Front Line Ibrutinib Without Corticosteroids for Newly Diagnosed Chronic Graft-versus-Host Disease

• INCLUSION CRITERIA:

1. Newly diagnosed moderate or severe chronic Graft versus Host Disease (GvHD) (according to the 2014 National Institutes of Health (NIH) Consensus Criteria,requiring systemic immunosuppression.

2. History of prior allogeneic Hematopoietic Stem Cell Transplant (HSCT) (anydonors, conditioning regimens and graft sources are allowed).

3. Subjects may have ongoing acute GvHD features (e.g., erythematous rash,elevated liver enzymes, diarrhea) which are in the opinion of the investigatorresponding to therapy.

4. Stable doses of other immunosuppressive medications (e.g., calcineurininhibitors, mycophenolate mofetil, rapamune, etc.) with no dose increase in the 2 weeks prior to study treatment initiation. Doses may be adjusted for troughlevels.

5. Age greater than or equal to 18 years old.

6. Karnofsky performance status greater than or equal to 60%.

7. Laboratory parameters as defined below:

• Serum creatinine less than or equal to 2.0 x upper limit of normal (ULN).
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) lessthan or equal to 3 x ULN (less than or equal to 5 x ULN if unequivocalliver GvHD).
• Total bilirubin less than or equal to 3 x ULN.
• Absolute neutrophil count greater than or equal to 1.0 x 10(9)/L (nogrowth factor support allowed).
• Platelets > 50 x 10(9)/L (no transfusions allowed less than or equal to 7days prior to enrollment).

8. Ability to understand and willingness to sign a written informed consent form.

9. The effects of ibrutinib on the developing fetus are unknown. For this reasonand because tyrosine kinase inhibitors may be teratogenic, female subjects ofchildbearing potential and men must agree to use highly effective methods ofbirth control (hormonal or barrier method of birth control; abstinence) priorto study entry, during the period of therapy, and for 30 days after the lastdose of study drug.

EXCLUSION CRITERIA:

1. Relapsed or progressive malignant disease (other than minimal residual disease).

2. History of other malignant diseases, including post-transplant lymphoproliferativedisease, with the following exceptions:

• Malignancy treated with curative intent and with no evidence of active diseasepresent for more than 3 years prior to prior to study treatment initiation andfelt to be at low risk for recurrence.

• Adequately treated non-melanomatous skin cancer or lentigo malignant melanomawithout current evidence of disease.

• Adequately treated cervical carcinoma in situ without current evidence ofdisease.

3. Received previous systemic treatment for chronic GvHD other than less than or equalto 0.5 mg/kg/day of prednisone equivalent for more than 7 days. Subject may be onsteroids that were used to treat acute GvHD and then developed chronic GvHD beforecompleting a taper. At the time of enrollment, the dose should be less than or equalto 0.5 mg/kg/day of prednisone equivalent with no dose increase in the preceding 2weeks before study treatment initiation.

4. Prior or current treatment with:

• Ibrutinib since the time of transplant (participants may have receivedibrutinib prior to transplant for indications other than chronic GvHD).

• Extracorporeal photopheresis (ECP) for acute GvHD less than or equal to 2 weeksprior to study treatment initiation; including any treatment with ECP forchronic GvHD.

• Rituximab or other anti-B cell specific antibodies less than or equal to 4weeks prior to study treatment initiation.

• Any systemic investigational agents less than or equal to 4 weeks prior tostudy treatment initiation.

5. Impaired cardiac function including any one of the following:

• Myocardial infarction, unstable angina or acute coronary syndrome less than orequal to 6 months prior to study treatment initiation.

• Class 3 or 4 congestive heart failure, uncontrolled arrhythmia or uncontrolledhypertension at any time.

6. Uncontrolled infections (including prior aspergillosis) not responsive toantibiotics, antiviral medicines, or antifungal medicines.

7. Known bleeding disorder or subjects who received a strong cytochrome P450 (CYP) 3Ainhibitor less than or equal to 7 days prior to the first dose of ibrutinib orrequirement for continuous treatment with a strong CYP3A inhibitor.

8. Active hepatitis C virus (HCV) or hepatitis B virus (HBV). Subjects who are positivefor hepatitis B core antibody or hepatitis B surface antigen or hepatitis C antibodymust have a negative polymerase chain reaction (PCR) result to be enrolled.

9. Known hypersensitivity to ibrutinib.

10. Pregnant women are excluded from this study because ibrutinib has potential forteratogenic and abortifacient effects. Because there is an unknown but potentialrisk for adverse events in nursing infants secondary to treatment of the mother withibrutinib, breastfeeding should be discontinued if the mother is treated withibrutinib. Women who are planning to become pregnant and men who plan to father achild while enrolled in this study or less than or equal to 30 days after the lastdose of study drug are excluded.

11. Any other reason at the discretion of the investigators and documented in themedical record that may raise concerns about the subject safety or ability toparticipate on this study.

12. Currently active, severe hepatic impairment Child-Pugh class C according to theChild Pugh classification.