Clinical trial NCT02410551
Conditions: Myeloproliferative Diseases
Keywords: Myeloproliferative Diseases Myeloproliferative Neoplasms MPN Myelofibrosis Polycythemia vera PV Essential thrombocythemia Allogeneic stem cell transplantation Allo TP Pacritinib Busulfan Busulfex Myleran Questionnaires Surveys Phone calls
Sponsor: M.D. Anderson Cancer Center
Start date: 2015-06-15; Completion date: 2017-01-20
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn if giving pacritinib before standard of care drugs followed by an allogeneic stem cell transplant can help to control myeloproliferative neoplasms. The safety of this therapy will also be studied.

Detailed description:
Study Drug Administration:

If you are found to be eligible to take part in this study, you will take pacritinib at about the same time each day by mouth, 2 times each day. Your doctor will tell you when to start and stop taking pacritinib. You may be able to take the drug for about 2-6 months depending on how you tolerate the drug and when your transplant date is. If you do not receive your transplant, you may be able to continue taking the study drug as long as the doctor thinks it is in your best interest.

You must swallow the capsules whole with a glass (about 8 ounces) of water. Do not open, break, or chew the capsules.

If you vomit or miss a dose of pacritinib, take your next dose of pacritinib at your regular time. Do not "make up" a missed or vomited dose.

You will be given a study drug diary to write down what time you take each dose of pacritinib. You need to bring the study drug diary, any leftover study drug, and any empty study drug containers with you to each study visit.

The dose of pacritinib you receive may be lowered or stopped, if the doctor thinks it is needed.

About 21 days after your last dose of pacritinib, you will given standard of care drugs and you will have an allogeneic stem cell transplant. Your doctor will explain this treatment and the stem cell transplant to you in more detail. You will be required to sign a separate consent form.

Study Visits:

One (1) time each month:

* You will have a physical exam.
* Blood (about 2 teaspoons) will be drawn for routine tests and to check your kidney and liver function.
* You will have an electrocardiogram (EKG -- a test that measures the electrical activity of the heart).

On Day 14 (+/- 2 days) of of Cycle 1, blood (about 2 teaspoons) will be drawn for routine tests and to check your kidney and liver function. You can have this blood drawn at a local lab or clinic that is closer to your home. The results will be sent to the study doctor at MD Anderson.

During Week 2 of Cycle 1, a member of the study staff will call to ask you about any symptoms you may be having. This call should last about 5-10 minutes.

Length of Study:

You will be on study for up to 1 year after the transplant. You may be taken off study early if the disease gets worse, if you have any intolerable side effects, of if you are unable to follow study directions.

Your participation on this study will be over after about 1 year of follow-up tests.

End-of-Study Visit:

Within about 7 days after your last dose of pacritinib, but before your stem cell transplant:

* You will have a physical exam and an ultrasound, MRI, or CT scan of your abdomen to measure your liver and spleen.
* You will have an EKG.

Before your transplant, you will have a bone marrow biopsy/aspiration to check the status of the disease.

Follow-Up Tests:

You will have follow-up visits at about 1, 3, 6, and 12 months after the transplant:

* You will complete 3 questionnaires about your symptoms and quality of life. It should take about 20-30 minutes to complete the questionnaires.
* At Month 3, you will have a physical exam and an ultrasound, MRI, or CT scan of your abdomen to measure your liver and spleen. This will be repeated at Month 12, if your doctor thinks it is needed.
* At Months 3 and 12, you will have a bone marrow biopsy/aspiration to check the status of the disease.

This is an investigational study. Pacritinib is not FDA approved or commercially available. It is currently being used for research purposes only. The study doctor can explain how the study drug is designed to work.

Up to 40 participants will be enrolled in this study. All will take part at MD Anderson.

Arms: arm 1: Participants start Pacritinib 200 mg by mouth twice a day. Participants proceed to transplant after 60 days of Pacritinib but not more than 180 days. Pacritinib stopped 21 days prior to starting preparative regimen for standard of care stem cell transplantation (SOC Allo TP). SOC transplant conditioning with Fludarabine and Busulfan AUC of 4000 microMol-min per day providing that pharmacokinetic can be done, otherwise Busulfan dose given as a fixed dose of 100 mg/m2 daily for four days. Questionnaires about symptoms and quality of life completed at baseline, 1, 3, 6, and 12 months after transplant. Phone calls made by study staff to participant on second and third week of each month.
Interventions: intervention 1: Pacritinib intervention 2: Busulfan intervention 3: Questionnaires intervention 4: Phone Calls intervention 5: Allogeneic Stem Cell Transplantation intervention 6: Fludarabine
Intervention descriptions: intervention 1: 200 mg by mouth twice a day for 60 days. intervention 2: Busulfan AUC of 4000 microMol-min per day providing that pharmacokinetic can be done, otherwise Busulfan dose given as a fixed dose of 100 mg/m2 daily for four days. intervention 3: Questionnaires completed at baseline, 1, 3, 6, and 12 months after transplant. intervention 4: Phone calls made by study staff to participant on second and third week of each month. intervention 5: Allogeneic stem cell transplantation (Allo TP) 60 days after starting Pacritinib but not more than 180 days. intervention 6: Fludarabine taken along with Busulfan as per standard of care as preparative regimen for allogeneic stem cell transplantation (Allo TP).

Protocol documents:
Prot_SAP_000.pdf: 
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Protocol Page
Pacritinib Prior to Transplant for Patients with Myeloproliferative Neoplasms (MPN)
2014-0786
Core Protocol Information
Short Title 
Pacritinib before transplant for MPN
Study Chair: 
Uday Popat
Additional Contact:
Becky A. McMullin
Peggy S. LeCompte
Tingting Liu
Department:
Stem Cell Transplantation and Cellular Therapy
Phone:
713-792-8750
Unit:
0423
Full Title: 
Pacritinib Prior to Transplant for Patients with Myeloproliferative Neoplasms (MPN)
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 01/20/2017
Version:
05
Submitted by:
Peggy S. LeCompte--1/14/2016 3:04:27 PM
OPR Action:
Accepted by:  Rosheta McCray -- 2/5/2016 2:35:16 PM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


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Protocol Body
1.0 Objectives
Primary Objective:
To compare the progression-free survival of adding Pacritinib prior to standard of care 
allogeneic stem cell transplantation (SOC Allo TP) conditioning with Fludarabine and Busulfan 
AUC of 4000 microMol-min per day to historical controls in patients with myelofibrosis.
Secondary Objectives:
To evaluate safety and efficacy of this therapy as determined by:
1.1 Neutrophil and platelet engraftment.
1.2 Non-relapse mortality at one year post transplant.
1.3 Overall survival at one year post transplant.
1.4 Liver and spleen response to Pacritinib.
1.5
Immune recovery.
1.6 Quality of life and symptom score.
1.7    Primary and secondary graft failure.
1.8
Complete remission.
1.9
Relapse.
To evaluate the use of marrow specific quantitative MRI (qMRI) sequences in assessment of 
disease burden, including:
1.10
Diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADP) maps
1.11
Marrow fat quantification sequences
2.0 Background
2.1. Overview of the myeloproliferative disorders:
The myeloproliferative disorders (MPD) are chronic hematological malignancies originating at 
the level of pluripotent hematopoietic stem cells.
1,2 The discovery that JAK2 mutations are found 
in virtually all patients with PV and approximately 50 percent of those with either ET or PMF, 
has refined current diagnostic criteria in classic MPN 
•  Polycythemia vera (PV) is considered to be present when an otherwise unexplained 
increased hematocrit/red blood cell mass is accompanied by the presence of a JAK2 
mutation along with a decreased erythropoietin level
•  Primary myelofibrosis (agnogenic myeloid metaplasia, chronic idiopathic myelofibrosis) 
is characterized by the presence of bone marrow fibrosis that cannot be attributed to 
another myeloid disorder such as CML, PV, ET, or MDS. 
•  Essential thrombocythemia (ET) is a diagnosis of exclusion, representing clonal or 
autonomous thrombocytosis not classifiable as PV, PMF, CML, or MDS. 
The concepts common to these disorders are:
 
1)
Clonal hematopoiesis
2)
Transformation to acute leukemia (AL): Up to 10% of PV & ET patients develop AL.


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3)
Progression to myelofibrosis: Up to 10% of patients with ET and PV progress to 
myelofibrosis with development of massive hepatosplenomegaly, cytopenias and 
transfusion dependency. Patients who have progressed to myelofibrosis and/or to acute 
leukemia have a poor prognosis.
2.2. Idiopathic Myelofibrosis: 
Idiopathic myelofibrosis (IM) (agnogenic myeloid metaplasia, myelofibrosis with myeloid 
metaplasia) is a clonal myeloproliferative disorder due to an acquired somatic mutation of a 
hematopoietic progenitor cell, resulting in clonal erythrocytes, platelets, granulocytes, 
monocytes and their precursors. These malignant megakaryocytes and monocytes secrete 
fibrogenic cytokines – TGF, PDGF, FGF, which cause polyclonal fibroblast proliferation, 
collagen and reticulin deposition, and eventual bone marrow fibrosis, the hallmark of the 
disease. This process progresses to bone marrow failure and extramedullary hematopoiesis.
1,3,4
The annual incidence of IM ranges from 0.5 –1.5 per 100,000, while the median age at 
diagnosis is 55-65 years. Most patients with IF present with anemia, marked splenomegaly, 
early satiety and constitutional symptoms. During the clinical course, most experience 
progressive anemia requiring frequent blood transfusions, and death occurs eventually due to 
bone marrow failure or leukemic transformation. Current treatment of IM is palliative, consisting 
of supportive care with blood transfusions, splenectomy 5, splenic radiation, hydroxyurea, and 
more recently thalidomide.
6-9  None of these therapies alters the natural history of this disease. 
The median survival is 6.5 years from diagnosis
10, but varies from 2 years to greater than 10 
years depending on presence or absence of well-defined prognostic indicators.  A simple but 
widely accepted scoring system using two of these factors, namely Hb <10 gm/dl and WBC 
>30,000/l or <4,000/l separates patients into three groups with low (0 factor), intermediate (1 
factor), and high (2 factors) risks, associated with a median survival of 93, 26, and 13 months. A 
more recent study that included anemia (Hb < 10 gm/dl), advanced age (> 64), constitutional 
symptoms (fever, night sweats, weight loss), leukocytosis (>25,000/l), circulating blasts (≥ 1%), 
thrombocytopenia, need for blood transfusion and high-risk cytogenetic abnormalities outlines 4 
prognostic group with a median survival of 185, 78, 35, and 16 months respectively.
4,11-13  Stem 
cell transplantation is an appropriate option for later two groups.  Molecular studies have shown 
that mutations are present in 31 - 44% patients with myelofibrosis in ASXL1, EZH2, SRSF2, IDH 
1 and 2, genes. These also have prognostic value independent of International prognostic 
scoring system with a median survival of 2.6, 7.0, and 12.3 years of 2 or more mutations, 1 
mutation, and no mutation in these 5 genes again identifying a poor prognostic subgroup 
suitable for stem cell transplantation.
14,15
2.3. Allogeneic stem cell transplantation: 
Allogeneic hematopoietic cell transplantation by eradicating the malignant clone and restoring 
normal hematopoiesis is expected to alter the natural history of IM.
Table 1: Allogeneic Transplantation for Myelofibrosis.
Study 
N
Median Age
NRM
Median Follow up
OS
Guardiola et al
16
55
42
27%
36 months
47%
Bacigalupo et al
17 
46
51
24%
44 months
45%
Robin et al
18
147
53
39%
35 months
39%
Patriarca et al
19
100
49
43%
34 months
42%


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Balen et al
20
289
47
35%/50%
41/46 months
37%/30%
Lussana et al
21
250
56
28%
13 months
55%*
Kroger et al
22
103
55
16%
33 months
67%
Ditschkowsk 
23 
76
45
36%
55 months
53%
Scott
24
170
51
34%
5.9 years
57%
Gupta
25
233
55
24%
50 months
47%
Rondelli et al
26
66
54
22%/59%
24/12 months
75%/32%
Popat et al
27
46
59
13%
25 months
69%
*outcomes for related and unrelated donors respectively, NRM non-relapse mortality, OS overall survival
Due to the uncommon occurrence of this disease and older age at disease onset, majority of 
studies are small and those that included more than 40 patients are summarized in Table 1.
16,28-31 
Transplantation in patients with myelofibrosis is a challenging task. Extramedullary 
hematopoiesis results in massive hepatosplenomegaly and impaired organ function, making 
these patients particularly at high risk of graft rejection and treatment related mortality. A special 
problem area is the treatment of older or debilitated patients. Guardiola published a series of 55 
patients demonstrating inferior results for older patients: Five year survival of 14% in patients 
older than 45 years compared to the 5 year survival of 62% in younger patients
16.  These inferior 
results in older patients and patients with comorbidity who comprise majority of patients with this 
disease make myeloablative transplantation a promising but not suitable therapy for most 
patients with myelofibrosis. Best results of myeloablative transplant using mainly Busulfan and 
cyclophosphamide regimen in patients with median age of 51 show NRM of 38% and OS of 
57%.
24
Another approach would be to use a reduced intensity or a nonmyeloablative conditioning 
regimen, which have been reported to extend allogeneic transplant to older patients and 
patients with other co-morbid medical conditions. We, and others, have shown that reduced 
intensity stem cell transplantation can be safely utilized in older patients and those with 
comorbidities in other hematological malignancies.
 32-37  Rondelli et al and Kroger et al have 
reported encouraging data in multi-institutional small studies of reduced intensity transplantation 
in older patients with myelofibrosis.
30,31  In these retrospective studies with a median age of 54 
years, a non-relapse mortality of 10% - 16% and 3 year overall survival of 84% - 85% was 
reported.  Based on these data multiple centers studied reduced intensity allogeneic 
transplantation in myelofibrosis. Recent analysis of worldwide experience reported to CIBMTR 
registry showed NRM of 24% and OS of 47% 
25. Outcome was significantly inferior with 
unrelated donor. Similarly high NRM of 53% was reported with unrelated donors in a 
prospective study done by MPD research consortium.
38 Best results to date with reduced 
intensity regimen were reported by Kroger et al. NRM was 16% and OS 67% with Busulfan and 
Fludarabine regimen; however 17% of patients had low risk disease and hence expected to 
have better outcome. Moreover, 13% of patients needed stem cell boost for graft failure or weak 
graft or declining chimerism.
 31
2.4 Allogeneic transplantation for Myelofibrosis: M D Anderson data:
At MDACC based on encouraging early data,
30,31 we did a prospective study to evaluate the role 
of allogeneic stem cell transplantation using reduced intensity conditioning regimen of 


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Fludarabine and Busulfan in patients with myelofibrosis (2005-0726). We used the regimen that 
we were using at that time for chronic myeloid leukemia.
39  The regimen was well tolerated with 
very low NRM of 15% even with unrelated donors in contrast to NRM of up to 50% seen in 
some studies. However, the relapse rate was high in the initial cohort of 15 patients.  We 
therefore increased the intensity of conditioning regimen for subsequent patients, giving a 
higher dose of Busulfan after pharmacokinetic analysis. We hypothesized that increased dose 
intensity delivered with PK guidance will reduce relapse rate without increasing non-relapse 
mortality (NRM), thereby improving overall outcome.
27 
23 males and 23 females with a median age of 58 years (27-74) were enrolled. They had   
intermediate (25) or high-risk (21) disease. Median peripheral blood CD 34 count was 52/μl 
(range 1-16430/μl). Donors were matched sibs (19), matched unrelated (23), or mismatched 
unrelated (4). With a median follow up of 2.1 years (range 0.1-6 years), 3 year overall 
survival(OS), event-free survival (EFS),  cumulative incidence (CI) of non-relapse mortality 
(NRM), and CI of relapse were 69%, 50%, 13%, and 37%, respectively. Multivariate Cox 
regression analysis showed that Bu-high dose (HR 0.41; p=0.04) and peripheral blood CD 34 
count (HR 1.7; p=0.03) were significantly associated with EFS, and high CD-34 count was 
significantly associated with OS (HR 1.87; p=0.04). Table 2 shows details of 3 year outcomes of 
low dose and high dose group (Figure 1).  
Table 2
@ 3 years
Bu-High 
(N=31)
B-Low 
(N=15)
Overall Survival
75%
60%
Event Free Survival
61%
27%
Cl of Relapse
29%
53%
Cl of NRM
10%
20%
Figure 1


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For this protocol, therefore we will use this regimen of PK guided Busulfan (daily AUC 4000 
µMol.min) and Fludarabine. We will compare the results of our current study with this historic 
cohort.
Major impediments to stem cell transplant in myelofibrosis:
Myelofibrosis results in extramedullary hematopoiesis, massive hepatosplenomegaly and 
fibrosis in the marrow and there are several major issues unique to it from transplant 
perspective. These include high incidence of graft failure and weak graft after transplant 
necessitating use of stem cell boost
22 and organ dysfunction - particularly involving liver - 
leading to a high incidence of veno-occlusive disease and non-relapse mortality.
40  A safe agent 
that can reduce organomegaly and disease burden pretransplant may improve transplant 
outcome by improving engraftment, reducing organ toxicity and lowering relapse risk. 
Furthermore, it may allow more patients to become eligible for transplant by improving their 
performance status.  A Jak 2 inhibitor might be the answer. 
Jak 2 inhibitors and stem cell transplantation:
Discovery of Jak2 V617F mutation, which makes kinase constitutionally active in patients with 
myeloproliferative disorders led to development several targeted agents including Pacritinib to 
inhibit this pathway. Jak 2 is mutated in up 60% of patients with ET and MF and 98% of patients 
with PV.
41-43  Even in patients without this mutation, this pathway is overactive. Ruxolitinib, a Jak2 
inhibitor, is licensed by FDA for MF reduces splenomegaly, improves constitutional symptoms, 
and improves survival
44,45 both in patients with and without Jak 2 V617F. Early data on its usage 
pre-transplant are conflicting
22,46 47 with excellent outcome reported in some studies, but a 
possible higher complication rate reported in other study. This later study presented as an 
abstract is difficult to interpret, because complications reported are hard to differentiate from 
usual complications seen post-transplant. Pacritinib causes less myelosuppression than 
Ruxolitinib and may be superior to ruxolitinib as a pre-transplant agent to reduce organomegaly 
and to reduce the disease burden.
Pacritinib:


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Pacritinib, a Jak2/Flt 3 inhibitor, has activity in myeloid and lymphoid malignancies.  Currently it 
is in Phase 3 studies in patients with myelofibrosis.  Details of this molecule are in the attached 
investigator brochure and a brief summary follows. It is a potent selective inhibitor of mutant as 
well as normal Jak2 kinase. Preclinical studies showed its activity in suppressing Jak 2 
mediated tumors. PK studies in clinical trials showed slow absorption (Tmax 4-6 hours) and 
dose related increase in systemic exposure up to 400 mg per day. Terminal elimination half-life 
was 47 hours. Food did not impair absorption. At 100 mg/day dose steady state levels 
exceeded IC50 values for inhibition of Jak2/Flt3 kinase. Phase I studies identified 400 mg daily 
as dose for further studies. Dose limiting toxicity included grade 3 QTc prolongation, grade 3 
diarrhea and grade 2 dizziness and blurred vision. Most common adverse events occurring in 
more than 20% were diarrhea, nausea, vomiting, constipation, dyspnea, fatigue and edema. 
Most events were mild to moderate severity. Only grade 3 or higher adverse event occurring in 
more than 10% of patients were anemia or thrombocytopenia (16%). MRI showed ≥ 25% spleen 
volume reduction in 55% of patients. An improvement in all symptoms relevant to myelofibrosis 
was seen. Thus, Pacritinib is very safe and highly effective therapy for patients with 
myelofibrosis and we would like study its role pre-transplant to improve transplant outcomes.
Correlative Research Studies (optional):
To evaluate the effect of the JAK2 inhibitor Pacritinib on immune recovery and 
graft-versus-host disease post-transplant
Janus kinase-2 (JAK2) conveys receptor-binding signals by several inflammatory cytokines, via 
phosphorylation of STAT3. Selective inhibition of JAK2 was shown to induce tolerance to 
allo-antigens, while preserving de novo responses to pathogens 48. Selective JAK2 inhibition 
was also shown to preserve Treg numbers through preservation of the IL-15/JAK3/pSTAT5 
pathway. 
Signaling through IFNγ-receptor, mediated by JAK1/JAK2 and STAT1, has been shown to result 
in increased surface expression of CXCR3, a key chemokine receptor involved in T-cell 
trafficking to sites of inflammation. A recent study in a murine model of GVHD, showed that 
pharmacologic inhibition of IFNγR signaling with inhibitors of JAK1/JAK2 resulted in decreased 
expression of CXCR3 associated with reduced GVHD, mediated by altered trafficking of effector 
T cells to GVHD target organs,
49 providing another mechanism through which selective JAK2 
inhibition could influence GVHD. 
We hypothesize that the Jak 2 inhibitor, Pacritinib will reduce the risk of GVHD in patients with 
myelofibrosis undergoing allogeneic stem cell transplantation, resulting in improved survival. 
To test this hypothesis we propose the following aims:
Aim 1: To determine how Pacritinib affects the balance of Treg/Th1/Th2/Th17 cells. T cells 
collected at multiple time points before and during therapy (as outlined below) will be activated 
via CD3/TCR and CD28 ligation and differentiated according to their cytokine profile into Th1 
(CD4+IFN-γ+), Th2 (CD4+IL-4+), Th17 (CD4+IL-17+) and Tr1 (CD4+IL-10+). Naturally occurring 
Tregs will be defined as CD4+CD25hiFoxp3+CD127lo.
Aim 2: To determine how Pacritinib influences the expression of chemokine receptors on the 
surface of T cells, including CXCR2, CXCR3, CXCR4, CXCR5, CCR3, CCR4, CCR5, CCR6, 


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CCR7, and CCR9 
Aim 3: To determine how Pacritinib influences the pathogen-specific immune responses. 
We will conduct analyses of T cell phenotype, estimate antigen-specific T cell precursor 
frequencies (by intracellular cytokine flow cytometry and peptide/dextramer staining) and 
determine antigen-specific cytokine production capacity (cytokine bead array assay). We will 
perform:
1) Immunophenotypic recovery of naive, stem-like memory, central and effector memory 
CD4+ and CD8+ T cells, using a 10 color flow cytometry panel (CD3, CD4, CD8, 
CD45RA, CD45RO, CCR7, CD62L, CD95, IL-7Rα, IL-2Rα); 
2) The number and function of recovering CMV, T cells capable of responding functionally to 
in vitro stimulation with overlapping pools of peptide by intracellular cytokine detection.
3,5,6  
Aim 4: To determine how Pacritinib influences the phenotype and function of dendritic cells 
(DCs). 
We will characterize DC subsets in PB collected at multiple time points before and during 
therapy (as outlined below) by: 
1) Analysis of DC subsets, myeloid/plasmacytoid and immature/mature, based on 
expression of CD3, CD4, CD14, CD123, CD11c, CD1a, CD1c and CD141; 
2) Determining the expression of DC co-stimulatory molecules involved in APC function 
(HLA-DR, CD80, CD83, and CD86) and chemokine receptors involved in DC homing 
(CCR4, CCR5, CXCR3, CCR10).
Serum samples collected from patients will be assayed for cytokine levels using the BD 
Cytometric Bead Array for Th1/Th2 cytokines (IL-2, IL-4, IL-5, IL-6, IL-10, TNF, IFN-γ) and for 
inflammation (IL-8, IL-1β, IL-6, IL-10, TNF, IL-12p70).
3.0 Patient Eligibility
Inclusion Criteria: 
1.
Patients with Idiopathic Myelofibrosis or Myelofibrosis secondary to Polycythemia Vera or 
Essential Thrombocythemia.
2.
Patients 18 to less than or equal to 70 years.
3.
Patients wanting to pursue transplant. 
4.
Patients must have a Zubrod PS equal or less than 2. 
5.
Calculated creatinine clearance greater than 50ml/min. using the Cockcroft-Gault equation.
6.
Ejection fraction equal or above 40%.
7.
Serum direct bilirubin less than 1 mg/dl (unless due to Gilbert’s syndrome or hemolysis).
8.
SGPT equal or less than 4 x normal values.
9.
Corrected DLCO equal or above 50% of expected.
10. Negative Beta HCG test in a woman with childbearing potential defined as not 
post-menopausal for 12 months or no previous surgical sterilization) and if fertile, males and 
females must agree to use contraceptives. 


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Exclusion Criteria:
1.
Patients with low risk myelofibrosis (Appendix J:DIPSS plus criteria).
2.
Uncontrolled life-threatening infections.
3.
HIV positive. 
4.
Patients with active viral hepatitis.
5.
Prior treatment with Pacritinib.
6.
Prior stem cell transplant.
7.
QTc greater than 450 ms.
8.
CYP3A4 strong or moderate inhibitors/inducers in the past 7 days.
4.0 Treatment Plan
4.1
The investigational agent for this study is Pacritinib.
4.1.1
Patients will start Pacritinib 200 mg po bid.
4.1.2
Patients can proceed to transplant after 60 days of starting Pacritinib but not more than 
180 days. 
4.1.3
Pacritinib will be stopped 21 days prior to starting preparative regimen for SOC Allo TP.
4.1.4 If for whatever reason a patient cannot pursue or receive SOC Allo TP, they will be able 
to continue treatment with Pacritinib until there is evidence of disease progression.
4.1.5   A patient will still be able to proceed to SOC ALLO TP if for any reason they cannot 
complete 60 days of treatment prior to transplant.
4.1.6
If a patient vomits or misses a dose, will continue treatment with the next scheduled 
dose. Missed doses and reason for non-compliance will be recorded.
4.1.7
Every effort should be made to avoid CYP3A4 inducers or inhibitors (see Appendix H) 
while patients are on pacritinib. If concomitant therapy with CYPsA4 inhibitors or 
inducers is medically necessary and there are no available or suitable substitutes, this 
should be documented in the patient's medical record and extreme caution taken with 
their continued use during the study duration. 
4.1.8
Patients will document compliance of taking medication on a patient diary.
4.2
Treatment Interruption:
Safety parameters including AEs, hematology, and serum chemistry will be monitored 
according to the protocol. Pacritinib treatment may be withheld for up to 4 weeks due to 
drug-related toxicities. A longer recovery period may be allowed based on the toxicity, 
but must be agreed upon between the investigator and medical monitor. After treatment 
interruption, patients may resume the pacritinib treatment at the same dose level or at a 
reduced dose level. No dose re-escalation is allowed.
4.3
Pacritinib Dose Management Guidelines for Pacritinib-Related Nonhematologic 
Toxicities:
4.3.1
A maximum of 2 dose reductions is allowed. The first dose reduction will be a 100 mg 
reduction from the original dose. The dose will be reduced to 200 mg Q AM and 100 mg 
Q PM.
4.3.2
The second dose reduction will be another 100 mg reduction and  the dose will be 
reduced to 100 mg BID.
4.3.3
Once the dose is reduced, no re-escalation is allowed.
4.3.4
Dose management for nonhematologic toxicities is summarized in Table 3. 


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Table 3
Treatment Toxicity and Dose Management: Pacritinib-Related Nonhematologic Toxicities
CTCAE Toxicity Grade Management/ Action
1 or 2
No change.
3
Hold treatment.
If the toxicity resolves to grade ≤ 1 or to the baseline grade within 7 days, 
treatment may be resumed at the same level or the next lower dose, at 
the discretion of the investigator after discussion with the sponsor.
Toxicity that does not resolve to grade ≤ 1 or to the baseline grade 
within 7 days requires dose reduction to the next lower dose level.
4
Hold treatment.
If the toxicity resolves to grade ≤ 1 or to the baseline grade within 7 days, 
treatment may be resumed, but dose will be reduced by one dose level 
from the level at which the toxicity was observed.
If grade 4 toxicity occurs at the lowest dose of 200 mg/day, the patient 
should be discontinued from the study.
4.3.6
The lowest dose of pacritinib used in the study will be 200 mg/day. If toxicity persists 
despite dose reduction to 200 mg/day, the patient should be discontinued from 
treatment.
4.4
Dose Management Guidelines for Hematologic Toxicities:
4.4.1
Myelosuppression is an expected event in patients with MF. However, myelosuppression 
with associated complications such as fever, infection, or bleeding or myelosuppression 
that worsens during treatment (based on local laboratory values) must be reported as an 
AE.
4.4.2
Patients with myelosuppression may receive supportive care including transient use of 
granulocyte colony stimulating factor for the treatment of febrile neutropenia and 
transfusion as clinically indicated.
4.4.3
Patients receiving pacritinib are not allowed to receive hematopoietic growth factors 
such as erythropoietin for the treatment of anemia.
4.4.4
Patients with clinically significant worsening of myelosuppression (as judged by the 
investigator and based on local laboratory values) for more than 7 days or 
myelosuppression associated with infection or bleeding should have pacritinib dosing 
interrupted. Pacritinib may be restarted at a reduced dose once the toxicity has resolved 
to grade ≤ 2 or to the baseline grade and the complications of myelosuppression such as 
infection or hemorrhage have resolved. 
4.5 
Allogeneic graft:
Peripheral blood (PB) or bone marrow (BM) progenitor cells may be used in this study   
peripheral blood will be preferred. 
4.6 
Preparative Regimen:
SOC transplant conditioning with Fludarabine and Busulfan AUC of 4000 microMol-min per day
providing that pharmacokinetic can be done, otherwise Busulfan dose will be given as a fixed 
dose of 100 mg/m
2 daily for four days. A SOC treatment plan and informed consent will be used 
for this.


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4.7
GVHD Prophylaxis and Supportive Care as per standard practice in patients 
receiving allogeneic transplant: 
Recipients of matched related and unrelated donors will receive tacrolimus and Mini 
Methotrexate as per institutional standard.
Recipients of matched  or one antigen mismatched unrelated donors will receive anti thymocyte 
globulin (ATG) tacrolimus and Mini Methotrexate as per institutional standard. Patients who do 
not have a suitable related or unrelated donor and who are going to undergo transplant from a 
haploidentical donor will come off study.
4.8  
Data Confidentiality Plan 
Patients registered in this protocol will be de-identified by using a unique identifier number that 
is automatically generated in BMTWeb, linkage to patient sensitive information is not possible 
outside BMTWeb. 
Access to the database is only available to individuals within the department and with authorize 
access. Data gathered for this study will not be reused or disclosed to any other person or 
entity, or for other research.
5.0 Evaluation During Study
5.1
Disease Assessment Prior to Start of Pacritinib (baseline):
a) Patient medical history and physical examination including measurement of liver and spleen 
size by physical examination or imaging (MRI or CT or ultrasound if possible) with addition 
of marrow-specific MRI sequences.
b) CBC, differential and platelet count
c)
Bone marrow aspiration and biopsy
d) Chemistry panel 
e) Serology for CMV, HBV, HCV and HIV
f)
B-HCG in women of childbearing potential
g) 2 D echo, EKG
i)
Pulmonary function tests with DLCO
j)
Chest x-ray
k) MF symptoms questionnaire (Appendix D.)
l)  Fact BMT questionnaire (Appendix E.)
m) Blood for immunological profile if patient agrees to consent to optional study. 
5.2
Follow up each month while on Pacritinib:
Patients will come to MDACC once each month to pick-up the next month's Pacritinib and have 
the following done. The monthly visits will continue as long as patient is taking Pacritinib.
a) Medical history and physical examination
b) CBC, differential and platelet count
c)
Chemistry panel 
d) EKG


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Cycle 1 only:  Day 14 (+/- 2 days) CBC, differential and platelet count and chemistry panel. 
These can be drawn locally and results sent to MDACC. The PI/treating physician must review 
outside lab results, determine clinical significance, sign and date the outside lab results.
Cycle 1 only:  During week 2, study personnel will call patient about any new symptoms. 
Patients treated on this protocol may require supportive care treatment (concomitant 
medications).  These medications are considered standard of care and have no scientific 
contribution to the protocol; therefore no data will be captured on various medications needed or 
their side effects. 
5.3  
Within about 7 days after completion of Pacritinib (but before transplant):   
1)  Physical examination including measurement of liver and spleen size by physical 
examination or imaging (MRI or CT or ultrasound if possible).
2) EKG
3) Bone marrow aspiration and biopsy
5.4
Post-transplant Evaluations:
5.4.1    Post-transplant evaluations will follow our standard practice and are done to monitor 
engraftment and disease status. 
5.4.2    Additional post-transplant follow-up specific to this study at approximately 1, 3, 6, and 12 
months post-transplant:
1)    At around 3 months: 
a)  Measurement of liver and spleen size by physical examination or imaging (MRI 
or CT or ultrasound if possible).  
b)  Bone marrow aspiration and biopsy
At around 12 months:  
a)  Repeat measurement of liver and spleen size, if liver and spleen were still 
enlarged at 3 months post-transplant.
b)  Bone marrow biopsy aspiration and biopsy
2)   Blood for immunological profile if patient agrees to consent to optional study. 
3)   MF symptoms questionnaire (Appendix D.)
4)   Fact BMT questionnaire (Appendix E.)
5)   Participant Follow-up Assessment questionnaire (Global Impression of Change Scale, 
Appendix F.) 
5.5
Correlative Research Studies (Optional):
60 cc of blood (5 green top tubes and 1 purple top tube) will be collected before the first dose of 
pacritinib, after the last dose of pacritinib (before transplant), and at approximately 1, 3, 6, and 
12 months post-transplant.
This research blood will be sent to Dr. Katy Rezvani's laboratory at MD Anderson.  Studies to be 
conducted are described in Section 2.4.
6.0 Statistical Considerations
General
This will be a single-arm, Phase II study of pacritinib, fludarabine, and busulfan as a preparative 


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regimen in allogeneic stem cell transplantation in patients with myelofibrosis.  The primary 
endpoint is progression-free survival (PFS) in patients undergoing matched related or at least 
7/8 matched unrelated donor transplant.  We will enroll at least 21 evaluable patients, defined 
as patients who undergo transplant with a matched related or at least 7/8 matched unrelated 
donor.  Patients who do not have a suitable related or unrelated donor will come off study and 
may receive a transplant from a haploidentical donor. For this reason and because some 
patients may decide not to undergo transplant after starting the drug, we may need to enroll up 
to 40 patients to ensure that 21 are evaluable for our primary endpoint.
Endpoints
6.1 Primary End Point (Progression-Free Survival): 
Progression-free survival is defined as the time of stem-cell transplant to the time of death or 
disease progression.
6.2 Secondary End Points:
Neutrophil Engraftment is defined as a sustained ANC > 0.5 x 10
9/L for 3 consecutive days 
and evidence of donor chimerism by D+28 (the first chimerism study will be done 3-4 weeks 
post-transplant).
Platelet Engraftment is defined as a sustained first of three consecutive laboratory values of 
platelet ≥ 20x109/L with no platelet transfusions administered for 7 consecutive days.
Non-relapse mortality is defined as death without disease progression.
Liver response will be defined by the change in the size of the liver measured below the 
coastal margin in the mid-clavicular line by palpitation.
Spleen response will be defined by the change in the size of the spleen measured below the 
coastal margin in the mid-clavicular line by palpitation.
Quality of life will be measured by the QOL FACT BMT.
Symptom score will be measured by the MPD symptom score.
Immune recovery will be measured by various cell subsets and cytokine levels.
Primary Graft Failure is defined as failure to achieve an ANC > 0.5 x 10
9/L for 3 consecutive 
days by day 28, with <10% cellularity on bone marrow biopsy and no evidence of donor 
chimerism. 
Secondary graft failure is defined as a sustained declined of ANC <0.5 x 10
9/L for 3 
consecutive days after initial documented engraftment with no evidence of disease progression.
Complete remission is defined as per response criteria defined by European Myelofibrosis 
network (Appendix G.). 
Relapse will be recorded by the day of detection. 


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Overall Survival is defined as the interval between day of transplant and day of death. 
 
Sample Size and Power
The historical 1-year PFS rate in this population is 61%.  Our goal is to improve this to 80%.  We 
expect to enroll patients over a 3-year period and follow all patients for 1 year after enrollment is 
complete.  Under these assumptions, assuming exponentially -distributed PFS times, and using 
a one-sided exponential MLE test with a 5% Type I error rate, we will need 21 patients to have 
80% power to detect an increase in 1-year PFS to 80%.  We will provide the 1-year PFS rate 
along with a corresponding 95% interval and test the hypothesis that it is greater than 61% 
using an exponential MLE test.  Only patients who undergo transplant with a matched related or 
at least 7/8 matched unrelated donor will be include in this analysis.
Secondary Analyses
We will use the Kaplan-Meier method to estimate the distribution of secondary time-to-event 
(TTE) endpoints overall survival, time to neutrophil engraftment, and time to platelet 
engraftment.  We will use Cox regression analysis will be used to assess the association 
between TTE endpoints (including PFS) and clinical and disease covariates of interest.  We will 
assess the cumulative incidence of non-relapse mortality (NRM) and disease relapse in a 
competing risks framework and use the method of Fine and Gray to fit regression models to 
these endpoints.  
Liver and spleen response to pacritinib will be measured by the change in the size of each 
organ measured below the coastal margin in the mid-clavicular line by palpation and imaging.
Quality of life (QOL) will be assessed using the QOL FACT BMT, and symptom score will be 
assessed by the MPD symptom score.  Changes in these over time will be analyzed by a 
generalized linear mixed model (GLMM) approach to account for intra-patient correlation.
For the immune studies, various cell subsets and cytokine levels will be assessed at several 
timepoints.  GLMM or other appropriate statistical models will be fit to assess changes over time 
in these parameters and relationships with other endpoints.
  We will use descriptive statistical methods to tabulate safety parameters such as the rate of 
adverse events.  Only patients who undergo transplant with a matched related or at least 7/8 
matched unrelated donor will be include in these analyses.
We will separately summarize safety and other data for patients who receive pacritinib but who 
do not undergo stem cell transplant.
We will perform a descriptive statistical analysis of the Participant Follow-up Assessment 
questionnaire (Global Impression of Change Scale, Appendix F.) data collected at 
approximately 1, 3, 6, and 12 months post-transplant.
7.0 Criteria for Removal from the Study
7.1
Any toxicity that is deemed unacceptable by the study PI. 
7.2
Disease progression.
7.3
Lack of compliance with the requirements of the study.
7.4
Withdrawal of consent.
7.5
After one year of transplant.


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7.6
No matched related or less than 7/8 matched unrelated donor.
8.0 Adverse Events and Reporting Requirements
8.1   AEs during Pacritinib phase 
The severity of the adverse events (AEs) will be graded according to the Common Terminology 
Criteria v4.0 (CTCAE). We will not capture expected Grade 1 and Grade 2 AEs.  Grade 3 and 4 
AEs will be collected and recorded in the medical record.  Only Pacritinib-related adverse 
events and protocol specific data will be entered into PDMS/CORe. PDMS/CORE will be used 
as the electronic case report form for this protocol.
Events not included in the CTCAE chart will be scored as follows:
General grading:
Grade 2: Moderate: discomfort present with some disruption of daily activity, require treatment.
Grade 3: Severe: discomfort that interrupts normal daily activity, not responding to first line 
treatment. 
Grade 4: Life Threatening: discomfort that represents immediate risk of death
Causality Assessment 
For the purpose of this study, events known to be caused by Pacritinib will be assessed as 
definitely related.
Events known to be caused by components of the transplant package and its direct 
consequences as well as those events known to be related to drugs used for the treatment of 
GVHD, infections and supportive treatment will be scored as unrelated.  
When the relationship of the adverse event cannot be ruled out with certainty the AE may be 
considered possibly related. 
The PI will be responsible for assessing the causality and will be final arbiter.  Documentation of 
grade, onset/resolution date and attribution will be entered into the patient's medical record and 
signed by the PI.
Collection of adverse events 
Collection of adverse events will reflect the onset and resolution date and maximum grade. 
Intermittent events should be labeled as such and followed until resolution. If a patient is taken 
off study while an event still ongoing, this will be followed until resolution unless another therapy 
is initiated. Pre-existing medical conditions will be recorded only if an exacerbation occurs 
during the active treatment period.  Co-morbid events will not be scored separately.
Adverse events related to Pacritinib will be collected and recorded for the duration of active 
treatment plus 14 days.
List of expected adverse events related to Pacritinib:
Occurring in >10% include:
1.
Nausea, vomiting, diarrhea, dehydration


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2.
Anemia, thrombocytopenia
3.
Fatigue
Treatment Duration Definitions:
Active Treatment: patients receiving Pacritinib. 
Last day of "Active Treatment": is the last day of Pacritinib.
Reporting Requirement:
Serious Adverse Event Reporting (SAE) Language 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes:
•
Death
•
A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it occurred in 
a more severe form, might have caused death.
•
Inpatient hospitalization or prolongation of existing hospitalization
•
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions.
•
A congenital anomaly/birth defect.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 312.32).
Important medical events as defined above, may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if deemed 
appropriate by the Principal Investigator or the IND Sponsor, IND Office.
All events occurring during the conduct of a protocol and meeting the definition of a SAE must 
be reported to the IRB in accordance with the timeframes and procedures outlined in “The 
University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Unanticipated Adverse Events for Drugs and Devices”.  Unless 
stated otherwise in the protocol, all SAEs, expected or unexpected, must be reported to the IND 
Office, regardless of attribution (within 5 working days of knowledge of the event).
All life-threatening or fatal events, that are unexpected, and related to the study drug, must 
have a written report submitted within 24 hours (next working day) of knowledge of the event to 
the Safety Project Manager in the IND Office. 
The investigator will inform CTI Biopharma of any SAE within 24 hours of being aware of the 
event via email and/or fax. 


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Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB. 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 14 days after the last dose of drug, unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of the event has stabilized, or 
there has been acceptable resolution of the event.
Additionally, any serious adverse events that occur after the 14 day time period that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy.
Reporting to FDA:
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager 
IND Office) according to 21 CFR 312.32.
Adverse events known to be related to SOC ALLO TP will not be recorded in PDMS. 
List of most common expected adverse events related to SOC ALLO TP:
1.
Infections in the presence or absence of neutropenia: fungal, bacterial and 
or viral infections.  
2.
Fever: Non-neutropenic or neutropenic without infection
3.
Acute graft versus host disease (aGVHD): most commonly manifested by 
skin rash, diarrhea and abnormal liver function tests could also present with some degree of 
fever, upper gastrointestinal symptoms (nausea and vomiting) mucositis and eye dryness.
4.
Gastrointestinal (GI tract):  the GI tract manifestations could be not only due 
5.
to direct damage from the preparative regiment but also be a manifestation of GVHD or 
infections. Therefore, the time course and its presentation are crucial when assessing these 
as adverse events. Nausea/vomiting, mucositis, diarrhea when presented within first 7 to 10 
days most likely will be related to the preparative regimen.  
6.
Skin rash: not related to GVHD could be caused by chemotherapy used for the preparative 
regimen or antibiotics used a supportive treatment. 
7.
Transaminitis: liver function test elevation.
8.
Pulmonary events: not related to CHF most likely caused by drug injury or infection.  These 
could present with a pneumonitis pattern manifested with shortness of breath, pulmonary 
infiltrates on chest radiograph, sometimes accompanied by fever and cough and progress to 
acute respiratory insufficiency and a diffuse bilateral alveolar pattern.  
9.
Cytokine Storm/ engraftment syndrome: most likely caused by released 
cytokines. 
10. Hemorrhagic cystitis: not related to chemotherapy agents used in the proposed preparative 
regimen is most likely caused by viral infection.
11. Thrombotic thrombocytopenic purpura (TTP).
12. Veno-occlusive Disease of the Liver (VOD): could be caused by Busulfan. Some 
antimicrobial agents have been also incriminated in its development. 
13. Fluid overload due to hydration required for conditioning regimen, blood product 
transfusions and or IV alimentation
14. Graft failure. 
15. Chronic GVHD.


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16. For the purpose of this study, the following events would not be considered adverse events 
and would not be recorded in the database:
a.
Flu-like symptoms not associated with infection
b.
Abnormal laboratory findings considered associated to the original disease
c.
Isolated changes in laboratory parameters such as electrolyte, magnesium and 
metabolic imbalances, uric acid changes, elevations of ALT, AST, LDH and alkaline 
phosphatase.
9.0 Background Drug Information
9.1
Pharmacologic Class of Pacritinib:  JAK2-FLT3 inhibitor
9.2
Formulation
For use in clinical studies as an oral agent, pacritinib is supplied as size #0 hard gelatin 
capsules with gray bodies and red caps.  Capsules contain 100 mg pacritinib (free base) and 
the following inactive ingredients: microcrystalline cellulose NF, polyethylene glycol 8000 (PEG 
8000) NF, and magnesium stearate NF. The capsule gelatin is bovine derived.   
Pharmacies at investigational sites will receive bottles with child-resistant closures containing 
100 capsules (100 mg).  
9.3
Storage Conditions
Drug product should be stored in the pharmacy, hospital, clinic, or warehouse at controlled 
room temperature, 20°C to 25°C (68°F to 77°F), with excursions allowed between 15°C to 30°C 
(59°F to 86°F). Patients should be instructed that storage temperatures for pacritinib in the 
home should be below 30°C (86°F). Unused or expired Pacritinib will be disposed per MDACC 
Investigational Drug policy,
9.4
Observed Risks
The adverse effects observed in toxicity studies, as well as data from phase 1 and 2 clinical 
studies in patients with advanced MF, AML, and lymphoma:
•
Hematologic: Reversible myelosuppression; leukopenia, neutropenia, thrombocytopenia, 
and anemia have been observed; these events are common in hematologic malignancies 
and may not be related to pacritinib administration. Thrombocytopenia, anemia, 
neutropenia, and leukopenia ADRs were more common in lymphoid than myeloid patients. 
Patients participating in clinical trials of pacritinib will be monitored frequently for 
myelosuppression.  Provisions for interruption of treatment and dose reduction in the event 
of myelosuppression are outlined in clinical trial protocols.
•
Gastrointestinal: Treatment with pacritinib is associated with dose-related diarrhea and 
nausea. Vomiting, abdominal pain, abdominal distension, anorexia, and constipation have 
also been reported to be related to pacritinib administration. Diarrhea and vomiting ADRs 
were more common in myeloid studies than lymphoid studies, but the reverse was true for 
constipation. Nausea was the same in both populations. Antiemetic and antidiarrheal 
medications should be prescribed prophylactically to control symptoms. Fluid and 
electrolytes should be replaced as needed to prevent dehydration. Pre-existing nausea, 
vomiting, and diarrhea should be adequately controlled before beginning therapy. Patients 


2014-0786
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Page 19
with significant GI symptoms despite optimal supportive care may have study drug 
interrupted or have the dose of study drug reduced per protocol.
•
Cardiac: QTc prolongation has been reported in association with pacritinib therapy. A 
post-hoc review of the patients in the phase 1-2 Studies SB1518-2007-001 and 
SB1518-2008-003 identified 9 patients with at least one reported QTc exceeding 500 ms; all 
but one  were treated at a pacritinib dose of ≥ 400 mg QD. Therapy was continued in most 
of these patients for extended periods of time after the observations of QTc prolongation. In 
addition, pre-study cardiac history was noted in 7 patients, and 8 patients were taking 
concomitant medications associated with QTc prolonga-tion. Other cardiac TEAEs and 
ADRs were rare in all pacritinib-treated populations. Based on these observations, 
investigators are advised to exclude any patient with a baseline QTc > 450 ms and to 
perform routine ECG monitoring during treatment. For patients with identified changes in 
treatment-emergent ECG abnormalities or other cardiac events, study drug may be 
interrupted or the dose may be reduced per protocol.
•
Hepatic: Animal studies suggest that pacritinib treatment may cause dose-related 
hepatotoxicity. There has been little evidence of hepatotoxicity in clinical trials to date. 
Significant increases in aminotransferases have been observed infrequently and have not 
been accompanied by concomitant  increases in bilirubin. Most reported hepatic toxicities 
were seen in the myeloid population. No instances of hepatic dysfunction meeting Hy's Law 
criteria have been observed. Hepatic function (AST/SGPT, ALT/SGOT, alkaline 
phosphatase, and total bilirubin) will continue to be assessed at frequent intervals during 
treatment with pacritinib. 
•
Renal: Animal studies suggest that treatment may cause dose-related renal toxicity. To 
date, little impact on renal function has been observed in human clinical trials.  Assessment 
of renal function (creatinine, BUN, sodium, potassium) will be undertaken frequently in 
patients participating in clinical trials of pacritinib.
•
General: Additional adverse effects commonly reported during pacritinib administration have 
included infections, fatigue, asthenia, peripheral edema, pyrexia, and rash. Infectious ADRs 
were more common in lymphoid patients, while the other adverse effects were more 
common in myeloid patients. Bleeding and bruising complications have been reported, most 
of which were low grade and generally more common in the myeloid population than in the 
lymphoid population.  Patients participating in clinical trials of pacritinib will be monitored 
closely for these adverse effects.
No reproductive or developmental toxicity studies have been performed; therefore, the effects of 
pacritinib on female and male fertility are unknown. If fertile, both males and females must agree 
to use effective birth control. Women of childbearing potential must use highly effective methods 
of birth control 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). 
No drug-drug interaction studies have been conducted with pacritinib. In vitro studies indicate 
that pacritinib has no significant potential to inhibit or induce CYP450 isozymes and has no 
significant involvement with p-glycoprotein mediated transport. Pacritinib is believed to be 
metabolized by CYP3A4. Therefore, caution is advised when considering the coadministration 
of potent inhibitors of CYP3A4 in conjunction with pacritinib. Specific exclusions are outlined in 
the protocols for human clinical trials of pacritinib.


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Barosi G, Elliott M, Canepa L, et al. Thalidomide in myelofibrosis with myeloid metaplasia: 
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Dupriez B, Morel P, Demory J, et al. Prognostic factors in agnogenic myeloid metaplasia: 
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Guardiola P, Anderson JE, Bandini G, et al. Allogeneic stem cell transplantation for 
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Patriarca F, Bacigalupo A, Sperotto A, et al. Allogeneic hematopoietic stem cell 
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Lussana F, Rambaldi A, Finazzi MC, et al. Allogeneic hematopoietic stem cell 
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Kroger N, Holler E, Kobbe G, et al. Allogeneic stem cell transplantation after 
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Ditschkowski M, Elmaagacli AH, Trenschel R, et al. Dynamic International Prognostic 
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