Clinical trial NCT02891603
Conditions: Graft Vs Host Disease GVHD
Sponsor: H. Lee Moffitt Cancer Center and Research Institute
Start date: 2017-06-08; Completion date: 2022-04-18
Enrollment: 40 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to examine a new approach to preventing a serious problem after transplant called graft vs. host disease (abbreviated as GVHD).

This is a 3 arm sequential phase I/II, study of Pacritinib with Sirolimus and Tacrolimus (PAC/SIR/TAC) for the prevention of acute GVHD after matched related and unrelated allogeneic hematopoietic cell transplantation (alloHCT).

Detailed description:
GVHD is a common problem that occurs after transplant despite the use of standard immune suppressive medications (these are called sirolimus and tacrolimus). GVHD can result in skin rash, nausea, vomiting, diarrhea, and liver damage. Severe GVHD can be life-threatening.

In this study, investigators will add a medication called pacritinib to the combination of sirolimus and tacrolimus to see if this approach can more effectively prevent GVHD. Pacritinib is a medicine used to treat a disease of the bone marrow called myelofibrosis Pacritinib turns off a switch in cells called Janus Kinase 2 (JAK2). Pacritinib is an investigational medicine used in several clinical trials and not FDA approved. JAK2 is an important regulator of inflammation. This inflammation is thought to contribute to GVHD. Pacritinib is able to turn this inflammation off by inhibiting JAK2. Research has shown that blocking JAK2 prevents GVHD in mice and also reduces severe GVHD in transplant patients. Doctors at Moffitt have identified that inflammation from JAK2 is an important cause of GVHD, and is present well before patients develop GVHD symptoms. This trial will study how well pacritinib turns off inflammation during the transplant and if it prevents GVHD when added to our standard medicines.

Pacritinib will begin the day of the participant's transplant (Day 0) and will continue until 70 days after the transplant.

Sirolimus will be given the day before transplant and continued daily for at least one year.

Tacrolimus will begin 3 days before transplant and will be given for at least 50 days.

Arms: arm 1: After standard of care allogenic hematopoietic cell transplantation, Pacritinib will be added to standard treatment with Sirolimus and Tacrolimus (PAC/SIR/TAC).

100 mg Pacritinib will begin taken by mouth the day of the participant's transplant (Day 0) and will continue until 70 days after the transplant..

Sirolimus will be given the day before transplant and continued daily for at least one year.

Tacrolimus will begin 3 days before transplant and will be given for at least 50 days. arm 2: After standard of care allogenic hematopoietic cell transplantation, Pacritinib will be added to standard treatment with Sirolimus and Tacrolimus (PAC/SIR/TAC).

100 mg Pacritinib will begin taken by mouth twice daily starting the day of the participant's transplant (Day 0) and continuing until 70 days after the transplant..

Sirolimus will be given the day before transplant and continued daily for at least one year.

Tacrolimus will begin 3 days before transplant and will be given for at least 50 days. arm 3: After standard of care allogenic hematopoietic cell transplantation, Pacritinib will be added to standard treatment with Sirolimus and Tacrolimus (PAC/SIR/TAC).

Patients will take Pacritinib at the MTD: 100 mg Pacritinib will begin taken by mouth twice daily starting the day of the participant's transplant (Day 0) and continuing until 70 days after the transplant..

Sirolimus will be given the day before transplant and continued daily for at least one year.

Tacrolimus will begin 3 days before transplant and will be given for at least 50 days.
Interventions: intervention 1: Pacritinib intervention 2: Sirolimus intervention 3: Tacrolimus intervention 4: Allogenic hematopoietic cell transplant (alloHCT)
Intervention descriptions: intervention 1: Pacritinib Dose and Schedule: 200 mg twice a day (BID) orally from day 0 until day +100. PAC will be tapered to 50% of the total dose at day +70, then 25% of total dose at day +84, then stop at day +100 (+/- 7 days). intervention 2: Sirolimus (SIR) will be administered and dosed according to Moffitt Cancer Center, Department of Blood and Marrow Transplantation standard practice. Attending physician discretion is permitted with regard to timing, rapidity, and completion of SIR taper. SIR levels will be monitored according to program standard operating procedures. Dose modifications of SIR for concurrent use of CYP3A4 inhibitors or inducers will be based on program standard operating procedures. intervention 3: Tacrolimus (TAC) will be administered and dosed according to Moffitt Cancer Center, Department of Blood and Marrow Transplantation standard practice. Attending physician discretion is permitted with regard to timing, rapidity, and completion of TAC taper. TAC levels will be monitored according to program standard operating procedures. Dose modifications of TAC for concurrent use of CYP3A4 inhibitors or inducers will be based on program standard operating procedures. intervention 4: Patients will undergo allogenic hematopoietic cell transplant (alloHCT) as a part of their standard of care treatment.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
A Phase I/II GVHD Prevention Trial Combining Pacritinib with Sirolimus-Based 
Immune Suppression 
 
NCT02891603 
 
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March 2, 2022 


 
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A Phase I/II GVHD Prevention Trial Combining Pacritinib with Sirolimus-Based Immune Suppression 
 
Protocol Number: MCC# 18783 
NCT Identified Number: NCT 02891603 
 
 
Principal Investigator: 
Joseph Pidala, MD, PhD 
IND/IDE Sponsor/IND number 
IND-131666 
Biostatistician: 
Jongphil Kim, PhD 
 
Additional sites 
Role 
Site 
 
Principal Investigator: 
 
 
Shernan Holtan, MD 
University of Minnesota 
 
Hugo Fernandez, MD 
Memorial Healthcare 
System 
 
 
Funded by:  NIH / NHLBI 
Version: 8.0 
 
02 March 2022 
 
 
 


 
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Table of Contents 
 
I. 
Background and Rationale ............................................................................................ 3 
II.  Trial objectives .............................................................................................................. 11 
a. 
Primary objective: ......................................................................................................... 11 
 
b. 
Secondary objectives: ................................................................................................... 11 
III.  Trial endpoints ............................................................................................................... 11 
a. 
Primary endpoint: .......................................................................................................... 11 
b. 
Secondary endpoints: ................................................................................................... 11 
IV.  Patient population ......................................................................................................... 11 
a. 
Inclusion Criteria ........................................................................................................... 11 
b.   Exclusion Criteria: ......................................................................................................... 12 
c. 
Donor eligibility.............................................................................................................. 13 
V.  Study Design ................................................................................................................. 13 
1.   Sample size .................................................................................................................. 13 
2. 
Withdrawal .................................................................................................................... 13 
3.   Intervention: Pacritinib .................................................................................................. 14 
4. 
Standard transplant care and practice .......................................................................... 14 
5.   Safety assessment ........................................................................................................ 16 
6. 
Endpoints 
 
 
 
 
 
 
 
 
 
 
     14 
7.  
Statistical considerations  
 
 
 
 
 
 
 
     16 
VI.  Data collection and safety monitoring ...................................................................... 21 
1. 
Data collection .............................................................................................................. 22 
2.   Safety monitoring .......................................................................................................... 22 
3. 
Safety: Monitoring of adverse events and pacritinib dose modifications for toxicity ...... 24 
4. 
Suspension/Termination ............................................................................................... 31 
5. 
Trial Discontinuation ..................................................................................................... 32 
VII. Ethics ............................................................................................................................... 35 
VIII.Publication policy ......................................................................................................... 35 
IX.  Records Retention ......................................................................................................... 35 
X.  References: .................................................................................................................... 36 
XI.  APPENDICES .................................................................................................................. 39 
Appendix A: Acute GVHD grading system ........................................................................... 39 
1994 Consensus Conference on Acute GVHD Grading. ................................................ 39 
Appendix B: comorbid conditions ......................................................................................... 40 
Appendix C: anticipated transplant related toxicities ............................................................ 41 
Appendix D: Study Calendar ................................................................................................ 42 


 
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I. 
Background and Rationale 
Allogeneic hematopoietic cell transplantation (HCT) is a curative intervention for patients with high risk 
hematologic malignancies and blood disorders. The success and survival of HCT is limited by graft-
versus-host disease (GVHD), which significantly contributes to transplant-related mortality. Janus 
kinase 2 (JAK2) and downstream STAT3 activation are biologically relevant in orchestrating T cell 
alloresponses and pathologic Th17 development1.  We have demonstrated that CD4+ T-cell STAT3 
activity is significantly elevated early after HCT among patients who go on to develop grade II-IV acute 
GVHD2.  We have also shown that alloreactive Th17 cells are significantly increased in target-organs at 
time of GVHD diagnosis2.  Selective JAK2 inhibition prevents allosensitization and induces a durable 
tolerant state, yet preserves immunity toward nominal viral antigens1.  Neutralization of JAK2 reduces 
pathogenic STAT3-directed Th1/Th17 differentiation, and permits STAT5-mediated regulatory T-cell 
development1.  Others have demonstrated that JAK2 blockade improves survival and reduces the 
severity of GVHD in MHC-mismatched murine models3,4.  More recently, JAK1/2 inhibition 
demonstrated clinical benefit in a series of patients with steroid refractory acute GVHD3.   
 
Pacritinib (PAC) is a highly selective JAK2 inhibitor, with significantly less off-target effects on JAK1 or 
JAK35-8.  This is advantageous during tolerance induction, as selective JAK2 inhibition allows for 
common gamma chain cytokine activity required for Treg differentiation1.  While JAK1/JAK2 inhibition 
limits anti-viral immune clearance and may increases susceptibility to opportunistic infections9,10; 
selective JAK2 blockade permits anti-viral activity by human T-cells and is not linked to infectious 
complications1,5,7.  Moreover, robust clinical trial data shows that PAC does not induce 
myelosuppression in patients with myelofibrosis – which distinguishes PAC from other existing JAK2 
inhibitors.  As reported at the 2015 annual ASCO meeting, PAC was administered at a dose of 400mg 
orally daily and showed significant benefit compared with best available therapy. 
 
Sirolimus is a specific inhibitor of the mTOR (mammalian target of rapamycin) pathway, where 
alloreactive T cells are selectively dependent upon this signaling route11. Sirolimus fosters the 
differentiation of regulatory T cells (Treg) by favoring their activation through the IL-2/JAK1/3/STAT5 
pathway12 and inhibiting the phosphorylation of STAT313, which can antagonize the expression of 
FOXP3 (Figure 1). STAT5 is vital to Treg development and function. This T helper cell subset down-
regulates GVHD12.  We have demonstrated that while rapamycin partially inhibits RORgammaT 
expression in allosensitized human T-cells, full elimination of Th17 differentiation is achieved by 
combining mTOR blockade with JAK2/STAT3 inhibition2.  A phase II trial at Moffitt Cancer Center 
(MCC) demonstrated that prophylaxis with sirolimus plus low-dose tacrolimus (SIR/TAC) was superior 
to methotrexate (MTX) and high dose TAC in preventing acute GVHD and promoting Tregs14,15. Despite 
the success of SIR/TAC, nearly 50% of patients still developed grade II-IV acute GVHD. SIR/TAC is an 
ideal platform to combine JAK2 inhibition with PAC, as both strategies favor Treg development and 
reduce Th17.  Selective JAK2 inhibition also promotes immune tolerance1.  Moreover, our data 
supports that combined inhibition of JAK2 and mTOR synergistically suppresses alloreactive human T-
cells.  A phase I/II, single arm, trial of PAC and our standard GVHD prophylaxis regimen of 
SIR/TAC is proposed, as a means to ablate STAT3 signaling, promote immune tolerance, and 
polarize Treg development over Th1 and Th17.   
 
Hypothesis: The selective JAK2 inhibitor, pacritinib, combined with sirolimus plus low-dose tacrolimus, 
will be safe in allogeneic HCT recipients and significantly reduce STAT3 activation and subsequent 
alloreactivity. 
 
Study objectives:  
Phase I: 1) Determine the lowest biologically active dose of pacritinib that is safe and well tolerated 
when combined with SIR/TAC. 


 
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Phase II: 2) Determine if PAC/SIR/TAC suppresses STAT3 activity in circulating CD4+ T-cells at day 
+21, 3) Investigate whether PAC/SIR/TAC reduces the cumulative incidence of grade II-IV acute GVHD 
by day +100, compared our published rate of 43% with SIR/TAC alone14,15, 4) Investigate the impact of 
PAC/SIR/TAC on Treg, Th1, and Th17 differentiation after allogeneic HCT, and 5) Determine how 
PAC/SIR/TAC impacts CD28 and IL-2 receptor signal transduction by measuring S6 (mTOR), H3 ser10 
(Aurora kinase), and STAT5 phosphorylation in CD4+ T-cells at days +21 and +100. 
Background:  
The role of JAK2/STAT3 activation and Th17 cells in acute GVHD 
Naïve CD4+ T cells are plastic and may develop into various functional phenotypes (Th1, Th2, Th17, 
Treg) through specific cytokine-mediated intracellular signaling events.  Th17 cells are implicated in 
murine and human GVHD2,16,17.  IL-6 mediates Th17 development by activating JAK2/STAT3 and 
influencing the expression of RORgammaT18.  Conversely, IL-2 signaling through STAT5 favors Foxp3 
expression and subsequent immune tolerizing Treg development19.  Studies in murine acute GVHD 
have shown that mice transplanted with CD4+ T cells deficient in IL-17 have significantly reduced 
mortality20.  We and others have demonstrated that tissue invading Th17 cells are significantly 
increased at time of acute GVHD diagnosis in humans as well2.  Additionally, we have demonstrated 
that increased tissue-resident Th17 cells correlates with GVHD severity and portends a poor response 
to upfront therapy with glucocorticoids (Figure 1A)2.  Deletion of STAT3 in donor T-cells favors Treg 
development and improves the survival of transplanted mice21.  We have shown that CD4+ T-cell 
STAT3 activation by IL-6 is significantly increased early after allogeneic HCT among asymptomatic 
patients who later develop grade II-IV acute GVHD (Figure 1B,C)2.  This observation uniquely identified 
JAK2 and downstream STAT3 as clinically dynamic, druggable targets in acute GVHD.  The degree of 
IL-6-induced CD4+ T-cell STAT3 phosphorylation was 11% for healthy non-transplant controls, 32% for 
those who did not develop acute GVHD, and 70% for recipients who did develop acute GVHD by day 
+100.  This trial biologically targets JAK2/STAT3 activation by combining pacritinib, a selective JAK2 
inhibitor, with SIR/TAC to reduce the CD4+ T-cell STAT3 phosphorylation to at least 35%.  This target 
coincides with the STAT3 phosphorylation range observed among HCT recipients who did not develop 
acute GVHD in our prior exploratory study.  The association of CD4+ T-cell STAT3 phosphorylation and 
acute GVHD risk is under prospective validation, but currently offers guidance in determining the 
degree of on-target pathway suppression for HCT recipients on this trial.  We will strengthen our current 
investigation by determining if JAK2/STAT3 pathway suppression reduces the cumulative incidence of 
acute GVHD.  The trial will be expanded by 17 patients to study the effect of PAC/SIR/TAC on GVHD 
prevention, if 9 or less of the 24 initial patients develop acute GVHD by day +100. 
Figure 1:  CD4+ T-cell STAT3 activity is increased among alloHCT recipients before acute GVHD onset.  (A) Tissue-resident Th17 cells are increased in 
among patients with glucocorticoid-refractory GVHD. (B,C) Day +21 CD4+ STAT3 activation (%phosphorylation and absolute number) is significantly increased 
in asymptomatic allograft recipients that go on to develop grade II-IV  acute GVHD by day +100 (N=18 patients). *P<.05, **P=.001-.01, ***P=.0001-.001, 
****P<.0001. 
A 
B 
C 


 
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Selective JAK2 inhibition 
induces allotolerance, 
while sparing anti-viral 
responses 
Selective JAK2 inhibition 
with TG101348, a 
nonclinical chemical tool, 
ablates IL-6 mediated 
phosphorylation of STAT3 
in human T-cells (Figure 
2A)1.  TG101348 did not 
prevent IL-2 activation of 
STAT5, which is required 
by Treg and cytotoxic T 
lymphocytes (Figure 2B)1.  
We have demonstrated 
that selective JAK2 
inhibition with TG101348 
significantly reduces the 
proliferative response of 
DC-allostimulated T-cells 
(5-day alloMLR, DC:T-cell 
ratio 1:30, Figure 2C)1.  
This suppressive effect is 
still observed upon re-
challenge with fresh 
allogeneic DCs from the 
original stimulating party, without additional exposure to the JAK2 inhibitor (Figure 2D)1.  TG101348 
also inhibits secondary responses by T cells, which have already been sensitized to alloantigen in a 
primary mixed lymphocyte reaction (MLR) without the JAK2 inhibitor (Figure 2E)1.  Conversely, 
responses to stimulation 
by influenza virus matrix 
peptide (fluMP) remain 
intact (Figure 2F)1.  
Altogether, we identified 
that JAK2 inhibition 
induces durable 
allotolerance without 
compromising antiviral 
activity.   
 
PAC is a highly selective 
JAK2 inhibitor, with no 
suppressive effect on 
JAK1 at therapeutic 
concentrations5-8,22-24.  
This is favorable in the 
transplant setting, as 
Figure 3:  Pacritinib selectively blocks 
JAK2 and delays xenograft rejection.   
(A) Pacritinib 2.5μM reduces IL-6 mediated 
STAT3 activity, and permits IL-2-induced 
STAT5 phosphorylation (representative 
contour plots, 1 of 2 experiments).  (B) 
Pacritinib impairs T-cell proliferation in 5-
day alloMLRs (n=3 experiments triplicate).  
(C) Graph shows human skin graft survival 
among pacritinib or vehicle treated NSG 
hosts after inoculum of human PBMCs 
(allogeneic to the skin) on day 0.  Pacritinib 
was given twice a day from days 0 to +14.  
n=2 experiments, 5-6 mice per arm.  
Representative images show skin at time of 
suture removal (day -30) and at day +35. 
A 
B 
C 
Figure 2:  Selective JAK2 inhibition promotes lasting 
allotolerance and preserves viral immunity.   TG101348 
(1μM) reduces IL-6 induced STAT3 phosphorylation in T-
cells (A), and permits IL-2 mediated STAT5 activity (B).  (C) 
TG101348 (1μM) significantly reduces T-cell proliferation in 
5-day alloMLRs (DC:T-cell ratio shown).  (D) Primary 5-day 
alloMLR (DC:T-cell 1:30) to which TG101348 (1μM) or 
DMSO was added, followed by 3-day restimulation of T-cells 
by DCs from original stimulating party. (E) Unadulterated 
primary 5-day alloMLR, after which T cells were restimulated 
by alloDCs for 3 days with TG101348 (1μM) or DMSO.  (F) 
T-cell responders from the primary alloMLR to which 
TG101348 (1μM) or DMSO was added in (Figure 2D), 
stimulated de novo against autologous DCs loaded with 
FluMP (3 days) free of addition drug.  Experiments 
performed 3 times.  Proliferation measured by colorimetric 
assay.  Dotted line = OD of T-cells alone.  Stimulation 
index=OD alloMLR/OD T-cells alone.  *P<0.05, **P = 
0.001—0.01. 
A 
B 
C 
E 
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agents like ruxolitinib that inhibit JAK1 are associated with reduced in vivo clearance of murine viral 
pathogens9.  We confirmed that PAC selectively reduces IL-6 stimulated STAT3 phosphorylation, while 
permitting IL-2-mediated STAT5 activity in human T-cells (Figure 3A).  We also demonstrate that PAC 
significantly reduces alloreactive T-cell proliferation in MLRs at 2.5-5μM (Figure 3B).  To investigate the 
effect of JAK2 inhibition on human T-cell alloresponses in vivo, a human skin / NSG 
(NOD/SCID/gamma chain deficient) mouse xenograft model was used.  This experimental approach 
was ideal, given that skin is a highly immunogenic target organ of acute GVHD.  A 1x1 cm split-
thickness human skin graft was transplanted onto the animal dorsally, followed by intraperitoneal 
injection of 5x106 allogeneic peripheral blood mononuclear cells (PBMC) 30 days after surgery. 
Irradiation was not required for human PBMC engraftment.  PAC was administered at 100mg/kg twice a 
day by oral gavage for 15 days beginning at time of PBMC injection. The treatment significantly delayed 
allograft rejection by the human donor PBMCs, compared with vehicle control (Figure 3C).  
Representative images from grafted mice show human skin at time of suture removal on day -30, and 
later at day +35, from both PAC- and vehicle-treated mice.  The viable, PAC-treated graft shows mild 
pigmentation changes at day +35, while the vehicle-treated graft is completely necrotic with thick 
hyperkeratosis (Figure 3C).  Collectively, these data clearly identify JAK2 as a therapeutic target 
to control donor alloreactivity after alloHCT. 
JAK2 inhibition 
spares Treg while 
suppressing 
Th1/Th17 
responses.   
We previously 
demonstrated that 
TG1010348 
permits the 
development of 
human allo-antigen 
specific, natural 
Tregs in vitro 
(Figure 4A)1.  
Similarly, PAC 
permits the 
differentiation of 
inducible Treg 
(iTreg) from 
isolated naïve 
CD4+ T-cells 
stimulated with 
allogeneic DCs.  
The PAC-
generated iTreg 
retain suppressive 
function comparable to the iTregs grown in the presence of DMSO (Figure 4B).  This suggests that 
JAK2 is not required for iTreg function.  With regard to Th1 and Th17 development, we observed that 
TG1010348 significantly decreases IFN-gamma and IL-17 respectively among DC-allostimulated CD4+ 
T-cells (Figure 4C)1.  Our preliminary data shows that JAK2 inhibition with PAC significantly suppresses 
expression of RORgammaT, a key Th17 differentiation factor (Figure 4D).  The immune effects 
directed by JAK2 inhibition are favorable following allo-HCT, as tolerizing Tregs securely 
develop while pathogenic Th1 and Th17 cells are greatly impaired. 
 
B 
D 
C 
Figure 4:  JAK2 inhibition spares Treg while 
suppressing Th1/Th17 responses. (A) TG101348 
(1μM) spares Treg populations in 5-day alloMLRs.  
Representative contour plots, 5 experiments.  (B) iTregs 
were generated from DC-allostimulated naïve CD4+ T-
cells (Treg-depleted at outset) with pacritinib (2.5μM) or 
DMSO for 5 days.  iTreg were then cultured with self T-
cell responders and fresh DCs without additional drug at 
varying iTreg:T-cell ratios.  T-cell proliferation was 
determined by 3H-thymidine incorporation.  1 of 2 
experiments shown, each performed in triplicate.  (C) 
TG101348 (1μM) or DMSO added to an alloMLR of DCs 
and CD4+ T cells. Th1 and Th17 cells were identified by 
CD3, CD4, and IFN-gamma or IL-17 expression 
respectively.  Bar graphs show data from 4 independent 
experiments.  (D) Pacritinib (2.5μM) dramatically 
suppresses Th17 differentiation among naïve CD4+ T-
cells stimulated by allogeneic dendritic cells (DC), 
compared with DMSO.  RORgammaT was measured by 
RT-PCR.  1 of 2 experiments shown, each performed in 
triplicate. *P<0.05, ****P <0.0001.


 
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Combined blockade of JAK2 and 
mTOR offers synergistic control 
over alloreactive T-cells 
CD28 costimulation of T-cells 
requires signaling via mTOR and 
Aurora kinase.  mTOR is a known 
therapeutic target in preventing 
acute GVHD (Figure 5A).  As 
described, IL-6 signaling 
contributes to GVHD by polarizing 
Treg recovery over pathologic Th1 
or Th17 (Figure 5A).  Our data 
supports that combined inhibition 
of JAK2 and mTOR is synergistic, 
and significantly reduces the 
proliferative response of 
allostimulated human T-cells (Figure 5B).  This concept will be studied in this innovative clinical trial, 
where PAC will be combined with sirolimus-based immune suppression to suppress these pathways 
concurrently and prevent GVHD after alloHCT. 
 
The Moffitt experience with sirolimus-based acute GVHD prevention 
A randomized phase II clinical trial conducted at MCC included 74 patients randomized 1:1 to a GVHD 
prophylaxis regimen of SIR/TAC or MTX/TAC25. The median patient age was 49 [23-69], with recipients 
receiving related or unrelated 8/8 HLA-matched peripheral blood HSC allografts25. Conditioning 
consisted of our standard, reduced-toxicity regimen of pharmacologically targeted busulfan and 
fludarabine25. The 100-day cumulative incidence of grade 2-4 acute GVHD for SIR/TAC was 43%, and 
89% for MTX/TAC, p<0.000125.  A multicenter, phase III trial of SIR/TAC versus MTX/TAC among HLA-
matched related alloHCT recipients by the BMT CTN did not identify a significant difference in the 
incidence of grade II-IV acute GVHD between the two prophylaxis regimens (26 versus 34%)26.  
However a post hoc analysis showed a potential trend in less cases of severe, grade III-IV acute GVHD 
with SIR/TAC compared to MTX/TAC27.  It is important to note that the Moffitt SIR/TAC regimen targets 
a higher therapeutic range for sirolimus with a goal of 5-14ng/ml25 as opposed to 3-12ng/ml27.  Our 
intensified dosing strategy may in part explain the clinical advantage seen with SIR/TAC versus 
MTX/TAC in our Moffitt GVHD prevention trial.  Additionally, we observed a greater frequency of acute 
GVHD on both arms of our SIR/TAC versus MTX/TAC study compared to the BMT CTN trial25,26.  This 
is likely explained by 1) our inclusion of unrelated allografts and 2) our practice of aggressively using 
endoscopic procedures to evaluate for stage I upper gastrointestinal GVHD in the setting of nausea and 
anorexia25,28.  No significant differences in survival, toxicities, or thrombotic microangiopathy (TMA) 
were observed between SIR/TAC and MTX/TAC in the Moffitt phase II trial25. Our trial also produced a 
favorable biologic impact on Treg expansion using SIR/TAC over MTX/TAC25.  Despite the significant 
decrease in acute GVHD, 43%25 of patients receiving SIR/TAC still developed this immune 
complication – underscoring the need for further optimization of this approach. The goal of 
PAC/SIR/TAC GVHD prophylaxis will be to ablate JAK2 and mTOR signaling early after HCT and 
reduce acute GVHD.   
 
Clinical development of pacritinib, a selective JAK2 inhibitor 
 
PAC was investigated in a phase I study of relapsed or refractory lymphoma7.  A total of 34 patients 
were treated on a dose escalation strategy, from 100 to 600mg daily for 28 days7.  On-target inhibition 
Figure 5:  Pacritinib added to sirolimus synergistically reduces DC-stimulated, 
allogeneic T-cell.  (A) Schema of CD28, IL-6, and IL-2 receptor signal transduction in human 
-cells.  (B) 5-day alloMLRs were treated with pacritinib at various concentrations, a fixed dose 
of sirolimus at 10ng/ml, both, or DMSO control.  The proliferative response by alloreactive T-
cells was significantly reduced by blocking JAK2 and mTOR together.  n=4 experiments in 
triplicate.   
A 
B 


 
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of JAK2 was noted at all dose levels7.  Unlike ruxolitinib, cytopenias were rare and limited to 9% grade 
1-2 and 6% grade 3-47.  The primary toxicity was grade I-2 gastrointestinal symptoms, chiefly diarrhea 
at 32%.  The MTD was not reached in this phase I study7.  A phase II study of PAC in myelofibrosis 
enrolled 35 patients5.  PAC was given at 400mg by mouth daily5.  Grade I-2 diarrhea was the most 
common toxicity at 69%5.  As reported at the 2015 ASCO Annual Meeting, the PERSIST-1 phase III 
trial of PAC versus best available therapy demonstrated that the JAK2 inhibitor was safe and effective 
reducing spleen size among 220 treated patients.  In this large study, PAC was associated with <5% 
grade III diarrhea in keeping with earlier phase trials.  Overall, PAC selectively inhibits JAK2 with 
reduced myelosuppression compared to other similar agents.  These favorable clinical characteristics 
identify PAC as an ideal JAK2 inhibitor to pair with sirolimus and low-dose tacrolimus in the allogeneic 
HCT setting. 
 
Trial Design: This is a single-arm, phase I/II, study of PAC/SIR/TAC for the prevention of acute GVHD 
after matched related and unrelated alloHCT.  First, a standard 3+3 dose escalation method will be 
performed combining PAC with SIR/TAC.  The MTD identified during phase I, as well as serial PK/PD 
data, will inform the recommended phase II dose.  Therefore, the recommended phase II dose will be 
the lowest dose that decreases the amount of pSTAT3+ CD4+ T-cells <35% at day +21 and does not 
exceed the MTD (see Table 1).  The phase II component is powered to determine if JAK2 inhibition with 
PAC significantly reduces CD4+ T-cell STAT3 activation early after allogeneic HCT compared to our 
historical benchmark.  Our published study showed the mean CD4+ T-cell STAT3 phosphorylation at 
day +21 was 50% among all HCT recipients, 70% for those who later developed acute GVHD, versus 
32% for those who did not2.  Therefore, success will be defined as a reduction in CD4+ T-cell STAT3 
phosphorylation to 35% or less at day +21.  This phosphorylation value not only estimates biologic 
activity, but also falls within the standard deviation of what was observed among HCT recipients who 
never acquired acute GVHD2.  The association of CD4+ T-cell STAT3 phosphorylation and acute 
GVHD risk is under prospective validation, but currently offers guidance in determining the degree of 
on-target pathway suppression for HCT recipients on this trial.  As pacritinib is a direct inhibitor of 
JAK2/STAT3 signal transduction, greater reduction in CD4+ T-cell pSTAT3 phosphorylation is possible 
in this patient population.  An initial 24 patients will be treated with PAC/SIR/TAC to investigate whether 
the biologic activity of STAT3 in CD4+ T-cells is reduced at day +21.   
 
Secondarily, we will monitor enrolled patients for acute GVHD by day +100.  To investigate the clinical 
efficacy of the PAC/SIR/TAC combination in GVHD prevention, the trial will be expanded by an 
additional 14 subjects if 9 or less of the first 24 patients develop grade II-IV acute GVHD.  This 
expansion threshold is based on our data from the SIR/TAC trial where the cumulative incidence of 
acute GVHD incidence by day +100 was 43%.  PAC/SIR/TAC will be considered favorable if the 
primary endpoint is met AND ≤12 of the total 38 (31.6%) patients develop acute GVHD by day +100.   
 
Protocol design:  A phase I dose 
escalation will first be performed to identify 
the maximum tolerated dose (MTD) of 
pacritinib when combined with SIR/TAC.  
SIR/TAC will be administered, dosed, and 
monitored per Moffitt BMT standard 
procedures.  Additionally, the 
recommended phase II dose will also be 
informed by pharmacodynamic data 
generated from the phase I trial.  As such, 
the dose escalation may stop once a 
tolerated dose is identified that suppresses 
CD4+ pSTAT3+ T-cells <35% at day +21.  
The pacritinib dose cohorts will include:  
Figure 6:   Protocol design schema. 


 
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(Dose level 1) PAC 100mg po daily, (Dose level 2) PAC 100mg po twice daily, and (Dose level 3) PAC 
200mg po twice daily.  Dose cohort 1 (PAC 100mg daily) represents the lowest dose level that would 
potentially inhibit CD4+ T-cell pSTAT3.  This is based on PK/PD data from the completed phase I trial 
of pacritinib in lymphoma7.  For all patients enrolled in the phase I portion of this study, pharmacokinetic 
sampling of plasma pacritinib levels will be drawn on days 0 and +21 at the following time points:  pre-
dose, +4 hours, +12 hours, and +24 hours  (window of +/- 1 hour on each timed PK sample).  
Pharmacodynamic, CD4+ T-cell pSTAT3 values will be assessed at baseline and day +21 as well.  
EKGs (on days 0 and +21) will be performed pre-dose and at 4 hours (pacritinib Tmax)7 – with +/- 1 
hour window on the 4-hour post-dose EKG.  The initial group of 3 patients will be enrolled in cohort 1. 
Dose escalation of pacritinib will proceed according to the following: If no DLT is observed among 3 
patients in a cohort AND the average %pSTAT3+ CD4+ T-cells are >35% at day +21, the next group of 
3 will be treated at the next highest dose level. If the current level (i.e., the level at which no DLTs are 
observed) is the highest dose level, three additional patients will be enrolled (total of six). If one DLT is 
observed among 3 patients in a cohort, the next group of 3 will be treated at this same dose level. If no 
more DLT is observed among the 3 additional patients (i.e. one DLT in total is observed among the 6 
patients) AND the average %pSTAT3+ CD4+ T-cells are >35% at day +21, then the next 3 patients will 
be treatment at the next highest dose level. If at least 1 more DLT is observed among the 3 additional 
patients, then the MTD is exceeded. If 6 patients have been treated at the next lower dose level, it will 
be considered as the MTD. If not, three additional patients will be enrolled. This escalation approach 
will then be continued until MTD or a tolerated dose (≤1/6 DLT) is identified at which <35% of the CD4+ 
T-cells are pSTAT3+.on day +21 (see Table 1).  That dose will be considered to be the recommended 
phase II dose. The total number treated on the phase I component will depend on the occurrence of 
dose limiting toxicity (DLT) or the average frequency of pSTAT3+ CD4+ T-cells at day +21 in a cohort, 
however the maximal number accrued on the phase I study would approximate 12 to 18 total evaluable 
subjects.  Patients in the phase I component of the trial will be monitored throughout their 100 days of 
pacritinib therapy for DLT events, however the minimum DLT observation period required prior to 
escalation to higher dose levels in the phase I component is 30 days from the last patient’s (within dose 
level) initiation of pacritinib therapy.  In addition to informing the recommended phase II dose, the 
PK/PD data from days 0 and +21 will be used to identify any dose-dependent patterns among serum 
pacritinib concentrations and 1) CD4+ T-cell STAT3 phosphorylation, 2) Treg reconstitution, 3) QTcF 
prolongation, or 4) changes in plasma tacrolimus and sirolimus levels. 
Table 1:  Phase I:  Identification of Recommended Phase II Dose 
Dose Level 
MTD exceeded 
Day +21 pSTAT3+ CD4+ T-cells <35% 
Dose cohort 1 (100 mg daily) 
Yes (Stop, do not proceed) 
Yes (treat a total of 6, RP2D identified 
if ≤1/6 have DLT) 
No (Proceed) 
No (Proceed to cohort 2) 
Dose cohort 2 (100 mg BID) 
Yes (Stop, return to complete 6 
subjects in cohort 1) 
Yes (treat a total of 6, RP2D identified 
if ≤1/6 have DLT) 
No (Proceed) 
No (Proceed to cohort 3) 
Dose cohort 3 (200 mg BID) 
Yes (Stop, return to complete 6 
subjects in cohort 2) 
 
No (RP2D identified, proceed to 
phase II component of trial)) 


 
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RP2D = recommended phase II dose 
 
The definitions for DLTs on PAC/SIR/TAC are as follows (CTCAE v4): 
1. 
Left ventricular systolic dysfunction grade 3 or above*   
2. 
Myocardial infarction grade 3 or above 
3. 
Atrial fibrillation or flutter grade 3 or above 
4. 
Supraventricular tachycardia grade 3 or above 
5. 
Ventricular arrhythmia grade 3 or above 
6. 
Upper or lower gastrointestinal hemorrhage grade 3 or above 
7. 
Intracranial hemorrhage grade 1 or above 
8. 
Any grade 3 or above adverse event considered at least possibly related to pacritinib 
 
* Patients demonstrating signs/symptoms of heart failure on PAC/SIR/TAC will undergo a 2-D 
echocardiogram to document the left ventricular ejection fraction.  Subsequent echocardiograms 
will be performed per the discretion of the attending physician based on clinical need. 
 
The recommend phase II dose will be based on the lowest biologically active dose of pacritinib, that is 
safe and well tolerated.  The patients treated at this dose during phase I will analyzed among those 
enrolled in the phase II component.  The overall PAC/SIR/TAC treatment plan is illustrated in Figure 6.  
CTI BioPharma has given Moffitt Cancer Center authorization to cross reference the Investigational 
New Drug application 78,406 for Pacritinib (SB1518, Serial No. 357).  A total daily dose of PAC 400mg 
(ie 200mg po twice a day) was investigated in a recently reported phase II study in myelofibrosis5.  The 
primary toxicity was mild-moderate diarrhea occurring within the first week of therapy.  Diarrhea from 
alkylators like busulfan and melphalan during transplant conditioning is a common toxicity after 
allogeneic HCT.  Alkylator-related diarrhea typically occurs after the first week of the transplant and 
may continue into the third week of the procedure, overlapping with gastrointestinal side effects from 
PAC.  Chemotherapy-induced diarrhea will be managed per Moffitt BMT standard practice (BMT-G-
102.0), where loperamide is often effective as a first-line agent.  Dose reductions of pacritinib will be 
made on a per patient basis, if stool volume exceeds 1500ml/day for 3 consecutive days in the absence 
of infectious etiology and if the diarrhea does not respond to antimotility medications (see Safety 
Assessment section).  Importantly, phase I pharmacodynamic data demonstrated on-target inhibition of 
JAK2 activity at doses as low as 100mg daily7, ensuring biologic activity in the setting of dose 
reductions for diarrhea.  The administration of PAC with SIR/TAC, will continue until day +100.  PAC 
will then be tapered to 50% of the total dose at day +70, then 25% of total dose at day +84, then stop at 
day +100 (+/- 7 days) (see Table 2 for dose reduction schedule).  This will allow for close monitoring of 
patients for GVHD during the taper phase, as standard practice requires patients to be within 30 
minutes of the transplant center until day +100.  SIR/TAC will be given according to program standards.  
Conditioning regimens may include busulfan and fludarabine or melphalan and fludarabine as detailed 
in Section V. “Study Design”.  Regimens that include total body irradiation or post-transplant 
cyclophosphamide are excluded to avoid compounding toxicities. 
Table 2:  Pacritinib taper schedule, based on day +69 dose 
Pacritinib dose at day +69 
Day +70 reduction 
Day +84 reduction 
200mg BID 
200mg daily 
100mg daily 
200mg daily 
100mg daily 
100mg every other day (QOD) 
100mg daily 
100mg QOD 
100mg on Sunday and 


 
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Thursday 
 
II. 
Trial objectives 
 
a. 
Primary objectives:  
i. 
Phase I: Determine the lowest biologically active dose of pacritinib that is safe and well tolerated 
when combined with SIR/TAC. 
ii. 
Phase II: Determine if PAC/SIR/TAC suppresses STAT3 activity in circulating CD4+ T-cells at 
day +212, to at least 35% phosphorylation.  
. 
 
 
b. 
Secondary objectives: 
i. 
Investigate whether PAC/SIR/TAC reduces the cumulative incidence of acute 
GVHD by day +100, compared to our published rate of 43% from SIR/TAC alone.  
This benchmark is bolstered by an ongoing retrospective analysis of 819 patients 
treated with SIR/TAC, MTX/TAC, or MMF/TAC, where the incidence of acute 
GVHD with SIR/TAC was similar to rates observed in our trial. 
ii. 
Study the effect of PAC/SIR/TAC on Treg, Th1, and Th17 differentiation among 
circulating T-cells at day +21 and day +100. 
a) 
A subset of 15 patients treated with standard SIR/TAC alone who are 
receiving a matched related or unrelated alloHCT will also be enrolled for blood 
sample collections only on day +21 and day +100. 
b) 
The effects of PAC/SIR/TAC versus SIR/TAC on Treg, Th1, and Th17 
development will be investigated. 
iii. 
Determine how PAC/SIR/TAC impacts CD28 and IL-2 receptor signal 
transduction by measuring S6 (mTOR), H3 ser10 (Aurora kinase), and STAT5 
phosphorylation in CD4+ T-cells at days +21 and +100.  Phosphoprotein values 
will be compared to SIR/TAC only patients (n=15) enrolled in the sample-only 
portion of the trial. 
III. 
Trial endpoints 
 
a. 
Primary endpoints:  
i. 
Phase I: The lowest biologically active dose of PAC that is safe and well tolerated 
with SIR/TAC 
ii. 
Phase II: STAT3 activity in circulating CD4+ T-cells at day +212. 
 
b. 
Secondary endpoints (phase II only): 
i. 
Cumulative incidence of acute GVHD by day +100 
ii. 
Treg, Th1, and Th17 differentiation among circulating T-cells at day +21 and day 
+100.   
iii. 
CD28 and IL-2 receptor signal transduction by measuring S6 (mTOR), H3 ser10 
(Aurora kinase), and STAT5 phosphorylation in CD4+ T-cells at days +21 and 
+100.   
IV. 
Patient population 
 
a. 
Inclusion Criteria 
1. 
Age ≥ 18.  
2. 
Patients must have an available 8/8 HLA-A, -B, -C, and -DRB1 matched-related 
or unrelated donor allogeneic hematopoietic peripheral blood stem cell graft. 


 
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3. 
Signed informed consent. 
4. 
Acute myeloid leukemia, myelodysplasia, acute lymphoblastic leukemia, chronic 
myeloid leukemia, chronic lymphocytic leukemia, myeloproliferative neoplasms, 
Hodgkin lymphoma, or non-Hodgkin lymphoma requiring a matched allogeneic 
HSCT. 
 
Acute Leukemia (AML or ALL) must be in complete remission defined as:  <5% 
marrow blasts with no morphologic evidence of leukemia, no peripheral blasts, 
marrow >20% cellular, and peripheral absolute neutrophil count >1000/uL 
(platelet recovery is not required). 
Myelodysplasia (MDS) and chronic myeloid leukemia (CML):  Must have <5% 
marrow blasts. 
Myeloproliferative neoplasms (MPN):  Must have <5% peripheral / marrow blasts.  
Note:  Prior use of a JAK2 inhibitor is allowed up to 4 weeks before day 0 of 
alloHCT. 
Hodgkin and non-Hodgkin lymphoma:  Must have a complete or partial response 
with prior therapy. 
5. 
Adequate vital organ function: 
a. LVEF ≥ 50% by MUGA scan or ECHO 
b. FEV1, FVC, and adjusted DLCO ≥ 50% of predicted values on pulmonary 
function tests  
c. Transaminases (AST, ALT) < 2 times upper limit of normal values 
d. Creatinine clearance ≥ 50 cc/min. 
 
6.  
Performance status:  Karnofsky Performance Status Score ≥ 80%. 
 
 
b.  
Exclusion Criteria: 
1.  Active infection not controlled with appropriate antimicrobial therapy. 
2.  History of HIV, hepatitis B, or active hepatitis C infection. 
3.  Anti-thymocyte globulin, alemtuzumab, bortezomib, or post-transplant 
cyclophosphamide as part of GVHD prophylaxis. 
4. Sorror’s co-morbidity factors with total score >4 (Appendix B). 
5. Any patient anticipating or scheduled to receive a tyrosine kinase inhibitor, FLT3 
inhibitor, or JAK2 inhibitor (outside of this study) post-HCT. 
6. QTc>450ms per Fridericia’s correction 
7. Thrombin time (TT), prothrombin time (PT), or partial thromboplastin time (PTT) >2x 
upper limit of normal 
8. Grade 3 or higher recent (within the past 6 months) or ongoing cardiac dysrhythmias, 
family history of long QT syndrome, or serum potassium <3.0 mEq/L that is persistent 
and refractory to correction. 
9. Grade 3 or higher recent (within the past 6 months) or ongoing bleeding events. 


 
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10. Symptomatic or uncontrolled cardiovascular disease, myocardial infarction or 
severe/unstable angina within the past 6 months, or New York Heart Association Class 
III or IV congestive heart failure 
 
c. 
Donor eligibility 
Eligible donors will include healthy sibling, relative or unrelated donors that are matched 
with the patient at HLA-A, B, C, and DRB1 by high resolution typing as defined by the 
Collaborative Trials Network29. 
 
V. 
Study Design 
 
1.  
Sample size 
 
 
a.  A total of up to 12-18 evaluable patients will be enrolled in phase I.  The 6 patients 
treated at the MTD (or lowest biologically active dose) in phase I will be analyzed among 
those treated in phase II.  In phase II, 24 evaluable patients will be enrolled to study 
CD4+ T-cell STAT3 phosphorylation at the MTD.  Additional 14 evaluable patients will be 
accrued to expansion stage if 9 or less of the initial patients treated at the MTD develop 
grade II-IV acute GVHD.  Thus, a total of up to 50 evaluable patients could be enrolled to 
the combined phase I and II components of the trial. We anticipate up to 63 total could 
be  enrolled and treated with PAC/SIR/TAC (which would account for  a 10% 
replacement for non-evaluable subjects in phase II, and possible 10 subjects non-
evaluable in the phase I component of the trial). 
 
 
2. 
Withdrawal 
a. Subject withdrawal from the study will take place under the following circumstances:  
i.  those patients who sign consent for the study, but fail to initiate treatment on 
account of: 
1.  denial of coverage from insurance provider 
2.  death prior to initiation of treatment 
3.  withdrawal of patient consent at any time after therapy 
 
Subjects who withdraw consent for pacritinib therapy after day +21 but before 
day +100 will be asked to continue on study for follow-up of their condition and 
allow collection of research blood samples.  These patients will be considered 
“off-therapy, on-study” reflecting partial withdrawal of consent.  These patients 
will inform the secondary endpoint of GVHD prevention, and only be excluded 
from the analysis if they are off pacritinib for more than 4 weeks and do not 
resume the drug thereafter for causes other than acute GVHD (treatment 
failure).  Subjects who withdraw consent for pacritinib therapy before day +21 
will be excluded from any study analysis reflecting full withdrawal of consent. 
Subjects who do not wish to permit follow-up of their condition and continued 
collection of their peripheral blood for research studies will also be called full 
withdrawal of consent. 
Withdrawal of consent (partial or full) will be documented in OnCore and within 
the patient’s medical record. 
 


 
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3.  
Intervention: Pacritinib 
a. Dose and Schedule:  Up to 200mg BID orally (or MTD) from day 0 until day +100.  
PAC will be tapered to 50% of the total dose at day +70, then 25% of total dose at 
day +84, then stop at day +100 (+/- 7 day window is provided around timing of 
tapering events at day +70 and day +84, as well as last dose stop date around day 
+100). 
 
 
4. 
Standard transplant care and practice 
a. Donor selection 
Donor must be a sibling, relative, or unrelated donor identical for HLA-A, -B, -C, and 
HLA-DRB1 by high resolution typing methods.   
 
b. Stem cell mobilization and collection 
1.  Peripheral blood stem cell mobilization: Donors will be mobilized and collected per 
institutional or National Marrow Donor Program (NMDP) standard operating protocol.  
The desired target CD34+ cell dose is 5-10 x 106 cells/kg.  Collection of <5 x 106 
CD34/kg is not a deviation. 
2.  Umbilical cord blood, HLA haploidentical, and bone marrow stem cells grafts are not 
included in this protocol. 
 
c. Conditioning regimen 
The conditioning regimen is per physician discretion but restricted to busulfan and 
fludarabine or melphalan and fludarabine.  The specific details of these two regimens will 
adhere to BMT Program standards.  


 
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d. GVHD prophylaxis 
In addition to the study drug, pacritinib, SIR/TAC will be administered and dosed 
according to Moffitt Cancer Center, Department of Blood and Marrow Transplantation 
standard practice.  Attending physician discretion is permitted with regard to timing, 
rapidity, and completion of SIR/TAC taper.  SIR/TAC levels will be monitored according 
to program standards.  The therapeutic target for SIR is 5-14 ng/ml.  The therapeutic 
target for tacrolimus is 3-7 ng/ml.  It is expected that pharmacologic fluctuations of SIR 
and TAC levels may occur during this treatment, and such fluctuations in dose levels 
outside the target ranges will not be considered a deviation.  Dose modifications of 
SIR/TAC for concurrent use of CYP3A4 inhibitors or inducers will be based on program 
standards.   
Note:  Pacritinib is neither an inhibitor nor an inducer of cytochrome P450 (CTI 
BioPharma Investigator Brochure). 
 
e. Concurrent use of CYP3A inhibitors 
While strong CYP3A inhibitors should be avoided when clinically feasible, it is 
understood that the use of azoles and other similar agents are necessary at times 
among allogeneic HCT recipients.   
Tacrolimus / Sirolimus:  Adherence to Moffitt BMT standard operating procedures (SOP 
BMT-G-105), including necessary dose reductions, is required when administering 
azoles with tacrolimus and sirolimus. 
Dose reductions for tacrolimus and sirolimus when using concurrent 
voriconazole or posaconazole (per SOP BMT-G-105) 
Tacrolimus 
Reduce tacrolimus dose by 50-66% 
Sirolimus 
Reduce sirolimus dose by 66-90% 
 
Pacritinib:  Data from phase I ADME studies using pacritinib in healthy participants (Al-
Fayoumi S et al) shows that coadministration of strong CYP3A inhibitors, such as 
clarithromycin, increases the Cmax from 3.68 to 4.79, and AUC from 173 to 316 (n=20 
per group), thus approximately increasing the systemic exposure by 50%. Therefore, 
patients requiring concurrent therapy with moderate to strong CYP3A inhibitors must 
reduce the dose of pacritinib by 50% as follows: 
Pacritinib dose prior to 
CYP3A Inhibitor 
Pacritinib dose reduction on CYP3A Inhibitor 
100 mg daily 
100 mg every other day 
100 mg twice a day 
100 mg daily 
200 mg twice a day 
100 mg twice a day 
Patients may resume the pre-CYP3A inhibitor dose of pacritinib once they have been off 
the CYP3A inhibitor for at least 5 days. 


 
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The following medications are considered moderate to strong CYP3A inhibitors that are 
potentially used among allogeneic HCT recipients:  
 
Fluconazole 
 
Clotrimazole 
 
Voriconazole 
 
Posaconazole 
 
Isavuconazonium sulfate 
 
Amiodarone 
 
Diltiazem 
 
Verapamil 
 
Erythromycin 
 
Clarithromycin 
Note: allogeneic HCT recipients are counseled to avoid herbal CYP3A inhibitors, such 
as grapefruit juice, Echinacea, wild cherry, chamomile, and natural licorice. 
 
5.  
Safety assessment 
 
a. 
Thrombotic microangiopathy (expected with SIR/TAC) 
 TMA definitions and grading system: 
TMA will be defined and graded per the BMT Clinical Trial Network consensus 
statement.  TMA is defined as:  RBC fragmentation and > 2 schistocytes per 
high-power filed on peripheral blood smear; concurrent increased serum LDH 
above baseline; concurrent renal (defined as doubling of baseline serum 
creatinine or decrement of > 50% of baseline creatinine clearance) and/or 
neurologic dysfunction without an alternate explanation; and negative direct and 
indirect Coombs test results. The primary management strategy for should be 
the dose reduction or discontinuation of calcineurin-inhibitors upon the 
recognition of post-transplant TMA. Calcineurin inhibitors may be replaced by 
alternative immunosuppressive agent(s).33 As per our completed trial, the 
expected incidence of TMA with SIR/TAC is 25%25.  This is not statistically 
different when compared with MTX/TAC (20%, P=0.48) 25. The grade of TMA 
between SIR/TAC and MTX/TAC did not differ as well25.  
 
 
Evaluation and management procedures: 
Active surveillance for this condition will take place in all patients. In those who 
meet criteria (RBC fragmentation and >2 schistocytes per high-power field on 
peripheral smear; Concurrent increased serum LDH above institutional 
baseline; Concurrent renal and/or neurologic dysfunction without other 
explanations; Negative direct and indirect Coombs test results). 
 


 
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Changes to the immunosuppression regimen is recommended as follows for 
TMA: 
For CTC grade 1-2, TAC dose reduction by 0-25% 
For CTC grade 3, TAC dose reduction by 50% 
For CTC grade 4, TAC will be discontinued  
No indication for Plasma exchange upon recognition of TMA 
 
 
b. 
Hepatic Veno-occlusive disease (VOD) (expected with SIR/TAC) 
 VOD definitions and risk factors: 
The clinical syndrome of hepatic VOD is associated with weight gain, 
hepatomegaly with abdominal pain, cholestasis and transaminitis, as well as 
anasarca.  Subsequent renal and pulmonary dysfunction may occur as well.  
Risk factors for VOD include pre-transplantation transaminitis, chronic hepatitis 
C and B, and exposure to cyclophosphamide-based transplant preparative 
regimens.34   
Contemporary clinical trials have observed rates of VOD ranging from 8-9%.35,36 
Severe VOD is associated with a mortality rate in excess of 90%.  The 
management of VOD primarily consists of eliminating exposure to offending 
agents and supportive care.  Early phase clinical trials investigating the use of 
defibrotide in VOD have reported complete response rates up to 60%.37  
Patients will be monitored closely for any clinical signs of VOD.  The specific 
management of any occurrence of VOD will be at the discretion of the physician 
of record. 
c. 
Non-infectious diarrhea 
Diarrhea is a known side effect of allogeneic HCT.  Additionally, phase I-III 
studies of pacritinib in hematologic malignancies shows that grade 1-2 diarrhea 
is a common side effect of this medication.  The pacritinib diarrhea typically 
occurs within 7 days of initiating the medication.  Clinical trial data supports that 
the diarrhea does respond to anti-motility agents, and does not typically require 
dose reduction of pacritinib.  Given the potential for compounding toxicities early 
after allogeneic HCT, dose reduction rules for diarrhea (1500ml/day x3 
consecutive days, not responding to anti-motility agents) are provided in Table 1 
of this protocol.   
d.  
QTc prolongation 
Life-threatening and sometimes fatal cardiac events have been observed in 
patients treated with pacritinib, including heart failure and arrhythmias, some 
of which may have been associated with sudden death.  As such, EKGs will 
be performed at baseline as part of vital organ testing (VOT) and repeated at 
day +30 and day +60.  Patients with a baseline QTc >450ms at time of VOT 
will be excluded from participation.  Instructions for QTc >450ms that develop 
while taking pacritinib are provided in appendix D. 
e. 
Coagulation parameters (TT, PT, and PTT) 
Serious bleeding events, specifically bleeding of the brain (intracranial 
hemorrhage, subdural hematoma, cerebral hemorrhage), have been observed 
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fatal outcomes.  TT, PT, and PTT will be performed at baseline as part of vital 
organ testing (VOT) and repeated at day +30 and day +60.  Patients with 
baseline TT, PT, and/or PTT >2x the upper limit of normal are excluded from 
participation.  Instructions for a TT, PT, and/or PTT lab value >2x the upper limit 
of normal while on pacritinib are provided in appendix D. 
 
6.  
Endpoints 
Primary Endpoints 
Phase I: The lowest biologically active dose of PAC that is safe and well tolerated with 
SIR/TAC 
 
Phase II: STAT3 activity in circulating CD4+ T-cells at day +212 
8 green top tubes will be collected at baseline (day -30 to -5), day +21, and day +100.  
This is equivalent to 5.5 tablespoons of blood for each assessment.  Peripheral blood 
mononuclear cells (PBMC) will be isolated by Ficoll density gradient.  PBMCs will be 
stimulated with IL-6 for 20 minutes to activate STAT3.  Phosphoproteins will be analyzed 
within T-cells by flow cytometry as described2.   
 
Secondary Endpoints 
1. Cumulative incidence of acute GVHD38 by day +100  
Acute GVHD severity grading and monitoring:  
Patients will be monitored for clinical signs of acute GVHD.  Acute GVHD will be graded 
per the 1995 consensus guidelines.27 (see Appendix A).   
 
Therapy for established acute GVHD: 
This protocol does not dictate any one specific therapy for acute GVHD.  The primary 
physician may direct the management of acute GVHD per their discretion and in 
accordance with MCC standard practice.   
 
2. 
Treg, Th1, and Th17 differentiation among circulating T-cells at day +21 and day 
+100 
Treg and Th1 will be analyzed by flow cytometry.  Treg will be identified by expression of 
CD4, bright CD25, lack of CD127, and intracellular expression of Foxp3.  Th1 will be 
identified by expression of CD4+, and intracellular T-bet+ and IFN-gamma+ [post 
PMA/ionomycin stimulation].  Th17 differentiation will be assessed functionally by IL-17 
Elispot using PBMCs on day +21 and day +100.  IL-17 Elispot is preferred to analyze 
Th17 as the anticipated frequency of circulating Th17 in the periphery is low post 
allogeneic HCT.  Treg and Th17 will be evaluated at baseline, day +21, and day +100.  
A subset of 15 patients treated with SIR/TAC alone per Moffitt standard practice will be 
enrolled for blood sample collection only on days +21 and +100 of their alloHCT.  The 
effects of PAC/SIR/TAC versus SIR/TAC alone on Tregs, Th1, and Th17 will be 
compared among the two groups. 
 


 
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3. 
CD28 and IL-2 signal transduction assessment by S6, H3 ser10, and STAT5 
phosphorylation in CD4+ T-cells at days +21 and +100   
Steady-state mTOR and Aurora kinase activity (S6 and Histone 3 ser10, respectively) 
and IL-2 mediated STAT5 activity will be evaluated at baseline, day +21, and day +100.  
Phosphoproteins will be analyzed within T-cells by flow cytometry as described2.   
 
4. 
Pharmacokinetic (PK) parameters:  For all patients enrolled in the phase I portion of 
this study, pharmacokinetic sampling of plasma pacritinib levels will be  drawn on days 0 
and +21 at the following time points:  pre-dose, +4 hours, +12 hours, and +24 hours.   
5. 
Analysis of tissue-infiltrating immune cell subsets:  We will obtain available GVHD 
target organ (e.g. skin, liver, GI) biopsy samples to study tissue-infiltrating CD4 T cell 
subsets (Th1, Th2, Th17, Treg) through tissue IHC (immunohistochemistry). These 
biopsies were obtained as part of routine clinical practice for GVHD diagnosis, and these 
available resources only will be used for this purpose (i.e. no clinical trial-specific 
biopsies will be obtained). At time of this protocol amendment when trial accrual is now 
complete, we expect approximately 25 total representative samples (respecting biopsy 
samples from skin, and GI sites including gastric, duodenal, and rectum) available to be 
included in this analysis. We will also enlist 25 representative historical control subject 
GVHD biopsy samples for comparison, arising from patients previously treated with 
standard of care sirolimus/tacrolimus GVHD prevention off-protocol. These will also be 
obtained from existing historical biopsy samples (no new biopsies to be performed). 
From these available biopsy samples, slides will be prepared, tissue stained for Th-
subset markers (CD4/Tbet, CD4/GATA3, CD4/RORy, and CD4/FoxP3), and data 
acquired in collaboration with the Moffitt Pathology department, Tissue/Histology Core, 
and Image Analysis Core. Statistical comparisons will be made across pacritinib trial-
treated subjects vs. standard of care off-protocol subjects to discern any differences. 
Other variables considered in this analysis will include clinical GVHD stage, time from 
transplant, and pathologic GVHD grade.  
 
7.   
Statistical considerations 
Clinical trial design, power calculations, and analysis 
Phase I consists of a standard 3+3 design with three PAC dose cohorts. The DLT 
definitions are described on page 9 of this protocol. The MTD is defined as the highest 
dose level at which one or none of 6 subjects develop a DLT, and the combination of 
safety and biologic activity of pacritinib will dictate selection of recommended phase II 
dose. A total of 12-18 patients will be enrolled to determine the PAC MTD. Patients 
treated at the MTD (or lowest biologically active dose) in phase I will be analyzed among 
those treated in phase II.   
 
An evaluable patient for the phase I portion of the trial must have either met one of the 
defined clinical events in the DLT definition, or if not, must have been receiving pacritinib 
within 72 hours of the planned day +21 blood sample for determination of pSTAT3 level. 
Those patients that have not had a clinical DLT event and are not actively taking 
pacritinib for any reason within 72 hours of day +21 will be considered not evaluable, 
and will be replaced. 
 
The phase II component of this trial is designed to detect a significant change in the 
biologic endpoint of STAT3 activity at day +21.  The preliminary data revealed that the 


 
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mean and standard deviation (SD) of CD4+ T-cell pSTAT3 activity among 18 HCT 
recipients at day +21 were ~50% and ~25%, respectively, regardless of acute GVHD 
severity.  We conservatively anticipate that mean of pSTAT3 level at day +21 will 
decrease to 35% or less by combining PAC to SIR/TAC. With a two-sided significance 
level of 0.05, a total sample size of 24 will achieve 80% power to detect a decrease of 
15% when the anticipated SD is 25%, which is equivalent to an effect size of 0.6. We 
anticipate that the actual SD will be lower than 25%. If the actual SD is 20%, the study 
will have 94% power to detect a difference of 15% (an effect size of 0.75). 
 
We also aim to understand whether the observed incidence of grade II-IV acute GVHD is 
sufficiently promising to warrant further study in a trial adequately powered to address 
this clinical endpoint.  Based on published and unpublished experience of over 300 
treated-patients, the incidence of GVHD with SIR/TAC is 43%. We hypothesize that the 
cumulative incidence rate of GVHD with PAC/SIR/TAC by day +100 will reduce to 23% 
(a decrease of 20%) by day +100. The study expansion will be considered if 9 or less of 
24 patients (37.5%) initially treated with PAC/SIR/TAC develop grade II-IV acute GVHD 
by day +100. The expansion will permit an additional 14 patients will be accrued.  
 
The expanded phase II trial (second stage of phase II) will be considered favorable if 12 
or less of the total 38 (31.6%) patients develop acute GVHD by day +100. This sample 
size was computed using Simon’s two-stage design with 10% one-sided significance 
level and 90% power. If this regimen is actually not effective, there is 9.8% probability of 
concluding that it is. If the regimen is actually effective, there is 8.6% probability of 
concluding that it is not. If the second stage is open (n=38), the study will achieve 95% 
power to detect a decrease of 15% when the SD is 25%. The Blood and Marrow 
Transplant Program at MCC performs approximately 190 allogeneic procedures 
annually. A conservative estimated accrual rate of 20% would provide at least 38 
patients each year allowing for full accrual by 24 months. 
 
An evaluable patient for primary endpoint is defined as patients who received 
PAC/SIR/TAC until at least day +21 of their alloHCT and who has neither relapsed nor 
died of any reasons without experiencing grade II-IV aGVHD until day +100. A non-
evaluable PAC/SIR/TAC patient will be replaced and we anticipate 41 patients will be 
accrued to the interventional study in order to account for 10% of competing risks 
(relapse or death without GVHD) at day +100. 
 
Additional 15 patients who receive the standard GVHD prevention regimen of SIR/TAC, 
will be enrolled for blood sample collection only (8 green top tubes of blood) on days +21 
and +100 of the alloHCT. The amount of circulating Treg, Th1, and Th17 cells will be 
analyzed.  The exact same eligibility criteria will apply for these subjects. 
 
A total of up to 68 (up to 18 patients in phase I [with the 6 treated at MTD included 
among those analyzed in phase II] + 32 [PAC/SIR/TAC] + 3 [non-evaluable replacement] 
+15 [blood sample collection only]) patients will be enrolled. 
 
Statistical analysis methods 
Patient baseline characteristics will be summarized using descriptive statistics including 
mean, median, standard deviation and range for continuous measures and proportions 
and frequencies for categorical measures. As the primary endpoint of the study, one 
sample t-test will be employed to examine if pSTAT3 at day +21 is decreased by 15% 
from historic mean of 50%. A two-sided p-value of <0.05 is considered statistically 


 
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significant. If data is not normally distributed, an appropriate transformation (i.e., log-
transformation) or nonparametric test will be considered. As the key secondary endpoint, 
the cumulative incidence of grade II-IV acute GVHD will be estimated using the 
competing risk approach, where relapse and non-relapse mortality are considered the 
competing risks. The one-sided 90% confidence interval for grade II-IV acute GVHD will 
be computed using log-log transformation.  
 
Overall and relapse-free survival (OS and RFS) will be analyzed using the Kaplan-Meier 
method. The association of time-to-event data with/without competing risks with other 
potential predictors will be explored by the Cox proportional hazards regression model 
and the Fine and Gray method39, respectively. Fifteen patients treated with SIR/TAC 
alone will be enrolled for blood sample collection only on days +21 and +100 of their 
alloHCT.  The effects of PAC/SIR/TAC versus SIR/TAC alone on Tregs, Th1, and Th17 
at day +21 and +100 will be compared using the generalized linear model with identity 
link function, adjusting for the effect of acute GVHD (grade 0-I vs. grade II-IV). In 
addition, the mixed effect model will be considered to explore the difference in trends 
between two groups. With a two-sided significance level of 0.05, the sample size of 39 
(24 in PAC/SIR/TAC and 15 in SIR/TAC) will have 84% power to detect an effect size 
(=difference/pooled SD) of 1 between two groups. If the second stage is open, the power 
will increase to 90% as the sample size of PAC/SIR/TAC increases to 38. No multiplicity 
adjustment will be considered for secondary and exploratory endpoints. 
 
VI. 
Data collection and safety monitoring 
The Data & Safety Monitoring Plan (DSMP) adopted by the H. Lee Moffitt Cancer Center & 
Research Institute, Inc. (MCC) will ensure that all clinical research conducted or coordinated by 
the Cancer Center is scientifically well designed, responsibly managed, appropriately reported 
and protects the rights and welfare of human participants. The methods and amount of 
monitoring required are dictated by the degree of risk involved to the individual participants and 
the complexity of the clinical research. Other entities that will assume responsibility for data and 
safety monitoring include:  
 
Principal Investigators (PI)  
 
The Scientific Review Committee (SRC);  
 
The Protocol Monitoring Committee (PMC);  
 
The Research Compliance Division (RCD) of the Cancer Center’s Corporate 
Compliance Office;  
 
Institutional Review Board (IRB) 
 
U.S. Food and Drug Administration (FDA) 
 
 
National Heart, Lung, and Blood Institute (NHLBI) 
 
 
CTI BioPharma 
 
Please see SAFETY AND REPORTING REQUIREMENTS for specifics regarding the collection 
and reporting mechanisms to the SRC, PMC, RCD, IRB, FDA, and CTI BioPharma. 
 
Any amendments to this protocol or accompanying consent form will be sent for IRB review.  
Approved changes to either of the documents will be disclosed with the NHLBI and the FDA. 


 
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1. 
Data collection 
The Principal Investigator and the Clinical Trial Coordinator(s) assigned to the case will be 
primarily responsible for maintaining all study related documents including clinical research 
forms, as applicable.  ONCORE is the database of record for all CRF entries and will be 
verified with source documentation.  The review of medical records within PowerChart will 
be done in a manner to assure that patient confidentiality is maintained. 
Data collected will be stored in Moffitt Cancer Center’s database system, ONCORE.  
Identifying patient information will be kept confidential.  Representatives of the IRB and the 
FDA will have access to patient information as it pertains to the study.  Privacy and 
confidentiality of the information will be protected to the extent provided by law. 
 
2.  
Safety monitoring  
a.  Safety monitoring 
i. The principal investigator will have the primary responsibility for data safety and 
monitoring. Input will be sought from sub-investigators and other members of the BMT 
Program concerning data and safety issues.   
The PI of the study will have primary responsibility for ensuring that the protocol is 
conducted as approved by the SRC and IRB.  The PI will ensure that the monitoring plan 
is followed, that all data required for oversight of monitoring are accurately reported to a 
DSMB and/or to the PMC and IRB as required.   
 
ii. The investigators and members of the BMT Research Staff will meet at least monthly. 
The following data will be reviewed:  
1. 
rate of accrual 
2.   adverse events and unanticipated problems 
3.  protocol deviations and/or violations.  
 
iii. If necessary, corrective action and/or educational programs will occur to ensure 
subject safety and data integrity. Reports to the SRC, PMC, and IRB will be submitted as 
required. 
 
iv. Stopping criteria for observed toxicity:  
The PI of this study will have responsibility for continuous monitoring of adverse events 
on this trial. Additionally, these events will be reviewed formally in monthly research 
meetings of the BMT program. As described in appendix C of this protocol, there are 
numerous anticipated adverse consequences of transplantation, which include, but are 
not limited to conditioning regimen related toxicity such as severe mucositis, idiopathic 
pneumonia syndrome, hepatic veno-occlusive disease and death, early and late 
infectious complications, potentially severe or fatal acute or chronic graft vs. host 
disease, and relapse of primary disease and its complications. As these are anticipated 
complications, they will not inform specific stopping criteria for toxicity in this study. If 
four related grade 4-5 unexpected adverse events occur in the conduct of this trial, an 
analysis will be performed, and further accrual to the trial will be temporarily halted. Data 


 
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will be analyzed, and a report will be submitted to the protocol monitoring committee 
(PMC). Further decisions regarding resuming accrual will be determined by the PMC 
with input from the PI of this study.  If the study requires suspension or termination, an 
NHLBI Program Official will be notified in writing. 
 
Scientific Review Committee (SRC) 
The Cancer Center’s internal SRC provides the review for scientific merit and prioritization and 
monitors scientific progress for all protocols at the Cancer Center.  The SRC has a defined 
membership representing all of the major research divisions of the cancer center, including 
biostatisticians.  The SRC reviews newly proposed clinical research studies based on the 
following categories:  
a. study significance to evaluate its potential for contribution to medical science.  
b. the adequacy of study objectives, design, specific aims and hypotheses.  
c. the methods to be employed to conduct the study. Ensuring that the study is adequately 
described, including inclusion/exclusion criteria, sample size, procedures and 
instruments to be used.  
d. Feasibility of the study. Ensuring the investigator has adequate staffing and facilities to 
conduct the study. Ensuring that the timeframe for the study and projected annual 
accrual are adequately addressed.  
e. Review of all data and safety monitoring plans.  
The SRC will also evaluate the risk/benefit assessment and corresponding Data & Safety 
Monitoring Plan (DSMP), evaluate and may recommend frequency of monitoring. The SRC will 
identify any potential conflicts of interest related to the proposed research.  The SRC may also 
evaluate and recommend the monitoring frequency of clinical trials they approve.  
 
The Protocol Monitoring Committee (PMC) 
The Protocol Monitoring Committee (PMC) is a multidisciplinary, peer review, standing 
committee established to oversee clinical research conducted at Moffitt Cancer Center to 
monitor scientific progress and data quality.  It also serves as a component of the Data Safety 
Monitoring Plan (DSMP) for oncology trials at MCC.  The membership of the PMC includes 
physicians and scientists from various program areas. 
The PMC provides ongoing monitoring of all clinical research studies for safety, validity and 
integrity of data, adverse events, conflicts of interest, and overall compliance with GCP or other 
applicable clinical research guidelines or regulations. In addition to the protocol stopping rules, 
the PMC is authorized to suspend a trial for non-compliance with a DSMP or as a result of audit 
findings deemed unacceptable.   
 
Research Compliance Division (RCD) 
The Cancer Center has established the RCD of the Corporate Compliance Office as the 
coordinating center for internal audits of clinical trials conducted at the Cancer Center and its 
affiliates.  These audits will provide for a systematic and independent examination of trial-related 
activities and documents to determine whether the evaluated trial-related activities were 
conducted, and the data was recorded, analyzed and accurately reported, according to the 
Institutional Review Board (IRB) approved protocol, Center’s policies, Good Clinical Practices 
(GCP): Consolidated Guidance, and applicable regulatory requirements.  


 
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Audits are conducted by the RCD in accordance with applicable regulatory standards.  The 
RCD will conduct and report the findings of audits to the PMC.  The PMC will determine the 
findings to be: acceptable, acceptable with corrective action, or unacceptable. The RCD will 
notify the IRB of the audit determinations made by the PMC. The RCD will follow up to ascertain 
whether corrective actions, which have been agreed to, are achieving the desired results. The 
PMC will be informed of all significant open follow-up items. For those observations where no 
action has been taken, the RCD will inform the PMC who may take action as appropriate.    
 
Internal Monitoring 
Monitoring will be performed regularly by the MCC Clinical Monitoring Core for accuracy, 
completeness, and source verification of data entry, validation of appropriate informed consent 
process, reporting of SAEs, and adherence to the protocol, Good Clinical Practice (GCP) 
guidelines, and applicable regulatory requirements. 
 
Institutional Review Board (IRB) 
The trial will not be initiated without approval of the appropriate Institutional Review Board (IRB).  
All administrative requirements of the governing body of the institution will be fully complied 
with.  This protocol, consent procedures, and any amendments will be approved by the IRB in 
compliance with current regulations of the Food and Drug Administration prior to initiation unless 
necessary to protect the safety and welfare of subjects; in which case, the IRB will be notified 
within 24 hours of implementing the change.  A letter of approval will be sent to the institution(s) 
funding the study prior to initiation of the study and when any subsequent modifications are 
made.  The IRB will be kept informed by the investigator as to the progress of the study as well 
as to any serious or unusual adverse events. 
 
Informed consent  
The investigator must explain to each subject (or legally authorized representative) the nature of 
the study, its purpose, the procedures involved, the expected duration, the potential risks and 
benefits involved and any discomfort it may entail. Each subject must be informed that 
participation in the study is voluntary and that he/she may withdraw from the study at any time 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician.  
This informed consent should be given by means of a standard written statement, written in 
non-technical language. The subject should read and consider the statement before signing and 
dating it, and should be given a copy of the signed document. If the subject cannot read or sign 
the documents, oral presentation may be made or signature given by the subject’s legally 
appointed representative, if witnessed by a person not involved in the study, mentioning that the 
patient could not read or sign the documents. No patient can enter the study before his/her 
informed consent has been obtained. The informed consent form is considered to be part of the 
protocol, and must be submitted by the investigator with it for IRB/IEC/REB approval. 
Reporting of changes or amendments to the protocol or consent form 
All changes or amendments to the protocol or consent form will be reviewed by the SRC and/or 
IRB.  Once the revised documents are approved, they will be distributed to the FDA, NHLBI, 
and CTI BioPharma. 
 
3. 
Safety: Monitoring of adverse events and pacritinib dose modifications for toxicity 
 
Dose Adjustments for Pacritinib  


 
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Specific dose adjustment rules are provided here for diarrhea, QTc prolongation, and left ventricular 
dysfunction (see below sections and tables).  For all other pacritinib-related (probably or definitely) > 
Grade 3 non-hematologic toxicity, the following rules apply:  
 
Discontinue pacritinib administration until toxicity resolves to Grade 2 or better 
 
Once toxicity has returned to grade 2 or better, patients can resume pacritinib at 100mg less per 
day than the previously administered dose at which they were discontinued.   Only two, 100mg, 
dose reductions are allowed before treatment with pacritinib is discontinued.  Patients cannot 
reduce the dose of pacritinib <100mg daily.  Patients that do not tolerate 100mg pacritinib daily 
must discontinue pacritinib.  Following dose reductions, pacritinib dose re-escalation is not 
permitted. 
 
Patients who do not recover (≤ Grade 2 or baseline) within 14 days of discontinuation of study 
drug will not be permitted to re-start study drug. 
 
Pacritinib Dose Management Guidelines for QTcF Interval Prolongation and Left Ventricular 
Dysfunction 
 
Dose management for QTcF interval prolongation is summarized below. 
 
QTc prolongation: CTCAEv4 Toxicity Grade 
Management/Action 
G1  (QTcF > 450ms) 
No change 
G2 (first occurrence)  
(QTcF > 480ms) 
Hold treatment: 
- hold minimum of one day, e.g. two doses on 
the 100mg BID dose level 
- then repeat EKG and consider resuming 
dosing if toxicity resolves to ≤ grade 1-If the 
toxicity resolves to ≤ grade 1 within 7 days, 
treatment may be resumed at next lowest 
dose level 
Toxicity that does not resolve to ≤ grade 1 
within 7 days requires treatment 
discontinuation 
G2 (second occurrence) 
Discontinue treatment 
G3 and G4 
(QTcF > 500ms) 
Discontinue treatment 
 
 
After dose reduction, no dose re-escalation is allowed. 
 
All patients are required to have an ECG at baseline, and then at month 1 (day 30 post-transplant) and 
month 2 (day 60 post-transplant). No further monitoring is required beyond this time, as pacritinib will 
be tapered off within the subsequent month on this trial. In the event of grade 1 or greater QTcF 
prolongation, EKG must be checked within 7 days of holding treatment to determine if treatment may 
be resumed by the above rules.  
All patients will have a pre-transplant ECHO or MUGA performed to evaluate left ventricular ejection 
fraction.  Patients will be monitored closely as standard care for allogeneic HCT (daily until engraftment 
and then at least once a week if not more until day +100).  A full cardiopulmonary exam will be 
performed at each scheduled visit to clinically monitor for any signs or symptoms of heart failure as 
recommended by the National Institute for Health and Care Excellence (NICE)40.  Repeat ECHO will be 
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from day 0) in keeping with monitoring recommended in the pacritinib Investigator Brochure.  Dose 
management for left ventricular dysfunction is as follows: 
 
LV dysfunction: CTCAEv4 Toxicity Grade* 
Management/Action 
G1 
No change 
G2 (first occurrence) 
*LVEF < 40% 
Hold treatment 
Repeat echocardiogram 14 days. 
If the treatment resolved to ≤ grade 1, 
treatment may be resumed at next lowest 
dose level. 
G2 (second occurrence) 
Discontinue treatment 
G3 and G4** 
Discontinue treatment 
 
*The CTCAE v4 term ‘left ventricular systolic dysfunction’ and its grading are based on the degree of 
clinical manifestations and therapy needed to control this issue. In contrast, specific cut-off values for 
abnormal ejection fraction are not provided, and grades 1 and 2 AE have no other descriptors. Detail is 
only provided for grade 3 (“symptomatic due to drop in ejection fraction responsive to intervention”). To 
be included on this trial, patients must have at least an ejection fraction of 45%. Adhering to accepted 
definitions of LV systolic dysfunction, we will consider a decline in LV ejection fraction to less than 40% 
as an event worthy of holding pacritinib therapy (and treat this as the equivalent of grade 2 per above). 
To resume therapy, a repeat echocardiogram within 14 days of stopping pacritinib must show return to 
> 45% ejection fraction.  
 
**As per above, symptomatic heart failure (grades 3 and 4 per CTCAE ver4) require complete 
discontinuation of pacritinib. 
 
After dose reduction, no dose re-escalation is allowed. 
 
Management of Gastrointestinal Toxicity  
The need for managing GI effects of pacritinib, particularly diarrhea, should be anticipated. A careful 
baseline evaluation of bowel habits (frequency and consistency of bowel movements) should be 
obtained at baseline for all patients.  
 
Dose reduction rules for pacritinib (combined with SIR/TAC) 
Diarrhea 
Current Dose (pacritinib) 
Dose Reduction (pacritinib) 
None / responds to 
antimotility agents 
200mg twice a day 
N/A 
≥1500ml/day x3 days* 
200mg twice a day 
200mg qAM and 100mg qPM 
200mg qAM and 100mg qPM 
200mg daily 
100mg twice a day 
Hold pacritinib until stools are 
formed or volume is <500ml/day, 
then resume at 100mg twice a day 
and continue until day +70 taper.  If 
diarrhea (≥1500ml/day x3 days) 
returns after holding pacritinib and 
does not respond to antimotility 
agents, patient comes “off-drug” but 
remains “on-study” for data 
collection and research labs. 
 
100mg daily  
Hold pacritinib until stools are 
formed or volume is <500ml/day for 
at least 5 days, then resume at 


 
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100mg a day and continue until day 
+70 taper.  If diarrhea 
(≥1500ml/day x3 days) returns after 
holding pacritinib and does not 
respond to antimotility agents, 
patient comes “off-drug” but 
remains “on-study” for data 
collection and research labs. 
Note diarrhea must be non-infectious and unresponsive to anti-motility agents 
 
*This total measured stool volume of > 1500mL/day has been approximated to > 7 episodes of diarrhea 
per day (Harris, et al. BBMT, 2016) based on review of diarrhea volume and stool frequency of over 
300 patients in this analysis.  Thus, we will treat either this measured volume, or > 7 episodes of 
diarrhea per day (when volume is not measured) as the threshold requiring dose modification. This rule 
also harmonizes with CTCAE ver4, as this same frequency of stools constitutes grade 3 diarrhea.  
 
General Administration Guidelines  
 
Missed or Vomited Doses 
 
Missed doses will not be replaced.  All missed doses should be documented in the patient diary. If a 
dose is vomited within one hour of ingestion, it will be considered a missed dose and recorded as such 
on the patient diary.  The dose will not be repeated that same day but the patient will follow regular 
schedule starting the next study dosing day.  If vomiting occurs more than 1 hour after dosing, it will still 
be considered a complete dose. 
 
SAFETY AND REPORTING REQUIREMENTS  
 
ASSESSMENT OF SAFETY  
Safety assessments will consist of monitoring and recording adverse events and serious adverse 
events and other protocol-specified tests that are deemed critical to the safety evaluation of the study 
drug(s) and should be consistent with institutional standards and Good Clinical Practice.  
 
DEFINITIONS  
 
Unanticipated Problems (UP) 
A UP includes any incident, experience, or outcome that involves risks to patients that are 1) 
unexpected with relation to the planned study or intervention, 2) related or possibly related to the 
research study or intervention, and 3) places patients at more risk than anticipated.  For the purposes 
of this clinical study, UPs include only treatment-emergent problems which are either new or represent 
detectable exacerbations of pre-existing conditions. 
 
Adverse Events (AE) 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the 
use of an investigational (medicinal) product or other protocol-imposed intervention, regardless of 
attribution. For the purposes of this clinical study, adverse events include only treatment-emergent 
events which are either new or represent detectable exacerbations of pre-existing conditions.  
 
This includes the following:  


 
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• Subjective or objective symptoms spontaneously offered by the subject and/or observed by the 
investigator or study staff including laboratory abnormalities of clinical significance.  
• Any adverse events experienced by the subject through the completion of final study procedures.  
• AEs not previously observed in the subject that emerge during the protocol-specified AE reporting 
period, including signs or symptoms associated with MCL that were not present before the AE reporting 
period  
• Complications that occur as a result of protocol-mandated interventions (eg, invasive procedures such 
as biopsies)  
 
The following are NOT considered an adverse event or unanticipated problem:  
• Pre-existing condition: A pre-existing condition (documented on the medical history CRF) is not 
considered an AE unless the severity, frequency, or character of the event worsens during the study 
period.  
• Preplanned hospitalization: A hospitalization planned before signing the informed consent form is 
not considered an SAE, but rather a therapeutic intervention. However, if during the pre-planned 
hospitalization an event occurs, which prolongs the hospitalization or meets any other SAE criteria, the 
event will be considered an SAE. Surgeries or interventions that were under consideration but not 
performed before enrollment in the study will not be considered serious if they are performed after 
enrollment in the study for a condition that has not changed from its baseline level. Hospitalizations for 
social reasons or due to long travel distances are also not SAEs.  
• Diagnostic Testing and Procedures: Testing and procedures should not be reported as adverse 
events or serious adverse events, but rather the cause for the test or procedure should be reported.  
 
Serious Adverse Event  
The terms “severe” and “serious” are not synonymous. Severity (or intensity) refers to the grade of an 
AE (see below). “Serious” is a regulatory definition and is based on patient or event outcome or action 
criteria usually associated with events that pose a threat to a patient’s life or functioning. Seriousness 
(not severity) serves as the guide for defining regulatory reporting obligations to applicable regulatory 
authorities.  
 
A serious adverse event (experience) or reaction is any untoward medical occurrence that at any dose: 
 
• It results in death (ie, the AE actually causes or leads to death).  
• It is life-threatening (with regards to determining if an AE is serious, “life-threatening” is defined as an 
AE in which the subject was at risk of death at the time of the event. It does not refer to an event which 
hypothetically might have caused death if it were more severe. If either the investigator or the Sponsor 
believes that an AE meets the definition of life-threatening, it will be considered life-threatening.).  
• It requires or prolongs in-patient hospitalization.  
• It results in persistent or significant disability/incapacity (ie, the AE results in substantial disruption of 
the patient’s ability to conduct normal life functions).  
• It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the 
investigational product.  
• It is considered a significant medical event by the investigator based on medical judgment (eg, may 
jeopardize the patient or may require medical/surgical intervention to prevent 1 of the outcomes listed 
above).  


 
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Severity  
Definitions found in the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) 
will be used for grading the severity (intensity) of AEs. The CTCAE v4.0 displays Grades 1 through 5 
with unique clinical descriptions of severity for each referenced AE. Should a patient experience any AE 
not listed in the CTCAE v4.0, the following grading system should be used to assess severity:  
 
• Grade 1 (Mild AE) – experiences which are usually transient, requiring no special treatment, and not 
interfering with the patient’s daily activities  
• Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or concern to the 
patient, and which may interfere with daily activities, but are usually ameliorated by simple therapeutic 
measures  
• Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly interrupt the 
patient’s usual daily activity, and require systemic drug therapy or other treatment  
• Grade 4 (Life-threatening or disabling AE) – experiences which cause the patient to be in imminent 
danger of death  
• Grade 5 (Death related to AE) – experiences which result in patient death 
 
Suspected Adverse Reaction  
• A Suspected Adverse Reaction is any adverse event for which there is a “reasonable possibility” that 
the drug caused the adverse event.  
• “Reasonable Possibility”, for the purposes of safety reporting, means there is evidence to suggest a 
causal relationship between the drug and the adverse event. Examples of evidence that would suggest 
a causal relationship between the drug and the adverse event are:  
• A single occurrence of an event that is uncommon and known to be strongly associated with drug 
exposure.  
• One or more occurrences of an event that is not commonly associated with drug exposure, but is 
otherwise uncommon in the population exposed to the drug. If the event occurs in association with 
other factors strongly suggesting causation (eg, strong temporal association, event recurs on 
rechallenge), a single case may be sufficiently persuasive; but often, more than one occurrence would 
be needed before the sponsor could make a determination of whether the drug caused the event.  
 
Unexpected  
An “unexpected” AE is an AE that is not listed in the Investigator Brochure or is not listed at the 
specificity or severity that has been observed. "Unexpected" also refers to AEs that are mentioned in 
the Investigator Brochure as occurring with a class of drugs or as anticipated from the pharmacological 
properties of the drug, but are not specifically mentioned as occurring with the study drug under 
investigation.  
 
 
DOCUMENTING AND REPORTING OF ADVERSE OR SERIOUS ADVERSE EVENTS AND 
UNANTICIPATED PROBLEMS 
 
The Sponsor-investigator is responsible for ensuring that AEs, SAEs, and UPs that are observed or 
reported during the study, as outlined in the prior sections, are recorded on the study adverse event log 


 
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with AE collection timelines adhering to the standards of the Institution. All SAEs also must be reported 
according to the local IRB guidelines as well as to the CTI PVG  
 
Adverse Event and Unanticipated Problem Reporting Period  
The AE and UP reporting period for this study begins after first dose of study drug administration until 
30 days after discontinuation of the study drug. Grade 3 or greater AEs, SAEs, or UPs that are 
encountered during the protocol specified AE reporting period should be collected, and followed to 
resolution or until the patient is lost to follow up or withdrawals consent.  Resolution/stable means the 
subject has returned to baseline state of health or the Investigator does not expect any further 
improvement or worsening of the event.  
 
Assessment of Adverse Events and Unanticipated Problems 
Investigators will assess the occurrence of AEs, SAEs, and UPs at all patient evaluation time points 
during the study. Grade 3 or greater AEs, SAEs, and UPs whether volunteered by the patient, 
discovered by study personnel during questioning, or detected through physical examination, clinically 
significant laboratory test, or other means will be recorded in the patient’s adverse event log.  
 
Each recorded AE, SAE, or UP will be described by its duration (ie, start and end dates), severity, 
regulatory seriousness criteria, if applicable, suspected relationship to the investigational product (see 
following guidance), and any actions taken.  
 
All deaths should be reported with the primary cause of death as the AE term, as death is typically the 
outcome of the event, not the event itself. The primary cause of death on the autopsy report (if done) 
should be the term reported.  
 
An SAE will qualify for expedited reporting to regulatory authorities if the SAE is considered a 
Suspected Adverse Reaction and is not listed in the current Investigator’s Brochure (ie, an unexpected 
event). To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline:  
 
Related to study drug: Any AE or UP (serious or not) that appears to have a reasonable possibility of 
causal relationship to the use of the study drug. Guidelines to determine whether an event might be 
considered related include (but are not limited to) the following:  
 
 
The event occurred in close temporal relationship to study drug administration. 
 
The event abated (diminished) or disappeared when treatment with the study drug was down-
titrated, interrupted, or discontinued.   
 
The event re-occurred when treatment was re-introduced.  
 
Unrelated to study drug: Any AE or UP (serious or not) that does not appear to have a reasonable 
relationship to the use of study drug. 
 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events  
Rules for contraception:   
If fertile, both males and females must agree to use effective birth control. Women of childbearing 
potential must use highly effective methods (defined as those resulting in a failure rate of <1% per year 
when used consistently and correctly) for the duration of study treatment and for 12 months after last 
dose of study drug. The contraceptive methods considered highly effective are intrauterine devices and 
hormonal contraceptives (contraceptive pills, implants, transdermal patches, hormonal vaginal devices, 
or injections with prolonged release). 


 
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31 
 
Before study enrollment, subjects must agree to take appropriate measures to avoid pregnancy. Report 
any pregnancy that occurs in a patient or patient’s partner from the time of consent to 365 days after 
the last dose of study drug. Record any occurrence of pregnancy in the patient’s medical records and 
notify the treating physician within 24 hours of learning of the event. Abortion, whether therapeutic, 
elective or spontaneous, will be reported as an SAE.  
 
A patient must immediately inform the investigator if the patient or patient’s partner becomes pregnant 
from the time of consent to 365 days after the last dose of study drug. Any female patients receiving 
pacritinib PO who become pregnant must immediately discontinue the drug. The investigator should 
counsel the patient, discussing any risks of continuing the pregnancy and any possible effects on the 
fetus. Although pregnancy itself is not regarded as an AE, the outcome will need to be documented. 
Report any pregnancy that occurs in a subject or subject’s partner from the time of consent to 365 days 
after the last dose of study drug. Record any occurrence of pregnancy on appropriate case report form 
and fax it to Cell Therapeutics, or designee, within 24 hours of learning of the event. The pregnant 
female will be followed for outcome, which is defined as elective termination of the pregnancy, 
miscarriage, or delivery of the fetus. For pregnancies with an outcome of live birth, the newborn infant 
will be followed until 30 days old by completing the Pregnancy Report Form Part II. Any congenital 
anomaly/birth defect noted in the infant must be reported as an SAE.  
 
Expedited Reporting Requirements for Serious Adverse Events  
 
Serious, unexpected, and suspected adverse events must be reported to FDA, local IRB, and Cell 
Therapeutics within 24 hours of the principal investigator’s knowledge of the event.  
Such IND safety reports should be submitted in a narrative format or on FDA Form 3500A or in an 
electronic format that FDA can process, review and archive.  
 
 
CTI Pharmacovigilance 
FAX #: + 1 866 660 8967 
E-mail: pv@ctiseattle.com 
 
The study number should be referenced on the fax or subject line of the notification. Additional follow-
up information should be completed on a SAE follow-up form as soon as it becomes available and 
should cross reference the initial SAE report form. 
 
Routine Adverse Event Reporting 
Adverse events which are not serious, unexpected and suspected do not require expedited reporting, 
but rather will be submitted per local IRB standards on an annual basis or more frequently as required. 
 
Type and Duration of Follow-up of Patients after Adverse Events  
AEs and SAEs that are encountered during the protocol-specified AE reporting period should be 
followed to resolution, or until the investigator assesses the patient as stable, or the patient is lost to 
follow-up or withdraws consent. 
 
4. 
Suspension/Termination 
The PMC and/or the IRB may vote to suspend or terminate approval of a research study 
not being conducted in accordance with the IRB, the Cancer Center and/or regulatory 
requirements or that has been associated with unexpected problems or serious harm to 
subjects.  The PMC/IRB will notify the PI in writing of such suspension or terminations.  It 
is the responsibility of the PMC/IRB Chairperson to ensure prompt written notification of 


 
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any suspensions or terminations of PMC/IRB approval to the relevant Federal Agencies, 
including OHRP, FDA, and if applicable, the Affiliate Program. 
 
5. 
Trial Discontinuation 
For reasonable cause the Investigator and/or Moffitt Cancer Center may terminate this 
study prematurely. Conditions that may warrant termination include, but are not limited 
to: the discovery of an unexpected, significant, or unacceptable risk to the patients enrolled 
in the study or if the accrual goals are met. A written notification of termination will be 
issued. 
External study site compliance 
 
Compliance to the Protocol and Adherence to Moffitt External Site Coordination Handbook 
Moffitt is responsible for monitoring each sites compliance to adherence to applicable Moffitt External Site 
Coordination Handbook. In coordination with the Monitoring office, the ESC Office assists to monitor 
compliance to the protocol.  
 
 
External Site Access to Clinical Trial Database 
To obtain access to OnCore, the External Site Coordinator will supply forms required to be completed by 
the site staff. Once the completed forms are received, the site coordinator will receive VPN access, 
logon/password, and information on how to access OnCore. The ESC office will provide OnCore training to 
the site once initial access is granted and on an ongoing basis, as needed.  
 
Registration Procedures for External Sites 
All external enrolled subjects must be registered with the External Site Coordination (ESC) office to be able 
to participate in a trial. The participating site must email the completed current eligibility checklist, 
registration form, all supporting documents, and signed, unredacted informed consent to the Coordinating 
Center. Unsigned or incomplete forms will be returned to the site. Once documents are received, the ESC 
Coordinator will review them to confirm eligibility and complete the registration process. If eligibility cannot 
be confirmed, the research coordinator will query the site for clarification or additional documents as 
needed. Subjects failing to meet all study eligibility requirements will not be registered and will be unable to 
participate in the trial. 
 
Upon completion of registration, the ESC Coordinator will provide the participating site with the study 
sequence number and, when applicable, randomization information. Within 48 hours after registration, it is 
the site’s responsibility to: 
Enter the on-study patient information into the Oncore database 


 
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33 
Order investigational agent(s) if indicated per protocol 
 
 
It is the responsibility of the participating Investigator or designee to inform the subject of the research 
treatment plan and to conduct the study in compliance with the protocol as agreed upon with Moffitt 
Cancer Center and approved by the site’s IRB. 
To register a patient, send the completed signed eligibility checklist along with the patient registration form 
and supporting documentation to the ESC via email at ESC_Partnerships@Moffitt.org, Monday through 
Friday between 8:00AM and 5:00PM (EST). If a short turnaround time is required between registration and 
first treatment, please consider discussing this with you ESC Coordinator and, if possible, submit a partial 
submission.  
 
Required Documentation for External Sites 
Before the study can be initiated at any site, the site will be required to provide regulatory documentation to 
the External Site Coordination (ESC) office at Moffitt Cancer Center. Sites must provide a copy of their 
informed consent to the ESC office for review and approval prior to submission of any documents to the 
site’s IRB. Any changes requested by the site’s IRB must be provided to the ESC staff for review and 
approval prior to resubmission to the IRB. 
 
The ESC office must receive the following trial specific documents either by hardcopy  or email before a 
site can be activated for any trial. All corresponding updates to these documents are required to be 
submitted to the ESC office throughout the trial: 
 
• 
IRB Approval Letter that includes the protocol version and date 
• 
FDA Form 1572 Protocol Signature Page 
• 
Investigator Brochure (or Package Insert) Signature Page(s) 
• 
IRB Approved Consent Form 
• 
Site Delegation of Authority Log 
• 
Signed Financial Interest Disclosure Forms ( For all individuals listed on the 1572) 
• 
Investigator/Personnel documents (CVs, licenses, GCP and HSP training certificates, etc.) as 
needed 
• 
Laboratory Documents (certifications, normal ranges, etc.) as needed  
• 
Signed Clinical Trial Agreement 
• 
Protocol specific documentation as needed 
 


 
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A study initiation teleconference will be held prior to the start of any study related activity at the site. 
Attendance is required for:  
The site PI and appropriate research staff 
Moffitt PI and ESC Coordinator 
 
The requirements of the protocol and all associated procedures and processes will be reviewed and 
agreed upon prior to the activation of the study. The ESC utilizes the EDC system, OnCore. OnCore 
training will be scheduled, if indicated, with the appropriate staff from the site. 
External 
sites 
are 
required 
to 
send 
updated 
documentation 
to 
the 
ESC 
Office 
at 
ESC_Partnerships@Moffitt.org within 10 business days of updating.   
 
SAE Reporting Special Language for External Sites 
 
Information about all serious adverse events will be collected and recorded. To ensure patient safety, each 
serious adverse event must be reported to the PI and to the sponsor expeditiously. Moffitt Cancer Center 
and all participating sites will report SAEs by completing an SAE report in OnCore, the electronic data 
capture system. The SAE Report from OnCore must be signed and reported by email 
(ESC_Partnerships@moffitt.org) to the External Site Coordination (ESC) office within 2 working days. If 
applicable, the site should also follow protocol guidelines for additional reporting to Financial Sponsors and 
government agencies. 
 
External Site Monitoring and Reporting  
The Coordinating Center will implement ongoing monitoring activities to ensure that Participating 
Institutions are complying with regulatory and protocol requirements, data quality, and participant safety. 
Monitoring practices may include but are not limited to source data verification, and review and analysis of 
eligibility requirements, informed consent procedures, adverse events and all associated documentation, 
review of study drug administration/treatment, regulatory files, protocol departures reporting, pharmacy 
records, response assessments, and data management. All monitoring efforts will occur based on the 
protocol specific monitoring plan. Following each monitoring visit, a monitoring follow-up report will be 
provided to the Participating Site (i.e. Site PI and Coordinator). The monitoring report will summarize any 
issued queries or data clarification requests, identify any reportable events or required follow-up on prior 
events and will specify details of any non-compliance. Participating Sites are requested to respond to all 
queries and data clarifications requests within 20 business days. The Moffitt Cancer Center Protocol 
Monitoring Committee will review all monitoring reports and issue resolution. This Committee reserves the 
right to close accrual for non-compliance to monitoring. 
 
 


 
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35 
 
 
 
 
 
 
 
 
VII. 
Ethics 
This study will be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines, 
including parts 50 and 56 concerning informed consent and IRB regulations) applicable 
government regulations and Institutional research policies and procedures. 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  This consent form will be submitted with the protocol for review and approval by the IRB 
for the study.  The formal consent of a subject, using the IRB-approved consent form, will be 
obtained before that subject undergoes any study procedure.   
This protocol and any amendments will be submitted to a properly constituted Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the study 
conduct.  IRB approval will be secured prior to commencement of this study. 
 
VIII. 
Publication policy 
a. The primary investigator is responsible for analyzing the data and drafting a manuscript for 
publication. 
b. Secondary investigators will offer critical review of this manuscript and therefore will be cited 
as secondary authors. 
 
IX. 
Records Retention 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents pertaining to the 
conduct of this study and the distribution of investigational drug, including CRFs, consent forms, 
laboratory test results, and medication inventory records, must be retained by the Principal 
Investigator for 2 years after marketing application approval.  If no application is filed, these 
records must be kept 2 years after the study is discontinued and the U.S. FDA and the 
applicable national and local health authorities, including the National Heart, Lung, and Blood 
Institute (NHLBI), are notified. 


 
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36 
 
X. 
References:  
 
 
1. 
Betts BC, Abdel-Wahab O, Curran SA, et al. Janus kinase-2 inhibition induces durable 
tolerance to alloantigen by human dendritic cell-stimulated T cells yet preserves immunity to recall 
antigen. Blood 2011;118:5330-9. 
 
2. 
Betts BC, Sagatys EM, Veerapathran A, et al. CD4+ T cell STAT3 phosphorylation 
precedes acute GVHD, and subsequent Th17 tissue invasion correlates with GVHD severity and 
therapeutic response. Journal of leukocyte biology 2015. 
 
3. 
Spoerl S, Mathew NR, Bscheider M, et al. Activity of therapeutic JAK 1/2 blockade in 
graft-versus-host disease. Blood 2014;123:3832-42. 
 
4. 
Choi J, Cooper ML, Alahmari B, et al. Pharmacologic blockade of JAK1/JAK2 reduces 
GvHD and preserves the graft-versus-leukemia effect. PloS one 2014;9:e109799. 
 
5. 
Komrokji RS, Seymour JF, Roberts AW, et al. Results of a phase 2 study of pacritinib 
(SB1518), a JAK2/JAK2(V617F) inhibitor, in patients with myelofibrosis. Blood 2015;125:2649-55. 
 
6. 
Jayaraman R, Pasha MK, Williams A, Goh KC, Ethirajulu K. Metabolism and Disposition 
of Pacritinib (SB1518), an Orally Active Janus Kinase 2 Inhibitor in Preclinical Species and Humans. 
Drug metabolism letters 2015. 
 
7. 
Younes A, Romaguera J, Fanale M, et al. Phase I study of a novel oral Janus kinase 2 
inhibitor, SB1518, in patients with relapsed lymphoma: evidence of clinical and biologic activity in 
multiple lymphoma subtypes. J Clin Oncol 2012;30:4161-7. 
 
8. 
Hart S, Goh KC, Novotny-Diermayr V, et al. Pacritinib (SB1518), a JAK2/FLT3 inhibitor 
for the treatment of acute myeloid leukemia. Blood cancer journal 2011;1:e44. 
 
9. 
Heine A, Held SA, Daecke SN, et al. The JAK-inhibitor ruxolitinib impairs dendritic cell 
function in vitro and in vivo. Blood 2013;122:1192-202. 
 
10. 
Heine A, Brossart P, Wolf D. Ruxolitinib is a potent immunosuppressive compound: is it 
time for anti-infective prophylaxis? Blood 2013;122:3843-4. 
 
11. 
Zorn E, Nelson EA, Mohseni M, et al. IL-2 regulates FOXP3 expression in human 
CD4(+)CD25(+) regulatory T cells through a STAT-dependent mechanism and induces the expansion 
of these cells in vivo. Blood 2006;108:1571-9. 
 
12. 
Zeiser R, Leveson-Gower DB, Zambricki EA, et al. Differential impact of mammalian 
target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional 
CD4+ T cells. Blood 2008;111:453-62. 
 
13. 
Kusaba H, Ghosh P, Derin R, et al. Interleukin-12-induced interferon-gamma production 
by human peripheral blood T cells is regulated by mammalian target of rapamycin (mTOR). J Biol 
Chem 2005;280:1037-43. 
 
14. 
Pidala J, Kim J, Alsina M, et al. Prolonged sirolimus administration after allogeneic 
hematopoietic cell transplantation is associated with decreased risk for moderate-severe chronic graft 
vs. host disease. Haematologica 2015. 
 
15. 
Pidala J, Kim J, Jim H, et al. A randomized phase II study to evaluate tacrolimus in 
combination with sirolimus or methotrexate after allogeneic hematopoietic cell transplantation. 
Haematologica 2012;97:1882-9. 
 
16. 
Yu Y, Wang D, Liu C, et al. Prevention of GVHD while sparing GVL effect by targeting 
Th1 and Th17 transcription factor T-bet and RORgammat in mice. Blood 2011;118:5011-20. 
 
17. 
Bossard C, Malard F, Arbez J, et al. Plasmacytoid dendritic cells and Th17 immune 
response contribution in gastrointestinal acute graft-versus-host disease. Leukemia 2012;26:1471-4. 
 
18. 
Littman DR, Rudensky AY. Th17 and regulatory T cells in mediating and restraining 
inflammation. Cell 2010;140:845-58. 
 
19. 
Laurence A, Tato CM, Davidson TS, et al. Interleukin-2 signaling via STAT5 constrains T 
helper 17 cell generation. Immunity 2007;26:371-81. 


 
Version 8.0 
 
 
 
Version date: 03-02-2022 
37 
 
20. 
Kappel LW, Goldberg GL, King CG, et al. IL-17 contributes to CD4-mediated graft-
versus-host disease. Blood 2009;113:945-52. 
 
21. 
Laurence A, Amarnath S, Mariotti J, et al. STAT3 transcription factor promotes instability 
of nTreg cells and limits generation of iTreg cells during acute murine graft-versus-host disease. 
Immunity 2012;37:209-22. 
 
22. 
Hart S, Goh KC, Novotny-Diermayr V, et al. SB1518, a novel macrocyclic pyrimidine-
based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies. Leukemia 2011;25:1751-
9. 
 
23. 
Poulsen A, William A, Blanchard S, et al. Structure-based design of oxygen-linked 
macrocyclic kinase inhibitors: discovery of SB1518 and SB1578, potent inhibitors of Janus kinase 2 
(JAK2) and Fms-like tyrosine kinase-3 (FLT3). Journal of computer-aided molecular design 
2012;26:437-50. 
 
24. 
Mesa RA, E. M, Szoke A, et al. Results of the PERSIST-1 phase III study of pacritinib 
(PAC) versus best available therapy (BAT) in primary myelofibrosis (PMF), post-polycythemia vera 
myelofibrosis (PPV-MF), or post-essential thrombocythemia-myelofibrosis (PET-MF). 2015 ASCO 
Annual Meeting2015. 
 
25. 
Pidala J, Kim J, Jim H, et al. A randomized phase II study to evaluate tacrolimus in 
combination with sirolimus or methotrexate after allogeneic hematopoietic cell transplantation. 
Haematologica 2012. 
 
26. 
Cutler C, Logan B, Nakamura R, et al. Tacrolimus/sirolimus vs tacrolimus/methotrexate 
as GVHD prophylaxis after matched, related donor allogeneic HCT. Blood 2014;124:1372-7. 
 
27. 
Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD 
Grading. Bone Marrow Transplant 1995;15:825-8. 
 
28. 
Martin PJ, McDonald GB, Sanders JE, et al. Increasingly frequent diagnosis of acute 
gastrointestinal graft-versus-host disease after allogeneic hematopoietic cell transplantation. Biology of 
blood and marrow transplantation : journal of the American Society for Blood and Marrow 
Transplantation 2004;10:320-7. 
 
29. 
Howard CA, Fernandez-Vina MA, Appelbaum FR, et al. Recommendations for donor 
human leukocyte antigen assessment and matching for allogeneic stem cell transplantation: consensus 
opinion of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). Biology of blood and 
marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 
2015;21:4-7. 
 
30. 
Pidala J, Kim J, Anasetti C, et al. Pharmacokinetic targeting of intravenous busulfan 
reduces conditioning regimen related toxicity following allogeneic hematopoietic cell transplantation for 
acute myelogenous leukemia. J Hematol Oncol 2010;3. 
 
31. 
Perkins J, Kim J, Anasetti C, et al. Pharmacokinetically Targeted Intravenous Busulfan 
Combined with Fludarabine (BuFlu) as Conditioning Prior to Allogeneic Peripheral Blood Hematopoietic 
Cell Transplant: Pretransplant Predictors of Outcomes. Blood 2009;114:1299-. 
 
32. 
Pidala J, Kim J, Anasetti C, et al. Targeted i.v. BU and fludarabine (t-i.v. BU/Flu) 
provides effective control of AML in adults with reduced toxicity. Bone marrow transplantation 
2011;46:641-9. 
 
33. 
Ho VT, Cutler C, Carter S, et al. Blood and marrow transplant clinical trials network 
toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell 
transplantation. Biol Blood Marrow Transplant 2005;11:571-5. 
 
34. 
McDonald GB, Slattery JT, Bouvier ME, et al. Cyclophosphamide metabolism, liver 
toxicity, and mortality following hematopoietic stem cell transplantation. Blood 2003;101:2043-8. 
 
35. 
Carreras E, Bertz H, Arcese W, et al. Incidence and outcome of hepatic veno-occlusive 
disease after blood or marrow transplantation: a prospective cohort study of the European Group for 
Blood and Marrow Transplantation. European Group for Blood and Marrow Transplantation Chronic 
Leukemia Working Party. Blood 1998;92:3599-604. 
 
36. 
Cutler C, Stevenson K, Kim HT, et al. Sirolimus is associated with veno-occlusive 
disease of the liver after myeloablative allogeneic stem cell transplantation. Blood 2008;112:4425-31. 


 
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38 
 
37. 
Ho VT, Revta C, Richardson PG. Hepatic veno-occlusive disease after hematopoietic 
stem cell transplantation: update on defibrotide and other current investigational therapies. Bone 
Marrow Transplant 2008;41:229-37. 
 
38. 
Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD 
Grading. Bone Marrow Transplant 1995;15:825-8. 
 
39. 
Fine JP, Gray RJ. A Proportional Hazards Model for the Subdistribution of a Competing 
Risk. Journal of the American Statistical Association 1999;94. 
 
40. 
Mant J, Doust J, Roalfe A, et al. Systematic review and individual patient data meta-
analysis of diagnosis of heart failure, with modelling of implications of different diagnostic strategies in 
primary care. Health Technol Assess 2009;13:1-207, iii. 
 


 
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39 
 
XI. 
APPENDICES 
 
Appendix A: Acute GVHD grading system  
 
Bone Marrow Transplant. 1995 Jun;15(6):825-8. 
1994 Consensus Conference on Acute GVHD Grading. 
Przepiorka D1, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. 
 


 
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 Appendix B: comorbid conditions 
 
i. Comorbidity score per Sorror, et al.  
 
Comorbidity 
Definition of comorbidities included in the new HCT-CI 
HCT-CI weighted scores 
Arrhythmia 
Atrial fibrillation or flutter, sick sinus syndrome, or venricular arrhythmias 
1 
Cardiac 
Coronary artery disease, congestive heart failure, myocardial infarction, or EF 
<50% 
1 
Inflammatory bowel diseases 
Crohn disease or ulcerative colitis 
1 
Diabetes 
Requiring treatment with insulin or oral hypoglycemics but not diet alone 
1 
Cerebrovascular disease 
Transient ischemic attack or cerebrovascular accident 
1 
Psychiatric disturbance 
Depression or anxiety requiring psychiatric consult or treatment 
1 
Hepatic, mild 
Chronic hepatitis, bilirubin > ULN to 1.5 X ULN, or AST/ALT > ULN to 2.5 X 
ULN 
1 
Obesity 
Patients with a body mass index >35 kg/m2 
1 
Infection 
Requiring continuation of antimicrobial treatment after day 0 
1 
Rheumatologic 
SLE, RA, polymyositis, mixed CTD, or polymyalgia rheumatica 
2 
Peptic ulcer 
Requiring treatment 
2 
Moderate/severe renal 
Serum creatinine >2 mg/dL, on dialysis, or prior renal trnasplant 
2 
Moderate pulmonary 
Adjusted DLCO and/or FEV1 66%=80% or dyspnea on slight activity 
2 
Prior solid tumor 
Treated at any time point in the patient’s past medical history, excluding 
nonmelanoma skin cancer 
3 
Heart valve disease 
Except mitral valve prolapse 
3 
Severe pulmonary 
Adjusted DLCO and/or FEV1 <65% or dyspnea at rest or requiring oxygen 
3 
Moderate/severe hepatic 
Liver cirrhosis, bilirubin > 1.5 X ULN, or AST/ALT > 2.5 X ULN 
3 
*composite score obtained by summing total points 
*psychiatric disturbance: only those with psychiatric disturbance (such as depression and/or anxiety) 
requiring therapy or treatment will be assigned 1 point on this measure. 
*modification made to “pulmonary” co-morbidity: given marked discrepancy in frequency distribution of 
reduced DLCO in analysis of 59 contemporary patients from our center compared to published 
standards, decrement in DLCO alone will not factor into calculation of “pulmonary” comorbidity. Only 
those with DLCO < 50% will be considered to have “severe pulmonary” comorbidity and be excluded 
from the trial. 
 


 
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Appendix C: anticipated transplant related toxicities 
 
 
 
 


 
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 Appendix D: Study Calendar 
Assessment 
Day ‐45 to ‐5 
(Screening 
period)* 
Day 
0 
Day 
+7 
Day 
+14 
Day 
+21 
Day 
+30 
Day 
+60 
Day 
+69 
Day 
+83 
Day 
+100 
Day 
+130 
2‐D Echocardiogram 
X 
 
X 
 
 
 
X 
 
History & Physical, CBC with 
diff, liver function tests, and 
comprehensive metabolic 
panel 
X  
X 
X 
X 
X 
X 
X 
 
 
X 
X 
Disease status 
X 
 
 
 
 
X 
 
 
 
X 
X 
PFT, hepatitis B, C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
X 
 
 
 
X 
X 
 
 
 
 
TT, PT, PTT 
X 
 
 
 
 
X 
X 
 
 
 
 
Acute GVHD scoring38 
(GVHD will be assessed and 
scored at least weekly per 
standard practice, and data 
will be captured at the 
defined intervals:  days 0‐
+30, +31‐60, +61‐+100, and 
+101‐+130) 
 
 
 
 
 
X 
X 
 
 
X 
X 
Research phone call to 
instruct patient to taper 
study drug** 
 
 
 
 
 
 
 
X 
X 
 
 
8 green top tubes (~5.5 
tablespoons) of peripheral 
blood for T cell subset and 
STAT3/STAT5/S6/H3ser10 
studies1  
X 
 
 
 
X 
 
 
 
 
X 
 
IDP‐Treg panel (flow 
cytometry) 
X 
 
 
 
X 
 
 
 
 
X 
 
Phase I trial only 
assessments:*** 
 
PK monitoring 
EKG  
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
PAC/SIR/TAC trial monitoring and interval assessments 
A 3‐day grace period is allowed for each study item from day‐45 to +30, and +14 days for all points 
thereafter.  
*Procedures (routine pre‐HCT vital organ testing) done prior to informed consent signing can be used 
for eligibility determination within the stated 45 day window 
** for research phone call to instruct patient on taper, a +/‐ 3 day window is provided. 
***for phase I assessments of timed PK samples and post‐dose EKG, a +/‐ 1 hour window is provided. 
1Day +21 and Day +100 samples will be collected on patients who partially withdraw consent 
As detailed in the protocol text, patients in the phase I component of the trial will also complete day 0 
and day 21 serial blood samples for PK monitoring of pacritinib, and will also have EKG monitoring. 
Patients in the phase I component will otherwise also complete all the other assessments outlined in 
this study calendar.