Novel BET Inhibitor PLX51107 for Steroid-Refractory Acute GVHD

Study Overview
=================
Brief Summary
-----------------
This phase Ib/II trial studies the side effects of PLX51107 in treating steroid-refractory acute graft versus host disease (GVHD). PLX51107 is a novel, potent non-benzodiazepine structured small molecule BET inhibitor with a unique binding mode selective for BRD4 inhibition and a more tolerable side effect profile. PLX51107 may work better in treating steroid-refractory acute GVHD.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of BRD4 inhibitor PLX51107 (PLX51107) as a single agent for allogeneic transplant recipients with steroid-refractory acute graft versus host disease (GVHD). II. To assess the pharmacokinetic (PK) and pharmacodynamic (PD) of orally administered PLX51107 in steroid-refractory acute GVHD patients. SECONDARY OBJECTIVE: I. To evaluate the preliminary efficacy of PLX51107 in steroid-refractory acute GVHD patients. OUTLINE: Patients receive BRD4 inhibitor PLX51107 orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then up to 6 months.

Official Title
-----------------
A Single Arm, Open Label, Phase 1b/2 Study of Novel BET Inhibitor PLX51107 for Steroid-Refractory Acute GVHD

Conditions
-----------------
Acute Graft Versus Host Disease, Steroid Refractory Graft Versus Host Disease

Intervention / Treatment
-----------------
* Drug: BRD4 Inhibitor PLX51107


Participation Criteria
=================
Eligibility Criteria
-----------------
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 3-5 days of therapy onset with >= 2 mg/kg/day of prednisone equivalent OR failure to improve within 5-7 days of treatment initiation with > 1-2 mg/kg/day of prednisone equivalent OR incomplete response after more than 28 days of immunosuppressive treatment including steroids Recipients of ablative and reduced-intensity conditioning regimens Recipients of human leukocyte antigen (HLA)-matched related and unrelated, 1-allele mismatched, 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 study drug. 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 growth factor 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 at Screening and must agree to use an effective form of contraception from the time of the negative pregnancy test up to 6 months after the last dose of study drug. Effective forms of contraception include abstinence, hormonal contraceptive in conjunction with a barrier method, or a double barrier method. Women of non-child-bearing potential may be included if they are either surgically sterile or have been postmenopausal for >= 1 year Fertile men must agree to use an effective method of birth control during the study and 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 28 days 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 a need 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 failure greater than New York Heart Association Class II. Subjects must not have unstable angina (angina symptoms at rest) or experienced either new-onset angina within the last 3 months or myocardial infarction (MI) within the last 6 months unless it was due to the underlying disease and there has been appropriate revascularization. Individuals with ambiguous troponin levels that are 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 cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism within the 6 months before start of study medication (except for 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, would preclude adequate absorption Active thrombotic microangiopathy (TMA) Women who are either pregnant or breast feeding Measured or calculated (Cockcroft-Gault formula) creatinine clearance (CrCl) < 45 mL/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 or registry studies are allowed)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment for aGVHD (BRD4 inhibitor PLX51107)<br>Patients receive BRD4 inhibitor PLX51107 PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: BRD4 Inhibitor PLX51107<br>* Given PO<br>* Other names: PLX51107;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) |  | Up to 28 days | 
| Incidence of adverse event | Adverse events by grade will be summarized. The occurrence of grade 3+ adverse events according to Common Terminology Criteria for Adverse Events will be summarized as well. Adverse events will initially be reviewed regardless of attribution, but also according to whether adverse events are possibly, probably, or definitely related to treatment. | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response (CR) | The proportion of CR with a 95% confidence interval will be reported, assuming a binomial distribution. | At day 28 | 
| Overall response rate | The overall response rate (ORR) will include CR and partial response (PR), while mixed response (MR) and no response (NR) will be classified as no response. The ORR will be similarly analyzed as CR. | At day 28 | 
| Non-relapse mortality (NRM) | The cumulative incidence curve accounting for competing risks will be generated to estimate the cumulative incidence of NRM rate at 6 months. The comparison in NRM between patient subgroups may be explored graphically. | From the date of starting PLX51107 to date of death with the competing risk as death due to disease, assessed at 6 months |