A Dose Finding Study of Weekly and Every-3-Week nab-Paclitaxel Followed by Carboplatin as First-Line Therapy in Patients with Advanced Non-small Cell Lung Cancer

INTRODUCTION: This nonrandomized study aimed to identify the optimal dose of every-3-week (q3w) and weekly nab-paclitaxel plus q3w carboplatin as first-line therapy in patients with advanced non-small cell lung cancer (NSCLC) for a phase 3 trial. METHODS: Previously untreated patients with advanced NSCLC enrolled sequentially into seven cohorts (25 patients/cohort, N = 175). Cohorts 1 to 4 and 5 to 7 received nab-paclitaxel q3w and weekly, respectively. Patients were evaluated for efficacy and safety. RESULTS: The most common treatment-related > or = grade 3 adverse events were neutropenia (60%), neuropathy (19%), fatigue (9%), and thrombocytopenia (29%) (no grade 4 neuropathy or fatigue). A 100 mg/m(2) weekly nab-paclitaxel produced less serious adverse events than other doses/schedules. Response rate (RR) was greater in the weekly versus q3w cohorts (47% vs. 30%). Median progression-free survival (PFS) ranged from 4.8 to 6.9 months, and overall survival (OS) ranged from 8.3 to 15.0 months (all cohorts). Patients receiving 100 mg/m(2) weekly nab-paclitaxel achieved 48% RR with 6.2 and 11.3 months of PFS and OS, respectively. In a retrospective analysis, patients with nonsquamous cell carcinoma receiving weekly nab-paclitaxel had significantly improved RR (59.4% vs. 23.5%, respectively, p = 0.003), and >2 months longer PFS and OS compared with q3w schedule. In patients with squamous cell carcinoma, the q3w schedule significantly increased PFS by 3 months (p = 0.014) and OS by >2 months (no difference in RR) compared with the weekly schedule. CONCLUSION: nab-Paclitaxel plus carboplatin is an effective therapy for advanced NSCLC. Based on favorable efficacy and safety profiles, a phase 3, randomized, multicenter study comparing 100 mg/m(2) weekly nab-paclitaxel plus q3w carboplatin to solvent-based paclitaxel plus carboplatin has enrolled patients

Novel 5-Nitrofuran-Tagged Imidazo-Fused Azines and Azoles Amenable by the Groebke–Blackburn–Bienaymé Multicomponent Reaction: Activity Profile against ESKAPE Pathogens and Mycobacteria

A chemically diverse set of 13 5-nitrofuran-tagged heterocyclic compounds has been prepared via the Groebke–Blackburn–Bienaymé multicomponent reaction. The testing of these compounds against the so-called ESKAPE panel of pathogens identified an apparent lead compound—N-cyclohexyl-2-(5-nitrofuran-2-yl)imidazo[1,2-a]pyridine-3-amine (4a)—which showed an excellent profile against Enterobacter cloacae, Staphylococcus aureus, Klebsiella pneumoniae, and Enterococcus faecalis (MIC 0.25, 0.06, 0.25 and 0.25 µg/mL, respectively). Its antibacterial profile and practically convenient synthesis warrant further pre-clinical development. Certain structure-activity relationships were established in the course of this study which were rationalized by the flexible docking experiments in silico. The assessment of antitubercular potential of the compounds synthesized against drug sensitive H37v strain of Mycobacterium tuberculosis revealed little potential of the imidazo-fused products of the Groebke–Blackburn–Bienaymé multicomponent reaction as chemotherapeutic agents against this pathogen