Oral Mucositis
Conditions
Brief summary
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.
Detailed description
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.
Interventions
BIOLOGICALAG013
AG013 is made up of genetically modified (GM) bacteria called Lactococcus lactis (L. lactis). Wild type L. lactis are commonly used to produce dairy products including cheeses and milk. To make AG013, the DNA of L. lactis has been changed in the laboratory to secrete a protein called human Trefoil Factor 1 (hTFF1). hTFF1 is normally secreted in saliva and intestines. Trefoil factors have been shown to be important in protecting and healing mucosal tissues, such as the tissue in the mouth, when these tissues are damaged by cancer therapies such as chemotherapy and radiation therapy.
OTHERPlacebo
Subjects assigned to the placebo group will receive appearance- and taste-matched placebo powder.
Sponsors
Oragenics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of AG013 Compared to Placebo for Reducing OM as Measured by Duration (in Days) of Severe Oral Mucositis (WHO Grades 3 or 4) | From the start of radiation therapy (RT) until 2 weeks following its completion, 7 to 9 weeks depending on the duration of CRT. | Duration (in Days) of Severe Oral Mucositis (WHO Grades 3 or 4) |
Countries
Belgium, Germany, United Kingdom, United States
Participant flow
Pre-assignment details
3 patients were randomized but never received study drug and are excluded from the safety analysis set.
Participants by arm
| Arm | Count |
|---|---|
| AG013 Three rinses per day with AG013 mouth rinse beginning from the start of radiotherapy until 2 weeks following its completion for 7 to 9 weeks, depending on the duration of radiotherapy. | 100 |
| Placebo Three rinses per day with placebo mouth rinse beginning from the start of radiotherapy until 2 weeks following its completion for 7 to 9 weeks, depending on the duration of radiotherapy. | 100 |
| Total | 200 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 2 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Non-compliance | 2 | 0 |
| Overall Study | Other | 14 | 8 |
| Overall Study | Symptomatic deterioration | 0 | 1 |
| Overall Study | Withdrawal by Subject | 12 | 27 |
Baseline characteristics
| Characteristic | AG013 | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 60.4 years STANDARD_DEVIATION 9.98 | 60.4 years STANDARD_DEVIATION 9.53 | 60.4 years STANDARD_DEVIATION 9.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 9 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 91 Participants | 172 Participants | 81 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants | 19 Participants | 12 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 7 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) White | 93 Participants | 185 Participants | 92 Participants |
| Region of Enrollment Europe | 35 participants | 70 participants | 35 participants |
| Region of Enrollment United States | 65 participants | 130 participants | 65 participants |
| Sex: Female, Male Female | 19 Participants | 35 Participants | 16 Participants |
| Sex: Female, Male Male | 81 Participants | 165 Participants | 84 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 100 | 4 / 97 |
| other Total, other adverse events | 98 / 100 | 95 / 97 |
| serious Total, serious adverse events | 43 / 100 | 25 / 97 |
Outcome results
Primary
Efficacy of AG013 Compared to Placebo for Reducing OM as Measured by Duration (in Days) of Severe Oral Mucositis (WHO Grades 3 or 4)
Duration (in Days) of Severe Oral Mucositis (WHO Grades 3 or 4)
Time frame: From the start of radiation therapy (RT) until 2 weeks following its completion, 7 to 9 weeks depending on the duration of CRT.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG013 | Efficacy of AG013 Compared to Placebo for Reducing OM as Measured by Duration (in Days) of Severe Oral Mucositis (WHO Grades 3 or 4) | US | 19.6 Days | Standard Deviation 25 |
| AG013 | Efficacy of AG013 Compared to Placebo for Reducing OM as Measured by Duration (in Days) of Severe Oral Mucositis (WHO Grades 3 or 4) | Europe | 17.2 Days | Standard Deviation 22.67 |
| Placebo | Efficacy of AG013 Compared to Placebo for Reducing OM as Measured by Duration (in Days) of Severe Oral Mucositis (WHO Grades 3 or 4) | US | 20.6 Days | Standard Deviation 25.2 |
| Placebo | Efficacy of AG013 Compared to Placebo for Reducing OM as Measured by Duration (in Days) of Severe Oral Mucositis (WHO Grades 3 or 4) | Europe | 15.3 Days | Standard Deviation 22.54 |