Phase 1b, multicenter, single blinded, placebo‐controlled, sequential dose escalation study to assess the safety and tolerability of topically applied AG013 in subjects with locally advanced head and neck cancer receiving induction chemotherapy

Abstract

BACKGROUND Oral mucositis (OM) is a significant toxicity of induction chemotherapy for locally advanced head and neck cancer (LAHNC). The safety and tolerability of AG013, an oral rinse containing recombinant Lactococcus lactis secreting mucosal protectant human trefoil factor 1 (hTFF1), was evaluated in a phase 1b study in LAHNC subjects who received induction with cisplatin, 5‐fluorouracil, with or without docetaxel. Preliminary efficacy data were also obtained. METHODS A total of 25 of 52 LAHNC subjects who were followed during induction cycle 1 developed ulcerative oral mucositis (UOM; World Health Organization grade > 2) and were randomized to AG013:placebo (5:2 ratio) for cycle 2. Dosing schedules of 1, 3, or 6 times daily were evaluated (2 × 1011, 6 × 1011, and 1.2 × 1012 colony forming units per day, respectively). OM was evaluated daily from cycle 2, day 1 through 14, using World Health Organization criteria. Pharmacokinetic assessment was also conducted. RESULTS AG013 bacteria were not detected in blood. Oral live AG013 bacterial and hTFF1 levels in saliva and oral mucosa were equivalent among treatment groups. The most frequently occurring adverse events were nausea, oral pain, fatigue, diarrhea, and mucosal inflammation. Only 12% (3 of 25 adverse events), mainly nausea, were attributed to the investigational medicinal product: AG013 or placebo. Efficacy analysis showed a 35% reduction in percentage of days with UOM in AG013‐subjects versus placebo. All placebo subjects experienced ≥ 2 days of UOM, whereas 29% of AG013 subjects had UOM for 0 or 1 day. AG013 use resulted in fewer unscheduled office and emergency room visits. No differences were noted in mouth and throat soreness, opioid use, or gastrostomy tube placement. CONCLUSIONS AG013 was safe and well tolerated. Preliminary efficacy data support further study. Cancer 2013;119:4268–4276. © 2013 American Cancer Society.

Genetically Engineered Immunomodulatory Streptococcus thermophilus Strains Producing Antioxidant Enzymes Exhibit Enhanced Anti-Inflammatory Activities

“…Our findings suggest that LAB strains that are able to modulate immune responses and that also express antioxidant enzymes could be useful in the development of novel therapeutic products that prevent IBD. Although genetically engineered strains are normally used to demonstrate a "proof of concept," some human clinical trials using modified lactic acid bacteria have already been performed without any significant negative side effects on the host: a phase 1 trial that evaluated the safety of a strain of L. lactis expressing human IL-10 for the treatment of Crohn's disease (29) and, more recently, a phase 1b study that evaluated a recombinant L. lactis strain secreting the mucosal protectant human trefoil factor 1 (30). These studies set the precedent for the clinical use of engineered probiotic microorganisms as potential treatment options.…”

Host-Microbiome Cross-talk in Oral Mucositis

“…A phase 1b study in patients with head and neck cancer receiving induction chemotherapy examined the use of an oral rinse (AG013) containing recombinant Lactococcus lactis, which was genetically engineered to secrete the mucosal protectant human trefoil factor 1 (a family of peptides that play important roles in the protection and repair of epithelial surfaces, including the gastrointestinal tract). The use of AG013 resulted in a 35% reduction in the number of days with ulcerative OM compared with placebo (Limaye et al 2013). Key concerns with the utilization of a bacterial vehicle stem from the potential risk of the development of clinically relevant infections.…”

Evaluation of the biosafety of recombinant lactic acid bacteria designed to prevent and treat colitis

“…In this regard, it was shown in a phase 1 trial that a strain of L. lactis expressing human IL-10 for the treatment of Crohn's disease was safe for use (Braat et al, 2006), and more recently, a recombinant L. lactis secreting the mucosal protectant human trefoil factor 1 was successfully used in a phase 1b study (Limaye et al, 2013). These studies clearly show the potential for the clinical use of recLAB as an alternative treatment option.…”