Study of Baricitinib, a JAK1/2 Inhibitor, in Chronic Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation

- Background:

- Chronic graft-versus-host disease (cGVHD) is the leading cause of non-relapse
morbidity and mortality in persons after allogeneic hematopoietic stem cell
transplantation (SCT).

- Approximately 50% of patients with cGVHD have disease refractory to systemic
corticosteroids; currently, there is no standard second-line therapy.

- The JAK-STAT pathway relays the signaling function of several inflammatory
cytokines that have a role in GVHD (IFN-gamma, IL-2, IL-6, IL-12).

- Murine models have demonstrated activity of JAK inhibitors in graft-versus-host
disease.

- Baricitinib is a potent and selective inhibitor of JAK1 and JAK2 that has
demonstrated anti-inflammatory effects and a good safety profile in patients with
rheumatoid arthritis, but has not been evaluated in GVHD.

- Objectives:

- To determine the safety and tolerability of baricitinib in patients with cGVHD that
is refractory to steroids

- To determine the efficacy of baricitinib in patients with cGVHD that is refractory
to steroids

- Eligibility:

- Inclusion:

- Age greater than or equal to 18 years

- Moderate or severe cGVHD per NIH consensus criteria

- Karnofsky performance status greater than or equal to 50%

- cGVHD that did not respond to high-dose corticosteroids (prednisone at 1.0
mg/kg/day for at least 1 week or prednisone at 0.5 mg/kg/day or 1 mg/kg every
other day for at least 4 weeks), or second-line therapy (any)

- Receiving stable or tapering doses of systemic therapy in the preceding 4
weeks if taking systemic therapy for cGVHD

- Exclusion:

- Neutrophils <1.0x10^9/L, platelets <50X10^9/L, creatinine greater than or
equal to 1.5 times the upper limit of normal or estimated creatinine clearance
<50mL/min/1.73m^2 (Cockroft-Gault formula), serum aspartate aminotransferase
or alanine aminotransferase concentration >3x ULN or total bilirubin greater
than or equal to 1.5x ULN

- Progressive malignancy, uncontrolled infection or any major organ dysfunction
as defined by the protocol

- Design:

- This is a Phase 1/2 trial to determine the safety and efficacy of baricitinib in
patients with cGVHD that is refractory to steroids.

- Patients will initially be treated with baricitinib at 2mg daily for 12 weeks. If
the response at 12 weeks is a CR and there has not been a DLT, the dose will be
remain at 2mg daily for an additional 12 weeks, with the primary response
assessment at 24 weeks of total treatment. If the response is a PR or stable
disease, the dose will be increased to 4mg daily for an additional 12 weeks, with
the primary response assessment at 24 weeks of total treatment. If there is
progression of disease at any time within the first 12 weeks, the dose can be
increased to 4mg daily at that time, and patients will continue for a total of 24
weeks of treatment. Patients will have the option to continue baricitinib for an
additional 6 months as tolerated if they have stable or responding disease.

- The co-primary endpoint of safety will be determined by rate, severity, and
duration of adverse events based on CTCAE v4 criteria. Assessment for DLTs will
occur every 2 weeks during the first 4 weeks of each dose level. Safety monitoring
will occur every 4 weeks thereafter.

- The co-primary endpoint of efficacy will be defined as rate of overall response at
24 weeks per NIH consensus criteria (CR or PR).

- Peripheral blood samples will be collected prior to treatment, at 2 weeks, at 12
weeks and every 12 weeks thereafter to evaluate cytokine and cellular profiles,
STAT phosphorylation, candidate chronic GVHD biomarkers. Pharmacokinetic studies
will also be performed at each dose level.

- In an initial futility analysis, if 0 of the first 7 patients enrolled in cohort 1
have responded at 12 weeks, then a 2nd cohort of patients will be accrued to start
treatment at the higher dose (4mg daily). Otherwise, if 1 or more of the first 7
patients respond in cohort 1, then 21 evaluable patients will be treated in cohort
1. Similarly, if the second cohort is used, and if 0 of the 7 patients enrolled in
this second cohort have responded at 12 weeks, then no further patients will be
accrued. Otherwise, if 1 or more of the first 7 patients respond in cohort 2, then
21 evaluable patients will be treated in cohort 2.

- A total of 21 evaluable patients will be enrolled in either cohort 1 or 2 as
appropriate, in order to have 80% power to detect a response rate consistent with
30% and ruling out 10%, with a one-sided significance level of 0.10 for the cohort.
As an early stopping rule for safety, if 2/3 or greater patients at any given dose
level experiences a dose limiting toxicity requiring dose reduction or
discontinuation, that dose will not be subsequently used and no further dose
escalation will take place.

-INCLUSION CRITERIA:

1. Moderate or severe cGVHD (after allogeneic hematopoietic stem cell transplantation)
diagnosed and staged per NIH criteria. Responses to JAK inhibitors have not been
restricted to specific organs, so any organ involvement is eligible.

2. Age greater than or equal to 18 years of age. Because inadequate dosing or adverse
event data are currently available on the use of baricitinib in patients <18 years of
age, children are excluded from this study.

3. Karnofsky performance score >50%

4. Chronic GVHD that did not respond to high-dose corticosteroids (prednisone at 1.0
mg/kg/day for at least 1 week or prednisone at 0.5 mg/kg/day or 1 mg/kg every other
day for at least 4 weeks), or second-line therapy (any).

5. If patient is taking systemic therapy for cGVHD at the time of enrollment, they must
be on a stable or tapering doses in the preceding 4 weeks.

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

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

absolute lymphocyte count greater than or equal to 500/mcL

platelets greater than or equal to 50,000/mcL

hemoglobin greater than or equal to 9 g/dL

total bilirubin less than or equal to 1.5 X institutional upper limit of normal,
unless there is a known history of Gilbert s disease

AST(SGOT)/ALT(SGPT) less than or equal to 3 X institutional upper limit of normal

- Creatinine < 1.5 times the upper limit of normal, or:

creatinine clearance greater than or equal to 50 mL/min/1.73 m^2. Creatinine clearance
should be calculated per institutional standard.

7. Primary malignancy for which the patient received transplant has been stable for 3
months prior to enrollment on study.

8. The effects of baricitinib on human fetal development are unknown. Women of
child-bearing potential and men must agree to use 2 effective forms of contraception
(hormonal or barrier method of birth control; abstinence) for the duration of study
participation and for at least 7 days after study drug exposure. Should a woman become
pregnant or suspect she is pregnant while she or her partner is participating in this
study, or if a man s partner becomes pregnant or suspects she is pregnant while he is
participating in this study, she or he should inform their treating physician
immediately.

9. Ability of subject to understand and the willingness to sign a written informed
consent document.

EXCLUSION CRITERIA:

1. Systemic immune suppression or systemic therapy for cGVHD started within preceding 4
weeks.

2. Hypersensitivity to JAK inhibitors.

3. Any serious medical condition within the previous 4 weeks which places the subject at
an unacceptable risk if he or she were to participate in the study or confounds the
ability to interpret data from the study, including, but not limited to, symptomatic
congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmias,
acute kidney injury, or psychiatric illness/social situations that would limit
compliance with study requirements.

4. Uncontrolled infection, including active HIV-1, Hepatitis B (HBV) and/or Hepatitis C
(HCV) infection (positive HBV or HCV viral load in the setting of positive HBV core
antibody or surface antibody or HCV antibody). History of HBV or HCV is allowed if
there is no uncontrolled viral infection. Because the study agent may impact response
to infections, patients with any active viral infection are excluded.

5. Recurrent or progressive malignancy requiring anticancer treatment.

6. Other cancer except that for which the transplant was done <2 years before study
entry, except non-melanoma skin cancer or carcinoma in situ of the uterine cervix or
breast.

7. Patients who are receiving any other investigational agents.

8. NIH lung score 3.

9. Pregnant women are excluded from this study because the teratogenic effects of
baricitinib are unknown. Because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with baricitinib,
breastfeeding should be discontinued if the mother is treated with this agent.