Effectiveness of Topical Thalidomide to Treat Chronic Graft-Versus-Host-Disease Related Stomatitis

Oncology patients undergoing allogeneic bone marrow/peripheral blood stem cell transplant
(HSCT) frequently experience an allo-immune condition termed graft-versus-host-disease
(GVHD). The pathogenesis of GVHD derives from an immune attack mediated by donor T-cells
recognizing antigens expressed on normal tissues of the patient. This condition occurs in
HSCT rather than autologous BMT because of disparities in minor histocompatibility antigens
between donor and recipient, inherited independently of HLA genes (Lazarus, Vogelsang, and
Rowe, 1997). GVHD may be conceptualized as a cytokine storm stemming from an outpouring of
endogenous cytokines resulting in many tissue effects (Lazrarus et al, 1997). Oral chronic
GVHD (cGVHD) presents with tissue atrophy and erythema, lichenoid changes (hyperkeratotic
striae, patches, plaques, and papules) and pseudomembranous ulcerations typically occurring
on the buccal and labial mucosa and the lateral tongue, mucoceles due to inflammation of
minor salivary glands, and xerostomia (Lloid, 1995). The ulcerative phase often leads to a
cascade of negative sequelae including oropharyngeal pain, critical treatment alterations or
cessation, diminished capacity for food intake, and decreased quality of life.

Optimal treatment strategies for cGVHD-related ulcerative stomatitis and related
oropharyngeal pain have not been established. Therefore, there is a critical need to examine
the pathogenesis of and to evaluate interventions for cGVHD-related ulcerative stomatitis
and related acute oropharyngeal pain in the randomized controlled clinical trial setting to
both advance the science of cancer treatment-related oral complications and to improve
patient care. We hypothesize that the mechanisms of tissue injury occurring at the mucosal
level leading to cGVHD-related stomatitis are similar to other types of stomatitis, such as
cancer chemotherapy-related stomatitis and aphthous stomatitis, and are therefore amenable
to treatment with anti-inflammatory strategies. Therefore, the purpose of this study is to
elucidate the role of inflammation in GVHD-related ulcerative stomatitis by testing the
efficacy of a topical thalidomide gel on the resolution of cGVHD-related stomatitis and
related oropharyngeal pain. The actions of thalidomide, which include inhibition of the
release of tumor necrosis factor-alpha (TNFa) and resultant alteration of the inflammatory
cascade, may provide insight into the role of local mucosal inflammation in cGVHD-related
stomatitis.

This study will be conducted in two parts. The first part is a pilot study testing the
effects of a thalidomide gel 20mg in patients who have developed oral cGVHD-related
ulcerative stomatitis following allogeneic bone marrow/peripheral blood stem cell transplant
(HSCT). Stomatitis is an inflammation of the lining of the throat and mouth that may lead to
ulcers and pain in the mouth and throat. GVHD - a condition in which the donor cells see
patient's cells as foreign and mount an immune response to them - may be related to
increased levels of a substance called TNF-alpha (TNFa) following HSCT. Thalidomide's
anti-inflammatory effects may lower TNFa levels and decrease cGVHD-related stomatitis and
oral pain in these patients.

If this pilot study is successful, then the second part of the study will be conducted. The
second part of this study will test the effects of a 0.1% (20mg) thalidomide mouthwash in
treating oral cGVHD-related stomatitis in patients following allogeneic HSCT. Applying
thalidomide directly to the GVHD-related mouth ulcer in gel form or to the entire oral
cavity in mouthwash form rather than taking the thalidomide in pill form may reduce the
amount of drug that enters the blood stream and cause fewer side effects.

Patients between 18 and 80 years of age who have received a HSCT and developed oral
cGVHD-related stomatitis as confirmed by surgical biopsy may be eligible for this study. The
only eligible female participants for the pilot study will be women who are unable to have
children. In the pilot study, participants will be randomly assigned to receive thalidomide
gel 20mg or placebo (a gel with no thalidomide) to use four times a day for 4 weeks. In the
mouthwash study, participants will be randomly assigned to receive 0.1% 20mg thalidomide
mouthwash or placebo (a mouth rinse with no thalidomide) to use four times a day for 4
weeks.

Participants will have the following data collected and undergo the following procedures
before beginning experimental treatment, then once a week for 4 weeks, and then
approximately 8 weeks after the first visit.

- Interview about current medications and use of alcohol and cigarettes.

- Self-report of mouth and throat pain ratings.

- Oral examination for stomatitis rating

- Quality of life questionnaire (The questionnaire is repeated only at week 8 of the
study.).

- Mouth photography to measure and record the oral ulcer response to treatment.

- Saliva sampling to look for proinflammatory cytokines (small proteins), including TNFa.

- Oral ulcer exudate collected by filter paper to obtain fluid for measuring TNFa levels.

- Gentle swabbing of oral ulcers to culture for virus, fungus, and bacteria that may be
present.

- Small punch biopsy of the area near the ulcer or affected area to check for presence of
TNFa. (The punch biopsy is repeated only at week 4 of the study.)

- Blood sampling to monitor TNFa levels.

- A urine pregnancy test for women who are able to have children. (The pregnancy test is
repeated at weeks 2, 4, and 8.)

- INCLUSION CRITERIA:

Participating in HSCT or cGVHD protocols and willing to participate in this study
concurrently;

Diagnosed with oral cGVHD stomatitis confirmed by surgical biopsy results;

Oral ulceration present

Able to understand and sign protocol informed consent;

Ages 18 to 80 years of age.

EXCLUSION CRITERIA:

Pregnant or lactating females;

For the proof of concept study, females who are not surgically sterilized by means of
hysterectomy or tubal ligation;

For the main study, females of childbearing potential who do not agree to the use of two
forms of highly effective contraception for at least four weeks prior, during, and for
four weeks following the last dose of study drug;

Sexually active males who do not agree to the use of a latex condom while receiving study
drug and for four weeks following the last dose of study drug;

Unwilling to follow precautions for use of thalidomide;

Unable to demonstrate appropriate use of study medication;

Concurrent use of non-protocol-related medications confounding assessment of the
inflammatory response (antihistamines, non-steroidal anti-inflammatory drugs);

Allergic reaction to thalidomide;

Pre-existing oral infection, which might maximize the possibility of an infection or
sepsis contributing to a drug-related adverse event;

Unwilling or unable to forego concurrent treatment for mucosal lesions and/or related oral
pain (including topical steroids, viscous lidocaine, topical anti-fungals);

Requiring addition of new systemic therapy including thalidomide, steroids, or radiation
therapy;

Use of sedatives (including CNS depressants);

Absolute neutrophil count (ANC) less than 750/mm(3)