Novel BET Inhibitor PLX51107 for Steroid-Refractory Acute GVHD

Inclusion Criteria:

• Age >= 18 years at the time of signing informed consent

• Steroid-refractory acute GVHD as defined as progression of acute (a)GvHD within 3-5days of therapy onset with >= 2 mg/kg/day of prednisone equivalent OR failure toimprove within 5-7 days of treatment initiation with > 1-2 mg/kg/day of prednisoneequivalent OR incomplete response after more than 28 days of immunosuppressivetreatment including steroids

• Recipients of ablative and reduced-intensity conditioning regimens

• Recipients of human leukocyte antigen (HLA)-matched related and unrelated, 1-allelemismatched, haploidentical, or umbilical cord blood donor grafts

• Prior lines of therapy for treatment of steroid-refractory acute GVHD are allowed.However, exposure to investigational therapies for the treatment of GVHD must be > 14 days or 5 half-lives (whichever is shorter) of first administration of studydrug. For patients treated with ruxolitinib for the treatment of acute GVHD,ruxolitinib must be discontinued by at least one day prior to initiation of PLX51107

• Eastern Cooperative Oncology Group (ECOG) performance status =< 3

• Absolute neutrophil count >= 1.0 x 10^9/L for 3 consecutive days). Use of growthfactor support is allowed

• Platelet count >= 50 x 10^9/L without transfusion support for 2 consecutive days

• Women of child-bearing potential must have a negative serum pregnancy test atScreening and must agree to use an effective form of contraception from the time ofthe negative pregnancy test up to 6 months after the last dose of study drug.Effective forms of contraception include abstinence, hormonal contraceptive inconjunction with a barrier method, or a double barrier method. Women ofnon-child-bearing potential may be included if they are either surgically sterile orhave been postmenopausal for >= 1 year

• Fertile men must agree to use an effective method of birth control during the studyand for up to 6 months after the last dose of study drug

Exclusion Criteria:

• Prior exposure to a bromodomain inhibitor

• Evidence of chronic GVHD

• Evidence of active relapse of disease

• Exposure to other investigational or anti-cancer therapies (not for GVHD) within 28days or 5 half-lives (whichever is shorter) of first administration of study drug

• Active, uncontrolled bacterial, fungal, or viral infection

• Known or suspected allergy to the study drug

• Clinically significant cardiac disease, defined as:

• Clinically significant cardiac arrhythmias, including bradyarrhythmia, and/or aneed for anti-arrhythmic therapy (excluding beta blockers or digoxin).Individuals with controlled atrial fibrillation are not excluded

• Fridericia-corrected QT interval (QTcF) >= 450 ms (male) or >= 470 ms (female)at screening

• History of clinically significant cardiac disease or congestive heart failuregreater than New York Heart Association Class II. Subjects must not haveunstable angina (angina symptoms at rest) or experienced either new-onsetangina within the last 3 months or myocardial infarction (MI) within the last 6months unless it was due to the underlying disease and there has beenappropriate revascularization. Individuals with ambiguous troponin levels thatare not diagnostic of an MI should be discussed with the principal investigator (PI) prior to enrollment

• Arterial or venous thrombotic or embolic events such as cerebrovascularaccident (including transient ischemic attacks), deep vein thrombosis, orpulmonary embolism within the 6 months before start of study medication (exceptfor catheter-related venous thrombosis

• Inability to take oral medication or significant nausea and vomiting, malabsorption,or significant small bowel resection that, in the opinion of the Investigator, wouldpreclude adequate absorption

• Active thrombotic microangiopathy (TMA)

• Women who are either pregnant or breast feeding

• Measured or calculated (Cockcroft-Gault formula) creatinine clearance (CrCl) < 45mL/min

• Prothrombin time or international normalized ratio > 1.5 x upper limit of normal (ULN)

• Activated partial thromboplastin time > 1.5 x ULN

• Requiring mechanical ventilation or vasopressor support

• Subject is participating in any other therapeutic clinical study (observational orregistry studies are allowed)