Study of Ruxolitinib in Sclerotic Chronic Graft-Versus-Host Disease After Failure of Systemic Glucocorticoids

Chronic graft-versus-host-disease (GVHD) is a major complication of allogeneic hematopoietic
cell transplant that impairs quality of life, and is associated with significant morbidity
and mortality. Management of chronic GVHD with prednisone is associated with an overall
response rate of approximately 60%, and a complete response rate of approximately 30% but
sclerotic features do not respond as well. Based on the biology of chronic GVHD and available
preliminary evidence, the investigators hypothesize that ruxolitinib will be effective in the
management of sclerotic chronic GVHD. The study is an open label, phase II multicenter trial
designed to evaluate the efficacy of ruxolitinib as a salvage treatment for patients with
sclerotic GVHD (sclerosis or fasciitis). The primary objective is to determine the proportion
of patients with response rate (complete and partial responses) in skin and/or joint, as
determined by 2014 NIH (National Institutes of Health) consensus criteria, at 6 months of
therapy with ruxolitinib. Eligibility criteria includes adult patients with chronic GVHD and
skin, joint and/or fascia sclerosis, who have received systemic corticosteroids for >12
months and at least one additional line of therapy OR systemic corticosteroids and at least
two additional lines of therapy for chronic GVHD. A sample size of 47 patients (43 evaluable
patients and estimated 10% dropout) will allow an α of 0.044 and a power of 84% to test the
null hypothesis response rate of 25% compared to an alternative of 45%. Subjects will receive
ruxolitinib for 6 months for the treatment of sclerotic chronic GVHD. Subjects will be
evaluated for GVHD status as well as non-relapse mortality, relapse of underlying malignancy
and quality of life/functional status. Plasma cytokine levels and T/Natural Killer (NK) cell
subset in peripheral blood will be measured at various time points. The response rate will be
reported as a proportion and 95% exact confidence interval. If positive, the trial results
will support other ongoing studies to establish the role of ruxolitinib in chronic GVHD in
general and specifically in sclerotic chronic GVHD.

Inclusion Criteria:

- Sclerotic chronic GVHD (classic chronic or overlap syndrome) that meets 2014 NIH
Consensus Criteria. Eligible patients will have superficial or deep skin sclerosis,
fasciitis or joint contractures.

- Receipt of systemic corticosteroids for >12 months and at least one additional line of
systemic therapy OR systemic corticosteroids and at least two additional lines of
systemic therapy for chronic GVHD (not necessarily for sclerotic manifestations). For
the purpose of this study, fluticasone, azithromycin and montelukast ("FAM") therapy
for lung GVHD will be considered a topical therapy. Investigators are encouraged but
not mandated to use ibrutinib for appropriate patients prior to enrollment in this
trial.

- Adults, Age ≥18 years (state of Nebraska, Age ≥19 years)

- Karnofsky performance status ≥60% at the time of enrollment

- All allogeneic donor sources and all conditioning regimens are allowed.

- Absolute neutrophil count (ANC) greater than 1000/µL, and platelet count ³50,000/µL
without the use of growth factors or platelet transfusion.

- Able to take orally-administered medication.

- Female patient of reproductive potential must have a negative serum or urine pregnancy
test ≤7 days prior to starting the study drug. Women are considered NOT to have
reproductive potential if they have had 12 months of amenorrhea with an appropriate
clinical profile (i.e. ≥51 years, history of vasomotor symptoms, OR supportive hormone
levels such as low estrogen and high follicle-stimulating hormone levels), OR surgical
sterilization.

- Male and female patients of reproductive potential must be willing to avoid pregnancy
or fathering children from enrollment to one month after the end of study treatment.
This will require either a total abstinence, OR exclusively non-heterosexual activity
(when this is in line with the preferred and usual lifestyle of the subject), OR two
methods of contraception (male or female condom with or without a spermicidal agent,
diaphragm or cervical cap with spermicide, or hormonal based contraception including
intrauterine device).

- Life expectancy greater than 6 months

- Written informed consent to participate in the study.

Exclusion Criteria:

- Fibrosis of internal organs such as gut, liver or lung as the sole manifestation of
sclerosis.

- Initiation of any new immunosuppressive agent within 2 weeks prior to enrollment. Dose
adjustment of existing immunosuppressive agents is allowed.

- Fluconazole at a dose more than 200 mg daily. Patients should stop fluconazole or
lower dose to less than or equal to 200 mg daily before starting ruxolitinib.

- Current evidence of malignancy after allogeneic transplant.

- History of progressive multifocal leuko-encephalopathy (PML)

- Active uncontrolled bacterial, fungal, parasitic, or viral infection. Infections are
considered controlled if appropriate therapy has been instituted and, at the time of
screening, no signs of infection progression are present. Progression of infection is
defined as hemodynamic instability attributable to sepsis, new symptoms, worsening
physical signs or radiographic findings attributable to infection. Persisting fever
without other signs or symptoms will not be interpreted as progressing infection

- Presence of known HIV infection, active hepatitis B or C infection.

- Active tuberculosis infection that developed after allogeneic hematopoietic cell
transplant (HCT)

- Total bilirubin 1.5 ´ the upper limit of the normal range

- Creatinine clearance <30 mL/min

- Presence of uncontrolled cardiopulmonary conditions such as ongoing cardiac
arrhythmias, unstable angina or myocardial infarction, uncontrolled hypertension, New
York Heart Association class III/IV congestive heart failure, or requirement of
supplemental oxygen or having a resting O2 saturation <90% by pulse oximetry

- Any other condition that is judged by the physician to potentially interfere with
compliance to the study protocol or pose a significant risk to the patient.

- Pregnancy, breastfeeding or planning to be pregnant.

- Exposure to Janus kinase inhibitors (JAK) inhibitor therapy for any indication after
allogeneic transplant

- Initiation of a new systemic immunosuppressant for management of chronic GVHD within 8
weeks prior to enrollment. However, patients who develop disease progression can
enroll as early as 4 weeks after initiation of a new systemic immunosuppressant. Also,
patients who are unable to tolerate current therapy can enroll any time after
initiation of a new systemic immunosuppressant, as long as the "new" immunosuppressant
is stopped in these cases prior to initiation of ruxolitinib. Initiation of any new
topical therapy and changes in dose of corticosteroids or calcineurin inhibitors are
acceptable at any time prior to enrollment.

- Treatment with any other investigational agent, device, or procedure, within 21 days
(or 5 half-lives, whichever is greater)

- Known allergies, hypersensitivity, or intolerance to any of the study medications,
excipients, or similar compounds.