L1) or phenol (L2) spacers that link two separate dien units confers to ligands interesting anion binding properties but also affords stable Zn(II)-dinuclear complexes (R1 and R2), which act as efficient metallo-receptors for such substrates. Potentiometric studies evidenced the great anion-coordination abilities of L1 and L2 , which both preferentially bind PMG over AMPA in a wide range of pH. However, the formation of metal complexes markedly influences their coordination properties, with R1 that displays a maintained capacity to discriminate PMG over AMPA and R2 that shows an opposite binding selectivity. 1H and 31P NMR experiments supported the effective coordination of such substrates by the R systems while fluorescence titrations were performed to assess whether the anion-recognition processes can be detected by fluorescence signalling. This study highlights that the structural characteristics of the metallo-receptors, along with the coordination requirements of their metal centers, are powerful tools that can be finely modulated to achieve suitable systems for the selective recognition/sensing of targeted species in aqueous solution. [ABSTRACT FROM AUTHOR]