Clinical trial NCT04910152
Conditions: Acute Graft Versus Host Disease Steroid Refractory Graft Versus Host Disease
Sponsor: Hannah Choe, MD
Start date: 2022-04-19; Completion date: 2023-09-28
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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.

Arms: arm 1: 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.
Interventions: intervention 1: BRD4 Inhibitor PLX51107
Intervention descriptions: intervention 1: Given PO

Protocol documents:
Prot_SAP_001.pdf: 
Protocol v.7 
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IRB Protocol Number: 
2020C0226 
 
         IRB Approval date:  07/17/2023 
 
Version date:  04/14/2023 
 
1 
 
 
 
A Single Arm, Open Label, Phase 1 Study of Novel BET 
inhibitor PLX51107 and Corticosteroids for Treatment-
Refractory Acute GVHD 
 
Principal Investigator: 
Hannah Choe, MD 
460 W 10th Ave 
1st Floor 
Columbus, OH-43210-1240 
Hannah.Choe@osumc.edu 
 
 
Multi-Center Trial Program 
Clinical Trials Office 
The Ohio State University Comprehensive Cancer Center 
Email: OSUCCC-CTO-MCTP@osumc.edu 
 
Synopsis 
 
Primary 
objectives 
To evaluate the safety and tolerability of PLX51107 and corticosteroids for 
allogeneic transplant recipients with treatment-refractory acute GVHD 
 
To assess the PK and PD of orally administered PLX51107 in treatment-
refractory acute GVHD patients 
Secondary 
objective 
To evaluate the preliminary efficacy of PLX51107 and corticosteroids in 
treatment-refractory acute GVHD patients 
Study design 
This is a Phase 1, open-label, single-center, dose-finding study to evaluate 
the safety, tolerability, and biologically effective and tolerable dose (BETD) 
of PLX51107 in combination with corticosteroids in treatment-refractory 
acute GVHD patients. We will determine the dose of PLX51107 that both 
shows biological activity (BA) and is tolerable when used in combination 
with corticosteroids. BA is assessed by pharmacokinetics (PK) for target 
exposure of AUC0-24 8300 ng•hr/mL at Day 1 based on preclinical in vivo 
pharmacological efficacy studies (PLX51107 IB). 
 
All diseases, transplant and donor types are included. PLX51107 will be 
administered orally daily as tolerated. All patients will concurrently receive 
prednisone 1mg/kg orally daily (may be divided into 2 doses) or MP IV 
equivalent. Corticosteroids may be tapered per institutional guidelines, but 
taper may not be initiated sooner than 7 days after Study Day 1 and to no 
less than prednisone 0.25mg/kg daily before Study Day 28. We will further 


Protocol v.7 
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IRB Protocol Number: 
2020C0226 
 
         IRB Approval date:  07/17/2023 
 
Version date:  04/14/2023 
 
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assess biological activity as compared across clinical responses at different 
dose levels to determine the recommended Phase 2 dose (RP2D) for 
additional evaluation. 
 
The observation period for DLT and BA will be the first cycle of 28 days. A 
dose level will be deemed the BETD if 5 or more out of 6 patients 
demonstrate a BA with 0-1 DLTs. This dose will be declared biologically 
effective and tolerable. The starting dose level is at Dose Level 1 (40 
mg/day). Refer to Table 1 for Dose Levels. 
 
This study design combines a standard rule-based Phase 1 3+3 trial 
design that simultaneously evaluates tolerability (DLTs) and evidence of 
biological activity at each dose level. Three patients are entered at each 
dose level and expanded to six patients if sufficient tolerability and BA is 
observed. See Figure 5 for a study schematic. If 2 or more patients out of 6 
at a given dose level experiences DLT, accrual at that dose level will stop, 
and the dose level will be de-escalated. If at the lowest dose level, accrual 
will be suspended and the study terminated.  
 
 After BETD is determined, we will review the tolerability, biological activity, 
and clinical responses observed to justify a RP2D. 
 
 
Table 1. Dose levels 
 
 
 
 
 
 
 
 
DLTs are defined as AEs or laboratory abnormalities occurring during the 
first cycle (28 days) of study drug administration that are at least possibly 
related to PLX51107, deemed to be clearly unrelated to disease 
progression, concurrent illness or concomitant medication and that meet 
one of the following NCI CTCAE v5.0 criteria below.  
 
• 
Hematological toxicities 
• 
Grade >3 neutropenia lasting >7 days  
• 
Grade ≥3 febrile neutropenia 
• 
Grade 4 thrombocytopenia lasting >14 days despite study 
drug discontinuation 
• 
Non-hematological toxicities 
• 
New onset non-hematological clinical and laboratory toxicity 
grade ≥3 lasting >72 hours with the exception of the following 
events: 
Cohort 
Dose level 
(mg/day) 
0 
20 
1 
40 
2 
80 
3 
120 


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 
Grade ≥3 nausea, vomiting or diarrhea that resolves 
to grade ≤2 within 72 hours, with maximal medical 
intervention  
 
Grade 3 fatigue, asthenia, anorexia, fever or 
constipation that resolves to grade ≤2 within 14 days  
 
Grade ≥3 asymptomatic changes in alkaline 
phosphatase, hypomagnesemia, hyperglycemia or 
hypophosphatemia 
 
Grade 3 increases in transaminases confirmed upon 
repeat testing lasting ≤ 5 days 
 
Any Grade ≥3 electrolyte abnormality that is corrected 
to Grade ≤2 within 24 hours 
 
Non-hematologic laboratory Grade 3 AE that is 
asymptomatic and/or rapidly reversible (returned to 
baseline or to Grade ≤ 1 within 7 days) unless 
identified as clinically relevant by the Investigator; and 
(in non-diabetic patients) singular or non-fasting 
elevations in blood glucose 
• 
Any case of Hy's law defined as AST or ALT >3 x ULN with 
concurrent total bilirubin >2 x ULN, absence of cholestasis 
(elevated ALP >2 x ULN), and no alternative etiology,  which 
can explain the combination of increased AST or ALT and 
total bilirubin, such as viral hepatitis A through E, other 
preexisting or acute liver disease, liver acute GVHD, or 
another drug capable of causing the observed injury 
• 
Any dose reduction required during Cycle 1 due to grade ≥3 
adverse events 
• 
Any treatment delay of >7 consecutive days during Cycle 1 
due to study drug-related Grade ≥3 adverse events that fails 
to resolve to baseline or grade ≤1 
• 
Any Grade ≥3 gastrointestinal, genitourinary or central 
nervous system hemorrhage 
• 
Any grade 4 or 5 nonhematological adverse reaction 
• 
Any death unless unequivocally due to underlying disease 
(or extraneous cause) 
 
Any adverse reaction unrelated to active GVHD that leads to the study drug 
PLX51107 dose reduction or withdrawal should be considered a DLT. 
 
Grade 3 or higher adverse events occurring past 28-days must be recorded 
and reviewed for final analysis and for Phase 2 dose evaluation. 
 
 
Eligibility 
Patients with a diagnosis of treatment-refractory acute GVHD are eligible. 
Patients must be refractory to first-line steroid therapy and failed one or 
more salvage therapy regimens. Patients with a contraindication to the use 
of steroids are not deemed steroid-refractory and are ineligible. Patients 


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who meet eligibility criteria, sign informed consent, and dose with 
PLX51107 are enrolled. 
 
Inclusion criteria 
1. Age ≥ 18 years 
2. Treatment-refractory acute GVHD as defined as patients who failed 
steroids (as defined as (a) progressed after 3 days of treatment with 
methylprednisolone (MP) 2 mg/kg/day equivalent, (b) did not 
improve after 7 days of treatment with MP 2 mg/kg/day equivalent, 
(c) progressed to a new organ after treatment with MP 1 mg/kg/day 
equivalent for skin and upper gastrointestinal (GI) GVHD, or (d) 
recurred during or after a steroid taper2) plus one or more salvage 
regimens with no limit to the number of prior lines of salvage 
therapies 
3. Recipients of ablative and reduced-intensity conditioning regimens 
4. Recipients of HLA-matched related and unrelated, 1-allele 
mismatched, haploidentical, or umbilical cord blood donor grafts 
5. Prior lines of therapy for treatment of steroid-refractory acute GVHD 
are allowed. There is no minimum or maximum to the number of 
prior therapies. However, exposure to investigational therapies for 
the treatment of GVHD must be > 14 days or 5 half-lives (whichever 
is longer) of first administration of study drug. Prior cell therapy trial 
exposure must be >14 days where no known half-life applies. 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. 
6. ECOG performance status 0-3. 
7. Absolute neutrophil count ≥1.0 x 109/L for 3 consecutive days). Use 
of growth factor support is allowed. 
8. Platelet count ≥50 x 109/L without transfusion support for 2 
consecutive days. 
9. 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. 
10. 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 
1. Prior exposure to a bromodomain inhibitor 
2. Evidence of active relapse of underlying disease 
3. 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 


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4. Active, uncontrolled bacterial, fungal, or viral infection 
5. Known or suspected allergy to the study drug 
6. Clinically significant cardiac disease, defined as: 
A. 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. 
B. Fridericia-corrected QT interval (QTcF) ≥ 470 ms (male and 
female) at Screening.  
C. 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 PI prior to enrollment. 
D. 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. 
7. Inability to take oral medication or significant small bowel resection 
that, in the opinion of the Investigator, would preclude adequate 
absorption. 
8. Active thrombotic microangiopathy (TMA) 
9. Women who are either pregnant or breast feeding 
10. Measured or calculated (Cockcroft-Gault formula) creatinine 
clearance (CrCl) <45 mL/min 
11. Prothrombin time or international normalized ratio >1.5 × ULN 
12. Activated partial thromboplastin time >1.5 × ULN 
13. Requiring mechanical ventilation or vasopressor support 
14. Subject is participating in any other therapeutic clinical study 
(observational or registry studies are allowed). 
15. Contraindication to steroids. 
 
Steroids may be concurrently weaned per institutional practice. 
Study 
endpoints 
The primary endpoints include: 
• 
To determine the biologically effective and tolerable dose (BETD) 
• 
Safety endpoints (adverse events) 
• 
PK analysis 
 
The secondary endpoints include:  
• 
Preliminary efficacy (CR at Day 28) among all patients treated and 
among all patients treated at BETD 
• 
Overall response rate (ORR at Day 28) among all patients treated 
and among all patients treated at BETD 


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• 
NRM at 6 months 
 
Data analysis 
To assess the safety and tolerability, adverse events by grade will be 
summarized. The occurrence of Grade 3+ adverse events according to 
CTCAE 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. Complete 
response (CR) at Day 28 among all patients treated and among all patients 
treated at BETD will be estimated. The proportion of CR with a 95% CI will 
be reported, assuming a binomial distribution. 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. To determine 6-month non-relapse mortality 
(NRM), the event will be death due to reasons other than disease and the 
time will be measured from the date of starting PLX51107 to date of death 
with the competing risk as death due to disease (relapse). 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. 
 
Table of Contents 
Synopsis ................................................................................................................................. 1 
Inclusion criteria .................................................................................................................. 4 
Exclusion criteria ................................................................................................................. 4 
Background & Significance ..................................................................................................... 8 
Objectives .............................................................................................................................13 
Primary objectives ..............................................................................................................13 
Secondary objective ...........................................................................................................13 
Eligibility ................................................................................................................................13 
Inclusion criteria .................................................................................................................15 
Exclusion criteria ................................................................................................................15 
Statistical Considerations ......................................................................................................16 
Study Design .........................................................................................................................16 
Study endpoints .................................................................................................................19 
Number of Subjects ...........................................................................................................20 
Duration .............................................................................................................................20 
Study Calendar ......................................................................................................................21 
Dose limiting toxicity (DLT) ................................................................................................23 
Treatment Plan ......................................................................................................................25 


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Investigational product .......................................................................................................25 
Treatment Dosage and Administration ...............................................................................25 
Dosing Delays or Missed Doses ........................................................................................25 
Duration of Therapy ...........................................................................................................25 
Duration of Follow-Up ........................................................................................................25 
Concomitant medications ...................................................................................................26 
Preparation, Reconstitution, and Dispensation ...................................................................27 
Study Drug Packaging and Labeling ..................................................................................27 
Storage and Handling ........................................................................................................28 
Correlative Studies ................................................................................................................28 
Study procedure and methods ...............................................................................................28 
Screening...........................................................................................................................29 
Follow-up ...........................................................................................................................29 
Withdrawal .........................................................................................................................29 
Differentiation Syndrome ....................................................................................................29 
Adverse Events and Adverse Event Management .................................................................30 
Sample Handling/Processing/Shipping Protocols ..................................................................32 
Data and Safety Monitoring Plan ...........................................................................................33 
Informed consent ...................................................................................................................34 
Patient confidentiality .............................................................................................................34 
Institutional Review Board .....................................................................................................34 
Potential risks for study participants ......................................................................................35 
Potential benefits of study participation..................................................................................35 
Costs and payments ..............................................................................................................35 
References ............................................................................................................................36 
APPENDIX 1: CYP3A4/CYP2C8 inhibitors and/or inducers ......................................................38 
 
 
 


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Background & Significance 
Acute GVHD is the most common cause of morbidity and mortality post-SCT, affecting 30-70% 
of transplant recipients.3–5 However, despite a high incidence of acute GVHD post-SCT, 
treatments options are severely limited. The primary initial treatment of acute Graft Versus Host 
Disease (GVHD) is uniformly high dose steroids, from which only 24-40% of patients have 
durable responses. Those that do not respond by four weeks after the initiation of systemic 
therapy have higher non-relapse mortality (48% vs. 16%).6 The majority (>90%) of those non-
responsive to steroids die with an estimated overall survival at 2-years of only 10%.7,8 Thus, 
treatment-refractory acute GVHD patients present a desperate need for new therapies. There is 
no standard therapy for steroid-refractory aGVHD due to limited response rates. Various 
treatment modalities have included cytokine signaling blockade via JAK/STAT inhibition, anti-IL-
622, anti-TNF-α6 monoclonal antibodies (mAbs), T-cell trafficking blockade23, and 
immunomodulation with alpha-1 antitrypsin24. Recently FDA approved oral JAK1/2 inhibitor, 
ruxolitinib, reported an overall response rate (ORR) of 62% and a modest complete response 
(CR) of 34% by Day 28 with no aGVHD survival benefit after treatment in combination with 
steroids25.The therapeutic potential of other more immunosuppressive agents such as anti-
thymocyte globulin and anti-CD52 mAb (alemtuzumab) is hindered by an increased risk of lethal 
infections and increased risk of relapse, negating improvement in survival26, 27. Thus, there is a 
need for more effective and novel therapies with improved tolerability. 
 
Bromodomain and extraterminal domain (BET) inhibitors have received high profile 
attention for their epigenetic antitumor activity seen across solid tumor and hematologic 
malignancies. BET proteins (including BRD2, BRD3, BRD4, and BRDT) modulate histone 
acetylation involved in the recruitment of positive transcription elongation factor complex (P-
TEFb) and RNA Pol II to specific locations on chromatin to control target pro-tumor gene 
expression, such as MYC and BCL2, which are highly up-regulated in malignancies such as 
AML. Most recently, the Byrd and Lapalombella labs at OSU published their findings of 
PLX51107 in vitro and in vivo in CLL models in Cancer Discovery.9 There is also an ongoing 
Phase 1b trial of PLX51107 in advanced malignancies, including AML and high-risk MDS 
(NCT02683395).  
 
Previous in vitro and in vivo studies of BET inhibition of key inflammatory genes have 
demonstrated that BET inhibition with iBET or JQ1 decrease cytokine and chemokine 
expression of NF-kB dependent genes IL-6, IFNb, IL-1b, IL-12a, CXCL9 in murine 
macrophages10 and decrease the differentiation of naïve T cells to Th17 cells without affecting 
Treg cell differentiation11 thus exhibiting powerful anti-inflammatory effects. Sun et al. 
additionally demonstrated that BET inhibition with iBET-151 decreased cytokine secretion of 
activated dendritic cells and decreased activated T cell proliferation by disrupting the interaction 
of BRD4 and the acetylated component important to NF-kB activation, RelA.12 NF-kB is an 
important transcriptional regulator of IL-2 expression, which is produced by activated T cells and 
is key to the development of a T cell alloantigen response, as seen in acute GVHD.13 Thus, NF-
kB signaling blockade in activated T cells reduces the pathologic hyper-responsiveness seen in 
acute GVHD. Given these anti-inflammatory properties via NF-kB suppression, Reddy et al. 
successfully tested iBET-151 in an in vivo acute GVHD mouse model, demonstrating for the first 
time that BET inhibition decreased GVHD severity and prolonged survival12. 
 
Unfortunately, the first generation BET inhibitors, including iBET, JQ1, and OTX015 have had 
disappointingly poor tolerability in human clinical trials due to hematologic dose-limiting toxicities 
and gastrointestinal adverse effects. However, unlike the first generation BET inhibitors that 


Protocol v.7 
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IRB Protocol Number: 
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         IRB Approval date:  07/17/2023 
 
Version date:  04/14/2023 
 
9 
 
share a benzodiazepine scaffold structure, 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. Importantly, in its first published description of 
its structure and binding mode by the Byrd and Lapalombella labs at OSU, the conformation of 
BRD4 bound by PLX51107 was confirmed to resemble the acetylated Lys310 binding 
conformation of RelA9 – pertinent to the hypothesis that PLX51107’s inhibitory effects would 
similarly mimic that of iBET-151 by NF-kB modulation but with an improved pharmaceutical 
profile. Thus, we propose the evaluation of the novel small molecule inhibitor PLX51107 for its 
anti-inflammatory and activated T cell dampening properties in clinical trial for treatment-
refractory acute GVHD patients that otherwise have no other therapeutic options. 
 
Pre-clinical data of PLX51107 in vitro and in vivo 
At American Society of Transplant and Cellular Therapy conference 2018, the Ranganathan lab 
at OSU presented the results from mirrored iBET-151 studies with PLX51107, analyzing the in 
vitro effects of activated dendritic cells and activated T-cell proliferation. In Figure 1, we show 
the analysis of supernatant for pro-inflammatory cytokine secretion of B6 T cells with PLX51107, 
demonstrated decreased IFN-g, IL-6, and TNF-a secretion. Figure 2 demonstrates the dose-
response decrease in activated T cell proliferation with continuous in vitro culture with 
PLX51107. T cells were activated with both allogeneic bone marrow derived cell and microbead 
CD3/CD28 activation with similar results. 
 
Figure 1. 
 
 
 
 
 
 
 
 
 
 
Figure 2. 
 
 
Early pre-clinical murine acute GVHD model studies of PLX51107 are currently ongoing with 
promising results. Unpublished data from the Ranganathan lab comparing GVHD severity and 
survival in a GVHD murine model of PLX51107 10mg/kg oral three times weekly dosage are 
below in Figure 3. Lethally irradiated F1 recipient mice received T cell depleted bone marrow 
cells (TCD-BM, 10x106) along with CD45.1 B6 splenocytes (15 x 106) transferred intravenously. 
Recipient mice were treated with PLX 51107 (10mg/kg) or vehicle by oral gavage three times 


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weekly starting at Day +7 post-transplant administered continuously until death or 
compassionate sacrifice. Studies evaluating outcomes at Day +1 treatment with dose-finding 
and tolerability are ongoing.  
 
Figure 3. 
 
 
 
 
The Mann-Whitney U-test was used for comparison of clinical scores between groups, and the 
log-rank test was used to compare survival. These results are based on the same formulation of 
PLX51107 as used in the MV4-11 AML xenograft study (EXP 14 AC8862 PLX51107 IB). In that 
study, continuous daily dosing of PLX51107 10mg/kg resulted in AUC0-24 = 29300 ng•hr/mL. 
The mean AUC0-24 for Figure 3 (three times weekly) is estimated to be ~12,000 ng•hr/mL, not 
significantly different from the target exposure (AUC0-24 = 8300 ng•hr/mL). This pre-clinical data 
supports the use of PLX51107 for acute GVHD given the reduced activated T cell proliferation 
and decreased cytokine secretion seen in vitro as well as the reduced clinical GVHD severity 
and improved survival in the mouse. 
 
PLX51107 was evaluated in a number preclinical efficacy models with PK analyses (PLX51107 
IB). The Ba/F3 splenomegaly model, a murine bone marrow-derived pro-B cell line, is most 
relevant for GVHD as NF-κB plays a role in the survival of Ba/F3 cells. When injected into the 
tail veins of nude mice, Ba/F3 cells home to the spleen and proliferate, leading to marked 
splenomegaly. PLX51107 treatment resulted in dose-dependent reduction in splenomegaly. The 
exposure required to produce approximately 50% efficacy is AUC0-24 8300 ng•hr/mL. This value 
defines the target exposure required for PLX51107 to be pharmacologically effective in vivo 


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(PLX51107 IB) and defines biological activity in the clinical trial design.Early phase human 
trials of PLX51107 
PLX51107 related adverse reaction that occurred in >15% of subjects based on study PLX122-
01 (A Phase 1b dose escalation study to assess the safety, pharmacokinetics, 
pharmacodynamics, and preliminary efficacy of PLX51107 in subjects with relapsed or 
refractory solid tumors (Group A) and hematological malignancies (Group B)) was nausea, 
fatigue, vomiting, diarrhea, blood bilirubin increased and decreased appetite.  The one and only 
subject enrolled in Group B developed fatal, suspected acute differentiation syndrome that was 
assessed as probably related to PLX51107. The subject had European LeukemiaNet (ELN) 
high risk AML with complex karyotype at relapse along with 17p deletion and TP53 mutation. 
The subject’s WHO classification was therapy-related AML. Please refer to the PXL51107 IB for 
additional safety information. 
 
In solid tumor patients, PLX51107 exhibited nearly dose-proportional increase in exposure from 
20 mg to 160 mg (MTD). At steady state, the daily exposures (AUC0-24) are 3820 and 9150 
ng•hr/mL at 40 and 120 mg doses, respectively. Refer to Table 2 below from PLX51107 IB. The 
exposure at the 120 mg dose (the proposed top dose in this study – Dose Level 3) is expected 
to be very close to the target (AUC0-24 is 8300 ng•hr/mL). However, patients with treatment-
refractory acute GVHD treated with PLX51107 may have a different safety profile compared 
with solid tumor patients. To ensure an adequate safety margin, a lower starting dose of 
PLX51107 at 40 mg/day is recommended in this study. The proposed starting dose of 40 
mg/day is 4x lower than the MTD for solid tumor patients. At the proposed starting dose (40 mg) 
in solid tumor patients, PLX51107 demonstrated a minimal pharmacodynamic effect in 
modulating the expression of BET target genes in peripheral blood cells (Figure 4 below from 
PLX51107 IB).  


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Table 2: 
Summary of Pharmacokinetic Data to Date 
Cohort 
(Dose) 
Na 
Geometric Mean 
Day 1 
Day 15 
Accum
u-
lation 
Ratio 
Tma
x 
(hr) 
Cmax 
(ng/mL
) 
AUC0-24 
(ng•hr/m
L) 
T1/2 
(hr) 
Tmax 
(hr) 
Cmax 
(ng/mL
) 
AUC0-24 
(ng•hr/mL
) 
T1/2 
(hr) 
Group A (solid tumors) 
1 (20 
mg/day) 
6/6 1.0
0 
596 
1070 
0.98
5 
0.794 
660 
1300 
1.19 
1.21 
2 (40 
mg/day) 
3/3 2.2
9 
721 
3460 
2.55 1.59 
1070 
3820 
2.29 
1.10 
3 (60 
mg/day) 
4/4 1.1
9 
1520 
3460 
1.49 1.19 
1510 
3810 
1.63 
1.10 
4 (90 
mg/day) 
4/3 1.1
9 
3170 
7560 
1.78 1.26 
2330 
6300 
1.50 
0.83 
5 (120 
mg/day) 
11/
9 
1.4
1 
3960 
11300 
1.71 1.61 
2990 
9150 
2.10 
0.81 
6 (160 
mg/day) 
11/
7 
1.5
1 
4950 
16200 
1.97 1.17 
4760 
11300 
1.99 
0.70 
7 (120 
mg/day)b 
3/3 1.0
0 
2980 
6970c 
1.63 1.44 
2310 
9220d 
1.72 
0.66 
8 (240 
mg/day) 
3/3 1.8
2 
7610 
29100 
2.69 1.71 
4190 
18900 
4.53 
0.65 
9 (20 
mg/day) 
4/1 2.2
1 
8470 
38700 
3.28 2.00 
4600 
32200 
2.63 
0.83 
Group B (AML) 
1 (120 
mg/day) 
0/1 ND 
ND 
ND 
ND 
2.00 
2990 
11500 
1.54 
ND 
AUC0-24 = area under the concentration-time curve from time 0 to 24 hours postdose;  
AUC0-∞ = area under the concentration-time curve from time 0 extrapolated to infinite time; BID 
= twice daily; 
Cmax = maximum concentration; Tmax = time of maximum observed concentration;  
T1/2 = terminal elimination half-life; ND = not determined 
a N:  number of patients with Day 1 PK/number of patients with Day 15 PK. 
b 60 mg BID. 
c AUC0-12. 
d AUC0-24 = 2 x AUCτ because of BID dosing schedule. 
 
 


Protocol v.7 
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IRB Protocol Number: 
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         IRB Approval date:  07/17/2023 
 
Version date:  04/14/2023 
 
13 
 
Figure 4: 
PLX51107 Pharmacodynamic Effect on Peripheral Blood Cells 
 
 
 
Hypothesis: PLX51107 is safe and effective in combination with corticosteroids in 
allogeneic stem cell transplant recipients with treatment-refractory acute GVHD 
 
Objectives 
Primary objectives:  
To evaluate the safety and tolerability of PLX51107 and corticosteroids 
for allogeneic transplant recipients with treatment-refractory acute GVHD 
 
To assess the PK and PD of orally administered PLX51107 in treatment-
refractory acute GVHD patients 
 
Secondary objective: To evaluate the preliminary efficacy of PLX51107 and corticosteroids in 
treatment-refractory acute GVHD patients 
 
Eligibility 
Patients with a diagnosis of treatment-refractory acute GVHD are eligible. Patients must be 
refractory to first-line steroid therapy and failed one or more salvage therapy regimens. Patients 
with a contraindication to the use of steroids are not deemed steroid-refractory and are 
ineligible. Patients who meet eligibility criteria, sign informed consent, and dose with PLX51107 
are enrolled. 
 
Subject Registration Procedures 


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For subsite patients, sites must send the signed consent form, documentation of the consent 
process, and the Screening Form (refer to Supplemental Forms Document) within 2 business 
days of initial consent. 
 
Patients will be registered after meeting all entry requirements and signing of the informed 
consent document. 
 
OSU patients will be registered by the OSU research coordinator, as per CTO standard practice. 
Subsite patients will have eligibility verified and will be entered on study centrally at The Ohio 
State University by the Multi-Center Trial Program (MCTP). All subsites must email the MCTP to 
verify slot availabilities prior to consenting patients. Once a patient signs consent, the signed 
consent document and documentation of the consenting process must be faxed or securely 
emailed to the MCTP. The required forms, including Eligibility Criteria Checklist and Registration 
Form, can be found in the Supplemental Forms Document. 
 
To register a subsite patient, the following documents must be completed by the subsite research 
team and faxed or securely e-mailed to the MCTP: 
• 
Copy of all baseline tests required per the protocol calendar. Tests must be within the 
specified window. 
• 
Signed Patient Consent Form, if not previously sent 
• 
Signed Patient HIPAA Authorization Form (if separate), if not previously sent 
• 
Consent Documentation Note, if not previously sent 
• 
Completed & Signed Eligibility Checklist (refer to Supplemental Forms Document) 
• 
Registration Form (refer to Supplemental Forms Document) 
• 
Source documents verifying every inclusion & exclusion criteria 
 
Upon receipt of registration documents, the MCTP will send an email confirming receipt. If 
confirmation of receipt is not received within 24 hours of submission, please contact the MCTP 
by phone and/or pager to confirm receipt. 
 
Upon receipt of all required registration documents and upon verification the subsite patient meets 
all eligibility criteria, the MCTP will: 
• 
Assign the patient a study sequence ID, if not already provided at time of consent 
• 
Register the patient on the study 
• 
Fax and/or e-mail the subsite the completed Registration Form with the assigned study 
sequence ID and registration date as confirmation of patient registration 
 


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IRB Protocol Number: 
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Following registration, patients should begin protocol treatment within 5 business days.  Issues 
that would cause treatment delays should be discussed with the Principal Investigator and MCTP 
as soon as possible. If a patient does not receive protocol therapy following registration, the PI 
and MCTP must be notified immediately within 1 business day. 
 
Each participating institution will order study agents directly.  Agents may be ordered by a 
participating site only after the required regulatory documents, including the initial IRB approval 
for the site, have been forwarded to the MCTP and all other study-specific requirements have 
been met (as outlined during site activation). 
 
 
Inclusion criteria 
1. Age ≥ 18 years 
2. Treatment-refractory acute GVHD as defined as patients who failed steroids (as defined 
as (a) progressed after 3 days of treatment with methylprednisolone (MP) 2 mg/kg/day 
equivalent, (b) did not improve after 7 days of treatment with MP 2 mg/kg/day equivalent, 
(c) progressed to a new organ after treatment with MP 1 mg/kg/day equivalent for skin 
and upper gastrointestinal (GI) GVHD, or (d) recurred during or after a steroid taper2) 
plus one or more salvage regimens with no limit to the number of prior lines of salvage 
therapies 
3. Recipients of ablative and reduced-intensity conditioning regimens 
4. Recipients of HLA-matched related and unrelated, 1-allele mismatched, haploidentical, 
or umbilical cord blood donor grafts 
5. Prior lines of therapy for treatment of steroid-refractory acute GVHD are allowed. There 
is no minimum or maximum to the number of prior therapies. However, exposure to 
investigational therapies for the treatment of GVHD must be > 14 days or 5 half-lives 
(whichever is longer) of first administration of study drug. Prior cell therapy trial exposure 
must be >14 days where no known half-life applies. 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. 
6. ECOG performance status 0-3 
7. Absolute neutrophil count ≥1.0 x 109/L for 3 consecutive days). Use of growth factor 
support is allowed. 
8. Platelet count ≥50 x 109/L without transfusion support for 2 consecutive days. 
9. 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. 
10. 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 
1. Prior exposure to a bromodomain inhibitor 
2.  
3. Evidence of active relapse of disease 


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4. 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 
5. Active, uncontrolled bacterial, fungal, or viral infection 
6. Known or suspected allergy to the study drug 
7. Clinically significant cardiac disease, defined as: 
A. 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. 
B. Fridericia-corrected QT interval (QTcF) ≥ 470 ms (male and female) at Screening. 
C. 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 PI prior to enrollment. 
D. 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. 
8. Inability to take oral medication or significant small bowel resection that, in the opinion of 
the Investigator, would preclude adequate absorption. 
9. Active thrombotic microangiopathy (TMA) 
10. Women who are either pregnant or breast feeding 
11. Measured or calculated (Cockcroft-Gault formula) creatinine clearance (CrCl) <60 
mL/min 
12. Prothrombin time or international normalized ratio >1.5 × ULN 
13. Activated partial thromboplastin time >1.5 × ULN 
14. Requiring mechanical ventilation or vasopressor support 
15. Subject is participating in any other therapeutic clinical study (observational or registry 
studies are allowed). 
16. Contraindication to steroids 
 
Steroids may be concurrently weaned per institutional practice.  
 
Statistical Considerations 
Study Design 
This is a Phase 1, open-label, single-center, dose-finding study to evaluate the safety, 
tolerability, and biologically effective and tolerable dose (BETD) of PLX51107 in combination 
with corticosteroids in treatment-refractory acute GVHD patients. The dose cohorts are as 
outlined in Table 1. We will determine the dose of PLX51107 that both shows biological activity 
(BA) and is tolerable when used in combination with corticosteroids. BA is assessed by 
pharmacokinetics (PK) for target exposure of AUC0-24 8300 ng•hr/mL at Day 1 based on 
preclinical in vivo pharmacological efficacy studies (PLX51107 IB). 
 
All diseases, transplant and donor types are included. PLX51107 will be administered orally 
daily as tolerated. All patients will concurrently receive prednisone 1mg/kg orally daily (may be 
divided into 2 doses) or MP IV equivalent. Corticosteroids may be tapered per institutional 


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17 
 
guidelines, but taper may not be initiated sooner than 7 days after Study Day 1 and to no less 
than prednisone 0.25mg/kg daily before Study Day 28. We will further assess biological activity 
as compared across clinical responses at different dose levels to determine the recommended 
Phase 2 dose (RP2D) for additional evaluation.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 5. Study schematic 
 


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The observation period for DLT and BA will be the first cycle of 28 days. A dose level will be 
deemed the BETD if 5 or more out of 6 patients demonstrate a BA with 0-1 DLTs. This dose will 
be declared biologically effective and tolerable. The starting dose level is at Dose Level 1 (40 
mg/day). Refer to Table 1 for Dose Levels. 
 
This study design combines a standard rule-based Phase 1 3+3 trial design that simultaneously 
evaluates tolerability (DLTs) and evidence of biological activity at each dose level. Three 
patients are entered at each dose level and expanded to six patients if sufficient tolerability and 
BA is observed. See Figure 1 for a study schematic. If 2 or more patients at a given dose level 


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Version date:  04/14/2023 
 
19 
 
experiences DLT, accrual at that dose level will stop, and the dose level will be de-escalated. If 
at the lowest dose level, accrual will be suspended and the study terminated.  
 
After BETD is determined, we will review the tolerability, biological activity, and clinical 
responses observed to justify a RP2D. 
 
Table 1. Dose levels 
 
 
 
 
 
 
Statistical analysis plan: 
To assess the safety and tolerability, adverse events by grade will be summarized. The 
occurrence of Grade 3+ adverse events according to CTCAE 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. Complete response 
(CR) at Day 28 among all patients treated and among all patients treated at BETD will be 
estimated. The proportion of CR with a 95% CI will be reported, assuming a binomial 
distribution. 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. To determine 6-month non-relapse mortality (NRM), the event will be 
death due to reasons other than disease and the time will be measured from the date of starting 
PLX51107 to date of death with the competing risk as death due to disease (relapse). 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.  
 
Study endpoints  
The primary endpoints include: 
• 
To determine the  biologically effective and tolerable dose (BETD) 
• 
Safety endpoints (adverse events) 
• 
PK analysis 
 
The secondary endpoints include:  
• 
Preliminary efficacy (CR at Day 28) among all patients treated and among all patients 
treated at BETD 
• 
Overall response rate (ORR at Day 28) among all patients treated and among all 
patients treated at BETD 
• 
NRM at 6 months 
 
GVHD Response Definitions 
Cohort 
Dose level 
(mg/day) 
0 
20 
1 (initial) 
40 
2 
80 
3 
120 


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Acute GVHD response will be in comparison to the acute GVHD staging upon Screening. The 
Mount Sinai Acute GVHD International Consortium (MAGIC) criteria14 will be used to assess 
staging and grading. Response will be defined as below (as previously used in BMT-CTN 1802 
clinical trial: https://web.emmes.com/study/bmt2/protocol/1802_protocol/1802_protocol.html) 
 
Complete Response (CR) is defined as complete resolution of all signs and symptoms of acute 
GVHD equivalent to staging 0 in all organs. 
 
Partial Response (PR) is defined as improvement in one or more organs involved at 
diagnosis/screening and without progression or new acute GVHD symptoms in any organ.  
 
Mixed Response (MR) is defined as improvement in one or more organs involved at 
diagnosis/screening but with progression or new symptoms in any organ.  
 
No Response (NR) is defined as no improvement and/or progression of acute GVHD symptoms 
in any organ. 
 
Number of Subjects 
The minimum number of patients accrued to the Phase 1 portion is 6 patients (3 patients with 
>=2 DLTs at Dose Levels 1 and 0) with maximum of 18 patients (6 patients each at Dose Levels 
1-3 .  
 
Duration 
We anticipate a screen failure rate of approximately 40% and enrolling a maximum 18 patients. 
The expected time to screen 45 patients at our center would span approximately 2 years. 
Patients will require at least 6 months of follow-up (6 months after initiation of study drug or 30 
days after discontinuation of study drug). Total duration of this trial is expected to take 
approximately 2.5 years.  
 
 
 


Protocol v.7 
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IRB Protocol Number: 
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         IRB Approval date:  07/17/2023 
 
Version date:  04/14/2023 
 
21 
 
Study Calendar 
 
  
Cycle 1 
Cycle 2 
†Cycle 
3+ 
SAE/DLT  
*6-mo 
F/U 
 EOT 
Screening 
Day 
1 
Day 
8 
Day 
15 
Day 
22 ±3 
Day 
1 
Day 
8 ±3 
Day 
15 ±3 
Day 
22 ±3 
Day 1 
±3 
±3 days 
±7 days 
±7 
days 
Informed Consent/Eligibility 
Review 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Concomitant Medication 
Review 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam with Vital 
Signs 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PLX51107 
  
Daily 
  
  
  
Adverse Event Evaluations 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Blood Count 
(CBC) 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive Metabolic 
Panel (CMP) 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT/aPTT/INR 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Pregnancy Test 
X 
  
  
  
  
  
  
  
  
  
  
  
  
GVHD Staging 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Relapse, Survival 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Peripheral Blood for PK 
  
X 
X 
X 
  
  
  
  
  
  
  
  
  
Peripheral Blood for PD 
  
X 
X 
  
  
  
  
  
  
  
X 
  
  
‡Peripheral Blood for MAP 
X 
X 
X 
X 
X 
  
  
  
  
  
  
  
Peripheral Blood for 
Immune Reconstitution 
  
X 
X 
X 
X 
X 
  
  
  
X 
X 
X 
X 
 


Protocol v.7 
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IRB Protocol Number: 
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Version date:  04/14/2023 
 
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†Applies to C3D1, C4D1, C5D1, and C6D1 
*6 month follow-up may overlap with EOT. In this case, these will be deemed EOT days. 
‡MAP refers to MAGIC Algorithm Probability 
Please note: CnD28=C(n+1)D1 
 


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Dose limiting toxicity (DLT) 
DLTs are defined as AEs or laboratory abnormalities occurring during the first cycle (28 days) of 
study drug administration that are at least possibly related to PLX51107, deemed to be clearly 
unrelated to disease progression, concurrent illness or concomitant medication and that meet 
one of the following NCI CTCAE v5.0 criteria below.  
 
• 
Hematological toxicities 
• 
Grade >3 neutropenia lasting >7 days  
• 
Grade ≥3 febrile neutropenia 
• 
Grade 4 thrombocytopenia lasting >14 days despite study drug discontinuation 
• 
Non-hematological toxicities 
• 
New onset non-hematological clinical and laboratory toxicity grade ≥3 lasting >72 
hours with the exception of the following events: 
 
Grade ≥3 nausea, vomiting or diarrhea that resolves to grade ≤2 within 72 
hours, with maximal medical intervention  
 
Grade 3 fatigue, asthenia, anorexia, fever or constipation that resolves to 
grade ≤2 within 14 days  
 
Grade ≥3 asymptomatic changes in alkaline phosphatase, 
hypomagnesemia, hyperglycemia or hypophosphatemia 
 
Grade 3 increases in transaminases confirmed upon repeat testing lasting 
≤ 5 days 
 
Any Grade ≥3 electrolyte abnormality that is corrected to Grade ≤2 within 
24 hours 
 
Non-hematologic laboratory Grade 3 AE that is asymptomatic and/or 
rapidly reversible (returned to baseline or to Grade ≤ 1 within 7 days) 
unless identified as clinically relevant by the Investigator; and (in non-
diabetic patients) singular or non-fasting elevations in blood glucose 
• 
Any case of Hy's law defined as AST or ALT >3 x ULN with concurrent total 
bilirubin >2 x ULN, absence of cholestasis (elevated ALP >2 x ULN), and no 
alternative etiology,  which can explain the combination of increased AST or ALT 
and total bilirubin, such as viral hepatitis A through E, other preexisting or acute 
liver disease, liver acute GVHD, or another drug capable of causing the observed 
injury 
• 
Any dose reduction required during Cycle 1 due to grade ≥3 adverse events 
• 
Any treatment delay of >7 consecutive days during Cycle 1 due to study drug-
related Grade ≥3 adverse events that fails to resolve to baseline or grade ≤1 
• 
Any Grade ≥3 gastrointestinal, genitourinary or central nervous system 
hemorrhage 
• 
Any grade 4 or 5 nonhematological adverse reaction 
• 
Any death unless unequivocally due to underlying disease (or extraneous cause) 
 
Any adverse reaction unrelated to active GVHD that leads to the study drug PLX51107 dose 
reduction or withdrawal should be considered a DLT. 
 
Grade 3 or higher adverse events occurring past 28-days must be recorded and reviewed for 
final analysis and for Phase 2 dose evaluation. 
 
 


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24 
 
Hold Parameters 
  
  
Occurrence Resume 
Dose 
Neutropenia 
Grade 4 (ANC 
<500/mm3) 
1st 
Upon improvement 
to Grade ≤2 (ANC 
>1000/mm3). GCSF 
support may be 
used. 
If improved within 
7 days, continue 
same dose. If no 
improvement 
within 7 days, 
permanently 
discontinue drug. 
  
  
2nd 
Upon improvement 
to Grade ≤2. GCSF 
support may be 
used. 
If improved within 
7 days, dose 
reduce by one 
level. If no 
improvement 
within 7 days, 
permanently 
discontinue drug. 
  
  
3rd 
Permanently 
discontinue study 
drug. 
  
Thrombocytopenia 
Grade 4 
(platelet count 
<25,000/mm3) 
1st 
Upon improvement 
to Grade ≤2 (platelet 
count >50,000/mm3) 
within 14 days  
If improved within 
14 days, 
continue same 
dose. If no 
improvement 
within 7 days, 
permanently 
discontinue drug. 
  
  
2nd 
Upon improvement 
to Grade ≤2 (platelet 
count >50,000/mm3) 
within 14 days  
If improved within 
14 days, dose 
reduce by one 
level. If no 
improvement 
within 7 days, 
permanently 
discontinue drug. 
  
  
3rd 
Permanently 
discontinue study 
drug. 
  
Other non-
hematologic 
Grade 3 
adverse events 
1st 
Hold until improved 
to Grade ≤1 
If improved within 
5 days, continue 
same dose. If >5 
days, dose 
reduce by one 
level. 
  
  
2nd 
Hold until improved 
to Grade ≤1.  
If improved within 
5 days, dose 
reduce by one 


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25 
 
level. If >5 days, 
permanently 
discontinue. 
Other non-
hematologic 
Grade 4 
adverse events 
1st 
Permanently 
discontinue study 
drug 
 
Treatment Plan 
 
Investigational product 
PLX51107 will be supplied by Plexxikon in 20 mg tablet formulations. Each participating site 
must have sufficient supply for one cycle (28 days) available prior to enrollment of each patient. 
Additional months’ supplies will be ordered by the site accordingly. 
 
All patients will receive prednisone 1-2 mg/kg orally daily (may be divided into 2 doses) or 
MP IV equivalent. Corticosteroids may be tapered per institutional guidelines but initiated no 
sooner than 7 days after Study Day 1 and to no less than prednisone 0.25mg/kg dailiy before 
Study Day 28. The minimum dose of prednisone at Study Day 1 is 1mg/kg (or MP IV 
equivalent).  
 
Treatment Dosage and Administration 
The first day of administration is deemed Study Day 1. The dosage administered is determined 
by dose level in Table 1 and in observance of DLT or SAE considerations. 
 
Treatment will be administered orally daily. The first day of administration is Study Day 1. 
PLX51107 should be taken at approximately the same time of day. On Study Days 1, 8, and 15 
when PK/PD sample collections are drawn, patients should fast 8 hours prior and 1 hour after  
daily dose administration. On other days when, there are no scheduled PK/PD sample 
collections, patients should fast 2 hours prior and 1 hour after  daily dose administration. 
 
Dosing Delays or Missed Doses 
Doses delayed by more than 2 hours should be skipped. Doses obscured by vomiting should 
not be re-administered. If more than 7 doses of the first 28 are missed due to noncompliance, 
the patient will be considered inevaluable and study subject replaced. Patients with missed 
doses removed from evaluation will continue to be monitored for safety. 
 
Duration of Therapy 
Dosing is continued until  
• 
6 months from initiation of study drug. If dose is greater than 20 mg at 6 months, drug 
should be tapered over maximum one additional month for a maximum of 7 months. 
• 
CR is reached with daily prednisone equivalent ≤ 10mg/day. If CR is reached within 
<6 months, study drug is then tapered by 20 mg over one month. 
• 
toxicity 
• 
relapse of underlying malignancy 
• 
progression of GVHD 
• 
lack of response as defined by No Response in any organ system by Study Day 28 
• 
voluntary withdrawal from study 
 
Duration of Follow-Up 


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26 
 
All patients will be followed for up to 6 months from initiation of study drug or 30 days from drug 
discontinuation (end of treatment, aka EOT) whichever is longer except in the cases of voluntary 
withdrawal from study or death. 
 
For subjects who withdraw consent, there must be clear documentation of whether the subject 
withdraws consents to treatment only (i.e. agrees to follow-up) or withdraws consent to 
treatment and follow-up. 
 
Follow-up 
Follow-up appointments will entail review of concomitant medications, physical exam with vital 
signs, assessment of ECOG performance status, adverse event evaluation, GVHD staging, and 
assessment for relapse/survival. Labs will also be collected for complete blood count (CBC), 
comprehensive metabolic panel (CMP), coagulation labs (PT, aPTT, INR). Peripheral blood for 
PK, PD, ELISA, and immune reconstitution will be collected as above in the Study Calendar and 
in the Correlative Studies section (below). Patients will be followed weekly for the first two 
cycles of study drug and monthly thereafter until study drug discontinuation. Additional 
evaluations will occur at time of SAE or DLT, scheduled 6-month follow-up from initiation of 
study drug, and end of treatment (30 days from drug discontinuation). All follow-up will be done 
in-person with the exception of Cycle 2 Days 8, 15, and 22, which may optionally be done via 
secure video, per the physician’s discretion. 
 
Concomitant medications 
Of the 5 major CYP isoforms, 3A4 and 2C8 may be involved in Phase I metabolism of 
PLX51107, with possibly CYP2B6 and CYP2D6 playing a minor role. Until information regarding 
exposure-toxicity and exposure-response relationships are available with PLX51107, 
concomitant CYP3A4 and CYP2C8 inhibitors and/or inducers should be administered with 
caution in the event they alter the systemic exposure to PLX51107 (see Appendix for a list of 
strong CYP3A4/2C8 inhibitors and inducers). In general, strong inhibitors or inducers of 
CYP3A4 and CYP2C8 should be avoided unless absolutely necessary. These include 
anticonvulsants (phenytoin, carbamazepine, phenobarbital), mycin antimicrobials, azole 
antifungals and anti-retrovirals. Strong CYP3A4 and CYP2C8 inducers or inhibitors should be 
discontinued at least 14 days or 5 drug half-lives, whichever is longer, prior to the initiation of 
dosing with PLX51107, unless there is no alternative and the medication is absolutely 
necessary. 
  
Should treatment with a strong CYP3A4 or strong CYP2C8 modulator be necessary, study drug 
should be discontinued during this time, and for at least 14 days or 5 drug half-lives afterwards, 
whichever is longer.  
  
Concomitant medications are recommended as prophylaxis for nausea, vomiting, and 
infections, and are allowed for managing myelosuppression. 
Initiation of QTc prolonging drugs should be performed with caution. QTc should be monitored 
closely with any new initiation or dose adjustment. Electrolytes should be monitored and 
repeated.  
 
The concurrent use of systemic immunosuppressants commonly used for GVHD prophylaxis 
(calcineurin inhibition (tacrolimus, cyclosporine), mycophenolate, mofetil, and sirolimus) may 
enhance the immunosuppressant effects of PLX51107. Because the interactive effects of 
these drugs with PLX51107 are as yet unknown, proceed with caution and monitor drug 


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levels (tacrolimus cyclosporine, sirolimus) at minimum twice weekly and dose adjust as 
necessary to desired concentration 
 
Steroids may be tapered based on starting steroid dose according to the below recommended 
schedule or per institutional guidelines: 
 
 
% of 
Starting 
dose 
Steroid Dose 
Days 
Number 
of days 
% Decrease 
from 
previous 
dose 
100% 
1 mg/kg/day 
Days 1-7 
7 
  
75% 
0.75 
mg/kg/day 
Days 8-14 
7 
25% 
50% 
0.5 mg/kg/day 
Days 15-21 
7 
33% 
25% 
0.25 
mg/kg/day 
Days 22-28 
7 
50% 
10% 
0.2 mg/kg/day 
Day ≥29 
and 
onwards 
  
20% 
 
% of 
Starting 
dose 
Steroid Dose 
Days 
Number 
of days 
% Decrease 
from 
previous 
dose 
100% 
2 mg/kg/day 
Days 1-7 
7 
  
75% 
1.5 mg/kg/day 
Days 8-14 
7 
25% 
50% 
1 mg/kg/day 
Days 15-21 
7 
33% 
25% 
0.5 mg/kg/day 
Days 22-28 
7 
50% 
13% 
0.25 
mg/kg/day 
Days 28-35 
7 
50% 
10% 
0.2 mg/kg/day 
Day ≥36 
and 
onwards 
  
20% 
 
 
 
 
Preparation, Reconstitution, and Dispensation 
PLX51107 is an anticancer drug and, as with other potential toxic compounds, caution should 
be exercised when handling PLX51107. 
 
Study Drug Packaging and Labeling 
PLX51107 tablets are manufactured, packaged, and labeled according to current Good 
Manufacturing Practice (cGMP) at the following address: 


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BioDuro LLC (Formerly known as Formex LLC) 
11011 Torreyana Road, #100 
San Diego, CA 92121 
 
Storage and Handling 
PLX51107 tablets should be stored at room temperature 20°C to 25°C (68°F–77°F); excursions 
permitted between 15°C and 30°C (59°F and 86°F). Subjects will be requested to store the 
study drug at the recommended storage conditions noted on the label. 
 
The study drug provided in accordance with this protocol will be kept in a secure place and will 
only be supplied to subjects participating in this study. The Principal Investigator is accountable 
for all study drug in accordance with this protocol. In addition, the Principal Investigator must 
keep accurate and up-to-date dispensation records. Any study drug accidently or deliberately 
destroyed must be recorded in a timely fashion, including an explanation for the destruction in 
writing. Any discrepancies between the amounts of study drug dispensed and returned must 
also be explained in writing.  
 
All unused and partially used study drug must be sealed and returned to the Sponsor or 
designee, or destroyed on site in accordance with the established procedures for drug 
destruction. Details of destruction, including, but not limited to, the number of boxes destroyed, 
batch number, and the date and method of destruction must be recorded on the study drug 
destruction logs. 
 
Correlative Studies 
Plasma will be collected for PK on Cycle 1 Days 1, 8, and 
15 and assessed pre-dose and at hours 1, 3, 5, and 7 post-
dose on Days 1 and 8 and pre-dose and at 3 hours post-
dose on Day 15. PD for markers of BRD4 target 
engagement will also be collected on Days 1 and 8 (pre-
dose and 3 hours post-dose). Notably, despite the short 
half-life of PLX51107, pre-clinical studies have shown that 
BRD4 target engagement persists despite drug metabolism 
(Figure 4).9 A separate PK and PD for GI GVHD patients will be sub-analyzed given possible 
malabsorption complications of this oral drug. Additional samples for PK and PD (with pre-dose 
and 3 hours post-dose times) may be collected if a subject experiences a DLT, serious adverse 
event (SAE), AE of special interest, dose modification, or at the PI’s request. 
 
Whole blood samples for immune reconstitution analyses by flow cytometry and epigenetic 
markers by mass cytometry will be collected on all patients from start of treatment and then 
weekly thereafter for 4 weeks total and monthly for up to 6 months after initiation and at time of 
an SAE, DLT, and end of treatment. 
 
Serum samples for GVHD biomarkers for Ann Arbor risk stratification (ST2 and REG3α ELISA) 
will be collected at time of study enrollment and weekly for four weeks after treatment 
initiation48. Ann Arbor scores will be correlated with response to therapy and NRM48. 
 
Study procedure and methods 
 


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Screening 
Patients who meet eligibility criteria and consent will begin treatment (Study Day 1) with 
PLX51107 per the designated dose level. Those who are ineligible per criteria are deemed 
screen failures and logged as such.  
 
Follow-up 
Due to the studied disease characteristics, patients are anticipated to be hospitalized initially, 
during which time close assessments may be made as standard of care. However, at a 
minimum, patients must be assessed weekly for GVHD or toxicity throughout study drug 
treatment. 
 
Withdrawal 
A patient may request at anytime and for any reason to be removed from the study, to have his 
or her data no longer be collected, to have his or her data removed from any data collection 
databases, and to stop further sample collection or drug administration. This request can be 
made through any member of the clinical team to the PI or study team or made directly to the 
study team members, including PI, co-Is, and CRCs. Based on the nature of the request, study 
drug administration, sample and data collection may cease, and/or samples and data may be 
destroyed, per the patient’s wishes. 
 
Differentiation Syndrome 
PLX122-01 was a Phase 1b dose-escalation study which assessed the safety, 
pharmacokinetics, pharmacodynamics, and preliminary efficacy of PLX51107 as single agent in 
subjects with advanced solid tumors (Group A) and hematological malignancies (Group B). 
Group B (hematologic malignancies) enrollment was initiated after the MTD for group A had 
been determined and with a starting dose of 120 mg/d, one dose level below the group A MTD. 
The first and only patient enrolled in Group B (120 mg/d) (with relapsed AML) developed 
suspected acute differentiation syndrome (DS) requiring hospitalization after being treated with 
PLX51107 120 mg/day for 22 days during cycle 1. The 73yo patient deteriorated quickly and 
expired after being made DNR/DNI. The Sponsor initially made a decision to halt further 
enrollment until additional safety measures to inform, monitor, and treat potential cases of 
differentiation syndrome were implemented in a protocol amendment. The FDA agreed and 
placed the study on clinical hold pending submission of amended documents. Plexxikon later 
elected not to pursue further enrollment in Group B of PLX122-01, and has terminated the 
study.  In subjects with relapsed or refractory AML or high risk MDS being treated with 
PLX51107, FDA requires implementation of appropriate risk management measures for 
potential complications such as differentiation syndrome and tumor lysis syndrome.  
 
In an acute GVHD patient population with no concern or evidence of active disease or suspicion 
of relapse, there is no known basis for the development of differentiation syndrome. Subjects 
with active disease/relapse are excluded from enrolling (exclusion criterion 3), and all enrolled 
subjects undergo a weekly physical examination with vital sign assessment and laboratory 
monitoring. In the event that an enrolled patient develops relapse of disease, PLX51107 must 
be discontinued immediately and the patient withdrawn from study. 


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Adverse Events and Adverse Event Management 
Safety and tolerability will be monitored and determined by serial physical examinations, vital 
signs, hematology and chemistry laboratory studies, and reported AEs (including deaths and 
other SAEs and treatment-emergent AEs). The Investigator will monitor the laboratory test 
findings. If any laboratory test is abnormal during the course of the study, it will be followed at 
the discretion of the Investigator. Abnormalities of laboratory tests are evaluated by the 
Investigator and assessed as either clinically significant or not clinically significant. Abnormal 
laboratory values deemed by the Investigator to be clinically significant and, thus, constitute or 
are associated with an AE, must be reported on the AE form. Abnormal laboratory values that 
require intervention must be reported on the AE form whether or not deemed clinically 
significant. 
 
Additionally, for this study, events as previously identified as resulting from administration of a 
stem cell transplant and/or related to the underlying disease will be considered as expected. 
The transplant regimen is well known to commonly affect multiple systems such as the 
hematologic, immunologic and gastrointestinal systems. The following are known complications 
of transplant: disseminated intravascular coagulation, febrile neutropenia, hemolysis, thrombotic 
thrombocytopenic purpura, adrenal insufficiency, colitis, constipation, diarrhea, enterocolitis, 
gastrointestinal pain, malabsorption, mucositis, nausea, pancreatitis, vomiting, dyspepsia, fever, 
pain, cholecystitis, allergic reaction, serum sickness, upper respiratory infection, urinary tract 
infection, weight gain/loss, acidosis, alkalosis, anorexia, dehydration, glucose intolerance, iron 
overload, generalized muscle weakness, reversible posterior leukoencephalopathy syndrome, 
bladder spasms, cystitis, hematuria, urinary frequency, urinary urgency, irregular menstruation, 
pruritis, hypertension, purpura, and petechiae.  
 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product, 
which does not necessarily have a causal relationship with the treatment. An AE can be any 
unfavorable and unintended sign (e.g., including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of the study drug, whether or not it is considered to 
be study drug related. This includes any newly occurring event or previous condition that has 
increased in severity or frequency since the administration of study drug. An AE includes, but is 
not limited to, the following: 
• 
Any clinically significant worsening of a preexisting condition except for events clearly 
consistent with progression of disease under study  
• 
An AE occurring from overdose (i.e., a dose higher than that indicated in the protocol) of 
a study drug, whether accidental or intentional 
• 
An AE occurring from abuse (e.g., use for nonclinical reasons) of a study drug 
• 
An AE that has been associated with the discontinuation of the use of a study drug 
 
Any treatment-emergent abnormal laboratory result which is clinically significant, i.e., meeting 1 
or more of the following conditions, should be recorded as an AE: 
• 
Accompanied by clinical symptoms 
• 
Leading to a change in study medication (e.g., dose modification, interruption or 
permanent discontinuation) 
• 
Requiring a change in concomitant therapy (e.g., addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment) 


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AEs will be graded in severity according to CTCAE v5.0 criteria. 
 
The Investigator will review each event and assess its relationship to study events to determine 
whether the event is unrelated or, unlikely, possibly, probably or definitely related to the study 
therapy. In the event that any of these known complications of transplant are thought to be at 
least possibly attributable to vitamin A supplementation, the event will be recorded and 
subsequently reported to the IRB and the PI according to current reporting requirements. All 
serious and medically significant adverse events considered related to PLX51107 by the 
Investigator will be followed until resolved or considered stable.   
  
Medical conditions/diseases present before starting study drug are only considered adverse 
events if they worsen after starting study drug. Abnormal laboratory values or test results 
constitute adverse events only if they induce clinical signs or symptoms, are considered 
clinically significant, or require therapy as determined by the PI.    
 
Serious Adverse Event Definition 
An SAE is any AE occurring at any dose and regardless of causality that: 
• 
Results in death. 
• 
Is life-threatening. Life-threatening means that the subject was at immediate risk of 
death from the reaction as it occurred, i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form. 
• 
Requires in-subject hospitalization longer than 24 hours or prolongation of existing 
hospitalization (see clarification in the paragraph below on planned hospitalizations). An 
emergency room visit without hospitalization is not considered a hospitalization. 
• 
Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
• 
Is a congenital anomaly/birth defect. 
• 
Is an important medical event. An important medical event is an event that may not 
result in death, be life-threatening, or require hospitalization but may be considered an 
SAE when, based on appropriate medical judgment, it may jeopardize the subject and 
may require medical or surgical intervention to prevent 1 of the outcomes listed in the 
definitions for SAEs. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in in-subject hospitalization, or the development of drug 
dependency or drug abuse. 
 
Clarification should be made between the terms “serious” and “severe” because they ARE NOT 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may be 
of relatively minor medical significance (such as a severe headache). This is NOT the same as 
“serious,” which is based on subject/event outcome or action criteria described above and are 
usually associated with events that pose a threat to a subject’s life or functioning. A severe AE 
does not necessarily need to be considered serious. For example, persistent nausea of several 
hours’ duration may be considered severe nausea but not an SAE. On the other hand, a stroke 
resulting in only a minor degree of disability may be considered mild but would be defined as an 
SAE based on the above noted criteria. Seriousness (not severity) serves as a guide for 
defining regulatory reporting obligations. 


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Plexxikon will be notified of all SAEs (initial and follow-up) regardless of causality and 
expectedness within 24 hours of awareness by emailing Plexxikon.Safety@premier-
research.com.  
 
Subsite/External Participating Site SAE Reporting Requirements 
 
NOTE: External participating sites are not permitted to report directly to the OSU IRB or 
FDA.  All external site SAEs are to be reported to the OSU Principal Investigator and Multi-
Center Trial Program (MCTP).  The MCTP will facilitate submission of external site SAEs to 
the OSU IRB and FDA. 
 
All serious adverse events (SAEs) and other adverse events must be recorded on case report 
forms. In addition, all SAEs must be reported to the OSU Principal Investigator and MCTP within 
24 hours of knowledge of the event using the FDA MedWatch 3500A mandatory reporting form. 
External participating sites must also submit the “SAE Submission Form” cover sheet (refer to the 
Supplemental Forms Document). 
 
Copies of de-identified source documentation pertaining to the SAE must be submitted to OSU. 
If a patient is permanently withdrawn from the study because of a SAE, this information must be 
included in the initial or follow-up SAE report form. 
 
All SAEs must be submitted to the local IRB per local IRB and institutional policy. 
 
Upon request of additional data or information that is deemed necessary must be reported to OSU 
as soon as possible but no later than 5 calendar days. 
 
 
Sample Handling/Processing/Shipping Protocols 
Biologic samples will be collected in the James Cancer Center inpatient or outpatient units and 
facilitated by the Clinical Trials Processing Lab (CTPL). 
 
Central laboratory kits will be provided for sample collection, shipment and storage for PK 
analyses.  Samples will be shipped to a central laboratory for forwarding to an analysis 
laboratory, which has been contracted by the Sponsor to process these samples. Refer to the 
associated laboratory manual for further information regarding sample handling for PK samples. 
 
Samples for PD, including BRD4 target engagement and RNA-sequencing, will be collected in 
EDTA purple top tubes (1 x 4 ml), gently mixed, and stored at RT. Samples for mass cytometry 
and immunophenotyping will be collected in ACD yellow top tubes (2 x 8 ml), gently mixed, and 


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stored at RT.  All PD, mass cytometry, immunophenotyping, and biomarker samples will be 
transferred same -day to the Choe laboratory in the Biomedical Research Tower at The Ohio 
State University. Samples for immunophenotyping may then be transferred to the laboratory of 
Gerard Lozanski (Dept of Pathology) for analysis by the flow cytometry immune reconstitution 
panel. 
 
Data and Safety Monitoring Plan 
The data and safety monitoring plan will involve the continuous evaluation of safety, data quality 
and data timeliness. Monitoring and auditing procedures will be followed to ensure that the 
study is conducted, documented, and reported in accordance with the IRB approved protocol, 
all applicable federal regulations and guidelines, and applicable regulatory requirements of The 
Ohio State University Wexner Medical Center. Serious adverse events and responses will also 
be reviewed by the OSUCCC Data and Safety Monitoring Committee (DSMC). The PI will also 
submit a progress report (quarterly for Phase I) that will be reviewed by the committee per the 
DSMC plan. All reportable Serious Adverse Events (SAE) will be reported to the IRB of record 
as per the policies of the IRB. Verification of eligibility will be performed and appropriate 
documentation of informed consent will be documented for all subjects enrolled into the study.  
The timeliness of Adverse Event and Serious Adverse Event reporting will be monitored to 
ensure regulatory compliance.  
 
The PI of the trial will review toxicities and responses of the trial where applicable and determine 
if the risk/benefit ratio of the trial changes. The PI will conduct continuous review of data and 
patient safety at a regular protocol review meeting at least monthly. Frequency and severity of 
adverse events will be reviewed by the PI and compared to what is known about the 
agent/device from other sources; including published literature, scientific meetings and 
discussions with sponsors or collaborators, to determine if the trial should be terminated before 
completion.  
 
Mandatory safety and trial review teleconferences will be scheduled and moderated by the Multi-
Center Trial Program (MCTP). All sites involved in the study are expected to have a representative 
present for every call to review and discuss patients on study and other applicable agenda items. 
Meeting minutes will be used to document each teleconference. The minutes will be stored in the 
MCTP protocol files. Teleconferences must minimally be held monthly and may be held more 
frequently, as needed. For studies closed to accrual with patients expected to remain on long-
term treatment and/or follow-up, teleconferences may be extended to occur every two months or 
quarterly. Decreasing frequency of teleconferences requires OSU PI and MCTP approval. 
 
Data Submission 
 
The study will be managed per the Multi-Center Trial Program (MCTP) policies. Subsite data must 
be submitted to the MCTP as outlined in the protocol-specific monitoring plan. The protocol-
specific monitoring plan will be provided by the MCTP to external participating sites prior to site 
activation. Data will be submitted using case report forms and the Data Submission Form cover 
sheet (refer to Supplemental Forms Document) supplied by the MCTP. Access to the OSU 
OnCore database may be provided to external participating sites for direct electronic data entry. 


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All data submitted must be accompanied by supporting source documents, where applicable and 
as outlined in the protocol-specific monitoring plan.  
 
 
Informed consent 
Study team members will consult with the patient to explain the procedures, risks, and benefits 
of the study at the patient’s level of understanding. Opportunity will be given to consider the 
study and have questions answered. Information will be given in a written format in the form a 
description of the study, which will include a signature space for consent to be given. Prior to the 
initiation of the study, acknowledgement of the receipt of this information and the subject’s freely 
tendered offer to participate will be obtained in writing from each subject in the study. 
Participation is voluntary, and all subjects will give informed consent to participate. Information 
will also be given verbally, and all patients will have an opportunity to ask questions. 
 
Non-English speaking patients are not excluded from this study. When possible, a short form or 
fully translated consent form will be provided. 
 
Patient confidentiality  
Data collected is treated in strictest confidence. No information provided from individual patient’s 
records may be discussed with anyone other than those individuals designated study staff or 
clinical care providers. In order to protect patient confidentiality, patients are identified by patient 
ID and case ID numbers, which are generated for each patient and stored separately. Clinical 
information is accessed, according to HIPAA requirements, by study personnel to complete 
study documents. All records generated are stored in a locked office area, only accessible by 
the PI and specified designees only.  Study records are maintained in a secure database with 
access restricted to only PI and specified designees. Personalized data will only be viewed by 
the PI and specified designees and the IRB if needed. The key matching codes to patient 
identification numbers is kept on password-protected computers in limited-access network 
folders by the PI and study research staff or in locked office cabinets if paper. All results from 
the analysis will be stored on password protected computers in laboratories and offices which 
are locked when not occupied. Identifying information will not be used in any publication of 
results. 
 
Institutional Review Board 
This study will be submitted to the OSU Cancer IRB. 
 
Auditing 
 
As the study sponsor, The Ohio State University Comprehensive Cancer Center (OSUCCC) will 
audit each site as per OSU policies. Audits will be performed by the OSUCCC Clinical Research 
Audit Team. For sites with an auditing mechanism in place that are able to share documentation 
of their auditing standards and processes followed, an agreement may be requested for the site 
to perform local auditing and provide formal audit reports to the OSUCCC Multi-Center Trial 
Program (MCTP) and the Quality Assurance Oversight Committee. 
 


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Potential risks for study participants  
There is a potential risk of breach of confidentiality, patient identity, and privacy during the 
study. Study personnel will employ standard measures to protect patient privacy and the 
confidentiality of all patient information. Study subjects will be assigned a unique identification 
number not related to PHI, and the code will be securely maintained by the PI or designee. All 
data collected will be stored on a secure, password-protected computer, and any paper copies 
or reports will be stored in a secure location. No research findings will be reported to individual 
patients or treating physicians. No identifiable data will be reported. Clinical study lab results 
may be shared with subjects. 
 
Potential benefits of study participation 
By study participation, patients are eligible to receive a novel therapy. PLX51107 may offer a 
therapeutic option for treatment-refractory acute GVHD, thereby improving non-relapse 
mortality. 
 
Costs and payments 
There are no direct costs to patients for participation in the study. Subjects or their insurance 
companies will be charged for hospitalizations including tests and treatments of any side effects. 
In the event that subjects’ insurance does not cover these costs, subjects may incur additional 
costs because of treatment side effects. 
 
 
 


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References 
1. Martin, P. J. et al. First- and second-line systemic treatment of acute graft-versus-host 
disease: recommendations of the American Society of Blood and Marrow Transplantation. 
Biol. Blood Marrow Transplant. J. Am. Soc. Blood Marrow Transplant. 18, 1150–1163 (2012). 
2. Przepiorka, D. et al. FDA Approval Summary: Ruxolitinib for Treatment of Steroid-Refractory 
Acute Graft-Versus-Host Disease. The Oncologist 25, e328–e334 (2020). 
3. Gooley, T. A. et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N. 
Engl. J. Med. 363, 2091–2101 (2010). 
4. Bhatia, S. et al. Late mortality after allogeneic hematopoietic cell transplantation and 
functional status of long-term survivors: report from the Bone Marrow Transplant Survivor 
Study. Blood 110, 3784–3792 (2007). 
5. Zeiser, R. & Blazar, B. R. Acute Graft-versus-Host Disease - Biologic Process, Prevention, 
and Therapy. N. Engl. J. Med. 377, 2167–2179 (2017). 
6. Saliba, R. M. et al. Prognostic value of response after upfront therapy for acute GVHD. Bone 
Marrow Transplant. 47, 125–131 (2012). 
7. Arai, S., Margolis, J., Zahurak, M., Anders, V. & Vogelsang, G. B. Poor outcome in steroid-
refractory graft-versus-host disease with antithymocyte globulin treatment. Biol. Blood 
Marrow Transplant. J. Am. Soc. Blood Marrow Transplant. 8, 155–160 (2002). 
8. Westin, J. R. et al. Steroid-Refractory Acute GVHD: Predictors and Outcomes. Adv. Hematol. 
2011, 1–8 (2011). 
9. Ozer, H. G. et al. BRD4 profiling identifies critical Chronic Lymphocytic Leukemia oncogenic 
circuits and reveals sensitivity to PLX51107, a novel structurally distinct BET inhibitor. Cancer 
Discov. CD-17-0902 (2018) doi:10.1158/2159-8290.CD-17-0902. 
10. 
Nicodeme, E. et al. Suppression of inflammation by a synthetic histone mimic. Nature 
468, 1119–1123 (2010). 


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11. 
Mele, D. A. et al. BET bromodomain inhibition suppresses T H 17-mediated pathology. J. 
Exp. Med. 210, 2181–2190 (2013). 
12. 
Sun, Y. et al. BET bromodomain inhibition suppresses graft-versus-host disease after 
allogeneic bone marrow transplantation in mice. Blood 125, 2724–2728 (2015). 
13. 
O’Shaughnessy, M. J. et al. Ex vivo inhibition of NF-kappaB signaling in alloreactive T-
cells prevents graft-versus-host disease. Am. J. Transplant. Off. J. Am. Soc. Transplant. Am. 
Soc. Transpl. Surg. 9, 452–462 (2009). 
14. 
Harris, A. C. et al. International, Multicenter Standardization of Acute Graft-versus-Host 
Disease Clinical Data Collection: A Report from the Mount Sinai Acute GVHD International 
Consortium. Biol. Blood Marrow Transplant. J. Am. Soc. Blood Marrow Transplant. 22, 4–10 
(2016). 
 
 
 


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APPENDIX 1: CYP3A4/CYP2C8 INHIBITORS AND/OR INDUCERS 
Strong CYP3A4 and/or CYP2C8 inhibitors and/or inducers and CYP2D6 substrates with a 
narrow therapeutic index 
CYP3A4 and/or CYP2C8 Strong Inhibitors 
CYP3A4 and/or CYP2C8 Strong Inducers 
• 
Protease inhibitors 
 
- Ritonavir 
 
- Indinavir 
 
- Nelfinavir 
 
• 
Macrolide antibiotics 
 
- Erythromycin 
 
- Telithromycin 
 
- Clarithromycin 
 
• 
Azole antifungals 
 
- Voriconazole 
 
- Ketoconazole 
 
- Itraconazole 
 
• 
Chloramphenicol (antibiotic) 
• 
Nefazodone (antidepressant) 
• 
Bergamottin (constituent of grapefruit juice) 
• 
Aprepitant (antiemetic) 
• 
Verapamil (calcium channel blocker) 
• 
Gemfibrozil (hypolipidemic) 
• 
Thiazolidinedione (antidiabetic) 
• 
Montelukast (Leukotriene receptor 
antagonist) 
• 
Quercetin (anti-inflammatory) 
• 
Anticonvulsants, mood stabilizers 
 
- Phenytoin 
 
- Carbamazepine 
 
- Oxcarbazepine 
 
• 
Non-nucleoside reverse transcriptase 
inhibitors 
 
- Efavirenz 
 
- Nevirapine 
 
- Etravirine 
 
• 
Phenobarbital (barbiturate) 
• 
Rifampicin (bactericidal) 
• 
Modafinil (stimulant) 
• 
Hyperforin (constituent of St John’s Wort) 
• 
Cyproterone (antiandrogen, progestin) 
 
CYP2D6 Substrates 
• 
Amiodarone 
• 
Dosulepin 
• 
Flecainide 
• 
Sotalol 
• 
Pimozide 
• 
Procainamide 
• 
Theophylline 
 
This list is not comprehensive and subject to change and all medications should be reviewed 
prior to administering. 

ICF_000.pdf: 
CONSENT & 
AUTHORIZATION 
OSU-20273 
Version  6 
 
 
 
IRB Protocol Number: 
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The Ohio State University Combined Consent to Participate in 
Research and HIPAA Research Authorization 
 
Study Title:                    A Single Arm, Open Label, Phase 1 Study of Novel BET 
inhibitor PLX51107 and Corticosteroids for Treatment-
Refractory Acute GVHD 
 
Principal Investigator: Hannah Choe, MD 
 
Sponsor:                         National Institute of Health 
Drug provided by:        Plexxikon Inc., 91 Bolivar Drive, Berkeley, CA 94710, 
USA 
 
 
 This is a consent form for research participation.  It contains important information 
about this study and what to expect if you decide to participate.  Please consider the 
information carefully. Feel free to discuss the study with your friends and family and 
to ask questions before making your decision whether or not to participate. 
 Your participation is voluntary.  You may refuse to participate in this study.  If you 
decide to take part in the study, you may leave the study at any time.  No matter what 
decision you make, there will be no penalty to you and you will not lose any of your 
usual benefits.  Your decision will not affect your future relationship with The Ohio 
State University.  If you are a student or employee at Ohio State, your decision will 
not affect your grades or employment status. 
 You may or may not benefit as a result of participating in this study.  Also, as 
explained below, your participation may result in unintended or harmful effects for 
you that may be minor or may be serious depending on the nature of the research. 
 You will be provided with any new information that develops during the study 
that may affect your decision whether or not to continue to participate.  If you 
decide to participate, you will be asked to sign this form and will receive a copy of the 
form.  You are being asked to consider participating in this study for the reasons 
explained below.   
 
Key Information About This Study 
The following is a short summary to help you decide whether or not to be a part of this study. 
More detailed information is listed later in this form.  
 
You are being asked to take part in a clinical trial, a type of research study. Your study doctor 
will explain the clinical trial to you. This consent form also gives you information about the 
study. You should read all of this information carefully and discuss your questions and 


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IRB Approval date: 
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concerns with your study doctor or healthcare team. You may also discuss your decision with 
your family and friends, and anyone you choose.  
 
The Sponsor of this study is The National Institute of Health (NIH). The study drug is 
provided by Plexxikon Inc. 
 
Purpose: Researchers at The Ohio State University have found that a new oral investigation 
drug, PLX51107, has anti-inflammatory effects that may be useful for the treatment of Graft 
Versus Host Disease GVHD. The purpose of this study is to determine the safety, best dose, 
and effectiveness of an investigation treatment with PLX51107 for GVHD that does not 
respond to steroids and/or other drugs used for GVHD treatment. 
 
Procedures: Before the treatment, you will have testing to see if you are a suitable candidate 
for this study. If you are found to be a suitable candidate, you will start treatment with 
PLX51107 around three weeks after screening. PLX51107 comes in the form of tablets and 
will be taken by mouth daily as tolerated for a maximum of 6 months. The treatment is 
organized in cycles, and each treatment cycle will last 4 weeks. The dose of PLX51107 you 
receive will be determined by when you enroll in the study and may be different from the 
dose other study participants receive.  
 
Risks: Most of the risks you may experience are from the medication you will receive. More 
details can be found in the following consent.  
 
Benefits: Information from this study may help doctors learn more about medications used to 
prevent GVHD for future transplant patients.  
 
 
Duration: You will be in the study for 1 year.  You will be treated for the first 6 months, and 
your study doctors will continue to watch you for side effects and follow your condition for 
an additional 6 months.  
 
The procedures and treatment plan are outlined in greater detail below. Your participation in 
this study is completely voluntary.  
 
1.   Why is this study being done? 
 
Acute graft versus host disease (GVHD) is the most common serious complication after 
receiving a bone marrow transplant. GVHD is an immune response and occurs when the 
donor cells (the graft) treat the recipient’s body as “foreign” and attack the cells in the 
recipient’s body. During this immune system response the donor cells damage body tissues, 
such as the skin, liver, stomach, and/or intestines. GVHD can be severe and potentially fatal 
to the transplant recipient. 
 


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Currently, the only proven effective treatment for patients with acute GVHD are steroids. 
Patients who do not respond to steroid treatment are at high risk for death. If patients do not 
respond to steroid treatment, then there is no standard next line treatment. There is one FDA 
approved drug, ruxolitinib, but it is not standard treatment. Other drugs may be used off-label 
to try and treat the GVHD. 
 
The goal of this research is to develop safer and more effective treatments for GVHD with the 
ultimate goal being safer and more effective transplant therapies for blood cancers such as 
leukemia, lymphoma, and multiple myeloma. 
 
This research study is a Phase 1b clinical trial. Phase 1b clinical trials test the safety of an 
investigation drug. Phase 1 studies also try to define the appropriate dose of the 
investigational drug to use for further studies. “Investigational” means that the drug is still 
being studied and that research doctors are trying to find out more about it. It also means that 
the FDA (U.S. Food and Drug Administration) has not approved PLX51107 as an effective 
therapy for use in patients, including people with your type of cancer or GVHD. 
 
PLX51107 works by targeting and slowing down certain activities within cells that promote 
inflammation. By inhibiting these activities, PLX51107 may help to stabilize or reduce the 
inflammation or growth of inflammatory cells. PLX51107 has anti-inflammatory effects in 
laboratory studies, but it is not yet known whether it will work in humans. 
 
We are looking for the highest dose of PLX51107 that can be given safely to patients with 
your type of disease, GVHD. We will also look at how your body absorbs and breaks down 
PLX51107 and how effective PLX51107 is in treating your disease. 
 
PLX51107 is not FDA-approved nor has it been used for treatment of GVHD, and is 
considered an experimental drug for treating patients wth GVHD. This treatment has also not 
been studied in pediatric patients (patients under the age of 18) for any disease. 
 
You may qualify to take part in this research study because you have developed acute GVHD 
and your doctor feels that treatment for the GVHD is necessary. If you have GVHD that is not 
responding to steroids, you may be eligible to take part in this research study. 
 
Plexxikon is providing the experimental drug and financial support to the study center and 
study doctor to conduct the study. 
 
2.   How many people will take part in this study? 
 
Design of the study: 
Approximately 24-34 patients will participate in this study. There will be several dose levels 
of PLX51107 that will be explored to determine the best dose. At the beginning of the study, 
one patient will be treated with a low dose of PLX51107. If this dose does not cause 


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significant side effects, the drug will be given at a higher dose for the next subject who takes 
part in the study. Dose increases will continue until the highest dose offered is reached or until 
a patient develops a serious side effect. The dose levels are then adjusted based on how 
patients tolerate the drug. Your study doctor will tell you which dose of PLX51107 you will 
be receiving prior to your enrollment. 
 
3.   What will happen if I take part in this study? 
 
Study procedures: 
Before the research starts (Screening) 
After signing this consent form, you will be asked to undergo some screening tests or 
procedures to find out if you can be in the research study. Many of these tests and procedures 
are likely to be part of your regular care and may be done even if it turns out that you do not 
take part in the research study. If you have had some of these tests or procedures recently, 
they may not have to be repeated. This screening period will happen within the 3 weeks 
before your first dose of PLX51107. 
• 
Recording of demographics, including date of birth, race, and ethnicity. 
• 
A medical history, including questions about your past and current health and any 
allergies. 
• 
Performance status evaluation (ECOG Performance Status), we will ask you questions 
about what type of daily activities you are able to do. 
• 
Complete physical exam, including height and weight. 
• 
Review of past and current medications and treatments. 
• 
Vital signs, blood pressure, pulse, body temperature, and respiratory rate. 
• 
Electrocardiogram (ECG), which is a painless test to check your heart’s rhythm. 
• 
Approximately 3 tablespoons of blood will be drawn for: 
o Routine blood tests for hematology, chemistry, coagulation (blood clotting 
ability). These tests measure how well your organs are functioning. 
o Additional cancer-specific blood collections including the pharmacogenomics 
blood sample. These may help to determine specific biological characteristics 
of your cancer, such as mutations from genes in tumor cells and develop 
information about how each person responds or reacts to the study drug. 
• 
Pregnancy test, if you are a woman and capable of becoming pregnant. 
 
Confirmation that you are eligible to participate in the research study: 
If these tests show that you are eligible to participate in the research study, you will begin the 
study treatment. If you do not meet the eligibility criteria, you will not be able to participate in 
this research study. 
 
Study drug (PLX51107): PLX51107 comes in the form of tablets and will be taken by 
mouth. PLX51107 tablets should be swallowed whole and not crushed, chewed, or dissolved 
in water. The dose of PLX51107 you receive will be determined by when you enroll in the 
study and may be different from the dose other study participants receive. 


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IRB Approval date: 
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Each treatment cycle will last 28 days (i.e., 4 weeks). 
 
You will be given a Study Drug Diary to track the dates and times that you take the study 
drug and whether you were fasting or not. It is important you complete the Drug Diary 
accurately and that you bring your study drug and diary to every visit. You should take the 
study drug at approximately the same time each day. 
 
Visit schedule of tests and procedures: 
You will come into the clinic on Cycle 1 Days 1, 8, 15, 22, and then on Day 1 of all 
subsequent cycles. Your visits will typically last a few hours, though on Cycle 1 Days 1 and 
8, study procedures will span an 8 hour period, and on Cycle 1 Day 15, study procedures will 
span a 4 hour period.   
 
At most visits when drug levels in your blood are to be measured (“pharmacokinetic” or “PK” 
collection days), you should come to the clinic without eating or drinking anything (except for 
low calorie drinks like water or unsweetened coffee/tea) for at least the previous 8 hours. You 
will take your dose of study drug in the clinic. Do not take your dose of study drug at home 
that morning. It is important that you bring your study drug and diary to every visit. 
 
On other days you take PLX 51107 at home you should not eat or drink anything except water 
2 hours before and 1 hour after you take the study drug. However, if you feel weak or 
nauseous, you can have a low fat snack (i.e., dry toast, crackers). 
 
If you agree to take part in this study, your doctor will perform a number of tests and 
examinations before, during and after the study. Some of these examinations, tests and 
procedures may be the same as those that are carried out as part of your regular medical care. 
You will also be asked to complete a number of questionnaires. Depending on the study visit, 
you may have the following tests and procedures:  
• 
Performance status evaluation (ECOG Performance Status), we will ask you questions 
about what type of daily activities you are able to do.  
• 
Physical exam, including weight.  
• 
A review of current medications and any side effects you may be experiencing.  
• 
Vital signs, blood pressure, pulse, body temperature, and respiratory rate.  
• 
Electrocardiogram (ECG), which is a painless test to check your heart’s rhythm.  
• 
Depending on the study visit, approximately 1-9 tablespoons of blood will be drawn 
for:  
o Routine blood tests, for hematology, chemistry, coagulation (blood clotting 
ability). These tests measure how well your organs are functioning.  
o Blood collections for pharmacokinetics (PK), to measure how much study drug 
(PLX51107) is in your blood.  
o Blood collections for biomarker assessments, to measure effects of PLX51107 
in your cells.  


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o Blood collection for inflammation markers, to track if the study drug is 
affecting your body’s response to inflammation.  
o Additional disease-specific blood collections, these may help to determine 
specific characteristics of your cancer, such as mutations from genes in 
inflammatory cells and develop information about how each person responds 
or reacts to the study drug. 
• 
Drug Diary, you will be sent home with your study drug diary to accurately track the 
dates and times that you take the study drug each day. It is important that you bring 
your study drug and completed diary to every visit 
• 
You may be asked for additional PK blood samples to be taken after your last dose of 
study drug or if there is a safety concern.  
• 
After your last day of treatment, the study center may continue to keep in touch with 
you (this may occur in the form a telephone call or a routinely scheduled office visit) 
to follow the status of your disease and to collect information on your GVHD 
treatments after discontinuation of treatment on this study. 
 
Follow Up 
You will be followed for up to 6 months from initiation of study drug or 30 days from drug 
discontinuation (end of treatment) whichever is longer. 
 
Your follow up appointments will involve: 
• 
A review of current medications and any side affects you may be experiencing.  
• 
Physical exam, including vital signs. 
• 
Performance status evaluation (ECOG Performance Status), we will ask you questions 
about what type of daily activities you are able to do.  
• 
Depending on the study visit, approximately 1-9 tablespoons of blood will be drawn 
for:  
o Routine blood tests, for hematology, chemistry, coagulation (blood clotting 
ability). These tests measure how well your organs are functioning.  
o Blood collections for biomarker assessments, to measure effects of PLX51107 
in your cells.  
o Blood collection for inflammation markers, to track if the study drug is 
affecting your body’s response to inflammation.  
o Additional disease-specific blood collections, these may help to determine 
specific characteristics of your cancer, such as mutations from genes in 
inflammatory cells and develop information about how each person responds 
or reacts to the study drug. 
 
You will have weekly visits for the first two cycles of study drug and monthly thereafter until 
study drug discontinuation. You will have additional evaluations at 6-months from the start of 
the study drug, and end of treatment (30 days after the last dose of the study drug). You might 
have additional evaluations if study doctor determines that they are needed, All visits will be 


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done in-person with the exception of Cycle 2 Days 8, 15, and 22, which may optionally be 
done via secure video, per the doctor’s determination.  
 
4.   How long will I be in the study? 
 
Duration of the study 
You may continue receiving study drug until one of the following happens: 
 Your study doctor determines that you should stop receiving the study drug due to 
side effects 
 Your blood disorder (e.g., leukemia, lymphoma) relapses 
 Your GVHD worsens or has no response by 28 days 
 Your GVHD response and completely resolves and you require less than ≤ 
10mg/day or prednisone. The study drug is then tapered by 20 mg over one month. 
 You decide to stop receiving study drug 
 You decide to stop being part of the study. 
 The study Sponsor (Plexxikon Inc.) or the IRB decides to end the study 
 You reach a maximum of 6 months from initiation of study drug. If the dose is 
greater than 20 mg, the study drug should be tapered over maximum one additional 
month. 
 
You will be in the study for 6 months. After you have stopped taking PLX51107, your study 
doctors will continue to watch you for side effects and follow your condition. 
 
5. Can I stop being in the study? 
 
You may leave the study at any time.  If you decide to stop participating in the study, 
there will be no penalty to you, and you will not lose any benefits to which you are 
otherwise entitled.  Your decision will not affect your future relationship with The Ohio 
State University.  
 
You can decide to stop at any time. If you decide to stop for any reason, it is important to 
let the study doctor know as soon as possible so you can stop safely. If you stop, you can 
decide whether or not to let the study doctor continue to provide your medical information 
to the organization running the study.  
 
If you decide to stop being part of the study altogether, no additional tests will be done as 
part of this study. Any data or blood samples obtained prior to your decision to stop 
participation in the study will still be analyzed by the Sponsor. The study staff may still 
use publicly available information to find out how you are doing.  
 
The study doctor will tell you about new information or changes in the study that may 
affect your health or your willingness to continue in the study.  


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The study doctor may take you out of the study:  
• 
If your health changes and the study is no longer in your best interest  
• 
If new information becomes available • If you do not follow the study rules  
• 
If the study is stopped by the sponsor or Institutional Review Board (IRB), a group of 
people who review the research with the goal of protecting the people who take part in 
the study  
• 
If the study is stopped by the Food and Drug Administration (FDA) you may ask your 
study doctor about alternative methods of treatment at any time. The total length of 
time that you will be on study depends on how you respond to the study drug you 
receive. If your disease worsens or if you stop study drug dosing because your disease 
has worsened or you stop dosing due to side effects, you will be asked to return to the 
study center for an end of treatment visit. 
 
6.   What risks, side effects or discomforts can I expect from being in the study? 
 
Risks:  
You may have side effects while on the study. Everyone taking part in the study will be 
watched carefully for any side effect, however, doctors don't know all the side effects that 
may happen. Side effects may be mild or very serious. Your health care team may give you 
medicines to help lessen side effects. Many side effects go away soon after you stop taking 
the study drug. In some cases, side effects can be serious, long lasting, or may never go away.  
 
There is a great deal of variability among side effects of different drugs and between 
individuals. For PLX51107, not all of the risks are known at this time. Since the effect of the 
study drug taken with other medications is not known, it is important that you tell the study 
doctor about all prescription and non-prescription drugs, herbal preparations and nutritional 
supplements that you are taking or planning to take.  
 
During the research study, you will be notified of newly discovered side effects or significant 
findings, which may affect your health or willingness to participate in this study. You may be 
asked to sign a new informed consent form that shows that you have been informed of new 
information relating to this research study. You should talk to your study doctor about any 
side effects which you experience while taking part in the study.  
 
One of the most serious side effects could be Differentiation Syndrome. Differentiation 
syndrome is a condition that affects your blood cells which may be life-threatening or lead to 
death if not treated. In an acute GVHD patient population with no concern or evidence of 
active disease or suspicion of relapse, there is no known basis for the development of 
Differentiation Syndrome. Subjects with active disease/relapse are excluded from enrolling 
(exclusion criterion 3), and all enrolled subjects undergo a weekly physical examination with 
vital sign assessment and laboratory monitoring. In the event that an enrolled patient develops 


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relapse of disease, PLX51107 must be discontinued immediately and the patient withdrawn 
from study. 
 
Risks associated with PLX51107 
PLX51107 is a new investigational drug and has been tested in a small number of patients 
with cancer. 
 
Side effects identified to date with patients who took PLX51107 are as follows: 
 
Common side effects (experienced by greater than or equal to 10% of patients) associated 
with the use of PLX51107 include the following: 
• 
Nausea 
• 
Fatigue 
• 
Vomiting 
• 
Diarrhea 
• 
Increase in blood tests that monitor for and indicate liver damage 
• 
Decreased appetite 
• 
Low red blood cells 
• 
Low platelets 
• 
Increase in blood tests that monitor risk of bleeding 
• 
Dizziness 
• 
Muscle aches 
• 
Cough 
• 
Shortness of breath 
• 
Constipation 
• 
Blood in urine 
• 
High blood sugar 
• 
Decrease in blood tests that measure the protein (albumin) in your body 
• 
Low levels of electrolytes in the blood 
 
Less common side effects (experienced by 5% to less than 10% of patients) associated with 
the use of PLX51107 include the following: 
• 
Headache 
• 
Chills 
• 
Blood creatinine increased 
• 
Low white blood cells 
• 
Protein in urine 
• 
Itching 
• 
Fever 
• 
Rash 
• 
Urinary tract infection 
• 
Decreased weight 
• 
Dry mouth 


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• 
Muscle spasm 
• 
Irritation of the mucus membranes (the lining inside areas of your body such as your 
mouth, nose, and digestive tract). 
 
Rare but serious: 
One patient with leukemia developed Differentiation Syndrome. Because patients with active 
underlying diseases (like leukemia, lymphoma) will not be eligible for the study, we do not 
anticipate that this will be a risk. Patients with any evidence of relapse of disease will be 
removed from study. 
 
Side effects identified in preclinical animal studies: 
• 
Gastrointestinal erosion and/or mucosal inflammation (erosion and/or inflammation 
affecting moist tissue lining parts of the inside of your body, such as mouth, nose, 
lungs, and digestive tract) 
• 
Toxicity affecting the bone marrow (responsible for producing red blood cells, white 
blood cells, and platelets) and lymphatic tissues (responsible for white blood cells) 
which may decrease the number of some or all of these cells and may make you feel 
weak or fatigued, may increase risk of infection, and/or may increase risk of bleeding. 
• 
Alteration in function of the tests which could result in reduced fertility 
• 
Increase in blood tests that monitor risk of bleeding 
  
Risks Associated with Study Procedures in This Study: 
• 
Electrocardiograms [ECGs]: To perform the test, electrodes, i.e., stickers with wires 
attached, will be placed on your skin to record your heart’s activity. No pain or other 
side effects are expected to be associated with these tests, but you may feel some 
discomfort, similar to pulling off an adhesive bandage, when the technician removes 
the electrodes after the procedure. 
• 
Blood Samples: Side effects of having your blood taken may include pain, redness, 
swelling, and/or bruising where the needle enters the body. Rare instances of fainting, 
excess bleeding, blood clotting, or infection have occurred. 
 
Unknown/Unexpected risks and discomforts 
In addition to the risks listed above, there may be some unknown or infrequent and 
unforeseeable risks associated with the use of PLX51107, including severe or life-threatening 
allergic reactions, interactions between study medications or interactions with another 
medication. You will be informed in a timely manner, both verbally and in writing of any new 
information, findings, or changes to the way the research will be done that might influence 
your willingness to continue your participation in this study.  
 
Pregnancy risks 
There also may be other side effects or discomforts that we cannot predict, especially to a 
fetus or embryo. Because the drugs in this study may affect an unborn baby, you should not 
become pregnant or father a baby while on this study.  


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For women of child-bearing potential, a pregnancy test will be performed during the 
screening period and must be negative before starting the study medication. Women of child-
bearing potential must agree to use an acceptable method of birth control from the time of the 
negative pregnancy test 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-childbearing potential may be included if 
they are either surgically sterile or have been postmenopausal for 1 year or longer. Fertile men 
must also agree to use an acceptable method of birth control while on study drug and for 6 
months after the last dose of study drug. You should discuss your birth control with the study 
doctor. Let your doctor know immediately if you think you have become pregnant or if you 
think you have fathered a child during the research study or within 6 months after your last 
dose of study drug.  
 
7.   What benefits can I expect from being in the study? 
 
Possible benefits of the study 
Taking part in this research study may or may not make your health better. We hope the 
information learned from this research study will help doctors learn more about PLX51107 as 
a treatment for GVHD in the future. 
 
8.   What other choices do I have if I do not take part in the study? 
 
You may choose not to participate without penalty or loss of benefits to which you are 
otherwise entitled. 
 
Treatment options: 
You are being asked to take part in this study because you have a type of inflammatory 
condition called acute Graft-versus-Host Disease (GVHD) that has not responded to 
treatment. You may ask your study doctor about alternative drugs or treatments available for 
your specific condition. There are benefits and risks to taking other drugs, which you should 
discuss with your study doctor. You will be made aware of any new findings that become 
available during the course of the study that may affect your willingness to take part. 
 
If you decide not to take part in this study, you have other choices. For example: 
• 
Alternative treatments 
o FDA approved: ruxolitinib 
o Off-label: including but not limited to alpha-1 antitrypsin, anti-thymocyte 
globulin, alemtuzumab, tocilizumab, infliximab, extracorporeal photopheresis 
• 
Choosing to not receive treatment 
• 
Participate in another research study 


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• 
Comfort care, also called palliative care. This type of care may help to reduce pain, 
tiredness, appetite problems and other problems caused by GVHD. It does not treat the 
GVHD directly but instead tries to treat the symptoms. 
 
Please talk to the research doctor about your options before you decide whether you will take 
part in this research study. 
 
9. What are the costs of taking part in this study? 
 
There are 2 types of procedures that will be done during this study. Some are part of your 
routine medical care and others are only for research.  
 
You or your insurer will be billed for the routine medical care, because you would receive it 
even if you were not participating in this study. You will be responsible for your copayments, 
deductibles, and any other charges that your insurer will not pay. There is a possibility that 
your insurer may not cover all routine medical care costs. Before participating in this study, 
we recommend that you ask your insurer if there are any limitations to your particular plan.  
 
Any procedures done only for research will not be charged to you or your insurer. This 
includes serial EKGs and research testing on your tissue and blood by a central lab. Your 
study doctor or coordinator can tell you, specifically, which costs are covered by the study.  
 
PLX51107 will be supplied at no charge while you take part in this study.  
It is possible that PLX51107 may not continue to be supplied while you are on the study. 
Although not likely, if this occurs, your study doctor will talk to you about your options.  
 
10. Will I be paid for taking part in this study? 
 
You will not receive any payment for participating in this study.  
By agreeing to participate in this study, you agree to waive any claim that you might have to 
the blood/body tissues that you are providing to the study and the study’s Sponsor, who will 
retain ownership of some of your samples for the sole purpose of research and performing the 
study. You will receive no payment for these samples or from any products, tests, or products 
that are developed in the future from the use of the samples. 
 
11. What happens if I am injured because I took part in this study? 
 
If you suffer an injury from participating in this study, you should notify the researcher or 
study doctor immediately, who will determine if you should obtain medical treatment at The 
Ohio State University Wexner Medical Center.   
 


CONSENT & 
AUTHORIZATION 
OSU-20273 
Version  6 
 
 
 
IRB Protocol Number: 
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IRB Approval date: 
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           Version: 
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The cost for this treatment will be billed to you or your medical or hospital insurance. The 
Ohio State University has no funds set aside for the payment of health care expenses for this 
study.  
 
12. What are my rights if I take part in this study? 
 
If you choose to participate in the study, you may discontinue participation at any time 
without penalty or loss of benefits.  By signing this form, you do not give up any personal 
legal rights you may have as a participant in this study. 
 
You will be provided with any new information that develops during the course of the 
research that may affect your decision whether or not to continue participation in the study. 
 
You may refuse to participate in this study without penalty or loss of benefits to which you 
are otherwise entitled.  
 
An Institutional Review Board responsible for human subjects research at The Ohio State 
University reviewed this research project and found it to be acceptable, according to 
applicable state and federal regulations and University policies designed to protect the rights 
and welfare of research participants. 
 
13. Will my de-identified information and bio-specimens be used or shared for 
future research?   
 
Yes, it/they may be used or shared with other researchers without your additional informed 
consent.  
 
14. Will my study-related information be kept confidential? 
 
Efforts will be made to keep your study-related information confidential.  However, there may 
be circumstances where this information must be released.  For example, personal information 
regarding your participation in this study may be disclosed if required by state law.   
 
Also, your records may be reviewed by the following groups (as applicable to the research): 
 
Office for Human Research Protections or other federal, state, or international 
regulatory agencies; 
 
U.S. Food and Drug Administration; 
 
The Ohio State University Institutional Review Board or Office of Responsible 
Research Practices; 
 
The sponsor supporting the study, their agents or study monitors; and 
 
Your insurance company (if charges are billed to insurance). 
 


CONSENT & 
AUTHORIZATION 
OSU-20273 
Version  6 
 
 
 
IRB Protocol Number: 
2020C0226 
IRB Approval date: 
07/27/2021 
           Version: 
07/20/2021 
 
 
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If we find information that significantly impacts your health, we will share it with you. 
However, we do not anticipate finding information that will significantly impact your health 
beyond the routine examinations and laboratory tests anticipated as part of your routine care. 
The research results we are obtaining do not significantly impact your health directly. Any 
pertinent information would be communicated directly to your study doctor who would 
contact you via phone or in-person visit for notification and further discussion.  
 
The NIH has issued a Certificate of Confidentiality for this study. This Certificate provides 
extra protection for you and your study information, documents, or samples (blood, tissue, 
etc.). The Certificates are issued so that we cannot be required to disclose any identifiable, 
sensitive information collected about you as a part of this study in a lawsuit or legal 
proceeding. We are also prevented from releasing your study information without your 
consent. This is a layer of protection over and above the already existing protections in place 
for you and your information, documents, or samples. 
However, these protections do not apply in some situations. For example, we may have to 
release your information if a law requires us to do so, the Agency that is funding this study 
requests the information, or if the FDA tells us to release this information. We may also use 
your information to conduct other scientific research as allowed by federal regulations. 
Study information that has health implications may be placed in your medical record where 
authorized employees may see the information. Further, authorized requests for your records 
(medical record release for continuity of care) may result in research-related information 
being released. 
Please talk to your study team, or contact the Office of Responsible Research Practices at 
614-688-8641, if you have questions. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. law.  This website will not include information that can identify you.  At 
most, the website will include a summary of the results.  You can search the website at any 
time.  
 
15. HIPAA AUTHORIZATION TO USE AND DISCLOSE INFORMATION FOR 
      RESEARCH PURPOSES  
 
I. What information may be used and given to others? 
 
 Past and present medical records; 
 Research records; 
 Records about phone calls made as part of this research; 
 Records about your study visits; 


CONSENT & 
AUTHORIZATION 
OSU-20273 
Version  6 
 
 
 
IRB Protocol Number: 
2020C0226 
IRB Approval date: 
07/27/2021 
           Version: 
07/20/2021 
 
 
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 Information that includes personal identifiers, such as your name, or a number 
associated with you as an individual; 
 Information gathered for this research about: 
HIV / AIDS 
Hepatitis infection 
Sexually transmitted diseases 
Other reportable infectious diseases 
Physical exams 
Laboratory, x-ray, and other test results 
Diaries and questionnaires 
The diagnosis and treatment of a mental health condition 
 Records about any study drug you received; 
 
II. Who may use and give out information about you? 
 
Researchers and study staff.   
 
III. Who might get this information? 
 
 The sponsor of this research.  “Sponsor” means any persons or companies that are: 
 working for or with the sponsor; or  
 owned by the sponsor. 
 Authorized Ohio State University staff not involved in the study may be aware that 
you are participating in a research study and have access to your information; 
 If this study is related to your medical care, your study-related information may be 
placed in your permanent hospital, clinic, or physician’s office record; 
 Others: Scientific Advisory Board members (Steven Devine, MD, Margaret 
MacMillan, MD, Corey Cutler, MD), Collaborators (OSU Department of 
Pathology), OSU Data Safety Monitoring Board (DSMB).  
 
IV. Your information may be given to: 
  
 The U.S. Food and Drug Administration (FDA), Department of Health and Human 
Services (DHHS) agencies, and other federal and state entities; 
 Governmental agencies in other countries; 
 Governmental agencies to whom certain diseases (reportable diseases) must be 
reported; and  
 The Ohio State University units involved in managing and approving the research 
study including the Office of Research and the Office of Responsible Research 
Practices. 
 
 


CONSENT & 
AUTHORIZATION 
OSU-20273 
Version  6 
 
 
 
IRB Protocol Number: 
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IRB Approval date: 
07/27/2021 
           Version: 
07/20/2021 
 
 
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V. Why will this information be used and/or given to others? 
 
 To do the research;  
 To study the results; and  
 To make sure that the research was done right.   
 
VI. When will my permission end? 
 
There is no date at which your permission ends. Your information will be used 
indefinitely. This is because the information used and created during the study may be 
analyzed for many years, and it is not possible to know when this will be complete. 
 
VII. May I withdraw or revoke (cancel) my permission? 
 
Yes. Your authorization will be good for the time period indicated above unless you 
change your mind and revoke it in writing. You may withdraw or take away your 
permission to use and disclose your health information at any time. You do this by 
sending written notice to the researchers at: 
 
 Hannah Choe,MD 
 460 W 10th Ave 
1st Floor 
Columbus, OH-43210-1240 
 
If you withdraw your permission, you will not be able to stay in this study. When you 
withdraw your permission, no new health information identifying you will be gathered 
after that date. Information that has already been gathered may still be used and given to 
others. 
 
VIII. What if I decide not to give permission to use and give out my health 
information? 
 
Then you will not be able to be in this research study and receive research-related 
treatment.  However, if you are being treated as a patient here, you will still be able to 
receive care. 
 
IX. Is my health information protected after it has been given to others? 
 
There is a risk that your information will be given to others without your permission. Any 
information that is shared may no longer be protected by federal privacy rules. 
 
 


CONSENT & 
AUTHORIZATION 
OSU-20273 
Version  6 
 
 
 
IRB Protocol Number: 
2020C0226 
IRB Approval date: 
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           Version: 
07/20/2021 
 
 
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X. May I review or copy my information? 
 
Signing this authorization also means that you may not be able to see or copy your study-
related information until the study is completed.   
 
16. Who can answer my questions about the study? 
 
For questions, concerns, or complaints about the study, or if you feel you have been 
harmed as a result of study participation, you may contact 
 
Study Doctor Name:  Dr Hannah Choe, MD 
Daytime Telephone Number(s): 614-293-3316 
24-hour Contact Number(s): 614-293-8000 
 
For questions related to your privacy rights under HIPAA or related to this research 
authorization, please contact HIPAA Privacy Manager, The Ohio State University 
Medical Center, Suite E2140, 600 Ackerman Road, Columbus, OH 43202 or at 614- 
293-4477. 
 
For questions about your rights as a participant in this study or to discuss other study-
related concerns or complaints with someone who is not part of the research team, you 
may contact the Office of Responsible Research Practices at 1-800-678-6251. 
 
If you are injured as a result of participating in this study or for questions about a study-
related injury, tell the study doctor or the study staff as soon as possible. 
 


CONSENT & 
AUTHORIZATION 
OSU-20273 
Version  6 
 
 
 
IRB Protocol Number: 
2020C0226 
IRB Approval date: 
07/27/2021 
           Version: 
07/20/2021 
 
 
Page 18 of 18 
Form date: 
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Signing the consent form 
 
I have read (or someone has read to me) this form and I am aware that I am being asked to 
participate in a research study.  I have had the opportunity to ask questions and have had them 
answered to my satisfaction.  I voluntarily agree to participate in this study.  
 
I am not giving up any legal rights by signing this form.  I will be given a copy of this 
combined consent and HIPAA research authorization form. 
 
 
 
 
 
Printed name of participant 
 
Signature of participant 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
 
 
 
 
 
 
 
Printed name of person authorized to consent for 
participant (when applicable) 
 
Signature of person authorized to consent for participant  
(when applicable) 
 
 
 
 
 
AM/PM 
Relationship to the participant 
 
Date and time 
 
 
 
Investigator/Research Staff 
 
I have explained the research to the participant or his/her representative before requesting the 
signature(s) above.  There are no blanks in this document.  A copy of this form has been given 
to the participant or his/her representative. 
 
 
 
 
 
Printed name of person obtaining consent 
 
Signature of person obtaining consent 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
Witness(es) - May be left blank if not required by the IRB 
 
 
 
 
 
Printed name of witness 
 
Signature of witness 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
 
 
 
Printed name of witness 
 
Signature of witness 
 
 
 
 
 
 
AM/PM 
 
 
Date and time