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

Cancer. 2013 Dec 15;119(24):4268-76. doi: 10.1002/cncr.28365. Epub 2013 Sep 24.


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 × 10(11) , 6 × 10(11) , and 1.2 × 10(12) 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.

Keywords: head and neck cancer; induction chemotherapy; mouth rinse; oral mucositis; safety and tolerability.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Topical
  • Adolescent
  • Adult
  • Aged
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects*
  • Female
  • Head and Neck Neoplasms / drug therapy*
  • Head and Neck Neoplasms / metabolism
  • Head and Neck Neoplasms / microbiology
  • Humans
  • Induction Chemotherapy
  • Lactococcus lactis / genetics
  • Lactococcus lactis / metabolism*
  • Male
  • Middle Aged
  • Mouth Mucosa / drug effects
  • Mouth Mucosa / microbiology
  • Mouthwashes / administration & dosage
  • Mouthwashes / adverse effects
  • Stomatitis / chemically induced*
  • Stomatitis / drug therapy
  • Stomatitis / microbiology
  • Stomatitis / prevention & control*
  • Trefoil Factor-1
  • Tumor Suppressor Proteins / administration & dosage*
  • Tumor Suppressor Proteins / biosynthesis
  • Tumor Suppressor Proteins / pharmacokinetics
  • Young Adult


  • Antineoplastic Agents
  • Mouthwashes
  • TFF1 protein, human
  • Trefoil Factor-1
  • Tumor Suppressor Proteins