Pembrolizumab in Treating Patients With High Risk Oral Intraepithelial Neoplasia

Study Overview
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Brief Summary
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This randomized phase II trial studies how well pembrolizumab works in treating patients with high risk oral intraepithelial neoplasia. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Detailed Description
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PRIMARY OBJECTIVE: I. To determine oral cancer-free survival of patients with high risk oral intra-epithelial neoplasias (IEN) treated with pembrolizumab versus observation. SECONDARY OBJECTIVES: I. To determine the safety and tolerability of pembrolizumab for patients with oral IEN. II. To determine the histologic and clinical response rates (in the subgroup of patients with clinically evident measurable oral IEN lesions) to pembrolizumab. III. To characterize the immune infiltrate in oral IEN lesions before and after treatment with pembrolizumab. EXPLORATORY OBJECTIVES: I. To assess predictive, tissue-and blood-based, biomarkers of benefit from pembrolizumab in oral IEN. II. To determine the presence of neo-antigens in IEN lesions before and after treatment, and their correlation with oral cancer-free survival and immune infiltrate characteristics. III. To evaluate the oral micro-biome before and after treatment with pembrolizumab and its association with neo-antigens and benefit from treatment. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients undergo observation. ARM B: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 6, 9, 12, 18, 24, 30, and 36 months and then periodically thereafter.

Official Title
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Personalized, Randomized, Phase 2 Study of Pembrolizumab (MK-3475) for High Risk Oral Intra-Epithelial Neoplasias

Conditions
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Oral Cavity Carcinoma, Oral Intraepithelial Neoplasia

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Other: Patient Observation
* Biological: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological evidence of oral intra-epithelial neoplasia within 12 months prior to enrollment; subjects with a history or clinical diagnosis suggestive of oral intra-epithelial neoplasia, or patients with a history of invasive oral cancer are eligible, but must have a confirmed histological diagnosis of oral intra-epithelial neoplasia before randomization; histological evidence of oral intraepithelial neoplasia on an invasive oral cancer resection specimen is acceptable; a visible, measurable, clinical lesion (such as leukoplakia and/or erythroplakia) is not required; only individuals with high risk profiles will be considered eligible for randomization; high risk profiles are defined as patients without a prior oral cancer and have loss of heterozygosity (LOH) at 3p14 and/or 9p21 plus at least at one additional chromosomal site (4q,8p,11p,13q, or 17p) or patients with a prior oral cancer history and have LOH at 3p14 and/or 9p21; all high risk patients must also meet the additional eligibility criteria Be willing and able to provide written informed consent Be greater than or equal to 18 years of age on day of signing informed consent for the trial Be willing to provide tissue from a newly obtained oral biopsy Have a performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG) performance scale Absolute neutrophil count >= 1,500/mcL Platelets >= 75,000/mcL Serum total bilirubin =< 1.5 X upper limit of normal (ULN) or direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN Female subject of childbearing potential should have a negative urine or serum pregnancy test < 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of study therapy through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses > 1 year Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of the study therapy Exclusion Criteria: Is currently participating and receiving study therapy with potential anti-neoplastic activity, or has participated in a study of an investigational agent and received study therapy with potential anti-neoplastic activity within 4 weeks of the first dose of treatment Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment Has a known history of active TB (Bacillus tuberculosis) Hypersensitivity to pembrolizumab or any of its excipients Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 2 at baseline) from adverse events due to agents administered more than 4 weeks earlier Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 2 or at baseline) from adverse events due to a previously administered agent; Note: If the subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy Has a known additional malignancy that is progressing or requires active treatment other than adjuvant hormonal therapy; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin or in situ cervical cancer Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment Has a known history of, or any evidence of active, non-infectious pneumonitis Has an active infection requiring systemic therapy Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial Is pregnant, or breastfeeding, or expecting to conceive or father children within the projected duration of treatment with pembrolizumab, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment Has received prior therapy with anti-PD-1, anti-PD-L1, or anti-PD-L2 agent Has a history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) Has received a live vaccine within 30 days of planned start of study therapy; Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines are live attenuated vaccines, and are not allowed

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A (observation)<br>Patients undergo observation. | Other: Patient Observation<br>* Undergo observation<br>* Other names: watchful waiting;|
| Experimental: Arm B (pembrolizumab)<br>Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oral cancer-free survival | Will be estimated by Kaplan-Meier method. | From randomization to the development of histologically confirmed oral cancer or death of any cause, whichever occurs first, assessed up to 7 years |