A phase 1 dose-escalation study of NEO-102 in patients with refractory colon and pancreatic cancer.

PURPOSE: NEO-102 is a novel chimeric IgG1 monoclonal antibody which recognizes a variant form of MUC5AC expressed specifically by human pancreatic and colorectal tumors. Preclinical models have demonstrated encouraging signs of anti-tumor activity through antibody-dependent cell-mediated cytotoxicity. METHODS: This is a phase 1, dose-escalation trial of NEO-102 (Ensituximab) for patients with refractory pancreatic and colorectal cancer. The primary objective was to determine safety and tolerability of escalating doses of NEO-102. Secondary objectives were to assess pharmacokinetics, anti-tumor activity and biologic correlates. Patients whose tumors express NPC-1 antigen were eligible. Dose-escalation was performed in a 3 + 3 design at doses of 1.5, 2, 3 and 4 mg/kg. RESULTS: A total of 19 patients (4 pancreatic and 15 colon cancer) were enrolled at participating institutions in the treatment phase. Most common treatment-related adverse events included anemia, fatigue, fevers, chills and flushing. There was no detectable hemolysis. Of twelve patients evaluable for disease response, the response rate at week 8 included 5 patients with stable disease and 8 patients with progressive disease (PD). Treatment-related grade 3/4 hyperbilirubinemia and anemia were observed at 4 mg/m2. Reversible hypoxia at 3 mg/kg was a dose-limiting toxicity. The maximum tolerated dose was established at 3 mg/kg. Of 74 patients who underwent tissue screening, positive NPC-1 expression was 47 % in colon and 59 % in pancreatic cancer. CONCLUSIONS: Treatment with the NEO-102, in this first-in-human study, is well tolerated with a manageable safety profile. A maximum tolerated dose of 3 mg/kg has been established. Toxicity profile is typical for this therapeutic class and allows for combination with conventional cytotoxic therapies.

Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis.

Atopic dermatitis (AD) has long been associated with Staphylococcus aureus skin colonization or infection and is typically managed with regimens that include antimicrobial therapies. However, the role of microbial communities in the pathogenesis of AD is incompletely characterized. To assess the relationship between skin microbiota and disease progression, 16S ribosomal RNA bacterial gene sequencing was performed on DNA obtained directly from serial skin sampling of children with AD. The composition of bacterial communities was analyzed during AD disease states to identify characteristics associated with AD flares and improvement post-treatment. We found that microbial community structures at sites of disease predilection were dramatically different in AD patients compared with controls. Microbial diversity during AD flares was dependent on the presence or absence of recent AD treatments, with even intermittent treatment linked to greater bacterial diversity than no recent treatment. Treatment-associated changes in skin bacterial diversity suggest that AD treatments diversify skin bacteria preceding improvements in disease activity. In AD, the proportion of Staphylococcus sequences, particularly S. aureus, was greater during disease flares than at baseline or post-treatment, and correlated with worsened disease severity. Representation of the skin commensal S. epidermidis also significantly increased during flares. Increases in Streptococcus, Propionibacterium, and Corynebacterium species were observed following therapy. These findings reveal linkages between microbial communities and inflammatory diseases such as AD, and demonstrate that as compared with culture-based studies, higher resolution examination of microbiota associated with human disease provides novel insights into global shifts of bacteria relevant to disease progression and treatment.