Phase Ib, 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 (LAHNC) receiving induction chemotherapy (ICT).

Abstract

9024 Background: Oral mucositis (OM) is a significant toxicity of ICT in LAHNC. AG013, a mouth rinse composed of a recombinant Lactococcus lactis (sAGX0085) engineered to secrete human Trefoil Factor 1 (hTFF1) and deficient in the gene encoding thymidylate synthase, was investigated in patients receiving ICT (cisplatin, 5-fluorouracil +/-docetaxel:PF+/-T). TFFs have wound-healing properties and are protective of mucosal tissues. Methods: To evaluate the safety, tolerability, PK profile and efficacy of AG013 in attenuating ICT-associated OM, 52 patients (pts) with newly diagnosed LAHNC receiving ICT (24TPF, 1PF) were screened in ICT cycle (Cy) 1 for symptomatic OM (SOM). 25 pts who developed SOM in Cy1 were enrolled into 3 successive groups of at least 7 pts each in the active phase and randomly assigned at the Baseline visit (d1 of ICT Cy2) in a 5:2 ratio to receive AG013 or placebo during ICT Cy2. Dose was escalated in successive groups from 1 x/day (qd) to 3 x/day (tid) and to 6 x/day, resulting in doses of 2 x 1011, 6 x 1011, and 1.2 x 1012 colony-forming units (CFU)/day respectively. Pts were assessed daily from Cy 2 d1 to d14 for OM using WHO criteria. Safety endpoints and PK (mucosal, salivary and blood samples) were assessed. Results: AG013-sAGX0085 could not be detected in blood. Recovered oral live bacterial levels were high immediately after dosing, decreased by 90 minutes post dose, and undetectable at study end. No differences in hTFF1 serum levels were seen. Pts in the placebo group had ulcerative OM (UOM) on nearly 60% of the days vs. 35-40% days in the AG013 group. 29 % pts who received AG013 had 0 or 1 day of UOM vs. at least 2 days of UOM in the placebo group. Pts who received AG013 on any dosing schedule had a lower % of days with OM, fewer unplanned office and emergency room visits compared to pts who received placebo. No differences were noted in mouth and throat soreness, opioid use, or gastrostomy tube placement. Conclusions: Topical administration of AG013 appears safe, well tolerated and effective in reducing the severity and course of OM in patients receiving ICT for HNC.