An Open Label Phase II Trial of Topical Sirolimus for the Treatment of Refractory Oral Chronic Graft-versus-Host-Disease

Study Overview
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Brief Summary
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This research study is evaluating the effectiveness of topical sirolimus combined with topical steroid therapy, as a possible treatment for oral cGVHD.

Detailed Description
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Topical steroid therapy can be effective in managing oral cGVHD symptoms. However, a certain proportion of participants will not experience an adequate response to topical steroids and continue to have some degree of discomfort. Sirolimus is a non-steroidal immunosuppressive medication that has demonstrated efficacy in the management of cGVHD. Based on this, it is believed that a topical formulation applied inside the mouth may also demonstrate efficacy on a localized basis. The purpose of this study is to assess the safety and efficacy of topical sirolimus as a swish and spit solution for the treatment of oral cGVHD in participants that have not had an adequate clinical response to topical steroid therapy alone.

Official Title
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An Open Label Phase II Trial of Topical Sirolimus for the Treatment of Refractory Oral Chronic Graft-versus-Host-Disease

Conditions
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Chronic Graft-versus-Host-Disease, Oral Mucosal Disease Due to Graft-versus-host Disease

Intervention / Treatment
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* Drug: Sirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: While there will be no restrictions on concurrent systemic medications, all subjects must be on a stable immunomodulatory medication regimen for 7 days prior to beginning the study without plans to adjust doses during the following four-week study period. Dose modifications to maintain therapeutic drug levels of immunosuppressants (i.e. tacrolimus and sirolimus) during the study intervention period are allowed and do not constitute a trial violation. Changes in medications for non-cGVHD medical conditions will not affect eligibility. Age 4 years and older. Patients with symptomatic oral chronic graft-versus-host disease (sensitivity score ≥ 4). Stable topical steroid therapy with dexamethasone, clobetasol, or budesonide oral solutions (5 min, four times a day) for seven days prior to study enrollment. Stable systemic cGVHD medication regimen for seven days prior to study enrollment. Dose modifications to maintain therapeutic drug levels of immunosuppressants (i.e. tacrolimus and sirolimus) for the month prior and during the study intervention period are allowed and do not constitute a trial violation. The effects of sirolimus on the developing human fetus are unknown. For this reason and because immunosuppressants agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of topical sirolimus administration. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Patients already using topical sirolimus therapy. Patients who have an allergy/intolerance to sirolimus. Sensitivity score ≤ 3. Inability to comply with study instructions. Pregnant or breastfeeding. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant women are excluded due to the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants, breastfeeding should be discontinued if the mother is treated with sirolimus. HIV-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with sirolimus. In addition, these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.

Ages Eligible for Study
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Minimum Age: 4 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: Supportive Care
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Topical Sirolimus + Steroid<br>A four week supply of topical sirolimus will be dispensed. The treatment instructions will be to rinse and spit (NOT swallow) with one teaspoon (5 mL) of sirolimus solution 0.1mg/mL, combined with one teaspoon (5 mL) of steroid solution (dexamethasone 0.1%, clobetasol 0.05%, or budesonide 0.03%, based on the ongoing topical steroid prescription at the time of study enrollment) four times a day for 5 minutes at a time, and not to eat or drink for 15 minutes afterwards. | Drug: Sirolimus<br> <br> * Other names: Rapamune®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Subjective Sensitivity Score Response | The sensitivity score is one question on a self-reported assessment tool from the NIH consensus documents. The question asks: Your mouth sensitivity at its WORST with a score 0-10, 10 being the worst. Response was defined as a 3 point reduction in sensitivity score from pre-to-post treatment. | Pre treatment and after the 28 day (4 weeks) cycle of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change Pre-to-post Treatment in Oral Health Impact Profile Assessment | Oral health related quality of life will be assessed before and after topical sirolimus therapy using the 14-item Oral Health Impact Profile instrument that measures subject's perceptions of the impact of oral conditions on their well-being. | Pre treatment and after the 28 day (4 weeks) cycle of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Graft-versus-Host-Disease, Oral mucosal disease