4015 Background: Mutations in the metabolic enzyme isocitrate dehydrogenase 1 (mIDH1) occur in patients (pts) with cholangiocarcinoma (CC) and are detected in up to 25% of intrahepatic CC. mIDH1 produce the oncometabolite, D-2-hydroxyglutarate (2-HG), resulting in epigenetic and genetic dysregulation and oncogenesis. AG-120 is a first-in-class, potent, oral inhibitor of mIDH1 tested in this phase I study in mIDH1 solid tumors, including CC. Methods: AG-120 was escalated in a 3+3 design from 100 mg twice daily to 1200 mg once daily (QD) in 28-day cycles (N = 60, mIDH1 advanced solid tumors). Key eligibility for CC: recurrence of progressive mIDH1 CC following standard therapy (dose escalation) or at least a prior gemcitabine-based regimen (expansion cohort). Response (RECIST 1.1) was assessed every 8 weeks. Plasma and tumor tissue were collected for exploratory analyses. Results: Based on the safety, pharmacokinetic, and pharmacodynamic data from dose escalation, the 500 mg QD dose was selected for expansion in mIDH1 CC and other mIDH1 solid tumors. As of Dec 16, 2016, 73 pts with mIDH1 CC had been dosed in the dose escalation (n = 24) and expansion (n = 49) cohorts. Demographics: M/F = 24/49, median number of prior therapies = 2 (range 1–5), ECOG 0–1 = 26/47. There were no dose-limiting toxicities. Treatment-related adverse events (AEs) in ≥5% pts: fatigue (21%), nausea (18%), vomiting (12%), diarrhea (10%), decreased appetite (8%), dysgeusia (5%), QT prolongation (5%). Two (3%) pts experienced related grade 3 AEs: fatigue and low phosphorus. There were no AG-120-related AEs leading to discontinuation. Among the 72 efficacy evaluable (≥1 post baseline response assessment or discontinued prematurely) mIDH1 CC pts (24 in escalation and 48 in expansion cohort), 6% (n = 4) had a confirmed partial response and 56% (n = 40) experienced stable disease. The progression-free survival rate at 6 months was 40%, and 8 pts have been treated with AG-120 for ≥1 year. Conclusions: In this pretreated mIDH1 CC population, AG-120 was associated with a favorable safety profile and prolonged stable disease. A global, phase III, randomized, placebo-controlled study of AG-120 in mIDH1 CC has been initiated (ClarIDHy). Clinical trial information: NCT02073994.

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New antimicrobial pH-responsive wound dressings consisting of immobilized human serum albumin/silk fibroin nanocapsules were developed.

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Candidatus Neoehrlichia is increasingly being recognized worldwide as a tickborne pathogen. We report a case of symptomatic neoehrlichiosis in an immunocompetent Austria resident who had recently returned from travel in Tanzania. The use of Anaplasmataceae-specific PCR to determine the duration of antimicrobial therapy seems reasonable to avert recrudescence.

4082 Background: Somatic mutations in isocitrate dehydrogenase 1 (IDH1) produce the oncometabolite D-2-hydroxyglutarate (2-HG). AG-120 is a first-in-class selective inhibitor of mutant IDH1 (mIDH1) under evaluation in an ongoing phase 1 study in patients with mIDH1 advanced solid tumors, including cholangiocarcinoma (CC) (NCT02073994). Objectives for this abstract were to 1) characterize the PK profile of AG-120 and the relationship between AG-120 exposure and 2-HG suppression, and 2) evaluate the influence of intrinsic patient factors on AG-120 clearance, in patients with mIDH1 CC. Methods: AG-120 was administered orally once daily (QD) or twice daily (BID) in continuous 28-day cycles. As of Dec 5, 2016, 60 of 73 patients enrolled with mIDH1 CC had PK/PD samples available for analysis at 100 mg BID, 300 mg QD, 400 mg QD, 500 mg QD, 800 mg QD, and 1200 mg QD in dose escalation (n = 24) and 500 mg QD (n = 36) in dose expansion. Blood (n = 60) and fresh tumor biopsy samples (n = 14) were collected to assess AG-120 and 2-HG using qualified liquid chromatography-tandem mass spectrometry methods. Results: Following both single and multiple doses, AG-120 plasma exposure increased less than dose proportionally from 100 to 1200 mg. Mean terminal half-life was 38.4–85.8 h, supporting a QD dosing regimen. Following multiple doses, steady state was reached within 15 days, with approximately 2-fold accumulation in plasma AG-120 exposure. No patient-specific factors were identified as clinically significant covariates affecting AG-120 plasma clearance. After multiple doses, plasma 2-HG levels were reduced (up to 98.4% inhibition, achieving levels similar to those in healthy volunteers) and tumor biopsy 2-HG levels were also substantially reduced (by up to 99.9%) at all dose levels tested. The 500 mg QD dose resulted in the largest magnitude of 2-HG inhibition vs. other dose levels. Conclusions: AG-120 demonstrated a long half-life in patients with mIDH1 CC and robustly inhibited 2-HG in plasma and tumor samples. These PK/PD data, along with emerging safety and clinical activity data, support the selection of 500 mg QD for future clinical investigation. Clinical trial information: NCT02073994.

Minerals and vitamins affect bone formation, genetics, nutrition, and hormones. Studies mainly focus on the elucidation of the metabolic pathways during biomineralization to get an idea of how to promote the process of biomineralization in vivo and in vitro. One qualified approach to reach this is to investigate the influence of different substances on the proliferation and differentiation of osteoblastic cell cultures in vitro. The aim of this study was to investigate the effects of different types of single B vitamins (B 6 , B 9 , and B 12) and a vitamin B complex (B 1 , B 2 , B 3 , B 5 , B 6 , B 9 , and B 12) on proliferation and differentiation of primary bovine osteoblastic cells in vitro. The proliferation of osteoblastic cells during the experiments was evaluated by cell number analysis while cultivating. The expression of marking proteins of the osteogenic differentiation was evaluated by immunohistochemistry. Previous experiments with seven different B vitamins in different concentrations revealed a positive effect on cell proliferation with increasing concentration caused by three B vitamins: pyridoxal (B 6), folic acid (B 9), and cobalamine (B 12). The use of vitamin B 6 , B 9 , and B 12 in different concentrations resulted in a significant increase of cell proliferation (p < 0.05). But neither the B vitamins nor the B vitamin complexes stimulated the expression of the typical bone cell proteins.