Safety and Chemopreventive Efficacy of Fenretinide Mucoadhesive System in Subjects With Premalignant Oral Intraepithelial Neoplasia (OIN) Lesions: In Conjunction With Pharmacokinetic Assessment in Healthy Subjects.
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 25
- 试验地点
- 2
- 主要终点
- Histopathologic grade (assessed using light microscopy)
研究概览
简要总结
The goal of this clinical trial is to determine the effect of a mucoadhesive system that releases the vitamin A derivative, fenretinide (FMS), on precancerous surface epithelial (lining tissue inside your mouth) changes. Specifically, does application of the FMS induce specific changes: 1) reduction in the clinical size, 2) reduction in the histologic grade of precancerous changes (determined by microscopic examination), 3) reduce the nuclear LOH events (changes in copy number of key genes to prevent oral cancer).
The first part of this study entails a single FMS application to persons having their wisdom teeth removed. This study is done to confirm how long the FMS needs to remain in place to release the cancer-preventive agent.
Participants will: 1) Have the FMS applied over the impacted wisdom tooth for 15 minutes, 2) FMS is removed, saliva is collected, and blood is drawn from a vein in the arm. 3) Tissue overlying the impacted wisdom tooth is removed and analyzed.
The second, multi-FMS application entails patients who have precancerous oral surface epithelial changes. These patients will have: 1) a piece of the precancerous tissue removed (biopsy) and examined under a microscope to ensure the diagnosis. Blood is drawn from a vein in the arm., 2) One week after the biopsy, return to discuss the results. If the changes are precancerous, this person will be given FMS to apply to the site twice a day. 3) Patients return every 7 to 10 days (for a total of six weeks) for an oral exam and clinical pictures, return the FMS, and obtain new FMS for the upcoming week., 4) At week 3 (midway), blood is drawn from a vein in the arm., 5) After the six weeks of treatment, clinical pictures are obtained, blood is drawn from a vein in the arm and all of the remaining treated tissue is completely removed. The patient is securely contacted and results are discussed. 6) Approximately 6 weeks after the final surgery, patients return for a complete oral examination and clinical pictures are obtained.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Prevention
- 盲法
- None
盲法说明
The research scientist who will be conducting the LOH analyses will be blinded as to whether the sample is pre or post treatment.
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •- Inclusion Criteria:
- •Adults, 18 years or older, with microscopically confirmed OIN. Only one clinically measurable OIN lesion (> 3x3 mm) and capable of full coverage by the FMS with a small zone of extension (2.1 x 2.1 cm smaller FMS, 2.8 x 2.8 larger FMS) will be evaluated in this study. If multiple suspicious lesions are noted, the most clinically advanced lesion will be selected for treatment. The patient will be provided the option to have the other lesions biopsied (self-pay and/or insurance) at another appointment or to schedule with another provider for management.
- •No use of tobacco products 6 weeks prior to and during the 6-week study. (confirmed via random cotinine saliva tests for former tobacco users).
- •Available for follow-up evaluations (every 7-10 days during trial), amenable to full 6-week study participation, and 6-week post-study recall.
- •All men and reproductive aged women of child bearing potential must agree to use contraception during treatment and 1 month after end of treatment. All reproductive aged, heterosexually active women must undergo monthly pregnancy testing.
- •Capable of providing informed consent.
排除标准
- •- Exclusion Criteria:
- •Previous history of OSCC.
- •Microscopic diagnosis of OSCC or carcinoma in situ at the pretreatment biopsy.
- •Undergoing cancer treatments except for basal cell carcinoma of the skin.
- •Inability to stop tobacco product use.
- •Incapable of providing informed consent.
- •Pregnancy or unwilling to comply with birth control and monthly pregnancy testing criteria.
研究组 & 干预措施
FMS impact on premalignant oral epithelial lesions
Evaluation of the impact of the fenretinide-releasing system on premalignant oral epithelial lesions
干预措施: Mucoadhesive fenretinide-releasing system (FMS) (Drug)
结局指标
主要结局
Histopathologic grade (assessed using light microscopy)
时间窗: The time frame is 12 months for participant recruitment and completion of the six week clinical trial.
Complementary outcome measures of the Multi-dose Chemoprevention Evaluation in Subjects with OIN described separately. To evaluate both intra-participant (pretreatment and post treatment parameters) and collective assessments (all pretreatment findings relative to all post treatment findings) of the following chemoprevention indicators: Pretreatment and posttreatment lesional histologic grade, which will be determined by a ABOMP certified pathologist using light microscopy.
Clinical size (determined by measurement with a flexible ruler)
时间窗: The time frame is 12 months for participant recruitment and completion of the six week clinical trial.
Clinical images including internal measurement device (flexible ruler) to be taken prior to biopsy, and weekly at every monitoring visit.
Loss of heterozygosity (measured by genomic analyses
时间窗: The time frame is 12 months for participant recruitment and completion of the six week clinical trial.
Loss of heterozygosity indices at tumor suppressor gene loci associated with progression of OIN lesions to OSCC \[3p14 (FHIT), 9p21 (INK4a/ARF), 9p22 (IFN-α), and 17p13 (p53)\] (FHIT, p53, p16)\] will be evaluated in DNA isolated from lesional epithelium.
次要结局
- CYP4A4 and UGT1A1 enzyme levels (measured by image analysis quantified immunohistochemistry)(The time frame is 12 months for participant recruitment and completion of the six week clinical trial.)
- fenretinide patch acceptance (measured by validated assessment tool completed by patients)(The time frame is 12 months for participant recruitment and completion of the six week clinical trial.)
研究者
Susan Mallery
Professor and Chair
Ohio State University Comprehensive Cancer Center