Topical Ruxolitinib for Cutaneous Chronic Graft Versus Host Disease (cGVHD)

Background:

- Chronic graft-versus-host disease (cGVHD) develops in approximately half of individuals
who undergo allogeneic hematopoietic cell transplant (HCT) and is the leading cause of
non-relapse mortality.

- There are no skin-targeted therapies for cutaneous cGVHD that are directed to the
pathogenesis of cGVHD.

- Many inflammatory cytokines involved in the pathogenesis of cGVHD signal through the
Janus kinase (JAK)-Signal Transducer and Activator of Transcription (STAT) pathway.

- Systemic JAK inhibitors have been studied in GVHD murine models and in humans with
improvement at the cellular and clinical level.

- Topical JAK inhibitors have not been studied in cutaneous cGVHD, but have demonstrated
the ability to decrease inflammatory markers as well as improve clinical findings of
psoriasis.

Objectives:

- To determine the safety and tolerability of topical ruxolitinib 1.5% cream in patients
with cutaneous cGVHD with epidermal involvement (non-sclerotic form)

- To determine the efficacy of topical ruxolitinib 1.5% cream in patients with cutaneous
cGVHD with epidermal involvement (non-sclerotic form)

Eligibility:

Inclusion:

- Age greater than or equal to 12 years old

- Histologically confirmed epidermal cGVHD (including lichen planus-like, papulosquamous,
erythematous) involving at least 2 separate, non-ulcerated sites that can be delineated
by body region (e.g. right forearm and left forearm)

- Stable systemic cGVHD treatment including immunosuppressant therapy for 4 weeks prior to
enrollment

- Karnofsky or Lansky score greater than or equal to 60%

Exclusion:

- Concurrent use of JAK inhibitors (topical or systemic) , fluconazole, or strong CYP3A4
inhibitors

- Known hypersensitivity to JAK inhibitors or their components

- Active infection including CMV, EBV, HIV, HBV, and/or HCV

- Recurrent or progressive malignancy requiring anticancer treatment

- Patients receiving other investigational agents

- Pregnancy

Design:

- This is a Phase II, placebo-controlled, double-blinded study to determine the safety,
tolerability and efficacy of topical ruxolitinib in patients with epidermal cGVHD.

- Participants with at least 2 non-ulcerated sites of epidermal cGVHD will apply topical
ruxolitinib 1.5% cream to 1 prespecified site and vehicle cream to the second
prespecified site twice a day for 6 weeks.

- Safety will be assessed according to CTCAE v5.0 criteria. Assessments will occur during
visits and/or phone follow-up every 2 weeks during treatment.

- Efficacy will be assessed at 6 weeks. The initial surface areas of the 2 target lesions
will be measured at baseline, week 2, and week 6 on evaluable patients, with the option
for an in-person assessment at week 4. The percent decline in the surface area of the 2
lesions will be determined, and the difference in decline between the 2 lesions will be
calculated, expressed consistently as ruxolitinib decline minus placebo decline.

- A skin biopsy and peripheral blood samples will be collected prior to treatment and at
week 6 to evaluate the cutaneous immune compartment cellular infiltrate, cytokine
profiling, STAT phosphorylation, and in situ cGVHD biomarkers.

- Pharmacokinetic studies will be performed at week 2.

- Up to 15 patients will be enrolled to achieve 10 evaluable patients, defined as
participants who remain active at the time of the primary endpoint. 10 evaluable
patients will provide 80% power to detect whether these paired differences in the
changes from baseline are equal to one SD of the difference of the changes (effect
size=1.0) using a two-tailed 0.05 significance level paired t-test. In practice, a
Wilcoxon signed rank test may be used instead of a t-test if the differences are not
consistent with a normal distribution (p<0.05 by a Shapiro-Wilks test).

- INCLUSION CRITERIA:

- Patients must have histologically confirmed epidermal cGVHD including lichen
planus-like, papulosquamous, and erythematous cGVHD with clinical involvement at 2
separate body regions (e.g. right forearm and left forearm).

- Patients must have measurable disease, defined as at least 2 areas of cutaneous,
nonulcerated, epidermal cGVHD involvement. Each site must involve at least 0.5% body
surface area (1 palm equivalent) and cannot be a site of current or previous
nonmelanoma skin cancer (NMSC).

- Stable immunosuppressant or immunomodulatory systemic cGVHD treatment, including
phototherapy and extracorporeal photopheresis, for 4 weeks prior to enrollment.

- Age greater than or equal to 12 years. There is no available safety or adverse events
data available for children younger than 12 years of age.

- Karnofsky or Lansky greater than or equal to 60

- Patients must have normal organ and marrow function as defined below:

- absolute neutrophil count greater than or equal to 1,000/mcL

- platelets greater than or equal to 50,000/mcL

- hemoglobin > 9 g/dL

- total bilirubin <1.5X institutional upper limit of normal except if known history
of Gilbert's disease

- AST(SGOT)/ALT(SGPT) less than or equal to 5X institutional upper limit of normal

- creatinine clearance greater than or equal to 50 mL/min/1.73 m2 for patients with
creatinine levels above institutional normal.

- Willingness to comply with twice daily application of 2 different creams to 2
separate, prespecified sites.

- The effects of ruxolitinib on the developing human fetus are unknown. For this reason,
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.

- Ability of subject or Legally Authorized Representative (LAR) to understand and the
willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

- Patients concurrently receiving a JAK inhibitor (topical or systemic).

- Patients receiving any other investigational agents.

- Patients concurrently taking oral fluconazole.

- Patients concurrently taking strong CYP3A4 inhibitors.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ruxolitinib or other agents used in study.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection including EBV, CMV, HIV, HBV, and HCV, 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 from this study because ruxolitinib is an agent with the
potential for teratogenic or abortifacient effects. Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with ruxolitinib, breastfeeding should be discontinued if the mother is treated
with ruxolitinib. These potential risks may also apply to other agents used in this
study.

- Recurrent or progressive malignancy requiring anticancer treatment.

- Other cancer (except that for which HCT was performed) within 2 years of study entry,
except nonmelanoma skin cancer or carcinoma in situ of the breast, uterus, or cervix.

- History of cutaneous malignancy at target lesion site.

- Any participant who, in the investigator s opinion, would be unable to comply with
study requirements or for whom participation may pose a greater medical risk.