In Phase II trials, treatment with ketorolac tromethamine oral rinse has been shown to block periodontal disease progression even in the absence of standard clinical intervention such as scaling and root planing which is routinely done to reduce the periodontal pathogen load that is driving the local destructive host inflammatory response. Resolution of periodontal disease has a favorable effect on normalizing the cellular and biochemical indices of inflammation as reflected by histological changes as well as the levels of prostaglandin E2 (PGE2) and interleukin I beta (IL-1beta). In this trial, we will prospectively evaluate if eliminating the inflammatory process (via inhibition of PGE2 biosynthesis) in the oral cavity has a favorable impact on reversing oropharyngeal leukoplakia. To test this hypothesis, up to 57 prospectively identified individuals with objective findings of oropharyngeal leukoplakia will be randomized to receive either a mouth rinse containing ketorolac or placebo. Ketorolac is a 7-fold selective inhibitor of cyclooxygenase-2 (Cox-2), which has been designed for local delivery to maximize the drug exposure to critical oral target tissues while minimizing gastric and systemic exposure to the drug. All responses will be determined at the three month completion of trial using the response criteria developed at MD Anderson Cancer Center. The drug will be given for three months and then all the patients will be followed for one additional month off all oral treatment to observe for late side effects. Based on the analysis of oral exam and photographically documented change in the pretreatment area of leukoplakia, the response of all patients will be determined.

The evaluation of the outcome will include a measurable secondary endpoint consisting of an assessment of histological change as determined by serial punch biopsies of the oral cavity. In addition, a panel of carcinogenesis and inflammatory markers will be serially measured at baseline, at one month follow up or at study conclusion. In the residual tissue, other bioassays will be evaluated to determine their suitability as intermediate endpoint markers. The purpose of this study is a preliminary evaluation of the effectiveness of ketorolac as a potential chemoprevention agent for oropharyngeal cancer. If ketorolac administration in this preliminary Phase IIB trial is associated with reversal of leukoplakia, then a definitive Phase III chemoprevention trial with a cancer reduction endpoint (most likely in a cooperative group-type setting) may be the next validation step.

Condition	Treatment or Intervention	Phase
Leukoplakia Periodontal Disease	Drug: Ketorolac Rinse	Phase II

Further Study Details: 

Expected Total Enrollment:  57

In Phase II trials, treatment with ketorolac tromethamine oral rinse has been shown to block periodontal disease progression even in the absence of standard clinical intervention such as scaling and root planing which is routinely done to reduce the periodontal pathogen load that is driving the local destructive host inflammatory response. Resolution of periodontal disease has a favorable effect on normalizing the cellular and biochemical indices of inflammation as reflected by histological changes as well as the levels of prostaglandin E2 (PGE2) and interleukin I beta (IL-1beta). In this trial, we will prospectively evaluate if eliminating the inflammatory process (via inhibition of PGE2 biosynthesis) in the oral cavity has a favorable impact on reversing oropharyngeal leukoplakia. To test this hypothesis, up to 57 prospectively identified individuals with objective findings of oropharyngeal leukoplakia will be randomized to receive either a mouth rinse containing ketorolac or placebo. Ketorolac is a 7-fold selective inhibitor of cyclooxygenase-2 (Cox-2), which has been designed for local delivery to maximize the drug exposure to critical oral target tissues while minimizing gastric and systemic exposure to the drug. All responses will be determined at the three month completion of trial using the response criteria developed at MD Anderson Cancer Center. The drug will be given for three months and then all the patients will be followed for one additional month off all oral treatment to observe for late side effects. Based on the analysis of oral exam and photographically documented change in the pretreatment area of leukoplakia, the response of all patients will be determined.

The evaluation of the outcome will include a measurable secondary endpoint consisting of an assessment of histological change as determined by serial punch biopsies of the oral cavity. In addition, a panel of carcinogenesis and inflammatory markers will be serially measured at baseline, at one month follow up or at study conclusion. In the residual tissue, other bioassays will be evaluated to determine their suitability as intermediate endpoint markers. The purpose of this study is a preliminary evaluation of the effectiveness of ketorolac as a potential chemoprevention agent for oropharyngeal cancer. If ketorolac administration in this preliminary Phase IIB trial is associated with reversal of leukoplakia, then a definitive Phase III chemoprevention trial with a cancer reduction endpoint (most likely in a cooperative group-type setting) may be the next validation step.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA:
Patients must have objective evidence of oral leukoplakia. This includes subjects who have had a previous diagnosis of head and neck or oral cancer, who are currently free of evidence of known cancer for at least three months.
Patients must have bidimensionally measurable lesions.
Patients must consent to serial photography and biopsy to document response to treatment.
All patients old enough to give their own informed consent (greater than or equal to 18 years old) are eligible.
Subjects must be excellent performance status (Performance Status 0-1).
In addition, they must be otherwise medically fit in the opinion of the PI with no other uncontrolled medical conditions.
EXCLUSION CRITERIA:
Patients with a hypersensitivity to aspirin, lidocaine or non-steroid anti-inflammatory agents or retinoids will be ineligible.
Patients using antibiotics, steroids, NSAID, aspirin, probenecid or antihistamines for an extended regimen of at least 10 or more consecutive days, or any immunosuppressants, anticoagulants, dilantin, lithium, methotrexate, phenothiazines, investigational drugs with pharmacological activity that could compromise the test product safety during the 30 days immediately preceding the first treatment visit.
Patients with serious or debilitating oral conditions that require extensive dental procedures in order to safely participate in this trial. This trial does not envision the need to do dental procedures (such as root canal or gingival procedure) in order to allow a potential participant to enroll on this study.
Individuals with a social or psychiatric situation interfering with study compliance or an unwillingness to undergo the serial oral biopsies will be excluded.
Patients with compromised respiratory function manifested by shortness of breath with mild exertion or dependency on supplemental oxygen.
Patients with compromised cardiovascular status including poorly controlled angina or congestive heart failure.
ELIGIBILITY FOR ORAL IMAGING SUBSTUDY:
Participation in this substudy requires that patients be enrolled in the parent trial.
Subjects must have given their consent and signed supplemental informed consent for the pilot study involving oral imaging.

Maryland
      National Cancer Institute (NCI), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States

Study ID Numbers:  980118; 98-C-0118
Record last reviewed:  June 24, 2004
Last Updated:  June 25, 2004
Record first received:  November 3, 1999
ClinicalTrials.gov Identifier:  NCT00001698
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08