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

NCT ID: NCT03234465

Last Updated: 2020-11-23

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 200 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-07-18
• Study Completion Date: 2020-07-13

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.

Conditions

Oral Mucositis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: EXPERIMENTAL

AG013

Intervention Type: BIOLOGICAL

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: 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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Subjects assigned to the placebo group will receive appearance- and taste-matched placebo powder.

Interventions

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.

Intervention Type: BIOLOGICAL

Placebo

Subjects assigned to the placebo group will receive appearance- and taste-matched placebo powder.

Intervention Type: OTHER

Eligibility 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, 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

• Minimum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Oragenics, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Alan Joslyn, Ph.D.

Role: STUDY_DIRECTOR

Sponsor GmbH

Locations

University of Connecticut Health Center

Farmington, Connecticut, United States

Helen F. Graham Cancer Center

Newark, Delaware, United States

UF Health Cancer Center

Orlando, Florida, United States

Columbus Regional Research Institute

Columbus, Georgia, United States

Decatur Memorial Hospital

Decatur, Illinois, United States

St. Vincent Anderson Regional, Cancer Center

Anderson, Indiana, United States

Norton Cancer Institute, Multicisciplinary Clinic

Louisville, Kentucky, United States

Ochsner Clinic Foundation

New Orleans, Louisiana, United States

Willis-Knighton Cancer Center

Shreveport, Louisiana, United States

University of Michigan

Ann Arbor, Michigan, United States

Comprehensive Cancer Centers of Nevada-Henderson

Henderson, Nevada, United States

Renown Regional Medical Center

Reno, Nevada, United States

Northwell Health Cancer Institute / Center for Novel Cancer Therapeutics

Lake Success, New York, United States

University of Rochester Medical Center

Rochester, New York, United States

Montefiore Medical Center, Albert Einstein College of Medicine, Department of Radiation Oncology

The Bronx, New York, United States

Caromont Regional Medical Center

Gastonia, North Carolina, United States

East Carolina Univ School of Dental Medicine

Greenville, North Carolina, United States

Mercy Medical Center

Canton, Ohio, United States

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, United States

Temple University Hospital, Radiation Oncology

Philadelphia, Pennsylvania, United States

UPMC Shadyside Hospital

Pittsburgh, Pennsylvania, United States

University of Texas MD Anderson Cancer Center

Houston, Texas, United States

Huntsman Cancer Hospital

Salt Lake City, Utah, United States

Radiation Oncology Moser

Charlottesville, Virginia, United States

PeaceHealth St. Joseph Medical Center

Bellingham, Washington, United States

Multicare Health Center

Gig Harbor, Washington, United States

Cancer Care NW

Spokane, Washington, United States

Jules Bordet Institute

Brussels, , Belgium

University Hospital Brussels

Brussels, , Belgium

University Hospital Antwerp

Edegem, , Belgium

University Hospitals Leuven

Leuven, , Belgium

St. Maarten General Hospital

Mechelen, , Belgium

University Hospital Aachen

Aachen, , Germany

Amper Hospital

Dachau, , Germany

University Hospital Freiburg

Freiburg im Breisgau, , Germany

University Hospital Giessen and Marburg

Giessen, , Germany

Hospital Kassel

Kassel, , Germany

University Hospital Schleswig-Holstein

Kiel, , Germany

Helios Hospital Krefeld

Krefeld, , Germany

University Hospital Johannes Gutenberg - University of Mainz

Mainz, , Germany

University Hospital Mannheim

Mannheim, , Germany

Clinics Maria Hilf - Hospital St. Franziskus

Mönchengladbach, , Germany

Ludwig Maximilians University Hospital

Munich, , Germany

University Hospital Regensburg

Regensburg, , Germany

Caritas Klinikum

Saarbrücken, , Germany

Derriford Hospital

Plymouth, Devon, United Kingdom

Beatson West of Scotland Cancer Center

Glasgow, , United Kingdom

Guy's Hospital

London, , United Kingdom

The Christie NHS Foundation Trust

Manchester, , United Kingdom

Royal Cornwall Hospital

Truro, , United Kingdom

Countries

United States; Belgium; Germany; United Kingdom

References

Limaye SA, Haddad RI, Cilli F, Sonis ST, Colevas AD, Brennan MT, Hu KS, Murphy BA. 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.

Reference Type: RESULT

PMID: 24114811 (View on PubMed)

Alexander LM, van Pijkeren JP. Modes of therapeutic delivery in synthetic microbiology. Trends Microbiol. 2023 Feb;31(2):197-211. doi: 10.1016/j.tim.2022.09.003. Epub 2022 Oct 8.

Reference Type: DERIVED

PMID: 36220750 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

AG013-ODOM-201

Identifier Type: -

Identifier Source: org_study_id