Description

1 Protocol Summary Overall Design The initial single patch application pharmacokinetic analysis on persons undergoing elective oral surgical procedures (third molar extraction) is being conducted to determine the requisite length of patch application time needed to achieve the predetermined fenretinide levels (0.1-3.0 µM) at the target tissue oral epithelium site.

Potential participants will be recruited during their mandatory pretreatment screening examination. Persons interested in participation will undergo informed consent. A single fenretinide patch will be applied to the oral mucosa overlying an impacted mandibular third molar and left in place for 15 minutes. Saliva and sera samples will be obtained immediately following patch removal. The treated oral mucosa will then be removed as the initial part of their surgical procedure for removal of a bony impacted third molar. If a 15-minute application is not sufficient to deliver the target fenretinide level in all 5 participants, subsequent participants (n=3) will be consented for a modified patch application time.

The multi-dose, investigator-initiated, single center, active formulation-only investigation is designed to assess the chemopreventive efficacy of a mucoadhesive fenretinide patch on microscopically confirmed premalignant oral epithelial lesions (oral intraepithelial neoplasia, OIN). Prospective patients will be recruited from persons with clinical lesions suspicious for OIN that are referred to Ohio State's College of Dentistry for management. We also have a large patient cohort (>200) of persons who are on long term follow up due to a previous diagnosis of premalignant oral epithelial lesions. Following the consultation and informed consent appointment, all participants will have an initial incisional biopsy of the lesion and this tissue will be used to establish baseline pretreatment parameters (histopathologic diagnosis and loss of heterozygosity indices). A diagnosis of premalignant oral epithelial disease (mild, moderate or severe epithelial dysplasia) is necessary to enter the chemoprevention study. Any person with advanced disease (i.e., oral squamous cell carcinoma) will be referred immediately for definitive care.

As this study will evaluate a novel drug delivery system, patients will be closely monitored (every 7 to 10 days) throughout the six-week fenretinide patch treatment period. At every recall appointment, a complete intraoral examination will be conducted and clinical images of the OIN lesion obtained. Participants will be instructed to return their used patches and additional fenretinide patches will be dispensed for the current treatment period. Random appointment saliva samples (2 over the treatment course) will be obtained for cotinine analyses to confirm no tobacco use. Sera samples will be obtained at the initial biopsy appointment and the final active study appointment (when the remaining OIN lesional tissue is excised). Patients will be given an after-hours call number and if complications arise, they will be instructed to discontinue patch administration and come to the clinical trial site for an evaluation the next day.

Following the six-week treatment course, the remaining OIN lesional tissue will be excised. Participants will be reappointed one week following the excisional biopsy to monitor healing and to discuss the final histopathologic biopsy results. All participants will be seen at a final recall appointment (approximately 6 weeks after cessation of treatment) during which time an intraoral examination and clinical image of treated OIN lesional site will be obtained. Instructions regarding the need to obtain follow up care will be provided.

1.1 Synopsis Title: Safety and Chemopreventive Efficacy of Fenretinide Mucoadhesive System in Subjects with Premalignant Oral Intraepithelial Neoplasia (OIN) Lesions; Preceded by Single Dose Pharmacokinetic Assessment in Healthy Subjects to Determine Application Time.

Study Description: A single 6.25 cm2 (12 mg fenretinide) mucoadhesive system (MS) pharmacokinetic analyses of target tissue (surface oral epithelium) from healthy subjects undergoing impacted mandibular third molar extraction to determine fenretinide patch application time necessary to achieve desired single dose drug level (0.1 to 3.0 µM fenretinide). Saliva and sera will also be obtained to assess drug absorption characteristics. 15-minute application time will be evaluated first; if tissue levels are insufficient, 30-minute application time will be evaluated. If 15-minute tissue levels exceed target, reduced application time will be pursued.

When application time is defined, a multi-dose clinical evaluation will proceed to determine chemopreventive efficacy of the fenretinide mucoadhesive system (FMS) on microscopically confirmed premalignant oral epithelial lesions (OIN, oral intraepithelial neoplasia).

Subjects will be trained in twice daily self-application of the FMS following mirror-guided patch placement. Subjects will be instructed to sit upright for the duration of their patch application.

Subjects will return to the study site every 7-10 days for 6 weeks to return used mucoadhesive systems and undergo applicable assessments.

Description of Study Intervention:

• Single Dose Pharmacokinetic Assessment in Healthy Subjects: Participants will be recruited at the mandatory screening appointment prior to their third molar surgery. A single 6.25 cm2 FMS (12 mg fenretinide) will be placed on the oral mucosa overlying the impacted mandibular third molar. Following a 15-minute application, the FMS will be removed, saliva and sera will be obtained, and the tissue underlying the patch excised to provide surgical access to the impacted third molar.
• Multi-dose Chemoprevention Evaluation in Subjects with OIN: Participants will apply the FMS to their OIN lesion, leave in place for 15 minutes, then remove and save the FMS to document use. This process will occur twice daily.

Study Duration:

• Single Dose Pharmacokinetic Assessment in Healthy Subjects: The anticipated study duration for accrual of five single-dose healthy subjects is approximately 2 months.
• Multi-dose Chemoprevention Evaluation in Subjects with OIN: The anticipated study duration for accrual of 25 multi-dose subjects with OIN is approximately 2 years, as funding permits.

Participant Duration:

• Single Dose Pharmacokinetic Assessment in Healthy Subjects: Individual participation is approximately 20 minutes.
• Multi-dose Chemoprevention Evaluation in Subjects with OIN: 6 weeks FMS application, 9 weeks/visits total Week/Visit 1: study explanation and consent; Week/Visit 2: incisional biopsy; Weeks/Visits 3-7: treatment (6 weeks, bid dosing, patient recall every 7 to 10 days); Week/Visit 8: recall appointment, excise remaining OIN tissue. Week/Visit 9: discuss final biopsy results, assess biopsy site healing. Visit 10, approximately six weeks post final biopsy. Clinical evaluation, provide instructions regarding need for follow up.

1.2 Schema

Single Dose Pharmacokinetic Assessment in Healthy Subjects:

1. All individuals undergoing elective third molar surgery must attend a consultation appointment. Potential study participants will be recruited during these consultation appointments. If the person is interested in study participation, the clinical trial will be discussed, and informed consent will be obtained.
2. Consented participants will arrive at their third molar surgical appointment 20 minutes prior to surgery to enable FMS placement and to obtain saliva and sera samples following FMS application. The overlying treated tissue will be removed as a portion of the third molar surgical procedure.

Multi-dose Chemoprevention Evaluation in Subjects with OIN:

1. Screen patient with suspicious oral lesion (white, white and red, or erythematous) tightly adherent, patch or plaque surface oral epithelial lesion with crisply delineated surface margins. Discuss clinical trial protocol, and if potential participant is interested, obtain informed consent. Subjects will be informed about the no-smoking policy. If patient is a current smoker, they will be requested to stop smoking and return in 6 weeks for incisional biopsy.
2. Conduct pretreatment incisional biopsy of suspicious oral lesion.
3. Participant recall, discuss initial biopsy results. If the suspicious lesion is microscopically confirmed to be premalignant, the participant will be enrolled in the study. Saliva sample obtained; cotinine levels checked at baseline then randomly throughout the study. Participants will be recalled every 7 to 10 days throughout the 6-week treatment period. Subjects will return used fenretinide mucoadhesive systems and obtain new FMS for the next treatment period.
4. Examination and excisional biopsy of residual OIN lesion after 6-week treatment.
5. Re-evaluation one week from excisional biopsy to discuss biopsy results and assess biopsy site.

Final study clinical assessment, approximately six weeks from excisional biopsy appointment to evaluate site and discuss final study results and need for clinical follow up.