Efficacy, Safety and Tolerability of AG013 in Oral Mucositis Compared to Placebo When Administered Three Times Per Day

A Phase 2, Multi-center, Randomized, Double-blind, Placebo-controlled Study to Assess the Safety and Efficacy of Topically-applied AG013 for the Attenuation of Oral Mucositis in Subjects With Cancers of the Head and Neck Receiving Concomitant Chemoradiation Therapy

The purpose of the study is to evaluate the efficacy, safety and tolerability of topically administered AG013 compared to placebo for reducing Oral Mucositis (OM) in patients undergoing chemoradiation for the treatment of head and neck cancer, as measured by the duration, time to development, and overall incidence of OM during the active treatment phase, beginning from the start of chemoradiation therapy (CRT) until 2 weeks following its completion.

The effect of AG013 on patient-reported symptoms and analgesic use during the active treatment phase, and on the cumulative radiation dose administered before the onset of OM will also be evaluated, as will biomarkers and, in a subset of subjects, the PK (pharmacokinetic) profile of AG013.

This is a Phase 2, double-blind, placebo-controlled, 2-arm, multi-center trial in which subjects will be randomized in a 1:1 ratio to receive either placebo or AG013. AG013 is a mouth rinse formulation of Lactococcus lactis strain sAGX0085, deficient in the gene coding for thymidylate synthase and producing human TFF1 (Trefoil Factor 1).

Approximately 200 subjects will be enrolled in the study. To protect subjects from unanticipated safety risks, enrollment and treatment in the double-blind study will continue until 10 subjects on AG013 have been recruited. The Data Safety Monitoring Board (DSMB) will review safety data after these 10 subjects on AG013 have completed study treatment. If there are no safety signals identified, the study will continue to recruit the planned number of subjects.

There are 4 study periods as described below: screening, active treatment, short term follow-up and long term follow-up. The screening phase will be no longer than 4 weeks. The active treatment phase will be between 7 and 9 weeks depending on the subject's prescribed CRT (chemoradiation therapy) plan. The short term follow-up phase will be 4 weeks in duration. The long term follow-up will continue until 12 months post CRT. Oral mucositis (OM) assessments will begin at the start of CRT and continue until the subject has completed short term follow-up or until the OM resolves (as defined by a WHO (World Health Organization) score of ≤ 1), whichever comes first. Long term follow-up will continue for 12 months to assure that AG013 does not adversely impact the tumor response to anti-neoplastic therapy.

Inclusion Criteria:

1. Willing and able to understand and sign the study specific Informed Consent Form

2. Pathologically-confirmed squamous cell carcinoma of the oral cavity, oropharynx, nasopharynx or hypopharynx or HPV-positive unknown primaries presumed to be of oropharyngeal, nasopharyngeal or hypopharyngeal origin

3. Tumor HPV status established

4. Planned to receive either primary or post-operative CRT

5. Planned IMRT (Intensity-Modulated Radiotherapy)

6. Planned administration of cisplatin administered weekly or tri-weekly during RT

7. Males or females 21 years or older

8. Karnofsky performance score (KPS) ≥ 70%

9. Screening laboratory assessments:

   • Hemoglobin ≥ 10g/dl
   • White blood count ≥ 3500 cells/mm3
   • Absolute neutrophil counts ≥ 1500 cells/ mm3
   • Serum AST (aspartate aminotransferase) and ALT (alanine aminotransferase) ≤ 3 x ULN
   • Calculated Creatinine Clearance ≥ 50 ml/min
   • Negative pregnancy test (serum or urine) for females of childbearing potential performed 7 days before IMP (Investigational Medicinal Product) administration.

10. Subjects of childbearing potential must confirm to use an effective method of birth control during study participation and for 30 days following the last treatment with IMP. Male subjects, when having hetero-sexual intercourse with a female of childbearing potential must use a condom during study participation and 90 days following the last treatment with IMP and their partner should use an effective method of birth control during that period as well.

Exclusion Criteria:

1. Prior radiation to the head and neck
2. Increased risk of developing infectious endocarditis
3. Prior gene therapy
4. Presence of active infectious oral disease
5. Presence of any oral lesions that may confound the ability to assess oral mucositis grade
6. Current use of antibiotic rinses or troches
7. Herbal, alternative remedies, and alcohol containing over-the-counter mouthwashes are excluded during the course of the study
8. Current alcohol abuse syndrome
9. Chronic immunosuppression
10. Known seropositive for HIV
11. Use of investigational agent within 30 days of signing informed consent
12. Tooth extraction prior to radiation in which the extraction site is not epithelialized
13. Signs and symptoms of active dental disease
14. Female subjects who are pregnant or nursing
15. Known allergy to excipients of the IMP
16. Inability to give informed consent or comply with study requirements
17. Unwilling or unable to complete subject diary
18. Any other clinical condition, psychiatric condition or prior therapy that, in the opinion of the Investigator, would make the subject unsuitable for the study or unable or to comply with follow-up visits