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

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.

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.