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

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ClinicalTrials.gov Identifier: NCT03234465
Recruitment Status : Recruiting
First Posted : July 31, 2017
Last Update Posted : December 17, 2018
Sponsor:
Information provided by (Responsible Party):
Oragenics, Inc.

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.


Condition or disease Intervention/treatment Phase
Oral Mucositis Biological: AG013 Other: Placebo Phase 2

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : July 18, 2017
Estimated Primary Completion Date : May 2020
Estimated Study Completion Date : May 2020

Arm Intervention/treatment
Experimental: AG013: three mouth rinses/day
Subjects will rinse three times per day with AG013 mouth rinse beginning from the start of radiotherapy until 2 weeks following its completion. The active treatment phase lasts for 7 to 9 weeks, depending on the duration of radiotherapy.
Biological: AG013
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.

Placebo Comparator: Placebo: three mouth rinses/day
Subjects will rinse three times per day with placebo mouth rinse beginning from the start of radiotherapy until 2 weeks following its completion. The active treatment phase lasts for 7 to 9 weeks, depending on the duration of radiotherapy.
Other: Placebo
Subjects assigned to the placebo group will receive appearance- and taste-matched placebo powder.




Primary Outcome Measures :
  1. Efficacy of AG013 compared to placebo for reducing OM as measured by the duration and time to development of OM during the active treatment phase. [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    The WHO grade will be the primary measure for assessing OM. The duration and time to development of OM will be calculated as number of days.

  2. Efficacy of AG013 compared to placebo for reducing OM as measured by the overall incidence of OM during the active treatment phase. [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    The WHO grade will be the primary measure for assessing OM. The overall incidence will be calculated as number of subjects in a treatment group.

  3. Safety and tolerability [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Safety will be evaluated on the basis of treatment-emergent AEs (TEAEs), vital signs, weight, physical examinations, clinical laboratory assessments and the presence of AG013-sAGX0085 in whole blood. Tolerability (taste, consistency and smell) will be collected from the patient diary.


Secondary Outcome Measures :
  1. Patient-reported symptoms [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Pain will be assessed with the Oral Mucositis Daily Questionnaire Question 2.

  2. Analgesic use [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Any analgesic use will be recorded.

  3. Cumulative radiation dose administered before the onset of OM [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Radiation dose delivery will be documented.

  4. Biomarkers [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Primarily pro and anti-inflammatory cytokines

  5. PK profile of AG013 in a subset of subjects (AG013-sAGX0085 bacteria) [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Buccal mucosa levels of AG013-sAGX0085 bacteria from buccal smears will be summarized using descriptive statistics.

  6. PK profile of AG013 in a subset of subjects (hTFF1) [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Levels of hTFF1 from serum samples and buccal mucosa levels of hTFF1 from buccal smears will be summarized using descriptive statistics.


Other Outcome Measures:
  1. Exploratory objective:genomic differentiation of AG013 responders/non-responders [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Blood samples to assess differences in genes expression

  2. Exploratory objective: efficacy of AG013 in patients with HPV (human papillomavirus) negative tumors/HPV positive tumors [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Recording of HPV status

  3. Exploratory objective: effect of AG013 on healthcare resources (US only) - hospitalizations [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Number of hospitalizations in each treatment group

  4. Exploratory objective: effect of AG013 on healthcare resources (US only) - unplanned office visits [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Number of unplanned office visits in each treatment group

  5. Exploratory objective: effect of AG013 on healthcare resources (US only) - gastrostomy tube feedings [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Number of non-prophylactic gastrostomy tube placements in each treatment group

  6. Exploratory objective: effect of AG013 on healthcare resources (US only) - emergency room visits [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Number of emergency room visits in each treatment group

  7. Exploratory objective: frequency of RT interruptions [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Number of subjects in each treatment group with an unplanned break in radiotherapy

  8. Exploratory objective: duration of RT interruptions [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Number of days of RT interruptions by treatment group



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Ages Eligible for Study:   21 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 or hypopharynx or HPV-positive unknown primaries presumed to be of oropharyngeal 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. Subjects of childbearing potential must agree to utilize effective contraceptive methods of birth control during study participation and for 30 days following the last treatment with IMP (Investigational Medicinal Product)
  10. Screening laboratory assessments:

    • Hemoglobin ≥ 10g/dl
    • White blood count ≥ 3500 cells/mm3
    • Absolute neutrophil counts ≥ 1500 cells/ mm3
    • Direct bilirubin ≤ 2x upper limit of normal (ULN)
    • Serum AST (aspartate aminotransferase) and ALT (alanine aminotransferase) ≤ 3 x ULN
    • Calculated Creatinine Clearance of 50 ml/min
    • Pregnancy test (serum or urine): negative for females of childbearing potential: a female is considered to be of child bearing potential unless she has had a tubal ligation or is postmenopausal (without a menstrual period for at least one year)

Exclusion Criteria:

  1. Prior radiation to the head and neck
  2. Presence of active infectious oral disease excluding oral candidiasis
  3. Presence of any oral lesions that may confound the ability to assess oral mucositis grade
  4. Current use of antibiotic rinses or troches
  5. Herbal, alternative remedies, and alcohol containing over-the-counter mouthwashes are excluded during the course of the study
  6. Current alcohol abuse syndrome
  7. Chronic immunosuppression
  8. Known seropositive for HIV
  9. Use of investigational agent within 30 days of signing informed consent
  10. Tooth extraction prior to radiation
  11. Signs and symptoms of active dental disease
  12. Female subjects who are pregnant or nursing
  13. 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03234465


Contacts
Contact: Alan Joslyn, Ph.D. + 1 (813) 286 7900 ajoslyn@oragenics.com

Locations
United States, Connecticut
University of Connecticut Health Center Active, not recruiting
Farmington, Connecticut, United States, 06030
United States, Florida
UF Health Cancer Center Active, not recruiting
Orlando, Florida, United States, 32806
United States, Georgia
Columbus Regional Research Institute Recruiting
Columbus, Georgia, United States, 31904
Contact: Douglas Ciuba, MD         
United States, Illinois
Decatur Memorial Hospital Recruiting
Decatur, Illinois, United States, 62526
Contact: James L Wade III, MD         
Cardinal Bernardin Cancer Center Active, not recruiting
Maywood, Illinois, United States, 60153
Loyola University Health System Not yet recruiting
Maywood, Illinois, United States, 60153
Contact: Newton J Hurst Jr, MD         
United States, Louisiana
Ochsner Clinic Foundation Recruiting
New Orleans, Louisiana, United States, 70121
Contact: Suma N Satti, MD         
Willis-Knighton Cancer Center Recruiting
Shreveport, Louisiana, United States, 71103
Contact: Sanford Katz, MD         
United States, Michigan
University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48109-5008
Contact: Francis P Worden, MD         
United States, Nevada
Comprehensive Cancer Centers of Nevada-Henderson Recruiting
Henderson, Nevada, United States, 89052
Contact: Matthew Schwartz, MD         
United States, New York
Montefiore Medical Center, Albert Einstein College of Medicine, Department of Radiation Oncology Recruiting
Bronx, New York, United States, 10467
Contact: Madhur K Garg, MD         
University of Rochester Medical Center Active, not recruiting
Rochester, New York, United States, 14642
United States, North Carolina
Carolina's Health Care System Withdrawn
Charlotte, North Carolina, United States, 28204
Caromont Regional Medical Center Recruiting
Gastonia, North Carolina, United States, 28054
Contact: Charles J Meakin, MD         
East Carolina Univ School of Dental Medicine Recruiting
Greenville, North Carolina, United States, 27834-4354
Contact: Brian Muzyka, MD         
United States, Ohio
Mercy Medical Center Recruiting
Canton, Ohio, United States, 44708
Contact: Edward J Walsh, MD         
United States, Washington
Multicare Health Center Recruiting
Gig Harbor, Washington, United States, 98405
Contact: Suraj Singh, MD         
Cancer Care NW Recruiting
Spokane, Washington, United States, 99216
Contact: Stephen Thatcher, MD         
Sponsors and Collaborators
Oragenics, Inc.
Investigators
Study Director: Alan Joslyn, Ph.D. Sponsor GmbH

Publications of Results:
Responsible Party: Oragenics, Inc.
ClinicalTrials.gov Identifier: NCT03234465     History of Changes
Other Study ID Numbers: AG013-ODOM-201
First Posted: July 31, 2017    Key Record Dates
Last Update Posted: December 17, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Mucositis
Stomatitis
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Mouth Diseases
Stomatognathic Diseases