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Randomized, Double Blind, Placebo-Controlled, Phase IIB Trial of Ketorolac Mouth Rinse Evaluating the Effect of Cyclooxygenase Inhibition on Oropharyngeal Leukoplakia: Collaborative Study of the NCI, NIDCD and the NIDCR

Phase 2
Not Enrolling
Leukoplakia, Periodontal Disease

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Trial Information

Randomized, Double Blind, Placebo-Controlled, Phase IIB Trial of Ketorolac Mouth Rinse Evaluating the Effect of Cyclooxygenase Inhibition on Oropharyngeal Leukoplakia: Collaborative Study of the NCI, NIDCD and the NIDCR

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.

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.


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.


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.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Primary Purpose: Treatment


United States: Federal Government

Study ID:




Start Date:

June 1998

Completion Date:

June 2004

Related Keywords:

  • Leukoplakia
  • Periodontal Disease
  • Chemoprevention
  • Direct Epithelial Delivery
  • Tobacco-induced Cancer
  • Field Cancerization
  • Leukoplakia
  • Periodontal Diseases



National Cancer Institute (NCI) Bethesda, Maryland  20892