Clinical trial NCT04884191
Conditions: Primary Myelofibrosis Post-Polycythemia Vera Myelofibrosis Post- Essential Thrombocythemia Myelofibrosis
Sponsor: CTI BioPharma
Start date: 2017-07-31; Completion date: 2019-09-04
Enrollment: 165 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was an open-label, randomized, dose-finding study in patients with primary or secondary MF (Dynamic International Prognostic Scoring System \[DIPSS\] risk score of Intermediate-1 to High-Risk) who were previously treated with ruxolitinib. The study was designed to support a pacritinib dosage selection decision with evaluation of 3 dosages.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Pacritinib
Intervention descriptions: intervention 1: Pacritinib

Protocol documents:
Prot_000.pdf: 
 
 
 
CTI BioPharma Corp. 
 
 
PAC203 Protocol 
Pacritinib 
 
An Open-Label, Randomized, Phase 2 Dose-Finding Study of 
Pacritinib in Patients with Primary Myelofibrosis, 
Post-Polycythemia Vera Myelofibrosis, or Post-Essential 
Thrombocythemia Myelofibrosis Previously Treated with 
Ruxolitinib 
 
 
 
IND 78,406 
 
EudraCT #2017-001772-28 
NCT04884191 
 
Amendment 6 
 6 May 2019 
 
 
 
Sponsor: 
CTI BioPharma Corp. 
3101 Western Avenue, Suite 800 
Seattle, WA 98121 
 
 
Medical Monitor 
Sarah Buckley, M.D. 
Medical Director 
206-272-4541 
 
 
© CTI BioPharma Corp. all rights reserved.  This document and its contents are the property of CTI BioPharma Corp.  Unauthorized copying or 
use of this information is prohibited. This document or information within may not be used, divulged, published, or otherwise disclosed without 
the written consent of CTI. 


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Table of Contents 
 
Protocol Synopsis ......................................................................................................................................................... 6 
Abbreviations ............................................................................................................................................................. 19 
1 
Background Information ................................................................................................................................... 22 
1.1  JAK2 in Hematologic Malignancies ............................................................................................................ 22 
1.2  Myelofibrosis ............................................................................................................................................... 22 
1.2.1 
Clinical Presentation and Disease-Related Symptoms .................................................................... 22 
1.2.2 
Current Strategies for Treating PMF, PPV-MF, and PET-MF ....................................................... 23 
1.2.3 
Targeted Therapy for Myeloproliferative Disease .......................................................................... 24 
1.3  Pacritinib ..................................................................................................................................................... 25 
1.3.1 
Pharmacology ................................................................................................................................. 25 
1.3.2 
Preclinical Toxicology .................................................................................................................... 25 
1.3.3 
Summary of Clinical Pharmacology and Phase 1 Studies with Healthy Volunteers with Pacritinib
 ........................................................................................................................................................ 26 
1.3.4 
Overview of Clinical Studies of Pacritinib in Patients with Myelofibrosis ..................................... 26 
2 
Study Rationale and Objectives ........................................................................................................................ 32 
2.1  Justification of Included Patient Population ................................................................................................ 32 
2.2  Independent Data Monitoring Committee ................................................................................................... 33 
2.3  Study Objectives .......................................................................................................................................... 33 
2.3.1 
Primary Objective ........................................................................................................................... 33 
2.3.2 
Secondary Objectives ...................................................................................................................... 33 
3 
Study Design ....................................................................................................................................................... 34 
3.1  Rationale for Dosage Selection ................................................................................................................... 35 
3.2  Progression of Disease................................................................................................................................. 37 
3.3  Treatment Continuation After Progression of Disease ................................................................................ 37 
4 
Patient Selection and Withdrawal ..................................................................................................................... 38 
4.1  Target Population ........................................................................................................................................ 38 
4.1.1 
Inclusion Criteria ............................................................................................................................ 38 
4.1.2 
Exclusion Criteria ........................................................................................................................... 39 
4.2  Criteria for Withdrawal of Patients .............................................................................................................. 40 
4.2.1 
Withdrawal from Study Treatment and Procedures ........................................................................ 40 
5 
Method of Treatment Assignment and Blinding ............................................................................................. 40 
6 
Study Treatment ................................................................................................................................................. 41 
6.1  Study Drug Administration ......................................................................................................................... 41 
6.2  Study Drug Description and Storage ........................................................................................................... 41 
6.3  Dosage, Route, and Mode of Administration .............................................................................................. 41 
6.4  Drug Accountability .................................................................................................................................... 41 
6.5  Pacritinib Treatment Adjustments for Adverse Events ............................................................................... 42 
6.5.1 
Treatment Interruption and Discontinuation ................................................................................... 42 
6.5.2 
Dosage Management Guidelines for Hematologic Toxicity and Related Complications ............... 42 
6.5.3 
Pacritinib Dosage Management Guidelines for QTc Interval Prolongation, Reduction in Ejection 
Fraction, and Other Cardiac Toxicities ........................................................................................... 43 


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6.5.4 
Pacritinib Dosage Management Guidelines for Diarrhea ................................................................ 45 
6.5.5 
Pacritinib Dosage Management Guidelines for Pacritinib-Related Nonhematologic Toxicities 
Other than QTc Prolongation, Decreased Cardiac Ejection Fraction, Other Cardiac Toxicities or 
Diarrhea .......................................................................................................................................... 46 
6.6  Concomitant and Excluded Therapies ......................................................................................................... 46 
6.6.1 
Management of Gastrointestinal Toxicity ....................................................................................... 47 
7 
Study Assessments .............................................................................................................................................. 47 
7.1  Criteria for Evaluation ................................................................................................................................. 47 
7.1.1 
Efficacy ........................................................................................................................................... 47 
7.1.1.1  Spleen Volume.................................................................................................................. 47 
7.1.1.2  Spleen Size Assessment by Physical Examination ........................................................... 48 
7.1.1.3  Disease-Related Signs and Symptoms .............................................................................. 48 
7.1.1.4  Other Assessments ............................................................................................................ 48 
7.1.2 
Safety .............................................................................................................................................. 48 
7.1.2.1  Adverse Events ................................................................................................................. 48 
7.1.2.2  Hematology ...................................................................................................................... 49 
7.1.2.3  Coagulation Testing .......................................................................................................... 49 
7.1.2.4  Serum Chemistry .............................................................................................................. 49 
7.1.2.5  ECG Assessment .............................................................................................................. 49 
7.1.2.6  Cardiac Ejection Fraction Assessment .............................................................................. 49 
7.1.3 
Pharmacokinetics and Pharmacodynamics ..................................................................................... 50 
7.1.4 
Informed Consent, Screening, and Washout of Prohibited Concomitant Medications Before 
Beginning Study Treatment ............................................................................................................ 50 
7.1.5 
Randomization and Start of Week 1 (Baseline; -1 day) .................................................................. 51 
7.1.6 
End of Week 4, Study Day 28 (± 3 days) ........................................................................................ 52 
7.1.7 
End of Week 12, Study Day 84 (± 7 days) ...................................................................................... 52 
7.1.8 
End of Week 24, Study Day 168 (± 7 days), or End of Treatment ................................................. 53 
7.1.9 
30-Day Post End of Treatment (30 ±3 days After End of Treatment) ............................................ 54 
8 
Pharmacokinetic and Pharmacodynamic Analysis ......................................................................................... 54 
8.1  Blood Sample Collection, Handling, and Shipping ..................................................................................... 54 
8.2  Pharmacokinetic and Pharmacodynamic Assessments ................................................................................ 54 
9 
Assessment of Safety ........................................................................................................................................... 55 
9.1  Adverse Events ............................................................................................................................................ 55 
9.1.1 
Definition of an Adverse Event ....................................................................................................... 55 
9.1.2 
Reporting Adverse Events .............................................................................................................. 55 
9.1.3 
Criteria for Assessing Adverse Events ............................................................................................ 56 
9.1.3.1  Severity ............................................................................................................................. 56 
9.1.3.2  Relationship ...................................................................................................................... 56 
9.1.3.3  Outcome ............................................................................................................................ 57 
9.1.3.4  Action Taken with Study Drug ......................................................................................... 57 
9.1.4 
Serious Adverse Events .................................................................................................................. 57 
9.1.4.1  Definition of a Serious Adverse Event ............................................................................. 57 
9.1.4.2  Exceptions ........................................................................................................................ 58 
9.1.4.3  Reporting Serious Adverse Events to the Sponsor ........................................................... 58 


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9.1.4.4  Reporting Serious Adverse Events to the Regulatory Agencies, Institutional Review 
Boards, and/or Ethics Committees .................................................................................... 59 
9.2  Laboratory Evaluation ................................................................................................................................. 60 
9.3  Vital Signs and Physical Examination ......................................................................................................... 61 
9.4  Safety Surveillance ...................................................................................................................................... 61 
9.4.1 
Routine Pharmacovigilance Monitoring ......................................................................................... 61 
10  Data Management .............................................................................................................................................. 61 
10.1  Data Collection ............................................................................................................................................ 61 
10.2  Data Entry and Quality Control ................................................................................................................... 61 
11  Statistical Analysis Plan ..................................................................................................................................... 62 
11.1  Variables for the Analysis ........................................................................................................................... 62 
11.2  Hypotheses .................................................................................................................................................. 62 
11.3  Analysis Populations ................................................................................................................................... 62 
11.3.1  Full Analysis Set ............................................................................................................................. 62 
11.3.2  Safety Population ............................................................................................................................ 63 
11.3.3  Pharmacokinetic/Pharmacodynamic Evaluable Population ............................................................ 63 
11.4  Efficacy Analysis ......................................................................................................................................... 63 
11.5  Multiplicity .................................................................................................................................................. 63 
11.6  Safety Analysis ............................................................................................................................................ 63 
11.7  Determination of Sample Size ..................................................................................................................... 63 
11.8  Interim Analyses .......................................................................................................................................... 64 
11.9  Safety Stopping Criteria .............................................................................................................................. 64 
12  Pharmacokinetic and Pharmacodynamic Analyses ......................................................................................... 64 
13  Independent Data Monitoring Committee ....................................................................................................... 64 
14  Study Administration and Investigator Obligations ....................................................................................... 64 
14.1  Study Drug Accountability .......................................................................................................................... 65 
14.2  Informed Consent ........................................................................................................................................ 65 
14.3  Disclosure of Data ....................................................................................................................................... 65 
14.4  Case Report Forms ...................................................................................................................................... 65 
14.5  Study Monitoring ......................................................................................................................................... 66 
14.6  Record Retention ......................................................................................................................................... 66 
15  Ethics ................................................................................................................................................................... 66 
15.1  Good Clinical Practice ................................................................................................................................. 66 
15.2  Institutional Review Board/Research Ethics Board/Independent Ethics Committee .................................. 66 
16  Termination of Study ......................................................................................................................................... 67 
17  Study Amendments ............................................................................................................................................ 67 
18  Use of Information and Publication .................................................................................................................. 67 
19  References ........................................................................................................................................................... 68 
Appendix 1 - Diagnostic Criteria for Primary Myelofibrosis, Post-Polycythemia Myelofibrosis, and 
Post-Essential Thrombocythemia Myelofibrosis .................................................................................................... 70 
Appendix 2 - Dynamic International Prognostic Scoring System in Primary Myelofibrosis ............................. 72 
Appendix 3 - Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score Version 2.0 
(MPN-SAF TSS 2.0) – 24-Hour Recall Period ........................................................................................................ 73 


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Appendix 4 - Eastern Cooperative Oncology Group Performance Status Scale Grade Description ................. 74 
Appendix 5 - Selected Strong Inhibitors of CYP3A4.............................................................................................. 75 
Appendix 6 – Selected Strong Inducers of CYP450 ................................................................................................ 75 
Appendix 7 - The Stages of Heart Failure, New York Heart Association Classification ..................................... 76 
Appendix 8 - Medications with Significant Arrhythmogenic Potential ................................................................ 77 
Appendix 9 - Common Terminology Criteria for Adverse Events: Diarrhea (Version 4.03) ............................. 81 
Appendix 10 - Investigator Responsibilities, Required Documentation, and Signature ..................................... 82 
Appendix 11 - Patient Global Impression Assessment ........................................................................................... 83 
 
List of Tables 
 
Table 1. 
PAC203 Study Assessments Calendar20 ................................................................................................. 13 
Table 2. 
Study Treatment Schedule ...................................................................................................................... 41 
Table 3. 
Treatment Toxicity and Dosage Management: Hematologic Toxicities and Related Complications
 ................................................................................................................................................................... 42 
Table 4. 
Pacritinib-Related QTc Prolongation, Decreased Cardiac Ejection Fraction and Other Cardiac 
Toxicities ................................................................................................................................................... 44 
Table 5. 
Pacritinib-Related Decreased Cardiac Ejection Fraction for Patients with Grade 2 Ejection 
Fraction (LVEF 45%-50%) at Baseline ................................................................................................. 44 
Table 6. 
Treatment Toxicity and Dosage Management: Diarrhea ..................................................................... 45 
Table 7. 
Treatment Toxicity and Dosage Management: Pacritinib-Related Nonhematologic Toxicities Other 
than QTc Prolongation, Decreased Cardiac Ejection Fraction, Other Cardiac Toxicities or 
Diarrhea .................................................................................................................................................... 46 
Table 8. 
Outcomes of Adverse Events .................................................................................................................. 57 
 
List of Figures 
 
Figure 1.  Exposure-response Relationships on Spleen Volume Response for Pacritinib in Phase 1/2 Studies 
and PERSIST-2 Study ............................................................................................................................. 37 
 


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Protocol Synopsis 
Name of Investigational Drug 
Pacritinib 
Protocol ID 
PAC203 
Protocol Title 
An Open-Label, Randomized, Phase 2 Dose-Finding Study of Pacritinib 
in Patients with Primary Myelofibrosis, Post-Polycythemia Vera 
Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis 
Previously Treated with Ruxolitinib 
Version 
Amendment 6
Study Phase 
2 
Primary Objective 
1. To determine a recommended dosage of pacritinib for further clinical studies 
Secondary Objectives  
1. To examine the dose–response relationship for efficacy, as measured by spleen volume reduction 
(SVR) using magnetic resonance imaging (MRI [preferred]) or computed tomography (CT) and total 
symptom score (TSS) using the MPN-SAF TSS 2.0 
2. To examine the dose–response relationship for safety with a focus on adverse events (AE) of interest 
3. To further characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of pacritinib 
 
Study Design 
This is a dose-finding study in patients with primary or secondary MF (DIPSS risk score of Intermediate-1 to 
High-Risk) who were previously treated with ruxolitinib. The study is designed to support a pacritinib dosage 
selection decision. Three dosages will be evaluated, with patients randomized 1:1:1 to pacritinib 100 mg QD, 
pacritinib 100 mg BID, or pacritinib 200 mg BID. Randomization will be stratified by baseline platelet count 
(≤50,000/µL; >50,000/µL and ≤100,000/µL; and >100,000/µL). The most recent platelet count obtained prior 
to start of treatment will be the basis of stratification by baseline platelet count. Assigned treatment will 
continue until the patient experiences progressive disease, intolerable AEs, withdraws consent, or until the 
assigned treatment arm is closed. No study treatment crossover will be allowed. All patients should complete 
all visit procedures through Week 24, including patients who stop pacritinib treatment or have protocol-
defined progressive disease prior to Week 24, unless patient withdraws consent, dies, undergoes splenic 
irradiation or splenectomy, or initiates any non-protocol-directed anti-myelofibrosis treatment.  Following 
regulatory, EC or IRB approval of Amendment 6, study treatment for patients at and beyond the week-24 
timepoint will terminate.  Study assessments will cease following the End-of-Treatment (EOT) or 30-day post 
EOT visit, as applicable.  Patients who are benefiting from therapy as of study treatment termination may be 
allowed to continue receiving pacritinib under single patient expanded access or named patient programs at 
the investigator’s discretion and subject to regulatory, Ethics or IRB approval.  
The dosage selection process will be based on efficacy and safety parameters, including model-based dose–
response.  
This study will utilize planned frequent monitoring by an IDMC.  At a minimum, the IDMC will consist of 
1 board-certified hematologist, 1 board-certified cardiologist, and 1 biostatistician experienced in adaptive 
design clinical trials.  The roles and responsibilities of the IDMC will be fully defined within the IDMC 
charter, including, but not limited to:  
 
Review safety data across arms, focusing on bleeding events, cardiac events, and deaths  
 
Evaluate cumulative safety as described in Section 11 
 
Make independent recommendations to the Sponsor on study continuation (continue without 
modification, continue with modification, or terminate) and on patient enrollment (hold or stop 
enrollment, enroll additional patients, close arm) as described in Section 11 
 
Make independent recommendation to the Sponsor on pacritinib dosage for further study  
The first IDMC meeting is planned to occur once 18 patients have been randomized and treated for 12 weeks 
and will meet approximately quarterly thereafter.  In addition to the IDMC, there will be an Independent 


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Adjudication Committee (IAC) that will review all grade 4 or 5 cardiac and bleeding events to assess the 
principal condition that resulted in the outcome.  The IAC will provide their assessment to the IDMC.  
Additional details on the IAC will be provided in the IAC charter. 
The determination of a dose or dosages of pacritinib for further study will be based on efficacy, safety, dose–
response, and PK/PD exposure–response relationship data after all enrolled patients reach Week 24 (or 
discontinue the study). Approximately 150 patients total or up to 50 patients per arm may be enrolled.  Spleen 
volume will be measured by MRI (preferred) or CT at baseline and Weeks 12 and 24.  Patient-reported 
disease-related symptoms as assessed by the validated Patient Reported Outcome (PRO) instrument MPN-
SAF TSS 2.0 will be collected daily using an electronic diary and evaluated as part of the dose–response 
relationship.  DNA samples will also be collected for analysis of mutations associated with myelofibrosis at 
baseline and Week 24.  In the event of 2 treatment-emergent Common Terminology Criteria for Adverse 
Events (CTCAE) grade ≥4 cardiac AEs or 2 treatment-emergent CTCAE grade ≥4 hemorrhage AEs in the 
same treatment arm, suspend study enrollment and the IDMC will be convened to review the events including 
the IAC’s assessment of the events. If the IDMC confirms the nature and grade of the events together with a 
relationship to study drug, the IDMC may recommend closure of one or more treatment arms. This 
recommendation is non-binding.  The FDA and other Competent Authorities will be notified of any IDMC 
meeting that is convened under these circumstances and the resultant recommendation will be reported to the 
FDA within 2 business days. The MHRA will be informed via a substantial amendment. In the event one or 
more arms are suspended or terminated for a safety observation, randomization into the arm(s) will be halted 
immediately, however patients who are experiencing benefit, in the opinion of the investigator and Sponsor, 
and who were randomized to an arm that is suspended or terminated, may continue treatment. 
Safety will be monitored with physical examinations, clinical laboratory assessments (including hematologic, 
chemistry, and coagulation testing), and cardiac monitoring (including ECG and echocardiogram testing); 
specified study treatment dosage modifications will be followed to address identified abnormalities.  Adverse 
event data will be collected throughout the study.  
The Sponsor will collect blood samples for PK assessment from all patients in each dosing arm at the 
following timepoints:  
 
Sparse Sampling (all patients): End of Week 12 and End of Week 24: 30 minutes to 0 hours 
(predose), 4 hours (± 10 minutes), and 8 hours (± 15 minutes) postdose 
 
Dense Sampling (performed at selected sites until approximately 6 to 8 patients per dose arm have 
completed PK evaluation, at which point all further patients will have PK evaluated by sparse 
sample collection): Week 1 Day 1: 2 hours (± 5 minutes), 4 hours (± 10 minutes), 6 hours 
(± 15 minutes), and 8 hours (± 15 minutes) postdose and 24 hours postdose (within 30 minutes 
before the Day 2 dose) , End of Week 12 and End of Week 24: 30 minutes to 0 hours (predose), 
2 hours (± 5 minutes), 4 hours (± 10 minutes), 6 hours (± 15 minutes), and 8 hours (± 15 minutes) 
postdose  
The PK parameters, minimum concentration observed, maximum concentration observed, and area under the 
curve will be determined and summarized using descriptive statistics for each pacritinib dosage arm.  
Exposure-response analyses will be conducted on both safety and efficacy populations in the study.  PD 
samples will be analyzed for biomarkers associated with the JAK/STAT pathway. 
The maximum duration of trial participation for an individual patient will be approximately 24 weeks. The 
estimated duration of the entire study is approximately 2 years if the maximum number of patients are 
enrolled. The definition of End of Trial for the PAC203 study is Last Visit of the Last Subject (LVLS). 
Number of 
Centers 
Approximately 60 centers globally 
Number of 
Patients 
Approximately 150 
Inclusion/ 
Exclusion 
Criteria 
Diagnosis and Inclusion Criteria 
1. PMF, PPV-MF, or PET-MF (as defined by Tefferi and Vardiman 2008) 
2. DIPSS Intermediate-1, Intermediate -2, or High risk (Passamonti et al 2010)   
3. Prior ruxolitinib treatment with failure to benefit or intolerance as defined by at 
least one of the following: 


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a. 
Treatment for ≥3 months with inadequate efficacy response defined as <10% 
spleen volume reduction by MRI or <30% decrease from baseline in spleen 
length by physical examination or regrowth to these parameters following an 
initial response; and/or 
b. Treatment for ≥28 days complicated by either 
i. Development of a red blood cell transfusion requirement (at least 
2 units/month for 2 months) 
ii. National Cancer Institute (NCI) CTCAE grade ≥ 3 AEs of 
thrombocytopenia, anemia, hematoma, and/or hemorrhage while being 
treated with a dosage of < 20 mg BID 
4. Palpable splenomegaly ≥5 cm below the lower costal margin in the midclavicular 
line as assessed by physical examination 
5. TSS of ≥ 10 on the MPN-SAF TSS 2.0 or patients with a single symptom score of 
≥ 5 or two symptoms of ≥ 3, including only the symptoms of left upper quadrant 
pain, bone pain, itching, or night sweats  
6. Age ≥ 18 years old 
7. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 
8. Peripheral blast count of < 10% throughout the screening period 
9. Absolute neutrophil count of > 500/µL 
10. Adequate liver and renal function, defined by liver transaminases (aspartate 
aminotransferase [AST]/serum glutamic oxaloacetic transaminase [SGOT] and 
alanine aminotransferase [ALT]/serum glutamic pyruvic transaminase [SGPT]), 
≤ 3 × the upper limit of normal (ULN) (AST/ALT ≤ 5 × ULN if transaminase 
elevation is related to MF), direct bilirubin ≤ 4× ULN, and creatinine ≤ 2.5 mg/dL  
11. Adequate coagulation function, defined by prothrombin time (PT)/international 
normalized ratio (INR), partial thromboplastin time (PTT), or thrombin time (TT) 
of ≤ 1.5 × ULN 
12. Left ventricular cardiac ejection fraction of ≥ 45% by echocardiogram or 
multigated acquisition (MUGA) scan 
13. If fertile, willing to use effective birth control methods during the study 
14. Willing to undergo and able to tolerate frequent MRI or CT assessments during the 
study 
15. Able to understand and willing to complete symptom assessments using a 
patient-reported outcomes instrument  
16. Provision of informed consent 
 
Exclusion Criteria 
1. Life expectancy < 6 months 
2. Completed allogeneic stem cell transplant (allo-SCT) or are eligible for and 
willing to complete allo-SCT 
3. History of splenectomy or planning to undergo splenectomy  
4. Splenic irradiation within the last 6 months 
5. Previously treated with pacritinib 
6. Patients receiving high-dose ruxolitinib (more than 10 mg BID or 20 mg QD) who 
cannot tolerate tapering down ruxolitinib to 10 mg BID or less prior to the first 
dose of pacritinib as described in Section 6.6 
7. Treatment with anticoagulation or antiplatelet agents, except for aspirin dosages of 
≤ 100 mg per day, within the last 2 weeks 


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8. Treatment with a strong CYP3A4 inhibitor or a strong cytochrome P450 inducer 
within the last 2 weeks  
9. Treatment with medications that can prolong the QTc interval within the last 
2 weeks (Appendix 8) 
10. Treatment with an experimental therapy within the last 28 days 
11. Significant recent bleeding history defined as NCI CTCAE grade ≥ 2 within the 
last 3 months, unless precipitated by an inciting event (e.g., surgery, trauma, 
injury) 
12. Any history of CTCAE grade ≥ 2 non-dysrhythmia cardiac conditions within the 
last 6 months. Patients with asymptomatic grade 2 non-dysrhythmia cardiac 
conditions may be considered for inclusion, with the approval of the medical 
monitor, if stable and unlikely to affect patient safety.  
13. New York Heart Association Class II, III, or IV congestive heart failure 
14. Any history of CTCAE grade 2 cardiac dysrhythmias within the last 6 months.  
Patients with non-QTc CTCAE grade 2 cardiac dysrhythmias may be considered 
for inclusion, with the approval of the medical monitor, if the dysrhythmias are 
stable, asymptomatic, and unlikely to affect patient safety. 
15. QTc prolongation >450 ms or other factors that increase the risk for QT interval 
prolongation (e.g., heart failure, hypokalemia [defined as serum potassium 
<3.0 mEq/L that is persistent and refractory to correction], family history of long 
QT interval syndrome, or concomitant use of medications that may prolong QT 
interval)  
16. Any active gastrointestinal or metabolic condition that could interfere with 
absorption of oral medication 
17. Active or uncontrolled inflammatory or chronic functional bowel disorder such as 
Crohn’s Disease, inflammatory bowel disease, chronic diarrhea, or constipation 
18. Other malignancy within the last 3 years, other than curatively treated basal cell or 
squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or 
treated nonmetastatic prostate cancer with negative prostate-specific antigen, in 
situ breast carcinoma after complete surgical resection, or superficial transitional 
cell bladder carcinoma 
19. Uncontrolled intercurrent illness, including, but not limited to, ongoing active 
infection or psychiatric illness or social situation that, in the judgment of the 
treating physician, would limit compliance with study requirements 
20. Known seropositivity for human immunodeficiency virus 
21. Known active hepatitis A, B, or C virus infection 
22. Women who are pregnant or lactating 
23. Concurrent enrollment in another interventional trial 
Study Treatments 
Pacritinib: 
Dosage Form:  100 mg capsules 
Dosage Levels:   
 
100 mg QD 
 
100 mg BID 
 
200 mg BID
Concomitant and 
Excluded 
Therapies, 
Including 
Procedures 
Ruxolitinib should not be administered concurrently with pacritinib at any time. 
Although there is no washout period required for ruxolitinib prior to the start of dosing 
with pacritinib, it should be understood that because of the difference in half-life 
between ruxolitinib (3 hours Jakafi package insert) and pacritinib (approximately 
40 hours), there will be a period of 10 to 14 days following the discontinuation of 
ruxolitinib and the start of dosing with pacritinib, during which pacritinib has not yet 


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reached steady state and during which patients may be at increased risk of ruxolitinib 
withdrawal, particularly after high doses of ruxolitinib (eg, more than 10 mg BID or 
20 mg QD). For this reason, patients who are on more than 10 mg BID (or 20 mg QD) 
of ruxolitinib at the time of consent for this study must taper the ruxolitinib dose down 
to 10 mg BID or lower and remain stable on the reduced dose for at least 2 weeks prior 
to starting pacritinib. Tapering should be done per institutional practice and may be 
done with concurrent addition of prednisone during the screening period. In addition to 
any steroids used during the screening period, the protocol permits short-term use (up 
to 14 days) of corticosteroids and/or hydroxyurea as prophylaxis or treatment of 
symptomatic ruxolitinib withdrawal during the first month of treatment with pacritinib. 
Supportive care therapies, except when prohibited by any of the below provisions, are 
permitted, including the use of low-dose aspirin. Corticosteroids (up to 20 mg/day of 
prednisone or equivalent) and/or hydroxyurea may be used for up to 2 weeks during 
the first month of treatment with pacritinib to reduce the risk or control symptoms of 
ruxolitinib withdrawal. Treatments for MF that might be considered supportive care are 
only allowable with medical monitor approval prior to administration.  
The following therapies and procedures are prohibited throughout the study: 
 
Chemotherapy, interferon, or other treatment for MF, with the exception of up to 
2 weeks of corticosteroids ( up to 20 mg/day prednisone or equivalent) and/or 
2 weeks of hydroxyurea as needed to reduce the risk of or treat the symptoms of 
ruxolitinib withdrawal  
 
Antiplatelet or anticoagulation agents, with the exception of ≤ 100 mg/day of 
aspirin 
 
Growth factor therapies, including erythropoietin and thrombopoietin 
 
Strong CYP3A4 inhibitors and strong CYP450 inducers, except as needed to treat 
AEs, with medical monitor approval 
 
Any drugs with significant potential for QTc prolongation, except as needed to 
treat AEs, with medical monitor approval 
 
Splenic irradiation or splenectomy 
Also refer to the Pacritinib Dosage Modifications section for guidelines on treatment of 
AEs. 
Safety 
Assessments 
Patients will have safety assessment as as described below until approval of 
Amendment 6, at which point safety assessments will cease following the End-of-
Treatment (EOT) or 30-day post EOT visit, as applicable. 
 
Adverse Events 
AEs will be identified and reported to the Sponsor, and the clinically indicated 
diagnostic, monitoring, treatment, and follow-up measures will be employed.  
Pregnancy and overdose cases shall be reported as SAEs, irrespective of whether they 
meet seriousness criteria or not.   
 
ECG 
A 12-lead ECG (collected in triplicate) will be checked at screening, baseline, the end 
of Week 4, the end of Week 12, the end of Week 24, or the end of treatment visit, and 
every 3 months while in the follow up period, including QTc calculation (and corrected 
by the Fredericia method), while on study treatment and 30 days after the last dose of 
study treatment.  Pacritinib dosage modifications and follow-up monitoring for 
clinically significant ECG changes will be implemented as per the guidelines for “QTc 
Prolongation, Decreased Cardiac Ejection Fraction, and Other Cardiac Toxicities”.  
Additional ECG testing shall be done as clinically indicated.   
 


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Ejection Fraction 
Ejection fraction will be checked at screening, the end of Week 4, the end of Week 12, 
the end of Week 24, or the end of treatment visit, and every 6 months while in the 
follow up period, and 30 days after the last dose of study treatment (such as with 
echocardiogram or MUGA scan).  Pacritinib dosage modifications will be implemented 
for clinically significant ejection fraction changes as per the guidelines for “QTc 
Prolongation, Decreased Cardiac Ejection Fraction, and Other Cardiac Toxicities”.  If 
pacritinib treatment is resumed after holding for ejection fraction abnormality, ejection 
fraction should be reassessed about 14 days later, then at least every 3 months as per 
the above schedule.  Additional ejection fraction testing shall be done as clinically 
indicated. 
 
Coagulation Testing 
Coagulation testing will include protim (PT),  international normalized ratio (INR), 
partial thromboplastin time (PTT), and thrombin time (TT) at screening, baseline, the 
end of Week 4, the end of Week 12, the end of Week 24, or the end of treatment visit, 
every 3 months during the follow up period, and 30 days after the last dose of study 
treatment. Additional coagulation testing should be done as clinically indicated. 
These results will be taken into account, together with baseline platelet counts and 
prior medical history of bleeding, to help guide ongoing hematologic monitoring of 
platelet counts and clinical monitoring for bleeding.  Pacritinib dosage modifications 
will be implemented for clinically significant AEs identified with this testing per the 
below guidelines for “Pacritinib-Related Nonhematologic Toxicities Other than QTc 
Prolongation, Decreased Cardiac Ejection Fraction, or Diarrhea”.  
 
Hematology 
Hematology parameters including CBC, differential, platelet count and hemoglobin 
A1C will be evaluated at screening, baseline, the end of Week 4, the end of Week 12, 
the end of Week 24, or the end of treatment visit, every 3 months during the follow up 
period, and 30 days after the last dose of study treatment.  Blood samples drawn at 
unscheduled visits for the assessment of hematology parameters should be submitted to 
the central laboratory for assessment in addition to any local laboratories needed for 
timely decisions regarding patient care.   
For patients with baseline platelet count of ≤ 50,000/L, the platelet count will be 
monitored weekly by the central laboratory for the first 8 weeks then monthly if counts 
remain ≤ 50,000/µL.  Samples for platelet counts must be submitted to the central 
laboratory for analysis, but in addition can be analyzed locally for assessment and 
management of patients in real time. Additional platelet count testing should be done 
as clinically indicated.  Pacritinib dosage modifications will be implemented for 
clinically significant AEs identified with this testing per the below guidelines for 
“Hematologic Toxicities and Related Complications.”   
 
Serum Chemistry 
Serum chemistry parameters (ALT/SGPT and AST/SGOT, alkaline phosphatase, 
bilirubin [total, direct, and indirect], creatinine, LDH, sodium, potassium, chloride, 
bicarbonate, calcium, phosphate, magnesium, BUN/urea, albumin, amylase, lipase, 
glucose, cholesterol, uric acid, and high sensitivity CRP) will be evaluated by a central 
laboratory at screening, baseline, and as clinically indicated and will include measures 
of hepatic and renal function and dysfunction.  Blood samples drawn at unscheduled 
visits for serum chemistry evaluation should be submitted to the central laboratory for 
assessment in addition to any local laboratories needed for timely decisions regarding 
patient care.  Pacritinib dosage modifications will be implemented for clinically 
significant AEs identified with this testing per the stated guidelines for “Pacritinib-


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Related Nonhematologic Toxicities Other than QTc Prolongation, Decreased Cardiac 
Ejection Fraction, or Diarrhea”. 
Pacritinib Dosage 
Modifications 
Pacritinib dosage may be interrupted or modified for hematologic toxicities, 
hemorrhage, severe infections, cardiac toxicities including QTc interval prolongation 
and reduction in ejection fraction, diarrhea, and other pacritinib-related 
nonhematologic toxicities.  Pacritinib dosage may also be held for invasive procedures.  
Refer to Section 6.5 for pacritinib dosage management guidelines.   
STATISTICAL METHODS 
The following variables will be used to evaluate efficacy and safety.  
Efficacy 
 
 
The primary efficacy variable for dosage selection is the percent reduction in spleen volume from 
baseline as measured by MRI or CT at Weeks 12 and 24.  
 
Other supportive measures for evaluation as part of the dose–response relationship include: the 
percentage of patients who achieve at least 35% reduction in spleen volume; % TSS reduction from 
baseline;and the percentage of patients with at least 50% reduction in TSS.  
 
Safety 
 
The primary safety measure for dosage selection is the percentage of patients with CTCAE grade ≥3 
cardiac AEs (Standardized MedDRA Query [SMQ]), CTCAE grade ≥3 hemorrhage AEs (SMQ), 
CTCAE grade ≥4 thrombocytopenia toxicity (central laboratory based), or CTCAE grade ≥4 anemia 
toxicity (central laboratory based).  
 
All other safety data including AEs, death, and clinical laboratory measures will be used as supportive 
measures for evaluation of pacritinib dose-safety relationship. 
There is no formal hypothesis to be tested in this study.  Efficacy, safety, and PK/PD data will be summarized 
by dosage group using descriptive statistics.  The dose–response and dose-exposure-response relationship 
will be explored using a modeling approach. 
References 
Harrison C, Kiladjian J-J, Kathrin H, et al.  JAK inhibition with ruxolitinib versus best available therapy for 
myelofibrosis. N Engl J Med 2012;366:787-98. 
Mesa RA, Cortes J.  Optimizing management of ruxolitinib in patients with myelofibrosis: the need for 
individualized dosing.  J Hematol Oncol 2013;6:79. 
Mesa RA, Komrokji RS, Verstovsek S.  Ruxolitinib dose management as a key to long-term treatment 
success.  Int J Hematol 2016;104:420-9. 
Passamonti F, Cervantes F, Vannucchi AM, et al.  A dynamic prognostic model to predict survival in primary 
myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms 
Research and Treatment).  Blood 2010;115:1703-8. 
Tefferi A, Vardiman JW.  Classification and diagnosis of myeloproliferative neoplasms: the 2008 World 
Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 2008;22:14-22. 
Verstovsek S, Mesa RA, Gotlib J, et al.  Efficacy, safety and survival with ruxolitinib in patients with 
myelofibrosis: results of a median 2-year follow-up of COMFORT-I. Haematologica 2013;98:1865-71. 


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Table 1. PAC203 Study Assessments Calendar20
Week 
Consent 
and 
Screen1 
Randomization 
and  
Start of 
Week 1 
(Baseline)2 
End of 
Week 43 
End of 
Week 124 
End of 
Week 244 
Post -24 Week 
Follow Up 
Assessments 
End of 
Treatment5 
30 Day Post 
End of 
Treatment21 
Day 
-35 to -7 
1 
28 
84 
168 
At 3-month 
intervals 
following 
Week 24 visit 
(ejection fraction 
assessment will 
be done at 
6-month 
intervals) 
 
+30 days 
from End of 
Treatment 
Window (d) 
 
-1 
+/-3 
+/-7 
+/-7 
+/-7 
+/-7 
+/-3 
Informed consent6 
x 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
Vital signs7 
x 
x 
x 
x 
x 
x 
x 
 
Physical exam, including 
spleen measurement8 
x 
x 
x 
x 
x 
x 
x 
 
12-lead ECG9 
x 
x 
x 
x 
x 
x 
x 
x 
Ejection fraction 
assessment (Echo or 
MUGA) 
x 
 
x 
x 
x 
x 
x 
x 
ECOG performance status 
x 
 
x 
x 
x 
x 
x 
 
Hematology10 
x 
x 
x 
x 
x 
x 
x 
x 
Coagulation testing 
x 
x 
x 
x 
x 
x 
x 
x 
Serum chemistry11 
x 
x 
As clinically indicated 
Serum pregnancy test12 
x 
 
x 
x 
x 
 
x 
 
Spleen volume by MRI 
(preferred modality) or 
CT1, 13 
x 
 
 
x 
x 
x 
x 
 


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Table 1. PAC203 Study Assessments Calendar20
Week 
Consent 
and 
Screen1 
Randomization 
and  
Start of 
Week 1 
(Baseline)2 
End of 
Week 43 
End of 
Week 124 
End of 
Week 244 
Post -24 Week 
Follow Up 
Assessments 
End of 
Treatment5 
30 Day Post 
End of 
Treatment21 
Day 
-35 to -7 
1 
28 
84 
168 
At 3-month 
intervals 
following 
Week 24 visit 
(ejection fraction 
assessment will 
be done at 
6-month 
intervals) 
 
+30 days 
from End of 
Treatment 
Window (d) 
 
-1 
+/-3 
+/-7 
+/-7 
+/-7 
+/-7 
+/-3 
Patient-reported outcome 
instrument: MPN-SAF 
TSS 2.014 
x 
x 
x 
x 
x 
x 
x 
 
Patient global impression 
assessment 
 
 
 
x 
x 
x 
x 
 
Pharmacokinetic (PK) 
assessment15 
 
x 
 
x 
x 
 
 
 
Pharmacodynamic (PD) 
assessments15 
 
x 
 
x 
x 
 
 
 
Dispense pacritinib 
 
x 
x 
x 
 
 
 
 
Begin pacritinib dosing 
 
x 
 
 
 
 
 
 
Perform pacritinib 
accountability16 
 
 
x 
x 
x 
 
x 
 
Baseline symptoms and 
AEs17 
x 
x 
x 
x 
x 
 
x 
x 
Concomitant medications 
x 
x 
x 
x 
x 
 
x 
x 
Transfusion history (RBC 
and platelets) 
x 
x 
x 
x 
x 
 
x 
 


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Table 1. PAC203 Study Assessments Calendar20
Week 
Consent 
and 
Screen1 
Randomization 
and  
Start of 
Week 1 
(Baseline)2 
End of 
Week 43 
End of 
Week 124 
End of 
Week 244 
Post -24 Week 
Follow Up 
Assessments 
End of 
Treatment5 
30 Day Post 
End of 
Treatment21 
Day 
-35 to -7 
1 
28 
84 
168 
At 3-month 
intervals 
following 
Week 24 visit 
(ejection fraction 
assessment will 
be done at 
6-month 
intervals) 
 
+30 days 
from End of 
Treatment 
Window (d) 
 
-1 
+/-3 
+/-7 
+/-7 
+/-7 
+/-7 
+/-3 
DNA sample 
 
x 
 
 
x 
 
 
 
Receipt of disease directed 
therapies19 
 
 
 
 
 
 
x 
 
Abbreviations: AEs = adverse events; ALT/SGPT = alanine aminotransferase/serum glutamic pyruvic transaminase; AST/SGOT = aspartate aminotransferase/serum glutamic 
oxaloacetic transaminase; BL = baseline; BUN = blood urea nitrogen; CBC = complete blood count; CT = computed tomography; CYP450 = cytochrome P450; DIPSS 
= Dynamic International Prognostic Scoring System; ECG = electrocardiogram; Echo = echocardiogram; ECOG = Eastern Cooperative Oncology Group; End of 
Study = 30 days after end of treatment visit; End of Treatment = study treatment end of treatment visit; GI = gastrointestinal; LDH = lactate dehydrogenase; MPN-SAF TSS 
2.0 = Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (version 2.0); MRI = magnetic resonance imaging; MUGA = multigated acquisition 
scan; PD = pharmacodynamic(s); PK = pharmacokinetic(s); QTc = corrected QT interval; SAE = serious adverse event. 
1 
Screening procedures must be completed between Days -35 and -7, before treatment initiation, with the exception of the screening (baseline) MRI or CT scan, which must 
be performed between Days -10 and -4. 
2 
Day 1 assessments are required to be performed prior to initiation of study treatment and can be performed up to 24 hours prior to initiation of study treatment.  At the 
baseline visit, all patients will be provided with a prescription (and instructions to fill that prescription) for loperamide (Imodium) or a similarly effective antidiarrheal drug.  
Patients will be instructed to start taking the prescribed loperamide or other antidiarrheal drug per package and physician instructions as soon as they notice any change in 
frequency or consistency of bowel movements after starting study treatment. 
3 
The study visit at week 4 has a scheduling window of ±3 days; however, all procedures other than MRI or CT should be performed on the same day’s visit within ±24 hours. 
4 
The study visits at weeks 12 and 24 have a scheduling window of ±7 days; however, all procedures other than MRI or CT should be performed on the same day’s visit 
within ±24 hours. 
 


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Table 1. PAC203 Study Assessments Calendar20
5 
The End of Treatment visit is scheduled within 7 days after terminating study treatment. A final visit to assess events is scheduled 30 ±3 days after the last dose of study 
treatment.  If treatment ends at a regularly scheduled visit, these procedures may be performed at that time. 
6 
Informed consent must be obtained before any study-specific washout.  This may require 2 weeks (A 2-week washout will be required for anticoagulation agents, antiplatelet 
agents (except aspirin doses of ≤ 100 mg/day), strong CYP3A4 inhibitors, strong CYP450 inducers, and QTc prolonging agents) or 28 days if patient was taking any 
experimental therapies.  Patients not requiring washout may sign the Informed Consent Form at any time prior to screening procedures. 
7 
Vital signs include blood pressure, pulse, respiratory rate, temperature, and body weight.   
8 
Height should be measured only at baseline. Spleen size assessed by physical examination as the distance below the LCM at the midclavicular line.   
9 
A single 12-lead ECG (collected in triplicate) will be performed at screening and within 1 hour prior to dosing and at 4 hours (± 10 minutes) post dosing on Day 1 of week 1 
and at the end of weeks 4, 12, and 24, 30 days postterm, and as clinically indicated.  ECGs will also be collected pre-dose during the post 24-week follow-up visits within 
1 hour prior to dosing. The ECGs will be read centrally by blinded independent cardiologist.  
10 
Hematology includes CBC, differential, platelet count and hemoglobin A1C. For patients with baseline platelet count of ≤ 50,000/L, platelet count will be monitored weekly 
for the first 8 weeks, then monthly if counts remain ≤ 50,000/L.  These platelet counts must be analyzed by the central laboratory, but local laboratory test results may be 
used for assessment and management of patients in real time.  Samples collected for local testing must also be submitted to the central laboratory and the results captured in 
the clinical database. Additional hematology testing should be done as clinically indicated. 
11 
Eligibility may be based on local or central laboratory values. Central serum chemistry values will include: ALT/SGPT, AST/SGOT, alkaline phosphatase, bilirubin (total, 
direct, and indirect) creatinine, LDH, sodium, potassium, chloride, bicarbonate, calcium, phosphate, magnesium, BUN/urea, albumin, amylase, lipase, glucose, cholesterol, 
uric acid,  and high sensitivity CRP.  Any samples collected at any visits must be analyzed by the central laboratory, although local laboratories may additionally be used for 
patient assessment and management in real time.   
12 
All women of child-bearing potential (WOCBP) must have a pregnancy test at screening. For WOCBP in the UK, the screening pregnancy test must occur no longer than 
7 days before the first study drug administration and again at the End of Week 4 visit. Additional pregnancy tests every 12 weeks while on study treatment may be mandated 
as a country-specific requirement. 
13 
Unscheduled imaging studies may be performed at physician discretion if he/she considers disease-related symptoms to be worsening.  All images generated as part of 
unscheduled evaluations must be submitted by the investigator for central review. Images generated as part of unscheduled evaluations may also be read locally if treatment 
discontinuation is being considered. MRI is the preferred modality; CT scan will be used for patients who cannot undergo MRI, or for whom MRI is not available.  Imaging 
should be performed without contrast agent.  For each patient, the same imaging modality should be used throughout the study.  An independent radiologist, blinded to all 
patient and site identifiers and treatment assignments, will measure spleen volume. 


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Table 1. PAC203 Study Assessments Calendar20
14 
Patient-reported disease-related symptoms as assessed by the MPN-SAF TSS 2.0 will be collected daily up to 48 weeks using an electronic diary starting at least 7 days prior 
to starting pacritinib treatment. After 48 weeks, the same questionnaire with 7 day recall period (paper) will be used at each visit for the rest of the study.  
15 
The Sponsor will collect PK samples from all patients in each dosing arm at the End of Week 12 and End of Week 24 visits: 30 minutes to 0 hours (predose), 4 hours 
(± 10 minutes), and 8 hours (± 15 minutes) postdose.  Dense PK sampling will be performed at selected sites for approximately 6 to 8 patients total per dose arm on Week 1 
Day 1: 2 hours (± 5 minutes), 4 hours (±10 minutes), 6 hours (± 15 minutes), and 8 hours (± 15 minutes) postdose and 24 hours postdose (within 30 minutes before the Day 
2 dose), End of Week 12 and End of Week 24: 30 minutes to 0 hours (predose), 2 hours (± 5 minutes), 4 hours (± 10 minutes), 6 hours (± 15 minutes), and 8 hours 
(± 15 minutes) postdose. In addition, PD samples will be collected on Day 1 (Baseline), Week 12, and Week 24 within 30 minutes prior to 0 hours (predose).  Given the 
sampling schedule, PK and PD samples should be collected before and after the morning dose for patients taking pacritinib twice a day (BID). 
16 
At time of dispensing, the lot number for capsules dispensed and the number of capsules in bottle(s) should be recorded.  Instruct patient to bring bottle(s) to every visit.  
When a patient returns one or more bottles, count the remaining capsules in all bottle(s).  
17 
Baseline symptoms and AEs: Patients will be evaluated from the time of signing the Informed Consent Form through 30 days following last dose of study treatment .  Each 
SAE assessed as related to study treatment or study procedures will be collected through 30 days following last dose of study treatment and will be followed until it is 
resolved, returns to baseline, stabilizes, or the patient is lost to follow-up, whichever occurs first. 
18 
Concomitant medications are recorded at the post-24-week follow-up assessments for those patients continuing on pacritinib. 
19 
Disease directed therapy includes any therapy that is specifically directed at controlling a disease or its symptoms and does not include standard supportive care, i.e. pain 
medications. Examples include growth factors, cytotoxics, interferons and other targeted agents. 
20 
Study assessments will be performed per schedule until approval of Amendment 6, at which point they cease following the patient’s End-of-Treatment, or 30-day post (EOT) 
visit, as applicable.  All patients will require End of treatment visit, however, patients who continue to receive pacritinib under expanded access will not require a 30 Day 
Post EOT visit. 
21 
Following approval of Amendment 6, patients who continue to receive pacritinib under expanded access will not require a 30 Day Post EOT visit. 
 
 


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Special Cases:  Modifications to Study Assessments Calendar 
All patients should complete all visit procedures through Week 24, including patients who stop pacritinib treatment or have protocol-
defined progressive disease prior to week 24, unless patient: 
 
withdraws consent 
 
dies 
 
undergoes splenic irradiation, splenectomy, or initiates any non-protocol-directed anti-myelofibrosis treatment 
*Patients who continue on pacritinib after Week 24 will receive efficacy and safety assessment every 3 months up to 2.5 years (with the 
exception of MRI/CT spleen assessment, which will only be followed up to 2 years and TSS assessment, which will only be followed up to 
48 weeks).  Study assessments will be performed per schedule until approval of Amendment 6, at which point they cease following the 
patient’s End-of-Treatment, or 30-day post (EOT) visit, as applicable.   
Patients who discontinue pacritinib treatment prior to Week 24 must complete the End of Treatment visit within 7 days of stopping the drug 
and 30 Day Post End of Treatment visit within 30 days of End of Treatment visit.  
Patients who discontinue pacritinib treatment prior to Week 24, with or without disease progression, will continue to follow this Study 
Assessments Calendar through Week 24. 
Patients who undergo splenic irradiation, splenectomy, or who initiate any non-protocol-directed anti-myelofibrosis treatment at any time 
must complete the End of Treatment visit within 7 days of stopping the drug and 30 Day Post End of Treatment visit within 30 days of End of 
Treatment visit, but will not complete any additional visits. 
If an arm is closed, patients randomized to that arm will end pacritinib treatment and complete the End of Treatment visit within 7 days of 
stopping the drug and 30 Day Post End of Treatment visit within 30 days of End of Treatment visit. 
Unscheduled visits should include physical examination, laboratory tests, and radiographic evaluations as clinically indicated in the judgement of 
the investigator and these results must be entered into the EDC. 
Additional visits may be required for patients with baseline platelet count ≤ 50,000/µL as well as patients who have pacritinib dose modifications 
due to hematologic, cardiac, diarrhea, or other non-hematologic toxicities in addition to those specified in Section 6.5.  Samples drawn for clinical 
laboratory assessments at unscheduled visits should be submitted to the central laboratory for analysis in addition to any local analysis that may be 
performed for the purpose of patient management.  See Section 6.5 for details.


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Abbreviations 
Abbreviation 
Full Term 
AE 
adverse event 
ALT 
alanine aminotransferase (syn: see SGPT) 
ASCT 
allogeneic stem cell transplantation 
AST 
aspartate aminotransferase (syn: see SGOT) 
AUC 
area under the curve 
AUCinf 
area under the curve to infinite time 
AUC0-t 
area of the curve up to the last measurable concentration 
BAT 
best available therapy 
BID 
twice per day 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
Cmax 
maximum concentration observed  
Cmin 
minimum concentration observed 
CRF(s) 
case report form(s) 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP450 
cytochrome P450 
DIPSS 
Dynamic International Prognostic Scoring System  
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EPs 
erythroid progenitors 
ET 
essential thrombocythemia 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FLT3 
fms-like receptor tyrosine kinase 3 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HR 
hazard ratio 
IC50 
50% inhibitory concentration 
ICF 
informed consent form 


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Abbreviations 
Abbreviation 
Full Term 
ICH 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Us 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IND 
investigational new drug 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
i.v. 
intravenous 
IWG 
International Working Group 
JAK 
Janus kinase 
LCM 
lower costal margin 
LDH
lactate dehydrogenase 
LVEF 
left ventricular ejection fraction 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
myelofibrosis 
MPD 
myeloproliferative disease 
MPN-SAF TSS 2.0 
Myeloproliferative Neoplasm-Symptom Assessment Form Total Symptom Score version 2.0 
MRI 
magnetic resonance imaging 
MUGA 
multigated acquisition scan 
NCI  
National Cancer Institute  
PD 
pharmacodynamic(s) 
PET-MF 
post-essential thrombocythemia myelofibrosis 
PK 
pharmacokinetic(s) 
PMF 
primary myelofibrosis 
PPV-MF 
post-polycythemia vera myelofibrosis 
PRO 
patient-reported outcome 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
PV 
polycythemia vera 
QD 
once daily 
QTc 
corrected QT interval 
RBC 
red blood cell 


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Abbreviations 
Abbreviation 
Full Term 
REB 
Research Ethics Board 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SGOT 
serum glutamic-oxaloacetic transaminase (syn: see AST) 
SGPT 
serum glutamic pyruvic transaminase (syn: see ALT) 
SMQ 
Standardized MedDRA Query 
STAT 
signal transducers and activators of transcription 
SVR 
spleen volume reduction 
TEAE 
treatment-emergent adverse event 
Tmax 
time of maximum concentration 
TSS 
total symptom score 
TT 
thrombin time 
ULN 
upper limit of normal 
uMPD 
unclassifiable myeloproliferative disease 
US 
United States 
WOCBP 
Woman of child-bearing potential 
WBC 
white blood cell 
 


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1 
Background Information 
 
1.1 
JAK2 in Hematologic Malignancies 
 
The Janus kinases (JAK) are a family of cytoplasmic tyrosine kinases consisting of JAK1, JAK2, JAK3, 
and TYK2.  They play a pivotal role in the signaling pathways of numerous cytokines, hormones, and 
growth factors.  Their intracellular substrates include the signal transducer and activator of transcription 
(STAT) family of proteins.  The JAK/STAT pathways, through the proper actions of the ligands, regulate 
important physiological processes, such as the immune response to viruses, hematopoiesis, lactation, and 
lipid homeostasis.  However, dysfunctional signaling caused by a myriad of factors results in pathological 
conditions, such as allergies, asthma, rheumatoid arthritis, severe combined immune deficiency, and 
hematological malignancies.  In particular, mutations in the JAK2 gene have been associated with 
myeloproliferative disorders (MPDs), including polycythemia vera (PV), essential thrombocythemia 
(ET), and idiopathic myelofibrosis (MF).   
The incidence of the JAK2V617F mutation, as determined by allele-specific polymerase chain reaction in 
granulocytes from patients with MPDs, occurs in 35% to 50% of patients with primary MF (PMF), 32% 
to 57% of patients with ET, and 74% to 97% of patients with PV.  This mutation, however, can also be 
found on rare occasions in patients with other chronic myeloid diseases, including myelodysplastic 
syndromes (MDS), MDS/MPDs, and unclassifiable MPD (uMPD).  There is strong evidence that the 
JAK2 mutation (and corresponding continuously active JAK2 tyrosine kinases) significantly contributes 
to the existence and progression of the disease.  Its inhibition thus presents a suitable target for drug 
development.  Even in patients without JAK2 mutation, the JAK/STAT pathway may be deregulated, and 
these patients may also benefit from JAK2 inhibitor therapy. 
 
1.2 
Myelofibrosis 
 
1.2.1 
Clinical Presentation and Disease-Related Symptoms 
 
MF may present as either a primary myeloproliferative disorder or follow a diagnosis of PV or ET.  
Regardless of the original diagnosis, PMF, post-polycythemia vera MF (PPV-MF), and post-essential 
thrombocythemia MF (PET-MF) have a common pathophysiological profile, characterized by elevated 
numbers of CD34-positive cells in the marrow in the early phase of the disease, followed in the later 
phases by marrow fibrosis, with decreasing numbers of CD34 cells in the marrow and a corresponding 
increase in splenic and liver engorgement by CD34 cells. 
PMF, PPV-MF and PET-MF usually present with a white blood cell (WBC) count <30,000/mm3, 
prominent teardrops on peripheral smear, normocellular or hypocellular marrow with moderate to marked 
fibrosis, an absence of the Philadelphia chromosome or the BCR-ABL translocation, and frequent 
positivity for the JAK2 mutation (Campbell and Green 2006).  In addition to the clonal proliferation of a 
multipotent hematopoietic progenitor cell, an event common to all chronic MPDs, these disorders are 
characterized by colonization of extramedullary sites, such as the spleen or liver (Barosi 1999, 
Tefferi 2000). 
About 70% of patients with MF are symptomatic at presentation.  The main physical findings are 
splenomegaly and hepatomegaly.  Other symptoms include those secondary to a hypercatabolic state 
(fever, weight loss, and night sweats) and peripheral blood abnormalities (fatigue and dyspnea resulting 
from anemia and bleeding; petechiae resulting from thrombocytopenia and/or abnormal platelet function).  
Gout and renal stones secondary to hyperuricemia are also common (Ahmed and Chang 2006).  Other 
clinical manifestations of the disease include thromboembolic episodes, hemorrhage, splenic pain, early 
satiety, anemia, and bone pain. 


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PMF, PPV-MF, and PET-MF have similar types and distributions of bone marrow cytogenetic 
abnormalities (Tefferi et al 2001), and they are known to harbor a common mutant allele, JAK2V617F 
(James et al 2005). 
Transformation from PV to PPV-MF significantly worsens survival.  JAK2 mutations are almost always 
present in patients with PV and PPV-MF.  Common clinical and laboratory findings in PPV-MF include a 
hyperproliferative bone marrow, National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE, version 4.0) grade 2 to 3 marrow fibrosis, anemia, splenomegaly, and 
constitutional symptoms (Passamonti et al 2008). 
Diagnostic tools for PMF, PPV-MF, and PET-MF include complete blood count (CBC), bone marrow 
aspiration and biopsy, cytogenetic analysis, peripheral blood smear analysis for teardrop-shaped red blood 
cells (RBCs), the number and kinds of WBCs, platelet count, and the presence of blast cells.  
 
1.2.2 
Current Strategies for Treating PMF, PPV-MF, and PET-MF 
 
Currently, as no therapeutic strategy has been efficacious at reducing overall mortality, medical therapy 
for PMF, PPV-MF, and PET-MF is administered with supportive intent.  Treatment is aimed at improving 
quality of life through palliation of symptoms and control of peripheral blood counts (Arana-Yi et al 
2006).  Therapeutic interventions usually are used only in symptomatic patients with MF, since 
asymptomatic patients demonstrate prolonged survival (Barosi 1999, Dupriez et al 1996). 
At present, allogeneic stem cell transplantation (ASCT) is the only available method for altering the 
natural history of PMF, PPV-MF, or PET-MF (Passamonti et al 2008, Rondelli et al 2005).  ASCT can 
completely reverse the fibrosis in bone marrow (Ni et al 2005) and restore normal hematopoiesis.  
However, while ASCT is potentially curative for patients with PMF, PPV-MF, and PET-MF, this form of 
treatment is largely limited to young patients with negligible comorbidities (Arana-Yi et al 2006).  The 
International Working Group (IWG) – Myelofibrosis Research and Treatment considers it “…reasonable 
to recommend ASCT for high- or intermediate-risk 2 patients” (Cervantes et al 2009).  Thus far, no 
therapy has proven effective in prolonging overall survival (OS) in PMF, PPV-MF, or PET-MF 
(Arana-Yi et al 2006). 
Current treatment approaches are aimed at mitigating specific disease symptoms, such as anemia.  
Transfusion therapy is the core strategy for treatment of disease-related anemia, and it is also used to 
manage thrombocytopenia.  Long-term RBC transfusion therapy should be accompanied by oral iron 
chelation therapy to avoid long-term consequences of iron overload.  Disease-associated anemia 
occasionally responds to erythropoietin, hydroxyurea, cladribine, thalidomide, lenalidomide, or interferon 
treatment (Ahmed and Chang 2006).  These and other agents have been used to correct cytopenias, halt 
the progression of splenomegaly, or reduce the size of a site of extramedullary hematopoiesis in patients 
with PMF, PPV-MF, and PET-MF. 
Danazol, a synthetic attenuated anabolic steroid with androgenic activity, has been used to treat anemia in 
PMF, PPV-MF, and PET-MF.  Erythropoietin has been administered to patients with these diseases for 
palliation of constitutional symptoms and anemia (Arana-Yi et al 2006).  The use of interferon-α can 
result in hematologic responses, including reduction in spleen size, but many patients do not tolerate this 
medication (Sacchi 1995, Gilbert 1998).  Antiangiogenic and immunomodulatory drugs, such as 
thalidomide and lenalidomide, have shown activity in patients with MF (Gilbert 1998, Barosi et al 2002, 
Marchetti et al 2004, Tefferi et al 2006, Mesa et al 2004, Strupp et al 2004), but they are not routinely 
used for the indications proposed in this study of pacritinib. 
Other antiangiogenic agents, such as vatalanib and sorafenib, have been studied in PMF, PPV-MF, and 
PET-MF, but the data are not promising.  Etanercept has been evaluated, but it was not superior to the 
combination of thalidomide and prednisone (Arana-Yi et al 2006). 


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The use of signal transduction inhibitors, such as imatinib, have resulted in an increase in the number of 
clonogenic megakaryocytic progenitors in bone marrow, suggesting they may be an effective treatment 
for thrombocytopenia in patients with MF (le Bousse-Kerdiles et al 2005). 
For patients with PMF, PPV-MF, or PET-MF who have painful splenomegaly and no other treatment 
options, splenectomy may be performed.  The decision to perform splenectomy involves weighing the 
benefits (long-term improvement in symptomatic splenomegaly, anemia, portal hypertension, and severe 
thrombocytopenia in 30% to 70% of patients) versus the risks (10% postoperative mortality, and 
30% postoperative morbidity caused by infection, bleeding, or thrombosis; additionally, some 
investigators have reported accelerated progression to blast crisis). 
 
1.2.3 
Targeted Therapy for Myeloproliferative Disease 
 
In 2011, the JAK 1/2 inhibitor ruxolitinib received approval in the United States (US) for the treatment of 
patients with intermediate or high-risk MF, including PMF, PPV-MF, and PET-MF based on the 
COMFORT I and II randomized controlled studies showing that treatment with ruxolitinib decreased 
spleen size and symptom score (Verstovsek et al 2012, Harrison et al 2012).  Entry criteria for both 
studies was limited to patients with platelet counts >100,000/µL.  The median platelet counts at entry for 
the two studies were 262,000/µL and 244,000/µL, respectively.   
Ruxolitinib causes significant dose-related thrombocytopenia, and the dosage must be adjusted in patients 
with platelet counts <200,000/µL.  In patients taking ruxolitinib who develop a platelet count 
<50,000/µL, withholding ruxolitinib is recommended until the platelet count recovers to over 50,000/µL.  
In clinical studies, patients taking ruxolitinib who had pretreatment platelet counts between 100,000/µL 
and 200,000/µL had a higher frequency of grade 3 or 4 thrombocytopenia (16.7%) than patients with 
higher initial platelet counts (7.2%). 
The incidence of thrombocytopenia (all grades) during randomized treatment in COMFORT I was 69.7% 
in the ruxolitinib arm compared with 30.5% in the placebo arm.  The dosage of ruxolitinib was adjusted 
downward for patients with platelet counts <100,000/L and withheld for those with platelet counts 
<50,000/L.  In COMFORT II, protocol-specified dosage modifications for thrombocytopenia were more 
frequent in the ruxolitinib arm than in the best available therapy arm (41% versus 1%).  Disease control is 
substantially reduced with patients on ruxolitinib who require dose reductions of ruxolitinib to less than 
20 mg per day and discontinuation of ruxolitinib is recommended for patients who are taking 5 mg twice 
daily and who are not responding at 6 weeks (Jakafi package insert, Jakafi SmPC).  
Median time to recovery of platelet counts to above 50,000/µL was 14 days in patients requiring 
interruption of treatment due to thrombocytopenia (Jakafi package insert, Jakafi SmPC).   
Patients who are taken off ruxolitinib due to lack of efficacy or toxicity have poor survival which is 
negatively impacted by starting and ending platelet count.  In a recent report from MD Anderson Cancer 
Center on patient outcome after ruxolitinib discontinuation, median survival was 14 months but was 
substantially shorter for patients starting ruxolitinib with platelets <260,000/L (HR = 2.7) or who 
stopped ruxolitinib at platelet counts <100,000/L (HR = 4.1) (Newberry et al 2017).  In a similar series 
from the MAYO Clinic, discontinuation rates at 1, 2, and 3 years were 51%, 72% and 89% with the most 
common causes of disease progression including loss of response (40%) and toxicity with or without loss 
of response (34%). Survival was dependent on DIPSS scores and was similar for intermediate-2 and high 
risk patients as compared to patients treated prior to ruxolitinib availability (Tefferi et al 2011).  
Patients who discontinue ruxolitinib with intermediate to high risk disease have no effective therapeutic 
options and a short survival. The current study is designed to test the efficacy and safety of pacritinib in 
this setting. 
 


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1.3 
Pacritinib 
 
Pacritinib is a novel JAK2/fms-like receptor tyrosine kinase 3 (FLT3) inhibitor that has demonstrated 
promising antitumor activity in two mouse models of human malignancies.  Preclinical toxicology studies 
have identified a safe starting dosage for clinical studies.  The potential indications that may be targeted 
include: (i) PV, ET, and MF, all of which are MPDs with a high frequency of a JAK2V617F mutation; 
(ii) certain leukemias and lymphomas where other forms of JAK aberrations have been reported; and 
(iii) acute myeloid leukemia, in which FLT3 inhibitors have shown preliminary clinical promise. 
 
1.3.1 
Pharmacology 
 
Pacritinib is a potent, selective inhibitor of JAK2 and FLT3 kinase activities (50% inhibitory 
concentration [IC50]=23 nM and 22 nM, respectively), as well as JAK2V617F mutant kinase activity 
(IC50=19 nM).  Pacritinib is also a potent inhibitor of cellular proliferation in human leukemia and 
lymphoma cell lines selected for their dependence on the target kinases (cellular IC50 ranges from 0.03 to 
0.24 M).  Consistent with these activities, exposure to pacritinib resulted in the reduction of 
phospho-JAK2, phospho-STAT3, or phospho-STAT5 in the relevant cell lines. 
The therapeutic effects of pacritinib were assessed in an orthotopic model of MPD induced with 
Ba/F3JAK2V617F cells.  Pacritinib treatment at 150 mg/kg orally twice daily (BID) was well tolerated 
and significantly ameliorated symptoms, with 60% normalization of spleen weight and 92% 
normalization of liver weight.  
 
Pharmacokinetics in Animals 
 
Pharmacokinetics (PK) following single intravenous (i.v.) or oral administration of pacritinib was 
evaluated in mice, rats, and dogs.  Following oral administration, pacritinib showed rapid absorption in 
mice (time of maximum concentration [Tmax] from 0.5 to 1.3 hours) and moderately fast absorption in rats 
and dogs (Tmax ~4 hours).  The oral terminal half-lives were 2.2, 5.7 and 4.4 hours in mice, rats, and dogs 
respectively.  As measured by liver blood flow, the systemic clearance of pacritinib from plasma was high 
in mice (8 L/h/kg) and dogs (1.6 L/h/kg) and moderate in rats (1.6 L/h/kg).  The i.v. terminal half-lives 
were 5.6, 6, and 4.6 hours in mice, rats, and dogs, respectively.  The oral bioavailability of pacritinib was 
39% in mice, 10% in rats, and 24% in dogs. 
 
1.3.2 
Preclinical Toxicology 
 
The adverse effects of pacritinib were evaluated in 30-day repeated oral dose toxicity studies with 14-day 
recovery in both mice and dogs, and in 26- and 39-week chronic toxicity studies in mice and dogs, 
respectively.  Key findings included dose-dependent leukopenia accompanied by neutropenia (dog) and 
neutrophilia (mice) that partially reversed during recovery.  Mice also showed dose-dependent but 
reversible thrombocytosis and anemia.  In the chronic toxicity studies, low-magnitude decreases in 
neutrophils and red blood cell parameters were observed.  No treatment-related hepatic changes were 
observed with the exception of increased aspartate transaminase (to +109%, male dogs) and increased 
triglycerides (to +57%, male and female dogs).   
In the 30-day study in dogs, animals receiving mid and high dosages of pacritinib experienced vomiting 
and diarrhea that increased in severity despite treatment with antiemetic and antidiarrheal medication.  
Similarly, in the 39-week study in dogs, an increased incidence of nausea and vomiting was observed at 
dosages of 20 mg/kg/day and higher.  Periods of low food consumption in individual animals receiving 
40 and 50 mg/kg/day were accompanied by rapid weight loss (which was controlled and reversed with 
subcutaneous fluid and supplemental food) and were considered treatment related and adverse.   


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Based on these studies, the no observed adverse effect level was determined to be 100 mg/kg BID in mice 
and 10 mg/kg BID in dogs. 
 
1.3.3 
Summary of Clinical Pharmacology and Phase 1 Studies with Healthy Volunteers with 
Pacritinib 
 
To date, the Sponsor has completed two PK studies for pacritinib in healthy volunteers, including a food 
effect study (SB1518-2010-006) characterizing the effects of a high calorie, high fat meal on the 
bioavailability and PK of pacritinib and a study assessing inter- and intra-individual variability of oral 
pacritinib in healthy volunteers under fasted conditions at 100 mg, 200 mg and 400 mg doses 
(SB15182010-004).  In addition, the single and multiple dose population PK of pacritinib has been 
characterized following multiple dose administration of pacritinib in two studies (SB1518-2007-001 and 
SB1518-2008-003) in patients with advanced myeloid malignancies.  
After administration of single doses of pacritinib in a randomized, three-treatment, three-period crossover 
study (SB1518-2010-004) in healthy volunteers under fasting conditions, peak plasma concentrations 
were reached at a median Tmax ranging from 4.5 to 5.5 hours across the 100 to 400 mg dose range.  While 
between-patient variability was relatively high (28% to 45%), the within-patient variability was low (13% 
to 15%), highlighting the consistent systemic exposure for pacritinib in individual patients.  The mean 
elimination half-life was approximately 34 hours and was not dependent on dose.  The systemic exposure 
of pacritinib in healthy volunteers was comparable to that in patients.  After oral administration of single 
200-mg doses (2100 mg capsules) of pacritinib under fed and fasted conditions in 
study SB1518-2010-006, the 90% confidence intervals for the geometric mean ratios (fed to fasted) for 
maximum concentration observed (Cmax), area of the curve up to the last measurable concentration 
(AUC0-t), and area under the curve to infinite time (AUCinf) were between 80% and 125%, demonstrating 
lack of an effect of food on absorption.  Given this data, pacritinib can be orally administered without 
regard to timing of meals.  
Pooled analyses of PK assessments from the two completed clinical studies in patients at pacritinib 
dosages up to 600 mg once daily (QD) showed slow absorption (Tmax 4 to 6 hours) and dose-related 
increases in systemic exposure up to 400 mg QD.  The rate of absorption was linear at doses up to 300 mg 
and thereafter appeared to be rate limited.  Therefore, modeling suggested that, at doses of over 200 mg 
per day, divided doses would yield increased steady study blood levels.  Beyond the 400 mg QD dosage, 
there was minimal increase in exposure with doses up to 600 mg QD suggesting involvement of a 
saturable process in oral absorption of pacritinib.  In addition, the results demonstrated a prolonged 
elimination half-life (mean Day 1 half-life=47 hours), supporting a QD regimen of pacritinib in clinical 
development.  Comparison of systemic exposure of pacritinib on Days 1 and 15 showed a 1.5- to 2-fold 
increase in systemic exposure at steady state.  
 
1.3.4 
Overview of Clinical Studies of Pacritinib in Patients with Myelofibrosis 
 
Approximately 967 individuals have received pacritinib in 15 completed studies, which includes 
552 patients with myelofibrosis who were assigned to a pacritinib arm. Completed studies include 
two controlled studies in myelofibrosis, four uncontrolled clinical studies in cancer patients and 9 clinical 
pharmacology/pharmacokinetic studies. The summary below describes efficacy and safety observations 
from across the completed controlled (phase 3) studies in myelofibrosis.   
 


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Summaries of Each Phase 3 Myelofibrosis Study 
 
PERSIST-1 was the first phase 3 study of pacritinib, comparing the efficacy of 400 mg QD with best 
available therapy (not including ruxolitinib) in patients with PMF, PPV-MF, or PET-MF.  Patients 
previously treated with JAK2 inhibitors were excluded.  There were no exclusion criteria based on 
platelet count.  Three hundred twenty-seven patients (327) were randomized in a 2:1 allocation to 
pacritinib or best available therapy (BAT).  PERSIST-1 demonstrated a statistically significant 
improvement in the primary endpoint of percent of pacritinib-treated patients achieving a ≥35% reduction 
in spleen volume at Week 24 compared to baseline, as assessed by centrally read MRI or computed 
tomography [CT] imaging), compared to best available therapy.  Pacritinib efficacy in SVR response was 
not affected by baseline thrombocytopenia (<50,000/µL or <100,000/µL platelets), compared to BAT 
(pre-specified subgroup intent-to-treat [ITT] <50,000/µL: 22.9% versus 0% SVR response, respectively; 
<100,000/µL: 16.7% versus 0% SVR response, respectively), although statistical significance could not 
be determined in accordance with the pre-specified statistical analysis plan.  More patients treated with 
pacritinib had improved MF-related symptomatology, meeting the predefined TSS response definition 
(≥50% reduction at Week 24 compared to baseline, as assessed by Myeloproliferative Neoplasm-
Symptom Assessment Form Total Symptom Score version 2.0 (MPN-SAF TSS 2.0) than those treated 
with BAT, but this trend was not statistically significant.  In general, safety was similar to that seen in 
early phase studies, although interim OS results were consistent with a negative trend in survival in 
pacritinib-treated patients, and there were imbalances in fatal and life-threatening events, including 
intracranial hemorrhage, and arrhythmias including sudden death. 
PERSIST-2 was the second phase 3 study of pacritinib, comparing the efficacy of 400 mg QD and 
200 mg BID with best available therapy, including ruxolitinib, in patients with PMF, PPV-MF, or 
PET-MF and thrombocytopenia (baseline platelet count ≤100,000/µL).  Patients previously treated with 
JAK2 inhibitors were included.  There were no exclusion criteria based on platelet count.  Three hundred 
eleven patients (311) were randomized in a 1:1:1 ratio to the 3 treatment arms.  Due to Full Clinical Hold 
on February 8, 2016, only 211 of the accrued patients were evaluable in the ITT (efficacy) population, 
having been randomized with sufficient time to reach the Week 24 evaluation window, thus limiting the 
power to detect differences in the efficacy endpoints.  PERSIST-2 demonstrated a statistically significant 
improvement in the coprimary endpoint comparing the pooled pacritinib arms with the BAT arm for the 
percent of pacritinib-treated patients achieving a ≥35% reduction in spleen volume at Week 24 compared 
to baseline (SVR response), as assessed by centrally read MRI or CT imaging, compared to best available 
therapy (18.1% vs. 2.8%, p=0.0011).  More patients in the pooled pacritinib had improved MF-related 
symptomatology, meeting the predefined TSS response definition (≥50% reduction at Week 24 compared 
to baseline, as assessed by MPN-SAF TSS 2.0, TSS response) than those treated with BAT, but this trend 
in the second co-primary endpoint was not statistically significant (24.8% vs. 13.9%, p=0.791).  
Comparing the individual pacritinib treatment arms to BAT, SVR response was nominally significant for 
BID (21.6%) vs. BAT (p=0.0007), and for QD (14.7%) vs. BAT (p=0.0173).  Unlike the pooled 
coprimary analysis, the BID arm had nominal significance for TSS response vs. BAT (32.4% vs. 13.9%, 
p=0.0106), but the QD arm did not (17.3%, p=0.6524).  Exploratory analyses most relevant to the current 
study showed that in comparison with the ruxolitinib-treated BAT patients, more pacritinib-treated 
patients achieved the SVR response than patients treated with either ruxolitinib or other BAT agents (QD 
11/75, 14.7%; BID 16/74, 21.6%; ruxolitinib 1/32, 3.1%; other BAT 1/40, 2.5%).  Similarly, more 
pacritinib 200 mg BID (but not 400 mg QD) patients achieved the MPN-SAF TSS2.0 response 
(pacritinib 24/74, 32.4% vs. ruxolitinib 6/32, 18.8%), despite the increased effect of ruxolitinib compared 
to all other BAT patients (4/40, 10%). 
Interim analyses of the PERSIST-2 study led to Full Clinical Hold due to interim OS results in which the 
pooled pacritinib treatment arms (QD + BID) were compared with BAT and concerns about fatal 
intracranial hemorrhage, cardiac failure, and cardiac arrest.  Updated analyses based on the locked 
database demonstrated that the QD dosing arm had a survival decrement compared to BAT (hazard ratio 


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[HR]=1.18; p=0.6615), but the BID dosing arm had a trend for survival benefit (HR=0.68; p=0.3458).  In 
general, the safety observed in PERSIST-2 was similar to that observed in PERSIST-1, although 
differences were seen between the QD and BID pacritinib dosing arms.  With the exception of 
hemorrhage, BID dosing generally was associated with lower rates of adverse events (AEs), including 
grade 3/4 and fatal events.  The pacritinib BID arm had greater apparent efficacy for both SVR and 
reduction in TSS than either pacritinib dosed at 400 mg QD or BAT.  Based on these efficacy data, the 
dose of 200 mg BID has been selected as the upper level dosage regimen for the current dose ranging 
study. 
Most relevant to the current study, the safety impacts of prior JAK2 inhibitor treatment in PERSIST-2 
were compared to patients who did not have such prior treatment. Incidences of treatment-emergent AEs 
(TEAEs) overall followed a similar pattern in the prior JAK2 inhibitor treatment and no prior JAK2 
inhibitor treatment subgroups in the pacritinib and BAT treatment arms (pacritinib, 98.1% and 96.3%, 
respectively; BAT, 90.4% and 87.0%, respectively), with comparable incidence in the QD and BID 
dosing arms. While thrombocytopenia showed similar rates between subgroups, anemia was increased in 
the no prior treatment group (pacritinib, 15.5% [13.5% QD and 17.6% BID] and BAT, 11.5% in the prior 
treatment group, and pacritinib, 35.5% [42.3% QD and 29.1% BID] and BAT, 19.6% in the no prior 
treatment group). Diarrhea, nausea, and vomiting had increases in incidence in the prior treatment group 
compared to the no prior treatment group. The percentages of patients who experienced TEAEs of 
CTCAE grade 3 in the pacritinib QD + BID pooled arms, and BAT arms were 35.9% and 26.9% 
respectively, in patients with prior treatment and 36.4% and 28.3%, respectively, in patients with no prior 
treatment. When comparing the incidence of grade 3 events in the QD and BID arm in each subgroup, 
there was an increased incidence of events in the QD arm in the prior treatment subgroup (44.2% 
compared to 27.5%) and an increased incidence of events in the BID arm in the no prior treatment 
subgroup (40.0% compared to 32.7%). The percentage of patients who experienced TEAEs of CTCAE 
grade ≥3 in the pacritinib and BAT arms were 70.9% and 42.3%, respectively, in patients with baseline 
prior treatment and 74.8% and 56.5% respectively, in patients with baseline no prior treatment. The rates 
of grade 3/4 TEAEs in the QD and BID pacritinib groups were similar to that observed in the pacritinib 
QD + BID pooled arms. The rates of grade 3/4 thrombocytopenia and more notably, anemia events were 
decreased in the prior treatment group (prior treatment: pacritinib, 12.6% [QD 11.5% and BID 13.7%] 
and BAT, 9.6%; no prior treatment: pacritinib, 35.5% [QD 42.3% and BID 29.1%] and BAT, 19.6%). 
Fatal TEAEs occurred at modestly higher rates in the prior treatment group compared to the no prior 
treatment group in the pacritinib arms, particularly in the pacritinib QD arm, (12.6% [QD 17.3% and BID 
7.8%] compared to 9.3% [QD 11.5% and BID 7.3%]). The BAT arm showed a reverse pattern, with fatal 
events increased in the no prior treatment group compared to the prior treatment group (13.0% versus 
5.8%).  
Adverse Events in the Myelofibrosis Population: 
Overall, amongst the MF subjects treated with pacritinib in the completed controlled and uncontrolled 
studies, 96% experienced a treatment emergent AE.  The most common TEAEs (> 10% of subjects) 
occurred in the SOCs of gastrointestinal disorders (including diarrhea [66%], nausea [37%], vomiting 
[24%], abdominal pain [16%] and constipation [13%]), blood and lymphatic system disorders (including 
anemia [28%] and thrombocytopenia [25%]) and general disorders (fatigue [22%], pyrexia [12%] and 
decrease appetite [13%]).  Events of dizziness (10%), dyspnea, epistaxis and pruritus (all 11%) were also 
observed.   
The most commonly (>10% of all subjects) reported treatment-related TEAEs by preferred term, were in 
the SOC of gastrointestinal disorders including diarrhea (62%), nausea (31%) and vomiting (18%), and 
the SOC of blood and lymphatic system disorders, including thrombocytopenia (16%) and anemia (15%).  
While GI-related events were common, they were generally reversible, of low grade and rarely led to 
treatment discontinuation.  The potential risk of hypersensitivity reaction with pacritinib is low.  
Pacritinib is contraindicated in patients with a known hypersensitivity to the active substance or to any of 


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the excipients. Potential mechanisms include an immune-mediated response to pacritinib or any of the 
excipients of the product. 
Safety Observations Across the Controlled Phase 3 Studies: 
In the controlled PERSIST-1/-2 studies, patients in the pacritinib arm (42.8% [184/430]) experienced 
treatment-related grade 3/4 AEs at a higher frequency than patients in the BAT arm (13.7% [28/204]). 
However, no notable patterns were observed in the type or frequency of specific AEs. The proportion of 
patients who experienced a treatment related grade 3/4 AE was similar in the 400 mg QD (42.0% 
[136/324]) arm compared to the 200 mg BID (45.3% [48/106]) arm. The most common treatment related 
grade 3/4 AEs for both the 400 mg QD and 200 mg BID arms were thrombocytopenia (12.7% and 18.9%, 
respectively) and anemia (15.4% and 10.4%, respectively). For both treatment arms, all other grade 3/4 
TEAEs occurred at a frequency of <6%. 
A greater proportion of patients in the pacritinib (50.9%) arm compared to BAT (27.5%), and in the 
400 mg QD arm (52.2%) compared to 200 mg BID (47.2%), experienced at least one SAE. The most 
common SAEs in patients treated with pacritinib by PT were anemia (6.7%), pneumonia (6.3%), disease 
progression (3.0%), thrombocytopenia and cardiac failure (both 2.8%), and pyrexia and acute renal failure 
(2.6% each). All of these SAEs occurred at a higher incidence in patients treated with pacritinib compared 
to BAT. In addition, the incidences of all of these SAEs, except for thrombocytopenia (1.9% of the 
400 mg QD arm and 5.7% of the 200 mg BID arm) were similar for the 400 mg QD and 200 mg BID 
arms  
The incidence of deaths reported was higher in the pacritinib arms than in the BAT arm over the entire 
reporting period for the pooled PERSIST-1/-2 studies, including more than 30 days after last dose of 
study treatment (27.2% of pacritinib vs. 9.3% of BAT patients) or while on study treatment and within 
30 days after treatment (10.9% of pacritinib vs. 5.4% of BAT patients). The higher incidence of deaths in 
the pacritinib arm was a result of a much higher incidence with 400 mg QD than with 200 mg BID 
(29.9% vs. 12.7%). In particular, during the period on study treatment or within 30 days after treatment, 
the difference in deaths between pacritinib and BAT was only seen for the 400 mg QD arm: 12.7% of 
400 mg QD died in this period compared to 5.7% of 200 mg BID patients and 5.4% of BAT patients. 
The SOCs with the highest number of patients reported in the 400 mg QD arm were general disorders and 
administration site conditions (4.3%), cardiac disorders (2.5%), and infections and infestations (1.9%). In 
contrast, for the 200 mg BID arm, the SOCs with the highest number of patients reported were general 
disorders and administration site conditions (3.8%) and nervous system disorders (2.8%). General 
disorders and administration site conditions (2.0%) was the most frequently reported SOC in patients 
treated with BAT. 
Thrombocytopenia 
While many patients had stable or increasing platelet counts during treatment, some decreases were 
observed. The incidence of the TEAE of thrombocytopenia was higher during treatment with pacritinib 
(27.9%) than with BAT (18.6%) in the PERSIST 1/-2 studies. The incidence of thrombocytopenia was 
generally higher in the 200 mg BID arm compared to the 400 mg QD arm. This was true for all TEAEs 
(34.0% vs. 25.9%, respectively), related TEAEs (20.8% vs. 16.0%), grade 3/4 TEAEs (21.0% vs. 32.1%), 
and SAEs (1.9% vs. 5.7%).   
Despite thrombocytopenia, most pacritinib patients continued treatment without dose modification. 
Overall, only 2.5% of patients on 400 mg QD and 1.9% on 200 mg BID, discontinued due to 
thrombocytopenia and only 2.8% on 400 mg QD and 1.9% on 200 mg BID, had a dose reduction due to 
thrombocytopenia. In patients with a platelet count below 100,000/µL, only 4.0% of patients on 400 mg 
QD and 1.9% of patients on 200 mg BID, discontinued due to thrombocytopenia. For those who had dose 
modifications due to thrombocytopenia, dose reduction or short term interruption allowed treatment 
continuation. Importantly, treatment emergent thrombocytopenia or worsening of baseline 


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thrombocytopenia did not appear to be associated with treatment-emergent AEs of bleeding. Hemorrhagic 
events were reported in pacritinib treated patients with or without severe thrombocytopenia. 
Anemia 
The TEAE of anemia was higher during treatment with pacritinib (28.1%) than with BAT (17.6%) in the 
PERSIST-1/-2 studies. However, the incidence of anemia was generally lower in the pacritinib 200 mg 
BID arm compared to the 400 mg QD arm. This was true for all TEAEs (23.6% vs. 29.6%, respectively), 
related TEAEs (13.2% vs. 17.9%), grade 3/4 TEAEs (21.7% vs. 26.2%), and TEAEs leading to dose 
reduction (0.9% vs. 3.7%).  
Mean (SD) baseline hemoglobin levels for the 400 mg QD and 200 mg BID arms were 103.9 (23.3) g/L 
and 98.9 (22.0) g/L, respectively, indicating in general, patients were anemic at study entry. 
Hemorrhage  
Patients with MPNs are at increased risks for thrombosis and major bleeding. Hemorrhagic events have 
been reported in pacritinib-treated patients with and without severe thrombocytopenia. 
The incidence of TEAEs in the SMQ hemorrhages was similar during treatment with pacritinib (33.7%) 
and BAT (30.4%) in the PERSIST-1/-2 studies. However, the incidence of hemorrhage events was lower 
in the 400 mg QD arm compared to the 200 mg BID arm for all categories of TEAEs, including SAEs. 
The most common bleeding events were epistaxis, contusion, hematoma and GI hemorrhage and these 
events occurred at a similar frequency to patients treated with BAT.  Importantly, one of the most 
common TEAEs in the “watch and wait only” patients was epistaxis (26.3%), indicating a baseline level 
of bleeding without any therapy, in this MF population. Most events in the SMQ hemorrhages were low 
grade, however, severe and sometimes life-threatening and fatal hemorrhagic events have been reported 
across the PERSIST-1/-2 studies. These outcomes comprised predominantly GI bleeding (including 
gastric variceal hemorrhage, melena, and esophageal hemorrhage) and intracranial hemorrhage, cerebral 
hemorrhage and meningorrhagia.  Overall, hemorrhagic TEAEs resulted in death in seven patients in the 
PERSIST-1/-2 studies, two treated with pacritinib 200 mg BID, four treated with pacritinib 400 mg QD, 
and one after crossover from BAT to pacritinib.   
The incidence of a new hemorrhage event TEAE was highest at the start of treatment and then diminished 
with continued treatment in all treatment groups.  Serious hematological events occurred in patients with 
complicated medical histories, severe comorbidities, concomitant antiplatelet use, and myelosuppression. 
The risk of bleeding episodes did not appear to be related to the degree of thrombocytopenia. 
Diarrhea 
Patients in the PERSIST-1/-2 studies were evaluated at baseline to assess usual bowel habits and 
instructed on the need for early intervention for possible GI adverse effects associated with treatment. 
During each study, standard supportive care measures were provided to control symptoms of GI toxicity.   
The incidence of the TEAE of diarrhea was higher during treatment with pacritinib (61.4%) than with 
BAT (14.2%) in the PERSIST-1/-2 studies. However, the incidence of diarrhea was generally lower in the 
pacritinib 200 mg BID arm than in the 400 mg QD arm for most categories of TEAEs. This was true for 
all TEAEs (48.1% vs. 65.7%, respectively), related TEAEs (48.1% vs. 60.2%), grade 3/4 TEAEs (3.8% 
vs. 6.5%), TEAEs leading to discontinuation (0% vs. 2.5%), and TEAEs leading to dose reduction (0.9% 
vs. 4.0%). However, the incidence of diarrhea reported as SAEs was similar in both the 200 mg BID and 
400 mg QD arms (1.2% vs. 1.9%). 
The incidence of diarrhea was highest in the pacritinib groups at the start of treatment and then 
diminished with continued treatment: 54.3% of patients in the 400 mg QD arm and 40.6% of patients in 
the 200 mg BID arm reported a new TEAE of diarrhea during the first eight weeks of treatment. Between 
Weeks 8 and 16, this had decreased to 10.9% of the 400 mg QD arm and 15.3% of the 200 mg BID arm. 
After Week 16, the incidence was <10% in either arm. 


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While patients in both pacritinib and BAT treatment arms experienced the onset of diarrhea within the 
first four weeks, overall the time to onset of the first episode of diarrhea was earlier for patients treated 
with pacritinib than BAT. Within the pacritinib treatment arms, the 200 mg BID arm was more likely to 
remain event-free both in the first eight to 12 weeks and over the duration of treatment compared to the 
400 mg QD arm. Similar results were seen for the time course of grade 3/4 diarrhea. 
Nausea and Vomiting 
The incidence of the TEAE of nausea was higher during treatment with pacritinib (32.8%) than with BAT 
(8.3%) in the PERSIST-1/-2 studies. However, the incidence of nausea was lower in the pacritinib 200 
mg BID arm compared to the 400 mg QD arm for related TEAEs (20.8% vs. 29.0%) and those TEAEs 
leading to dose reduction (0.9% vs. 1.9%). Very few patients in any group reported grade 3/4 TEAEs or 
SAEs of nausea or nausea AEs leading to discontinuation or dose reduction, and almost all of these were 
in the 400 mg QD arm. 
The incidence of vomiting was higher during treatment with pacritinib (20.7%) than with BAT (5.4%) in 
the PERSIST-1/-2 studies. However, the incidence of vomiting was lower in the pacritinib 200 mg BID 
arm than in the 400 mg QD arm for related TEAEs (10.4% vs. 16.4%) and grade 3/4 TEAEs (0% vs. 
2.5%). Very few patients in any group reported grade 3/4 TEAEs or SAEs of vomiting or vomiting AEs 
leading to discontinuation or dose reduction, and almost all of these were in the 400 mg QD arm. 
Cardiac Toxicities 
The incidence of TEAEs of cardiac disorders was higher during treatment with pacritinib (13.7%) than 
with BAT (9.8%) in the PERSIST 1/-2 studies. However, the incidence of cardiac disorders was generally 
lower in the pacritinib 200 mg BID arm than in the 400 mg QD arm. This was true for all TEAEs (10.4% 
vs. 14.8%, respectively), grade 3/4 TEAEs (3.8% vs. 8.6%), SAEs (4.7% vs. 9.3%), and related SAEs 
(0.9% vs. 2.2%). 
The most commonly reported TEAEs of cardiac disorders were cardiac failure (3.5% of pacritinib 
patients, with a similar incidence in the 400 mg QD and 200 mg BID arms, and 2.5% of BAT patients) 
and atrial fibrillation (3.0% of pacritinib patients, all in the 400 mg QD arm, none in the 200 BID arm, 
and 2.5% of BAT patients). All other cardiac TEAEs occurred with an incidence of <2% in any treatment 
group.  Approximately half of the cardiac events were grade 3/4 in severity in both the pacritinib and 
BAT arms, but in the pacritinib arm these were mainly in the 400 mg QD arm (8.6% of patients vs. 3.8% 
of the 200 mg BID arm). Very few of the cardiac events led to discontinuation (1.5% of the 400 mg QD 
arm, 0.9% of the 200 mg BID arm, and 0.5% of the BAT arm).  
Although the rate of serious cardiac events among MF patients was modestly higher than what was 
expected in the BAT arm, no clear pattern of individual cardiac events or event onset was discernable. 
Some appeared to be associated with other manifestations of worsening of a pre-existing cardiac 
condition. In support of this, none of the cardiac events in the BAT arm and only a few in the pacritinib 
arm were considered to be related to study drug. More specifically, the two most common cardiac events 
were considered related in four (0.9%) pacritinib patients (all 400 mg QD) with atrial fibrillation and 
three (0.7%) pacritinib patients (two with 400 mg QD and one with 200 mg BID) with cardiac failure.   
While diarrhea was one of the most commonly reported TEAEs for pacritinib-treated patients, severe 
diarrhea associated with hypokalemia was not observed. Hypokalemia measured by clinical laboratory 
showed a 2 grade negative shift (0 to 2) in 5.7% of patients in the pacritinib 200 mg BID arm, 7.8% in the 
400 mg QD arm, and 2.9% in the BAT arm.   
There were 13 cardiac disorder TEAEs leading to death in the PERSIST-1/-2 studies and the incidence 
was higher in the 400 mg QD arm (8 patients [2.5%]) than either the 200 mg BID arm (no patients) or the 
BAT arm (2 patients [1.0%]).  Of these deaths, only two were reported by the investigator to be related to 
study treatment (one event of cardiac arrest and one event of congestive cardiac failure). 


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2 
Study Rationale and Objectives 
 
Two phase 2 studies of pacritinib have been conducted in patients with MF.  Data from these studies 
show that pacritinib can be safely administered to patients with MF, including those who also have 
thrombocytopenia.  Pacritinib treatment led to clinically meaningful reduction in spleen size and volume 
in a substantial proportion of patients with MF in the phase 2 studies.  Pacritinib treatment improved 
disease-associated symptoms regardless of the degree of thrombocytopenia and in patients who had 
received prior ruxolitinib.  These findings warrant further investigation to confirm the efficacy and safety 
of pacritinib, in patients who have been previously treated with ruxolitinib including those with 
thrombocytopenia. Pacritinib may address a significant unmet need as salvage therapy, especially in 
patients with low platelet counts or red blood cell transfusion requirements who are intolerant of 
ruxolitinib.  
The current study is being proposed to address the Food and Drug Administration (FDA) 
recommendation to perform a study to determine if a lower dosage of pacritinib might prove optimal in 
patients with MF.  This study is an open-label, randomized, phase 2 study with 3 dosages that aims to 
identify the most appropriate dosage for future studies based on risk/benefit profile.  The 3 dosages 
include a low dosage (100 mg QD), an intermediate dosage (100 mg BID), and a high dosage with a 
demonstrated efficacy profile and acceptable safety profile (200 mg BID).  These dosage levels have been 
selected because they span the dose–response curve and allow adequate characterization of dose–response 
relationship for pacritinib and allow for establishment of a minimally effective dosage that conserves the 
known effect of pacritinib on the surrogate marker of spleen volume response as determined by 
independently assessed MRI.   
Recruitment to 3 dosages simultaneously is justified based on the large safety database available at the 
highest planned dosage level from PERSIST-2 (i.e., 200 mg BID), and the planned frequent monitoring 
by an Independent Data Monitoring Committee (IDMC; see Section 2.2) in addition to rigid entry criteria 
for patients with pre-existing bleeding episodes and patients with existing cardiac disease, with increased 
monitoring for cardiac and hemorrhage AEs.  
 
2.1 
Justification of Included Patient Population 
 
MF is a serious, life-limiting condition with severe morbidity in advanced stages.  Ruxolitinib is the only 
approved agent for treatment of MF.  Patients who are intolerant or who have failed to maintain a robust 
response to ruxolitinib have no alternative therapies and are at high risk for early mortality. 
 
Overview of Included Patient Population 
 
Patients to be included in this study will have failed therapy with ruxolitinib on the basis of intolerance or 
lack of efficacy.  This requirement is based on the unmet medical need in patients who failed to maintain 
benefit from the only approved agent.  Intolerance is defined by a minimum of 28 days therapy with 
pre-defined safety issues as previously used in a phase 3 clinical study of a JAK inhibitor in MF patients 
(https://clinicaltrials.gov/ct2/show/NCT02101268).  Suboptimal efficacy is defined based on consensus 
criteria and is based on a lack of spleen reduction and symptom improvement after 6 months of attempted 
treatment (Mesa et al 2016). 
In addition, patients will be highly symptomatic (Dynamic International Prognostic Scoring System 
[DIPSS] risk score of Intermediate-1 to High Risk), and have splenomegaly as assessed by physical 
examination. 
Patients must have had no recent cardiac or bleeding history, and meet cardiac and bleeding safety 
screening evaluations including electrocardiogram (ECG), echocardiogram and coagulation testing 


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results.  Patients with baseline corrected QT interval (QTc) ≥450 ms will be excluded from the study.  
Patients requiring concomitant medications with a significantly increased risk of QTc prolongation or 
bleeding will be excluded.  Based on the observed limited increase in pacritinib concentration in the 
cytochrome P450 (CYP3A4) inhibitor interaction study with clarithromycin (Study PAC104), caution 
should be exercised when coadministering such inhibitors with pacritinib. For the PAC203 clinical study, 
patients requiring such inhibitors will be excluded (Appendix 5). Based on the substantive pacritinib 
concentration reduction observed in the cytochrome P450 (CYP450) inducer interaction study with 
rifampin (Study PAC106), patients requiring such inducers (Appendix 6) will be excluded.  Patients are 
also required to have adequate hepatic and renal organ function and the absence of known medical issues 
which might affect efficacy assessments, tolerability, or safety on study. 
 
2.2 
Independent Data Monitoring Committee 
 
This study will utilize planned frequent monitoring by an IDMC.  At a minimum, the IDMC will consist 
of 1 board-certified hematologist, 1 board-certified cardiologist, and 1 biostatistician experienced in 
adaptive design clinical studies.  The role and responsibilities of the IDMC will be fully defined within 
the IDMC charter, including, but not limited to:  
 
 
Review safety data across arms, focusing on bleeding events, cardiac events, and deaths  
 
Evaluate cumulative safety as described in Section 11 
 
Make independent recommendations to the Sponsor on study continuation (continue without 
modification, continue with modification, or terminate) and on patient enrollment (hold or stop 
enrollment, enroll additional patients, close arm) as described in Section 11. 
 
Make independent recommendation to the Sponsor on pacritinib dose or dosages for further study  
 
The IDMC charter will be written in collaboration between the Sponsor and members of the IDMC.  In 
keeping with the terms of the charter, each IDMC meeting will have an open and closed session.   
The first IDMC meeting for safety review is planned tooccur once 18 patients have been randomized and 
treated for 12 weeks and will meet approximately quarterly thereafter.  Meeting minutes will be generated 
from each meeting and provided to the FDA within 10 business days of the meeting conclusion.   
In addition to the IDMC, there will be an Independent Adjudication Committee (IAC) that will review all 
grade 4 or 5 cardiac and bleeding events to assess the principal condition that resulted in the outcome.  
The IAC will provide their assessment to the IDMC.  Additional details on the IAC will be provided in 
the IAC charter. 
 
2.3 
Study Objectives 
 
2.3.1 
Primary Objective 
 
The primary objective is to determine a recommended dosage of pacritinib for further clinical studies. 
 
2.3.2 
Secondary Objectives 
 
The secondary objectives are as follows: 


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1. To examine the dose–response relationship for efficacy, as measured by spleen volume reduction 
(SVR) using MRI (preferred) or CT and TSS using the Myeloproliferative Neoplasm Symptom 
Assessment Form Total Symptom Score version 2.0 (MPN-SAF TSS 2.0) 
2. To examine the dose–response relationship for safety with a focus on AEs of interest 
3. To further characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of pacritinib 
 
3 
Study Design 
 
This is a dose-finding study in patients with PMF, PPV-MF, and PET-MF (DIPSS risk score of 
Intermediate-1 to High-Risk), who were previously treated with ruxolitinib.  The study is designed to 
support a pacritinib dosage selection decision. Three dosages will be evaluated, with patients randomized 
1:1:1 to pacritinib 100 mg QD, pacritinib 100 mg BID, or pacritinib 200 mg BID. Randomization will be 
stratified by baseline platelet count (≤50,000/µL; >50,000/µL and ≤100,000/µL; and >100,000/µL). The 
most recent platelet count obtained prior to start of treatment will be the basis of stratification by baseline 
platelet count. Assigned treatment will continue until the patient experiences progressive disease, 
intolerable AEs, or withdraws consent, or until the assigned treatment arm is closed. No study treatment 
crossover will be allowed.  All patients should complete all visit procedures through Week 24, including 
patients who stop pacritinib treatment or have protocol-defined progressive disease prior to Week 24, 
unless patient withdraws consent, dies, undergoes splenic irradiation or splenectomy, or initiates any non-
protocol-directed anti-myelofibrosis treatment.  Following regulatory, Ethics or Institution Review Board 
approval of Amendment 6, study treatment for patients at and beyond the week-24 timepoint will 
terminate.  Study assessments will cease following the End-of-Treatment or 30-day post (EOT) visit, as 
applicable.  Patients who are benefiting from therapy as of study treatment termination may be allowed to 
continue receiving pacritinib under single patient expanded access or named patient programs at the 
investigator’s discretion and subject to regulatory and Ethics or IRB approval. 
The dosage selection process will be based on efficacy and safety parameters, including model-based 
dose response as described in Section 3.1.     
An IDMC consisting of subject matter experts will be convened and chartered to perform an assessment 
of safety throughout the study.  See Section 2.2 for additional information. 
The following criteria (non-binding) have been established to guide the decision: 
 
In the event of the occurrence of 2 treatment-emergent CTCAE grade ≥4 cardiac AEs or 
2 treatment-emergent CTCAE grade ≥4 hemorrhage AEs in the same treatment arm, suspend study 
enrollment and the IDMC will be convened to review the events including the IAC’s assessment of 
the events.  If the IDMC confirms the nature and grade of the events together with a relationship to 
study drug, the IDMC may recommend closure of one or more treatment arms.  In the event one or 
more arms are suspended or terminated for a safety observation, randomization into the arm(s) will be 
halted immediately, however patients who are experiencing benefit, in the opinion of the investigator 
and Sponsor, and who were randomized to an arm that is suspended or terminated, may continue 
treatment. 
 
The FDA and other Competent Authorities will be notified of any IDMC meeting that is convened 
under these circumstances, and the resultant decision will be reported to the FDA within 2 business 
days. The MHRA will be informed via a substantial amendment.   
 
If closure of an arm occurs, patients will continue to be enrolled into each of the remaining treatment 
arms. 
 
 


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The determination of dose or dosages of pacritinib for further study will be based on efficacy, safety, 
dose–response, and PK/PD exposure–response relationship data after all enrolled patients reach Week 24 
(or discontinue the study).  Approximately 150 patients total or up to 50 patients per arm may be enrolled. 
Spleen volume will be measured by MRI (preferred) or CT at baseline and Weeks 12 and 24 (Table 1).  
Patient-reported disease-related symptoms as assessed by the validated PRO instrument MPN-SAF TSS 
2.0 will be collected daily using an electronic diary and evaluated as part of the dose–response 
relationship.  DNA samples will also be collected for analysis of mutations associated with myelofibrosis 
at baseline and Week 24. 
Safety will be monitored with physical examinations, clinical laboratory assessments (including 
hematologic, chemistry, and coagulation testing), and cardiac monitoring (including ECG and 
echocardiogram testing); specified study treatment dosage modifications will be followed to address 
identified abnormalities.  Adverse event data will be collected throughout the study.   
The Sponsor will collect PK samples from patients in each dosing arm at the following timepoints: 
 
Sparse Sampling (all patients): End of Week 12 and End of Week 24: 30 minutes to 0 hours 
(predose), 4 hours (± 10 minutes), and 8 hours (± 15 minutes) postdose 
 
Dense Sampling (performed at selected sites for approximately 6 to 8 patients total per dose arm, 
at which point all further patients will have PK evaluated by sparse sample collection): Week 1 
Day 1: 2 hours (± 5 minutes), 4 hours (± 10 minutes), 6 hours (± 15 minutes), and 8 hours 
(± 15 minutes) postdose and 24 hours postdose (within 30 minutes before the Day 2 dose), End of 
Week 12 and End of Week 24: 30 minutes to 0 hours (predose), 2 hours (± 5 minutes), 4 hours 
(± 10 minutes), 6 hours (± 15 minutes), and 8 hours (± 15 minutes) postdose 
The PK parameters, minimum concentration observed (Cmin), maximum concentration observed (Cmax), 
and area under the curve (AUC) will be determined and summarized using descriptive statistics for each 
pacritinib dosage arm.  Exposure-response analyses will be conducted on both safety and efficacy 
populations in the study.  PD samples will be analyzed for biomarkers associated with the JAK/STAT 
pathway.   
 
3.1 
Rationale for Dosage Selection 
 
The primary objective of the study is to determine a recommended dosage of pacritinib for further clinical 
development; thus the study is designed to characterize the dose–response relationship for pacritinib in 
patients with MF.  Three dosage levels have been selected based on previous clinical phase 1/2 studies 
and the phase 3 study PERSIST-2, to span the dose–response curve and allow adequate characterization 
of dose–response relationships for efficacy and safety of pacritinib.  These three dosages include a low 
dosage (100 mg QD), an intermediate dosage (100 mg BID), and a higher dosage with potentially 
acceptable efficacy and safety profiles (200 mg BID).  As the systemic exposure of pacritinib is linear up 
to the 300 to 400 mg dosage (see dose-proportionality clinical study report; Study SB1518-2010-004), it 
is projected that the 100 mg QD regimen would result in pacritinib systemic exposure levels similar to 
those of a 50 mg BID regimen.  
The lowest dosage level selected for the study (100 mg QD) is 4-fold lower than the highest dosage level 
in the study (200 mg BID) in terms of total daily dose, allowing for adequate separation between dosage 
levels selected in the study, which should in turn support characterization of the dose–response 
relationship in the study.  The 100 mg QD regimen produced minimal clinical disease responses in 
6 patients in phase 1/2 studies and was not associated with any safety concerns, pointing to limited 
efficacy at the 100 mg QD dosage level.  Moreover, integrated exposure-response data from across the 
clinical program indicate that the exposure-response relationship for pacritinib is relatively steep whereby 
marked efficacy is only observed at exposure levels higher than those associated with the 100 mg QD 


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regimen (Figure 1).  Median geometric mean Cmin of pacritinib at steady-state following administration of 
200 mg BID regimen in PERSIST-2 was 6,783 ng/mL.  Given the observed linearity following single-
dose administration of pacritinib capsules up to 400 mg, median steady-state Cmin levels of pacritinib with 
administration of 100 mg QD would be projected at around 1,700 ng/mL, where there no evidence for 
efficacy as measured by SVR as evident from the exposure-response relationship for pacritinib  
(Figure 1).  Overall, the 100 mg QD regimen is likely to show minimal efficacy and is a reasonable 
choice for the lowest dosage in the study.  Dosage levels lower than 100 mg QD are unlikely to offer any 
advantage in terms of better characterization of the dose–response relationship of pacritinib in the study. 
Given the observed incidence of SAEs, the 200 mg BID regimen will be the highest dosage studied in the 
current study. The 200 mg BID regimen has already demonstrated robust efficacy and a potentially 
acceptable safety profile in the PERSIST-2 study. An intermediate dosage of 100 mg BID will be tested 
that is likely to have efficacy based on the phase 1 studies and clinical experience in patients who 
underwent dose reduction in the phase 3 studies.  
Based on the efficacy observed in clinical studies in MF to date, the selected dosage levels of pacritinib 
are projected to provide reasonable likelihood of efficacy responses while allowing for full 
characterization of the dose–response and dose-safety relationships for pacritinib. 


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Figure 1. Exposure-response Relationships on Spleen Volume Response for Pacritinib in Phase 1/2 Studies 
and PERSIST-2 Study 
 
 
Phase 1/2 
PERSIST-2
 
Source: Section 5.3.5.4, PAC-011-03 Exposure-Response Report, Section 5.3.5.4 PAC-011-03 dataset, and 
Section 5.3.5.4 PAC-011-04 Dose Justification Memo. 
 
3.2 
Progression of Disease 
 
Patients may experience one or more of the following: splenic progression, splenic irradiation, 
splenectomy, or leukemic transformation.  All of these events represent progression of disease and must 
be reported. A patient who has experienced one event will continue to be followed for other progression 
events through Week 24.  Although the date of the first event is considered the date of progression of 
disease, subsequent events must also be reported.   
 
Progression of disease is defined as one or more of the following: 
 
 
Splenic progression, defined as an increase in splenic volume of ≥25% from baseline, based on MRI 
(preferred) or CT scan 
 
Splenic irradiation 
 
Splenectomy 
 
Leukemic transformation, defined as one or more of the following: 
- 
Increase in peripheral blood blast percentage to ≥20%  
- 
Bone marrow blast count ≥20% (bone marrow performed as standard of care) 
 
3.3 
Treatment Continuation After Progression of Disease 
 
Patients who have progression of disease on MRI (preferred) or CT scan, defined as an increase in splenic 
volume of ≥25% from baseline on MRI or CT scan, will not be allowed to continue study treatment. 
Patients should continue the visit schedule through Week 24 (including imaging and all protocol-specified 
study assessments) despite treatment discontinuation or disease progression prior to Week 24, unless 
patient withdraws consent, dies, undergoes splenic irradiation or splenectomy, or initiates any 
non-protocol-directed anti-myelofibrosis treatment.   


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4 
Patient Selection and Withdrawal 
 
4.1 
Target Population 
 
4.1.1 
Inclusion Criteria 
 
1. PMF, PPV-MF, or PET-MF (as defined by Tefferi and Vardiman 2008; Appendix 4) 
2. DIPSS Intermediate-1, Intermediate -2, or High risk (Passamonti et al 2010; Appendix 3)   
3. Prior ruxolitinib treatment with failure to benefit or intolerance as defined by at least one of 
the following: 
a. Treatment for ≥3 months with inadequate efficacy response defined as <10% spleen 
volume reduction by MRI or <30% decrease from baseline in spleen length by physical 
examination or regrowth to these parameters following an initial response; and/or 
b. Treatment for ≥28 days complicated by either: 
i. Development of a red blood cell transfusion requirement (at least 2 units/month 
for 2 months) 
ii. NCI CTCAE grade ≥3 AEs of thrombocytopenia, anemia, hematoma, and/or 
hemorrhage while being treated with a dosage of <20 mg BID 
4. Palpable splenomegaly ≥5 cm below the lower costal margin (LCM) in the midclavicular line 
as assessed by physical examination 
5. TSS of ≥10 on the MPN-SAF TSS 2.0 or patients with a single symptom score of ≥5 or two 
symptoms ≥3 including only the symptoms of left upper quadrant pain, bone pain, itching or 
night sweats (Appendix 3) 
6. Age ≥18 years old 
7. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 (Appendix 6) 
8. Peripheral blast count of <10% throughout the screening period 
9. Absolute neutrophil count of >500/µL 
10. Adequate liver and renal function, defined by liver transaminases (aspartate aminotransferase 
[AST]/serum glutamic oxaloacetic transaminase [SGOT] and alanine aminotransferase 
[ALT]/serum glutamic pyruvic transaminase [SGPT]), ≤3 × the upper limit of normal (ULN) 
(AST/ALT ≤5 × ULN if transaminase elevation is related to MF), direct bilirubin ≤4× ULN, 
and creatinine ≤2.5 mg/dL  
11. Adequate coagulation function, defined by prothrombin time (PT)/international normalized 
ratio (INR), partial thromboplastin time (PTT), or thrombin time (TT) of ≤1.5 × ULN 
12. Left ventricular cardiac ejection fraction (LVEF) of ≥45% by echocardiogram or multigated 
acquisition (MUGA) scan 
13. If fertile, willing to use effective birth control methods during the study 
14. Willing to undergo and able to tolerate frequent MRI or CT assessments during the study 
15. Able to understand and willing to complete symptom assessments using a patient-reported 
outcomes instrument  
16. Provision of informed consent 
 


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4.1.2 
Exclusion Criteria 
 
1. Life expectancy <6 months 
2. Completed allo-SCT or are eligible for and willing to complete allo-SCT 
3. History of splenectomy or planning to undergo splenectomy  
4. Splenic irradiation within the last 6 months 
5. Previously treated with pacritinib 
6. Patients receiving high-dose ruxolitinib (more than 10 mg BID or 20 mg QD) who cannot 
tolerate tapering down ruxolitinib to 10 mg BID or less prior to the first dose of pacritinib as 
described in Section 6.6 
7. Treatment with anticoagulation or antiplatelet agents, except for aspirin dosages of ≤100 mg 
per day, within the last 2 weeks 
8. Treatment with a strong CYP3A4 inhibitor or a strong cytochrome P450 inducer within the 
last 2 weeks (Appendix 5 and Appendix 6, respectively) 
9. Treatment with medications that can prolong the QTc interval within the last 2 weeks 
(Appendix 8) 
10. Treatment with an experimental therapy within the last 28 days 
11. Significant recent bleeding history defined as NCI CTCAE grade ≥2 within the last 3 months, 
unless precipitated by an inciting event (e.g., surgery, trauma, injury) 
12. Any history of CTCAE grade ≥2 non-dysrhythmia cardiac conditions within the last 
6 months.  Patients with asymptomatic grade 2 non-dysrhythmia cardiac conditions may be 
considered for inclusion, with the approval of the medical monitor, if stable and unlikely to 
affect patient safety.  
13. New York Heart Association Class II, III, or IV congestive heart failure (Appendix 7) 
14. Any history of CTCAE grade 2 cardiac dysrhythmias within the last 6 months.  Patients 
with non-QTc CTCAE grade 2 cardiac dysrhythmias may be considered for inclusion, with 
the approval of the medical monitor, if the dysrhythmias are stable, asymptomatic, and 
unlikely to affect patient safety. 
15. QTc prolongation >450 ms or other factors that increase the risk for QT interval prolongation 
(e.g., heart failure, hypokalemia [defined as serum potassium <3.0 mEq/L that is persistent 
and refractory to correction], family history of long QT interval syndrome, or concomitant 
use of medications that may prolong QT interval) (Appendix 8) 
16. Any active gastrointestinal or metabolic condition that could interfere with absorption of oral 
medication 
17. Active or uncontrolled inflammatory or chronic functional bowel disorder such as Crohn’s 
Disease, inflammatory bowel disease, chronic diarrhea, or constipation 
18. Other malignancy within the last 3 years, other than curatively treated basal cell or squamous 
cell skin cancer, carcinoma in situ of the cervix, organ-confined or treated nonmetastatic 
prostate cancer with negative prostate-specific antigen, in situ breast carcinoma after 
complete surgical resection, or superficial transitional cell bladder carcinoma 


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19. Uncontrolled intercurrent illness, including, but not limited to, ongoing active infection or 
psychiatric illness or social situation that, in the judgment of the treating physician, would 
limit compliance with study requirements 
20. Known seropositivity for human immunodeficiency virus 
21. Known active hepatitis A, B, or C virus infection 
22. Women who are pregnant or lactating 
23. Concurrent enrollment in another interventional trial 
 
4.2 
Criteria for Withdrawal of Patients  
 
4.2.1 
Withdrawal from Study Treatment and Procedures 
 
Patients may discontinue or be withdrawn from treatment at any time. All reasonable efforts should be 
made to retain patients who discontinue treatment in the study and to conduct visits through Week 24 
required by the protocol, including MRI (preferred) or CT scanning and follow-up for progressive 
disease, and leukemic transformation.  Reasons for discontinuing treatment may include but are not 
limited to the following: 
 
Documented disease progression as defined in Section 3.2. 
 
Unrelated intercurrent illness that, in the judgment of the principal investigator, will affect 
assessments of clinical status to a significant degree 
 
Pregnancy 
 
Patient’s decision 
 
Patient noncompliance with study drug 
 
Clinical need for concomitant therapy that is not permitted in the study 
 
Decision on the part of the investigator or CTI BioPharma Corp. medical monitor that it is in the 
patient’s best interest to withdraw from study treatment 
 
Sponsor decision to terminate study 
 
Death 
 
5 
Method of Treatment Assignment and Blinding 
 
Initially, eligible patients will be centrally randomized in a 1:1:1 allocation ratio to pacritinib 100 mg QD, 
pacritinib 100 mg BID, or pacritinib 200 mg BID using a central interactive web response system. If 
interim monitoring analysis indicates that any one of the treatment arm meets the stopping criteria 
(Section 11.9) for efficacy or safety and is thus dropped, then the randomization will be updated to a 
1:1 ratio of the two remaining study arms. In the case of two arms being dropped by interim efficacy or 
safety monitoring, then all eligible patients will be enrolled to the remaining one active arm until up to 
30 evaluable subjects are enrolled for that arm. 
Randomization will be stratified by geographic region (North America, Europe, versus rest of the world 
[ROW]) and baseline platelet count (≤50,000/µL; >50,000/µL and ≤100,000/µL; and >100,000/µL). The 
most recent platelet count obtained prior to start of treatment will be the basis of stratification by baseline 
platelet count. 
A patient’s treatment assignment will be known to all except the independent radiographic and cardiology 
assessors who will remain blinded to patient treatment assignment throughout the study. 
 


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6 
Study Treatment 
 
6.1 
Study Drug Administration 
 
Patients will be supplied with 100 mg capsules of the drug.  If assigned to the once per day dosing arm, 
patients will take 100 mg (1 capsule) of pacritinib QD, at the same time of day, orally, with or without 
food.  Patients assigned to twice per day dosing will take 100 mg (1 capsule) of pacritinib BID at the 
same times of day, orally, with or without food or 200 mg (2 capsules) of pacritinib BID orally, at the 
same times of day, with or without food (Table 2).  
 
Table 2. Study Treatment Schedule 
Treatment 
Dosage/Regimen 
Pacritinib 100 mg QD 
Pacritinib 100 mg (1 capsule) QD orally, at the same time of day, with or without food 
Pacritinib 100 mg BID 
Pacritinib 100 mg (1 capsule) BID orally, at the same time of day, with or without 
food 
Pacritinib 200 mg BID 
Pacritinib 200 mg (2 capsules) BID orally, at the same time of day, with or without 
food 
 
6.2 
Study Drug Description and Storage  
 
Pacritinib for oral administration is supplied in capsules containing 100 mg (as the free base) in red 
cap/gray body size 0 opaque hard gelatin capsules.  The inactive ingredients are microcrystalline 
cellulose, magnesium stearate, and polyethylene glycol 8000. 
Each capsule contains 146 mg of pacritinib citrate, which is equivalent to 100 mg pacritinib free base. 
Pacritinib capsules should not be opened or crushed.  Direct contact of the powder in pacritinib capsules 
with the skin or mucous membranes should be avoided.  If such contact occurs, affected areas should be 
washed thoroughly with water. 
Pacritinib capsules should be stored at controlled room temperature 20°C to 25°C or 68°F to 77°F, with 
excursions allowed from 15°C to 30°C or 59°F to 86°F.  All pacritinib supplies must be kept in a 
restricted-access area. 
 
6.3 
Dosage, Route, and Mode of Administration 
 
Patients in each arm will be supplied with 100-mg capsules of pacritinib. If assigned to the twice per day 
dosing arms, patients will either take 100 mg (1 capsule) or 200 mg (2 capsules) of pacritinib twice per 
day, orally, at the same time of day, with or without food.  On days when PK and PD samples and ECGs 
are to be obtained, pacritinib will be administered in the clinic.  
 
6.4 
Drug Accountability 
 
At every study visit, patients will return bottles in which pacritinib is supplied with all remaining untaken 
pacritinib capsules, if any.  Patient compliance will be evaluated by pill count.   
 


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6.5 
Pacritinib Treatment Adjustments for Adverse Events 
 
6.5.1 
Treatment Interruption and Discontinuation 
 
Safety parameters including AEs, hematology, cardiac monitoring, and serum chemistry will be assessed 
according to the protocol. Pacritinib treatment may be withheld for up to 7 days 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.   
Pacritinib should be withheld 7 days prior to planned invasive procedures and concurrently with any 
unplanned invasive procedure.  Pacritinib may be restarted after 2 days without active signs or symptoms 
of active bleeding. 
After treatment interruption, patients may resume pacritinib treatment per dose management guidelines 
below.   
 
6.5.2 
Dosage Management Guidelines for Hematologic Toxicity and Related Complications 
 
Myelosuppression is common in patients with MF and this study allows enrollment of patients with 
severe cytopenias.  Patients with complications of myelosuppression may receive standard supportive 
care, including transient use of granulocyte-colony stimulating factor for the treatment of febrile 
neutropenia and red blood cell and platelet transfusion as clinically indicated.  Patients receiving 
pacritinib are not allowed to receive erythropoietin for the treatment of anemia or platelet stimulating 
factors for the treatment of thrombocytopenia. 
Hematology parameters, including CBC, differential, and platelet count will be evaluated at regular 
intervals during the study.  These parameters should be monitored more frequently if clinically required. 
Patients with a baseline platelet count of ≤ 50,000/µL must be monitored weekly by central laboratory 
assessment for the first 8 weeks, then monthly if counts remain ≤ 50,000/µL.  Unscheduled local 
laboratory test results may be used for assessment and management of patients in real time.  Samples 
collected for local testing must also be submitted to the central laboratory and the results captured in the 
clinical database. 
Table 3 indicates required dose interruptions and modifications for hematologic toxicities and 
complications such as hemorrhage and febrile neutropenia.  Of note, if more than one toxicity is 
experienced simultaneously, the higher-grade toxicity should determine the dose 
interruption/modification.  
Table 3. Treatment Toxicity and Dosage Management: Hematologic Toxicities and Related Complications 
Event 
CTCAE Grade 
Management/Action 
Thrombocytopenia 
 
≥ 2 grade decrease in platelets to 
grade 3 or 4 
 
Hold pacritinib for up to 7 days until 
recovery of platelet count to 
൑ grade 2.  Restart at the next lower 
dose level.  If at 100 mg QD dose 
level, discontinue. 
 
For patients starting treatment with 
grade 3 thrombocytopenia who 
progress to grade 4 
thrombocytopenia that lasts at least 
14 days or is complicated by 
hemorrhage or a new platelet 
transfusion requirement 
 
Pacritinib may be held for up to 7 days 
at the treating physician’s discretion 
until recovery of platelets to baseline.  
Restart either at the same dose or at 
the next lower dose level. 


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Table 3. Treatment Toxicity and Dosage Management: Hematologic Toxicities and Related Complications 
Event 
CTCAE Grade 
Management/Action 
 
If grade 4 thrombocytopenia recurs 
after restarting drug, pacritinib must be 
discontinued. 
Hemorrhage 
 
Treatment-emergent grade 2 
hemorrhage  
 
Hold pacritinib for up to 7 days until 
hemorrhage resolves.  Restart 
pacritinib at the same dose.   
 
If event recurs, hold until resolution 
then restart at the next lower dose.  If 
at 100 mg QD dose level, discontinue.
 
grade 3 
 
Hold pacritinib for up to 7 days and 
start at the next lowest dose level once 
resolved.  If at 100 mg QD dose level, 
discontinue. 
 
grade 4 
 
Discontinue pacritinib 
Febrile neutropenia 
 
grade 4 
 
Hold pacritinib for up to 7 days and 
start at the next lowest dose level once 
resolved.  If at 100 mg QD dose level, 
discontinue. 
Neutropenic infections, 
including neutropenic 
sepsis 
 
grade 4 
 
Hold pacritinib for up to 7 days and 
start at the next lowest dose level once 
resolved.  If at 100 mg QD dose level, 
discontinue. 
 
Coagulation Testing 
 
Coagulation testing will include PT, INR, PTT, and TT at screening, baseline, the end of Week 4, the end 
of Week 12, the end of Week 24, or the end of treatment visit, and 30 days after the last dose of study 
treatment. Additional coagulation testing should be done as clinically indicated. 
These results will be taken into account, together with baseline platelet counts and prior medical history 
of bleeding, to help guide ongoing hematologic monitoring of platelet counts and clinical monitoring for 
bleeding.  Pacritinib dosage modifications will be implemented for clinically significant AEs identified 
with this testing per the guidelines in Table 7. 
 
6.5.3 
Pacritinib Dosage Management Guidelines for QTc Interval Prolongation, Reduction in 
Ejection Fraction, and Other Cardiac Toxicities 
 
A 12-lead ECG (collected in triplicate) will be checked at screening, baseline, the end of Week 4, the end 
of Week 12, the end of Week 24 or the end of treatment visit, including QTc calculation, and 30 days 
after the last dose of study treatment.   
Ejection fraction will be checked (echocardiogram or MUGA scan) at screening, the end of Week 4, the 
end of Week 12, the end of Week 24, or the end of treatment visit, every 6 months during the follow up 
period, and 30 days after the last dose of study treatment.  These assessments will be performed until 
approval of Amendment 6, at which point assessment ceases following the patient’s End-of-Treatment, or 
30-day post (EOT) visit as applicable. Pacritinib dosage modifications will be implemented for clinically 
significant ejection fraction changes as per Table 4 and Table 5.  For patients with a grade 2 decreased 


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cardiac ejection fraction at baseline (LVEF 45%-50%), Table 5 should be used for any further decreases 
in LVEF. If pacritinib treatment is resumed after holding for ejection fraction abnormality, ejection 
fraction should be reassessed approximately 14 days later, then at least every 3 months as per the above 
schedule.  Additional ejection fraction testing shall be done as clinically indicated. 
Treatment should be modified as shown in the following table (Table 4), as recommended by FDA in case 
of QTc interval prolongation.  
 
Table 4. Pacritinib-Related QTc Prolongation, Decreased Cardiac Ejection Fraction and Other Cardiac 
Toxicities 
CTCAE v4 Toxicity Grade 
Management/Action 
1 
No change. 
2 (First occurrence) 
For patients with grade 2 LVEF decreased 
at baseline (LVEF 45%-50%) and further 
decreases in LVEF on study, see Table 5) 
 
Hold pacritinib.  
 
If the toxicity resolves to grade ≤1 within 7 days, treatment 
may be resumed at the next lower dosage level (or 
discontinued, if toxicity occurred while taking 100 mg QD). 
 
Toxicity that does not resolve to grade ≤1 within 7 days 
requires treatment discontinuation. 
2 (second occurrence) 
Discontinue treatment. 
3 
Discontinue treatment. 
4 
Discontinue treatment. 
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; LVEF = left ventricular ejection 
fraction; QD = once daily; QTc = corrected QT interval. 
 
Table 5. Pacritinib-Related Decreased Cardiac Ejection Fraction for Patients with Grade 2 Ejection 
Fraction (LVEF 45%-50%) at Baseline 
CTCAE v4.0 Toxicity Grade 
Management/Action 
3 
 
Hold pacritinib for 1 week and reassess LVEF. If LVEF returns to 
baseline, patient may resume treatment at the next lower dose 
level; if grade 3 does not resolve, pacritinib should be 
discontinued. 
4 
Discontinue treatment.   
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; LVEF = left ventricular ejection 
fraction 
 
In patients who resume pacritinib treatment after holding treatment for grade 2 QTc interval prolongation, 
follow-up ECGs (in triplicate) are recommended on Days 1, 7, 14, 28, and 56 after pacritinib restart.  
After restart of pacritinib, QTc monitoring should follow this schedule with ECGs obtained in triplicate: 
 
 
Restart Day 1 at 4 hours (± 1 hour) after ingestion of the first reduced dosage 
 
Restart Day 7 (± 2 days) 4 hours after dosing (± 1 hour) 
 
Restart Day 14 (± 2 days) 4 hours after dosing (± 1 hour) 
 
Restart Day 28 (± 2 days) at any time relative to dosing 
 
Restart Day 56 (± 7 days) at any time relative to dosing 
 


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If grade 2 toxicity does not resolve to grade ≤1 within 7 days, discontinue all treatment with pacritinib.  If 
grade 2 toxicity recurs despite dosage reduction discontinue all treatment with pacritinib. 
For grade 3 and 4 QTc prolongation, discontinue all treatment with pacritinib. 
 
Other Cardiac Toxicities 
 
Discontinue treatment with pacritinib for all other grade 3 and 4 cardiac toxicities. 
 
6.5.4 
Pacritinib Dosage Management Guidelines for Diarrhea 
 
Treatment with antidiarrheals is advised for all patients who experience new onset diarrhea (Table 6). 
 
Table 6. Treatment Toxicity and Dosage Management: Diarrhea 
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 dosage.  
Concomitant antidiarrheal treatment is required for patients restarting 
pacritinib at the 100 mg QD dosage level. 
 
If the toxicity recurs after restart at the same dosage level, treatment may only 
be resumed at the next lower dosage level. 
 
If the toxicity resolves to grade ≤1 or to the baseline grade after more than 
7 days, treatment may be resumed only at the next lower dosage level.  
Discontinuation is required if on hold from the 100 mg QD dosage level.  
Concomitant antidiarrheal treatment is required for patients restarting 
pacritinib at the 100 mg QD dosage level. 
 
If the toxicity recurs after restart at the lower dosage level, pacritinib 
treatment must be discontinued. 
4 
 
Hold treatment.   
 
If grade 4 toxicity occurs at the lowest dosage of 100 mg QD, the patient will 
be discontinued from the study. 
 
If the toxicity resolves to grade ≤1 or to the baseline grade within 7 days, 
treatment may be resumed, but dosage will be reduced by 1 dosage level from 
the level at which the toxicity was observed.  Concomitant antidiarrheal 
treatment is required for patients restarting pacritinib at the 100 mg QD 
dosage level. 
 


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6.5.5 
Pacritinib Dosage Management Guidelines for Pacritinib-Related Nonhematologic Toxicities 
Other than QTc Prolongation, Decreased Cardiac Ejection Fraction, Other Cardiac 
Toxicities or Diarrhea 
 
As defined in Table 7, a maximum of 2 dosage reductions are allowed for pacritinib-related 
nonhematologic toxicities other than QTc prolongation, decreased cardiac ejection fraction, or diarrhea.   
 
Table 7. Treatment Toxicity and Dosage Management: Pacritinib-Related Nonhematologic Toxicities 
Other than QTc Prolongation, Decreased Cardiac Ejection Fraction, Other Cardiac Toxicities or 
Diarrhea 
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 dosage, 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 dosage reduction to the next lower dosage. 
4 
 
Hold treatment. 
 
If the toxicity resolves to grade <1 or to the baseline grade within 7 days, 
treatment may be resumed, but dosage will be reduced by one dosage from 
the level at which the toxicity was observed. 
 
If grade 4 toxicity occurs at the lowest dosage of 100 mg QD, the patient 
should be discontinued from the study. 
 
6.6 
Concomitant and Excluded Therapies 
Ruxolitinib should not be administered concurrently with pacritinib at any time. Although there is no 
washout period required for ruxolitinib prior to the start of dosing with pacritinib, it should be understood 
that because of the difference in half-life between ruxolitinib (3 hours Jakafi package insert) and 
pacritinib (approximately 40 hours), there will be a period of 10 to 14 days following the discontinuation 
of ruxolitinib and the start of dosing with pacritinib, during which pacritinib has not yet reached steady 
state and during which patients may be at increased risk of ruxolitinib withdrawal, particularly after high 
doses of ruxolitinib (eg, more than 10 mg BID or 20 mg QD). For this reason, patients who are on more 
than 10 mg BID (or 20 mg QD) of ruxolitinib at the time of consent for this study must taper the 
ruxolitinib dose down to 10 mg BID or lower and remain stable on the reduced dose for at least 2 weeks 
prior to starting pacritinib. Tapering should be done per institutional practice and may be done with 
concurrent addition of prednisone during the screening period. In addition to any steroids used during the 
screening period, the protocol permits short-term use (up to 14 days) of corticosteroids and/or 
hydroxyurea as prophylaxis or treatment of symptomatic ruxolitinib withdrawal during the first month of 
treatment with pacritinib.  
Supportive care therapies, except when prohibited by any of the below provisions, are permitted, 
including the use of low-dose aspirin.  Corticosteroids (up to 20 mg/day of prednisone or equivalent) 
and/or hydroxyurea may be used for up to 2 weeks during the first month of treatment with pacritinib to 
control symptoms of ruxolitinib withdrawal if they occur.  Treatments for MF that might be considered 
supportive care are only allowable with medical monitor approval prior to administration.   


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The following therapies and procedures are prohibited throughout the study: 
 
 
Chemotherapy, interferon, or other treatment for MF, with the exception of up to 2 weeks of 
corticosteroids (up to 20 mg/day prednisone or equivalent) and/or 2 weeks of hydroxyurea as needed 
to reduce the risk of or treat the symptoms of ruxolitinib withdrawal 
 
Antiplatelet or anticoagulation agents, with the exception of  100 mg/day of aspirin 
 
Growth factor therapies, including erythropoietin and thrombopoietin 
 
Strong CYP3A4 inhibitors (Appendix 5) and strong CYP450 inducers (Appendix 6), except as 
needed to treat AEs, with medical monitor approval  
 
Any drugs with significant potential for QTc prolongation (Appendix 8), except as needed to treat 
AEs, with medical monitor approval 
 
Splenic irradiation or splenectomy 
 
Also refer to the Pacritinib Dosage Management Guidelines (Section 6.5) for guidelines on treatment of 
AEs. 
 
6.6.1 
Management of Gastrointestinal Toxicity  
The need for managing gastrointestinal (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. 
At the baseline visit, all patients will be provided with a prescription (and instructions to fill that 
prescription) for loperamide (Imodium®) or a similarly effective antidiarrheal drug.  Patients will be 
instructed to start taking the prescribed loperamide or other antidiarrheal drug per package and physician 
instructions as soon as they notice any changes in frequency or consistency of bowel movements after 
starting study treatment.  
Early intervention for diarrhea should be initiated for patients with increases of one grade or more in 
diarrhea (Appendix 9).  At the investigator’s discretion, prophylactic use of antidiarrheals may be initiated 
for patients or populations in whom it is judged necessary to enhance patient safety. Standard supportive 
care measures to control symptoms of GI toxicity such as diarrhea, constipation, and nausea should be 
provided.   
 
7 
Study Assessments 
 
7.1 
Criteria for Evaluation 
 
7.1.1 
Efficacy 
 
Efficacy assessments will be performed as described below until approval of Amendment 6, at which point 
assessments cease following the patient’s End-of-Treatment, or 30-day post (EOT) visit as applicable. 
 
7.1.1.1 
Spleen Volume 
 
MRI is the preferred modality; CT scan will be used for patients who cannot undergo MRI, or for whom 
MRI is not available.  Imaging should be performed without contrast agent.  For each patient, the same 
imaging modality should be used throughout the study.   
Spleen volume will be measured by MRI (preferred) or CT at screening and at the end of weeks 12 and 24 
visits.  Spleen volume will also be measured at the end of treatment if this does not occur at the end of 


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Week 24. For patients who continue on pacritinib past Week 24, spleen volume will be assessed by MRI 
or CT every 3 months up to 2 years.  Patients who discontinue treatment (except withdraw of consent or 
death) will be required to complete the end of treatment visit within 7 days of stopping treatment.  
Unscheduled imaging studies may be performed at physician discretion if he/she considers disease-related 
symptoms to be worsening.  All images generated as part of unscheduled evaluations must be submitted 
by the investigator for central review.  An independent radiologist, blinded to all patient and site 
identifiers and treatment assignments, will measure spleen volume.  While images generated as part of 
unscheduled visits may be read locally if treatment discontinuation is being considered, only the 
scheduled centrally read images will be used for the efficacy analysis.  
 
7.1.1.2 
Spleen Size Assessment by Physical Examination 
 
Spleen size, assessed by physical examination as the distance below the LCM at the midclavicular line, 
will be performed with each scheduled physical examination.   
 
7.1.1.3 
Disease-Related Signs and Symptoms 
 
Patient-reported disease-related symptoms as assessed by the validated PRO instrument MPN-SAF TSS 
2.0 (Appendix 5) will be collected daily using an electronic diary and will be evaluated as a part of the 
dose–response relationship.  Patients must begin reporting symptoms via electronic diary at least 7 days 
before starting pacritinib treatment and will continue until the Week 48 visit.  After Week 48, the patient 
will fill out the questionnaire (Appendix 3) at each follow up visit. The questionnaire is the same PRO 
instrument and uses a 7 day recall period. The MPN-SAF TSS 2.0 will be translated and available on the 
eDiary device in several different languages to accommodate an international study.   
In addition, the patient global impression assessment questionnaire (Appendix 11) will be completed at 
the end of Week 12, the end of Week 24 or the end of treatment visit, and every 3 months up to 2.5 years. 
 
7.1.1.4 
Other Assessments 
 
Patients will be followed for leukemic transformation and frequency of RBC and platelet transfusions. 
DNA samples will also be collected for analysis of mutations associated with myelofibrosis at baseline 
and Week 24. 
 
7.1.2 
Safety 
 
Safety assessments will be performed as described below until approval of Amendment 6, at which point 
assessments cease following the patient’s End-of-Treatment, or 30-day post (EOT) visit as applicable. 
 
7.1.2.1 
Adverse Events 
 
All AEs, including serious adverse events (SAEs), will be collected during the clinical study from the 
time the patient signs the informed consent through 30 days following last dose of study treatment.  For 
screened patients who are not randomized, only SAEs occurring between the time of informed consent 
and determination of screen failure are to be reported; AEs occurring in this time period that do not meet 
the definition of an SAE do not need to be reported.  SAEs that occur after study completion and are 
considered by the investigator to be related to pacritinib should be reported to the Sponsor. 
 


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7.1.2.2 
Hematology 
 
Hematology parameters including CBC, differential, platelet count, and hemoglobin A1C will be 
evaluated at screening, baseline, the end of week 4, the end of Week 12, the end of Week 24 or the end of 
treatment visit, every 3 months during the follow up period, and 30 days after the last dose of study 
treatment.  In addition, for patients with baseline platelet count of ≤ 50,000/µL, the platelet count will be 
monitored weekly by the central laboratory for the first 8 weeks, then monthly if counts remain 
≤ 50,000/µL. Samples collected at any visits for platelet counts must be submitted to the central 
laboratory for analysis, but in addition can be analyzed locally for assessment and management of patients 
in real time. Additional platelet count testing should be done as clinically indicated. 
 
7.1.2.3 
Coagulation Testing 
 
Coagulation testing will include PT, INR, PTT, and TT at screening, baseline, the end of week 4, the end 
of Week 12, the end of Week 24 or the end of treatment visit, every 3 months during the follow up period, 
and 30 days after the last dose of study treatment. Additional coagulation testing should be done as 
clinically indicated. 
These results will be taken into account, together with baseline platelet counts and prior medical history 
of bleeding, to help guide ongoing hematologic monitoring of platelet counts and clinical monitoring for 
bleeding. 
 
7.1.2.4 
Serum Chemistry 
 
Screening laboratory assessments should be performed at least 1 week after the end of prior therapy.  
Serum chemistry parameters (ALT/SGPT and AST/SGOT, alkaline phosphatase, bilirubin [total, direct, 
and indirect], creatinine, lactate dehydrogenase (LDH), sodium, potassium, chloride, bicarbonate, 
calcium, phosphate, magnesium, blood urea nitrogen (BUN)/urea, albumin, amylase, lipase, glucose, 
cholesterol, uric acid, and high specificity CRP) will be evaluated by a central laboratory at screening, at 
baseline, and as clinically indicated.  Unscheduled chemistry assessments may be performed locally 
and/or centrally whenever clinically indicated.  Blood samples drawn at unscheduled visits for serum 
chemistry evaluation should be submitted to the central laboratory for assessment in addition to any local 
laboratories as needed for timely decisions regarding patient care. 
 
7.1.2.5 
ECG Assessment 
 
All patients will have a 12-lead ECG (collected in triplicate) ), including QTc calculation corrected by the 
Fredericia method, at screening, baseline, the end of Week 4, the end of Week 12, the end of Week 24 or 
the end of treatment visit, and every 3 months while in the follow-up period (pre-dose only for the 
post-24-week follow-up visit and 30 days after the last dose of study treatment.  Additional ECGs may be 
required in the event patient demonstrates QTc prolongation.  See Section 6.5.3 for appropriate pacritinib 
dose adjustment guidelines and additional ECG requirements.  All ECGs will be centrally read by a 
blinded independent cardiologist.  
 
7.1.2.6 
Cardiac Ejection Fraction Assessment 
 
All patients will have ejection fraction checked (echocardiogram or MUGA scan) at screening, the end of 
Week 4, the end of Week 12, the end of Week 24, or the end of treatment visit, and every 6 months while 
in the follow up period, and 30 days after the last dose of study treatment.  If pacritinib treatment is 
resumed after holding for ejection fraction abnormality, ejection fraction should be reassessed about 


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14 days later, then at least every 3 months as per the above schedule.  Additional ejection fraction testing 
shall be done as clinically indicated (see dosage modifications in Section 6.5). 
 
7.1.3 
Pharmacokinetics and Pharmacodynamics 
 
The Sponsor will collect PK samples from all patients in each dosing arm at the following timepoints:  
 
Sparse Sampling (all patients): End of Week 12 and End of Week 24: 30 minutes to 0 hours 
(predose), 4 hours (±10 minutes),  and 8 hours (±15 minutes) postdose 
 
Dense Sampling (performed at selected sites for approximately 6 to 8 patients total per dose 
arm, at which point all further patients will have PK evaluated by sparse sample 
collection): Week 1 Day 1: 2 hours (± 5 minutes), 4 hours (± 10 minutes), 6 hours 
(± 15 minutes), and 8 hours (± 15 minutes) postdose and 24 hours postdose (within 
30 minutes before the Day 2 dose), End of Week 12 and End of Week 24: 30 minutes to 
0 hours (predose), 2 hours (± 5 minutes), 4 hours (± 10 minutes), 6 hours (± 15 minutes), and 
8 hours (± 15 minutes) postdose 
On the day prior to PK and PD blood sampling, the patient must note the time of dosing and report it to 
the site during their visit the following day.  On the day of PK and PD blood sampling, patients must not 
take the daily dose of pacritinib prior to the clinic visit.  Given the sampling schedule, PK and PD 
samples should be collected before and after the morning dose for patients taking pacritinib twice per day 
(BID).   
Results will be used to evaluate the relationship between drug exposure and safety and efficacy as well as 
biomarkers associated with the JAK/STAT pathway. 
 
7.1.4 
Informed Consent, Screening, and Washout of Prohibited Concomitant Medications Before 
Beginning Study Treatment 
 
Informed consent must be obtained before study procedures and screening evaluations are performed, 
unless those evaluations are performed as part of standard of care. Patients who do not meet eligibility 
criteria at screening may be rescreened at a later date. 
Informed consent must be obtained before any protocol-defined assessments including drug washout. The 
informed consent process should be documented in the patient’s medical chart. A 2-week washout will be 
required for anticoagulation agents, antiplatelet agents except aspirin dosages of ≤100 mg/day, strong 
CYP450 inducers, and QTc prolonging agents. A 28-day washout period will be required for any 
experimental therapies. 
The screening evaluations listed below are to be carried out between 35 and 7 days prior to the start of 
treatment, with the exception of MRI or CT scan, which must be performed between 10 and 4 days 
prior to the start of the study.   
 
Medical history 
 
Vital signs, including pulse, systolic and diastolic blood pressure, respiratory rate, temperature, and 
body weight 
 
Physical examination, including spleen measurement 
 
12-lead ECG (collected in triplicate)  
 
Ejection fraction assessment (Echocardiogram or MUGA) 
 
ECOG performance status 
 
Hematology: CBC with differential, platelet count and hemoglobin A1C 


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 
Coagulation testing including PT, INR, PTT, and TT 
 
Serum chemistry, including ALT/SGPT and AST/SGOT, alkaline phosphatase, bilirubin (total, direct, 
and indirect), creatinine, LDH, sodium, potassium, chloride, bicarbonate, calcium, phosphate, 
magnesium, BUN/urea, albumin, amylase, lipase, glucose, cholesterol, uric acid, and high specificity 
CRP 
 
Serum pregnancy test for women of childbearing potential (WOCBP). For WOCBP in the UK, the 
screening pregnancy test must occur no longer than 7 days before the first study drug administration. 
If fertile, males and females must agree to use effective birth control methods during the study.  
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). Males must use 
a condom for the duration of the study and for 90 days after the last dose of study treatment. When 
abstinence is used as a method of birth control, only true abstinence is acceptable, when this is in line 
with the preferred and usual lifestyle of the patient.  Periodic abstinence (calendar, ovulation, 
symptothermal, and post-ovulation methods) and withdrawal are not acceptable methods of 
contraception.  
 
MRI (preferred) or CT scan (without contrast) for measurement of spleen volume (to be performed 
between Days -10 and -4 prior to the start of treatment). 
 
Begin collecting patient-reported disease-related symptoms on MPN-SAF TSS 2.0 via electronic 
diary.  Patient must complete daily for 7 consecutive days prior to starting treatment.  
 
Baseline symptoms and AEs 
 
Concomitant medications 
 
Transfusion history (RBC and platelets) 
 
7.1.5 
Randomization and Start of Week 1 (Baseline; -1 day) 
 
Randomization: Patient must first sign informed consent, then complete all screening procedures, and 
meet all eligibility criteria. 
 
Vital signs, including pulse, systolic and diastolic blood pressure, respiratory rate, temperature, and 
body weight 
 
Physical examination, including height, clinical signs and symptoms, and spleen measurement 
 
12-lead ECG (collected in triplicate)  
 
Hematology: CBC with differential, platelet count and hemoglobin A1C; patients with baseline 
platelet count of ≤ 50,000/µL, platelet count will be monitored weekly by the central laboratory for 
the first 8 weeks, then monthly if counts remain ≤ 50,000/µL. Blood samples drawn at unscheduled 
visits for the assessment of hematology parameters should be submitted to the central laboratory for 
assessment in addition to any local laboratories as needed for timely decisions regarding patient care. 
Additional hematology testing should be done as clinically indicated.   
 
Coagulation testing including PT, INR, PTT, and TT 
 
Serum chemistry, including ALT/SGPT and AST/SGOT, alkaline phosphatase, bilirubin (total, direct, 
and indirect), creatinine, LDH, sodium, potassium, chloride, bicarbonate, calcium, phosphate, 
magnesium, BUN/urea, albumin, amylase, lipase, glucose, cholesterol, uric acid, and high sensitivity 
CRP. Blood samples drawn at unscheduled visits for the assessment of serum chemistry parameters 
should be submitted to the central laboratory for assessment in addition to any local laboratories as 
needed for timely decisions regarding patient care. 


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 
Continue collecting patient-reported disease-related symptoms on MPN-SAF TSS 2.0 via electronic 
diary daily 
 
For patients participating in dense PK sampling: PK sample at 2 hours (± 5 minutes), 4 hours 
(± 10 minutes), 6 hours (± 15 minutes), and 8 hours (± 15 minutes) postdose and 24 hours postdose 
(within 30 minutes before the Day 2 dose) 
 
PD sample within 30 minutes prior to 0 hours (predose)   
 
DNA sample 
 
Dispense pacritinib  
 
Begin pacritinib dosing 
 
Baseline symptoms and AEs 
 
Concomitant medications 
 
Transfusion history (RBC and platelets) 
 
Provide prescription for loperamide (Imodium®) or a similarly effective antidiarrheal drug 
 
7.1.6 
End of Week 4, Study Day 28 (± 3 days) 
 
 
Vital signs, including pulse, systolic and diastolic blood pressure, respiratory rate, temperature, and 
body weight 
 
Physical examination, including spleen measurement 
 
12-lead ECG (collected in triplicate)  
 
Ejection fraction assessment (Echocardiogram or MUGA) 
 
ECOG performance status 
 
Hematology: CBC with differential, platelet count and hemoglobin A1C 
 
Coagulation testing including PT, INR, PTT, and TT 
 
Serum chemistry as clinically indicated 
 
Serum pregnancy test for women of childbearing potential within the United Kingdom 
 
Continue collecting patient-reported disease-related symptoms on MPN-SAF TSS 2.0 via electronic 
diary daily 
 
Dispense pacritinib  
 
Perform pacritinib accountability 
 
AEs 
 
Concomitant medications 
 
Transfusion history (RBC and platelets) 
 
7.1.7 
End of Week 12, Study Day 84 (± 7 days) 
 
 
Vital signs, including pulse, systolic and diastolic blood pressure, respiratory rate, temperature, and 
body weight 
 
Physical examination, including spleen measurement 
 
12-lead ECG (collected in triplicate) 
 
Ejection fraction assessment (Echocardiogram or MUGA) 
 
ECOG performance status 
 
Hematology: CBC with differential, platelet count and hemoglobin A1C 
 
Coagulation testing including PT, INR, PTT, and TT 


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 
Serum chemistry as clinically indicated 
 
Serum pregnancy test, if mandated by country-specific requirement 
 
MRI (preferred) or CT scan (without contrast) for measurement of spleen volume (for each patient, 
the same imaging modality should be used throughout the study) 
 
Continue collecting patient-reported disease-related symptoms on MPN-SAF TSS 2.0 via electronic 
diary daily   
 
Patient global impression assessment 
 
For all patients: PK samples at 30 minutes to 0 hours (predose), 4 hours (± 10 minutes), and 8 hours 
(±15 minutes) postdose 
 
For patients participating in dense PK sampling: 30 minutes to 0 hours (predose), 2 hours (± 
5 minutes), 4 hours (± 10 minutes), 6 hours (± 15 minutes), and 8 hours (± 15 minutes) postdose 
 
PD sample within 30 minutes prior to 0 hours (predose) 
 
Dispense pacritinib  
 
Pacritinib accountability  
 
AEs 
 
Concomitant medications 
 
Transfusion history (RBC and platelets)  
 
7.1.8 
End of Week 24, Study Day 168 (± 7 days), or End of Treatment  
 
 
Vital signs, including pulse, systolic and diastolic blood pressure, respiratory rate, temperature, and 
body weight 
 
Physical examination, including spleen measurement 
 
12-lead ECG (collected in triplicate) 
 
Ejection fraction assessment (Echocardiogram or MUGA) 
 
ECOG performance status 
 
Hematology: CBC with differential, platelet count, and hemoglobin A1C 
 
Coagulation testing including PT, INR, PTT, and TT 
 
Serum chemistry as clinically indicated 
 
Serum pregnancy test, if mandated as a country-specific requirement 
 
MRI (preferred) or CT scan (without contrast) for measurement of spleen volume (for each patient, 
the same imaging modality should be used throughout the study) 
 
Continue collecting patient-reported disease-related symptoms on MPN-SAF TSS 2.0 via electronic 
diary daily  
 
Patient global impression assessment 
 
For all patients: PK samples at 30 minutes to 0 hours (predose), 4 hours (±10 minutes), and 8 hours 
(±15 minutes) postdose 
 
For patients participating in dense PK sampling: 30 minutes to 0 hours (predose), 2 hours (± 
5 minutes), 4 hours (± 10 minutes), 6 hours (± 15 minutes), and 8 hours (± 15 minutes) postdose 
 
PD sample within 30 minutes prior to 0 hours (predose) [collected at Week 24; not collected at End of 
Treatment] 
 
Dispense pacritinib (for patients continuing to receive treatment) 
 
Perform pacritinib accountability 
 
AEs 


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 
Concomitant medications 
 
Transfusion history (RBC and platelets) 
 
DNA Sample [collected at Week 24; not collected at End of Treatment] 
 
7.1.9 
30-Day Post End of Treatment (30 ±3 days After End of Treatment) 
 
For patients who transition to and continue treatment under an expanded access program, the 30-Day Post 
End of Treatment assessment will not be performed.   
 
 
12-lead ECG (collected in triplicate) 
 
Ejection fraction assessment (Echocardiogram or MUGA) 
 
Hematology: CBC with differential, platelet count and hemoglobin A1C  
 
Coagulation testing including PT, INR, PTT, and TT 
 
Serum chemistry as clinically indicated 
 
Last time point for collection of patient-reported disease-related symptoms on MPN-SAF TSS 2.0 via 
electronic diary.  Patient to return electronic diary device during visit.   
 
Last time point for collection and follow-up of nonserious AEs (related or not related) and SAEs 
deemed not related to study treatment or procedures.   
 
Concomitant medications 
 
 
8 
Pharmacokinetic and Pharmacodynamic Analysis  
 
8.1 
Blood Sample Collection, Handling, and Shipping 
 
Blood samples for PK and PD analyses should be collected in appropriate blood collection tubes as 
defined in the study manuals.  On the days when blood samples for PK and PD analyses are collected, 
patients should be instructed not to take pacritinib at home.  The time/date when the prior dose was 
administered must be recorded in the source documents and on the appropriate eCRF page. The Sponsor 
will provide the investigator with sample collection kits as well as a manual containing details for the 
preparation of blood samples to be collected.  Shipping supplies and instructions will also be provided.  
 
8.2 
Pharmacokinetic and Pharmacodynamic Assessments 
 
The Sponsor will collect PK samples from all patients in each dosing arm at the following timepoints: 
 
Sparse Sampling (all patients): End of Week 12 and End of Week 24: 30 minutes to 0 hours 
(predose), 4 hours (±10 minutes), and 8 hours (± 15 minutes) postdose 
 
Dense Sampling (performed at selected sites for approximately 6 to 8 patients total per dose arm, 
at which point all further patients will have PK evaluated by sparse sample collection): Week 1 
Day 1: 2 hours (± 5 minutes), 4 hours (± 10 minutes), 6 hours (± 15 minutes), and 8 hours 
(± 15 minutes) postdose and 24 hours postdose (within 30 minutes before the Day 2 dose), End of 
Week 12 and End of Week 24: 30 minutes to 0 hours (predose), 2 hours (± 5 minutes), 4 hours 
(± 10 minutes), 6 hours (± 15 minutes), and 8 hours (± 15 minutes) postdose 
Given the sampling schedule, PK and PD samples should be collected before and after the morning dose 
for patients taking pacritinib twice a day (BID).  The PK parameters, minimum concentration observed, 
maximum concentration observed, and area under the curve will be determined and summarized using 


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descriptive statistics for each pacritinib dosage arm. Exposure-response analyses will be conducted on 
both safety and efficacy populations in the study.  PD samples will be analyzed for biomarkers associated 
with the JAK/STAT pathway.   
 
9 
Assessment of Safety 
 
9.1 
Adverse Events 
 
9.1.1 
Definition of an Adverse Event 
 
An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with this 
treatment.   
Examples of AEs include, but are not limited to: 
 
 
Any unfavorable and unintended sign, including an abnormal laboratory finding, symptom, medical 
diagnosis, or concomitant disease temporally associated with the use of the study drug, whether 
considered related to study drug or not 
 
Abnormalities observed during the study that meet any of the criteria below: 
- 
A laboratory or other test result that is clinically significant or requires active intervention, 
retesting, or ongoing medical monitoring 
- 
Requires discontinuation, dosage reduction, or delay of study drug  
- 
Requires that the patient receive specific corrective or supportive therapy 
- 
Clinically significant changes noted during physical examinations, cardiac monitoring, imaging 
studies, biopsies, and other safety assessments, whether or not these procedures were required by 
the protocol 
Progressive disease is not an AE. 
 
9.1.2 
Reporting Adverse Events 
 
Adverse events will be collected as described below until approval of Amendment 6, at which point 
assessments cease following the patient’s End-of-Treatment, or 30-day post (EOT) visit as applicable. 
 
All baseline conditions and AEs will be collected during the clinical study from the time the patient signs 
the informed consent through 30 days following last dose of study drug.  
For screened patients who are not randomized, only SAEs occurring between the time of informed 
consent and determination of screen failure are reported; AEs occurring in this time period that do not 
meet the definition of an SAE do not need to be reported.  
AEs can be spontaneously reported or elicited during open-ended questioning, examination, or evaluation 
of the patient, or may be detected through a clinically meaningful procedure. To prevent bias, patients 
should not be questioned regarding the specific occurrence of one or more AEs. 
The following information should be captured for all AEs: date of onset and resolution, severity per 
CTCAE, seriousness, the investigator’s assessment of relationship to study drug, event outcome, and 
action taken with study medication due to the reported event. If concomitant treatment is given for the 
AE, this information should be captured on the appropriate eCRF.   
When recording AEs, the diagnosis of the underlying illness or disorder should be used as the event term 
or description on the eCRF and symptoms of the illness or disorder should not be reported as separate 


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AEs. It is expected that whenever possible the clinical term, rather than the laboratory term, for the AE 
will be used by the reporting investigator (e.g., “anemia” versus “low hemoglobin value”). 
If an AE results in early termination of the patient’s study treatment period, “AE” should be selected as 
the reason for discontinuation on the eCRF.  However, if the AE that resulted in early termination was a 
sign or symptom of progressive disease, “progressive myelofibrosis” should be selected as the reason for 
discontinuation on the eCRF.  
 
Special Considerations 
 
 
Elective procedures or routinely scheduled treatments are not AEs.  However, any untoward medical 
event occurring during a prescheduled elective procedure or routinely scheduled treatment should be 
documented as an AE. 
 
Baseline conditions are not AEs; however, worsening of a baseline condition following study drug 
administration is an AE. 
 
Death alone is not considered an AE; it can be an outcome of an AE. Reports of death should be 
accompanied by the corresponding AE term for the event that led to the outcome of death. However, 
sudden death or death due to unexplainable cause(s) should be reported as an SAE, while follow-up is 
pursued to determine the cause.  
 
If progressive disease is the primary cause of death, the term “progressive myelofibrosis” should be 
reported on the death eCRF. 
 
All AEs ongoing at the time of death that are not the primary cause of death will remain not resolved on 
the eCRFs.  
 
9.1.3 
Criteria for Assessing Adverse Events 
 
9.1.3.1 
Severity 
 
The term “severe” is a measure of intensity; a severe event is not necessarily serious.   
The NCI CTCAE version 4.0 should be used to assess and grade AE severity, including laboratory 
abnormalities identified as AEs.  A copy of these criteria is provided in the study manual, however minor 
version updates (i.e., 4.01, 4.02 and above) may be used at the discretion of the Sponsor.  Central 
laboratory values will be used to grade and record AEs in EDC. 
 
9.1.3.2 
Relationship 
 
The relationship of an AE to the study treatment(s) will be assessed using the guidelines described below.  
If an AE is deemed related to study treatment(s) but the investigator cannot attribute the relationship 
solely to a single treatment, the investigator should indicate that the AE is related to all possible agents.  
Any AE for which there is no assessed causal relationship shall be assessed by the Sponsor as related, and 
will require immediate follow up with the site to determine the investigator’s assessment.   
 
Possible 
 
There is a reasonable causal relationship between the event and study treatment, the event occurred within 
a plausible time relationship to study treatment administration, but the event could also possibly be 
explained by the condition under study, concurrent disease, other drugs or chemicals, or other 
circumstances.  Dechallenge information is lacking or unclear. 


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Unlikely 
 
There is a temporal relationship of the event to study treatment but not a reasonable causal relationship, or 
there is no temporal relationship to study treatment administration or the condition under study, 
concurrent disease, other drugs or chemicals, or other circumstances provide a plausible explanation for 
the event. 
 
9.1.3.3 
Outcome 
 
AEs will be characterized according to the outcomes described in Table 8. 
 
Table 8. Outcomes of Adverse Events 
Outcome 
Description 
Recovered/Resolved 
One of the possible results of an adverse event outcome that indicates that the event 
has improved or recuperated 
Recovered/Resolved with 
Sequelae 
One of the possible results of an adverse event outcome where the patient recuperated 
but retained pathological conditions resulting from the prior disease or injury 
Recovering/Resolving 
One of the possible results of an adverse event outcome that indicates the event is 
improving 
Not Recovered/Not 
Resolved 
One of the possible results of an adverse event outcome that indicates that the event 
has not improved or recuperated 
Fatal 
The termination of life as a result of an adverse event 
Unknown 
Not known, not observed, not recorded, or refused  
 
9.1.3.4 
Action Taken with Study Drug 
 
Action taken with the study drug in relation to the AE will be characterized as follows: 
 
 
Dosage not changed 
 
Dosage reduced 
 
Drug interrupted 
 
Drug withdrawn 
 
Not applicable 
 
Unknown 
 
9.1.4 
Serious Adverse Events 
 
9.1.4.1 
Definition of a Serious Adverse Event 
 
A SAE is an AE that, at any dosage, suggests a significant hazard or side effect, regardless of its 
relationship to the study drug.  An AE is serious if it meets any of the criteria below:  
 
1. Results in death  


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2. Is life-threatening: in the view of the investigator, the event placed the patient at immediate risk of 
death. This does not include an AE that, had it occurred in a more severe form, might have caused 
death. 
3. Requires inpatient hospitalization or prolongation of an existing hospitalization (see Exceptions 
below) 
4. Results in persistent or significant disability or incapacity or substantial disruption of the ability to 
conduct normal life functions 
5. Is a congenital anomaly/birth defect 
6. Is an important medical event that is not fatal, life threatening, or requiring hospitalization, but may 
be considered serious if, based on appropriate medical judgment, the event jeopardized the patient 
and required medical or surgical intervention to prevent one of the outcomes listed above (Items 1 to 
5) 
7. Cancer/overdose: All cases of new cancers, with the exception of disease progression/transformation 
to acute myeloid leukemia, and drug overdose (defined as accidental or intentional ingestion of any 
dosage of a product that is considered both excessive and medically important) must be reported 
immediately using the SAE form. All cases of drug overdose, irrespective of seriousness or 
association with AE(s), must be reported to the Sponsor within 24 hours. Determination of 
seriousness will be reached in consultation with the Safety Physician, CTI BioPharma Corp. 
Pharmacovigilance US Headquarters or designee.  Additional instructions for reporting 
cancer/overdose information will be provided by the Sponsor in the study binder. 
 
9.1.4.2 
Exceptions 
 
Hospitalizations not reported as SAEs include admissions for:  
 
1. Planned, non-life-threatening medical/surgical procedures (e.g., admission for transfusion as required 
per local medical practice) 
2. Routine health assessments requiring admission for health status documentation (e.g., routine 
gastroscopy, colonoscopy, etc.) 
3. Other life circumstances that have no bearing on health status and require no medical/surgical 
intervention (e.g., lack of housing, family circumstances, etc.) 
4. Administration of study medication 
 
9.1.4.3 
Reporting Serious Adverse Events to the Sponsor 
 
AEs, including SAEs, irrespective of causal relationship, will be collected during the clinical study from 
the time the patient signs the informed consent through 30 days following the last dose of study drug. The 
site will notify the Sponsor of the SAE via the EDC system by recording the event on the SAE eCRF and 
checking the appropriate box on the eCRF indicating that the event meets SAE criteria.  The EDC system 
will send an auto-generated email notification to CTI BioPharma Corp Pharmacovigilance that an SAE 
has been identified and will be reported.  The site must send the paper SAE form via email 
(SAE@CTIbiopharma.com) within 24 hours of the site’s first awareness of an SAE.   
 
Special Considerations: 
 
 
SAEs considered to be related (i.e., assessed as possibly related) to study drug or study procedure by 
the investigator or Sponsor shall be followed until the event resolves, stabilizes or the patient is lost to 
follow up.  


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 
SAEs assessed as unlikely related to study drug or study procedures shall be followed for 30 days 
after the last dose of study treatment, or until the event resolves, returns to baseline, stabilizes or the 
patient is lost to follow-up, whichever comes first.  
 
For screened patients who are not randomized, only SAEs occurring between the time of informed 
consent and determination of screen failure are reported.  
 
All SAEs for randomized patients must have a corresponding AE recorded on the eCRF with an exact 
match to the event term or description.  
 
An SAE form should be completed for any event for which doubt exists regarding its seriousness. 
 
If an ongoing SAE changes in intensity, relationship to study drug, or as new information becomes 
available and/or known for the event, a follow-up SAE report should be completed and sent to the 
Sponsor within 24 hours of the change in SAE assessment.   
 
Any SAE that occurs after study completion and is considered by the investigator to be related to 
pacritinib should be reported to the Sponsor. 
 
A brief narrative outlining the details of the SAE and treatment and outcome are to be included on the 
SAE form.  Follow-up information, such as laboratory reports, discharge summaries, autopsy reports, and 
information concerning outcome of the event, should be provided as soon as the information becomes 
available and provided to CTI Pharmacovigilance via email at SAE@CTIbiopharma.com or fax 
(1-866-660-8967).  
Source documents should be submitted in English.  If source documents are not in English, the 
investigator must summarize the source documents and provide a complete English narrative that includes 
a description of the event as it evolved, the results of all diagnostic procedures performed and treatments 
administered, and the outcome of the event. 
 
9.1.4.4 
Reporting Serious Adverse Events to the Regulatory Agencies, Institutional Review Boards, 
and/or Ethics Committees 
 
The Sponsor will assess SAEs for expedited reporting against the most current approved version of the 
Investigator Brochure.  Until an AE is identified in the Reference Safety Information of the IB or SmPC, 
it is considered unexpected, regardless of whether the AE has been submitted previously as an expedited 
report. 
Expedited reporting will be performed by the Sponsor in accordance with local regulation.   
Upon receiving an expedited report, the investigator must review and retain the notice with the 
Investigator Brochure and shall be responsible for submitting expedited reports to their Institutional 
Review Board (IRB)/EC in accordance with institutional guidelines. Regardless of institutional 
guidelines, investigators shall submit expedited reports to their IRB/EC in the event that the Sponsor 
identifies an expedited report to represent a new and/or unforeseen risk.  
In support of required progress reports, the Sponsor will provide the investigator and/or Ethics Committee 
with a summary of all SAEs reported for the study at predefined intervals (e.g., quarterly) and/or upon 
request. 
 
Pregnancy 
 
Pregnancy alone is not considered an AE. However, if a patient becomes pregnant or causes a pregnancy 
during treatment and/or within one month of ending treatment even if the patient is withdrawn from 
study, this must be reported to the Sponsor immediately on the Pregnancy Reporting Form.  The 


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investigator must obtain written authorization (medical records release) from a female partner of a male 
patient prior to obtaining follow-up.   
The investigator must follow the pregnancy either to term or termination and will collect data on both 
maternal and fetal outcome.  All pregnancy outcomes will be recorded on the Pregnancy Reporting Form.  
Additional instructions for reporting pregnancy information will be provided by the Sponsor in the study 
binder. 
Normal outcomes will be communicated to the Sponsor within 30 calendar days of birth/delivery.  
Abnormal pregnancy outcomes and/or any AE for the child or fetus (including miscarriage) will also be 
recorded in the AE eCRF and on the SAE form.  The associated SAE Report Form should be sent to the 
Sponsor per the procedure and timelines described within Section 9.1.4.3, Reporting Serious Adverse 
Events to the Sponsor.  
 
Overdose 
 
Overdose is defined as any deviation from the defined or prescribed use of study drug as applicable for 
the drug and study design. Occurrences of overdose should be reported to the Sponsor on an SAE Report 
Form.  Reports of overdose will be evaluated on a case by case basis. Additional instructions for reporting 
overdose information will be provided by the Sponsor in the study binder. 
 
Deaths 
 
All deaths that occur during the study must be recorded on the appropriate eCRF.  As described in 
Sections 9.1.2 and 9.1.3.1, death alone is not considered an AE; it is an outcome of an AE. Reports of 
death should be accompanied by the corresponding AE term for the event that led to the outcome of 
death. Progressive disease is not an AE.  
Sudden death or death due to unexplainable cause(s) should be reported as an SAE, while follow-up is 
pursued to determine the cause.   
 
9.2 
Laboratory Evaluation 
 
All scheduled clinical laboratory test values collected as part of the study will be evaluated by a central 
laboratory.  In addition, any laboratory test samples collected at unscheduled visits will be submitted to 
the central laboratory, although laboratory tests performed for patient management in real time may be 
analyzed locally. 
The investigator may use local or central laboratory evaluations (as dictated by local standards of care) to 
facilitate real-time decisions about study treatment administration, eligibility, and dosage modifications 
and for evaluation of signs and symptoms.  Samples collected at unscheduled visits that are analyzed in a 
local laboratory must also be submitted to the central laboratory and the results entered into the EDC. 
Treatment decisions (such as dose delays) and adverse events may be based on either local or central 
laboratory results.  For reporting purposes, central lab values are to be used to grade adverse events. 
Regardless of whether serum samples, radiologic material and other patient data are sent to a central lab 
or independent review panel for study purposes, treatment decisions must be made by the investigator 
based on his or her clinical assessment of the patient and his or her interpretations, radiology assessments, 
and other tests. 
 
 


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9.3 
Vital Signs and Physical Examination 
 
Vital signs (including blood pressure, pulse, respiratory rate, temperature, and body weight) and physical 
examinations (including spleen measurement) will be obtained at screening, baseline, the end of week 4, 
the end of Week 12, the end of Week 24 or the end of treatment visit.  Height will be measured only at 
baseline. 
 
9.4 
Safety Surveillance 
 
9.4.1 
Routine Pharmacovigilance Monitoring 
 
The Sponsor’s pharmacovigilance committee will monitor safety data every month during the clinical 
study by examining the incidence and severity of AEs, changes in laboratory results, and other data (such 
as aggregate analysis of data from other pacritinib studies) as appropriate.  The committee will 
communicate clinically important increases in the rate of serious adverse reactions to the IDMC (see 
Section 2.2), investigators, and regulatory agencies, as appropriate.  A clinically important increase will 
be considered an increase in frequency and/or severity in an event which leads to a serious outcome and 
exceeds the rate(s) of the reported event listed in the Investigator Brochure reference safety information.   
Single events assessed as serious, unexpected and related will continue to be reported on an expedited 
basis per regulatory requirement.   
 
10 Data Management 
 
The CTI BioPharma Corp. Clinical Data Management Department or its designee will prepare guidelines 
for data entry and data handling, which will include procedures for data verification and electronic edit 
checks.  The complete data management process will be described in the Data Management Plan. 
 
10.1 Data Collection 
 
An electronic data capture (EDC) system will be used for this study. Designated site personnel will enter 
patient data required by the protocol into eCRFs based on source documents.  Personnel will not receive 
access to the EDC system until they have completed all training requirements.  The EDC system will 
provide an automatic audit trail of all changes made to the clinical database. 
 
10.2 Data Entry and Quality Control 
 
Data items will be entered directly from source documents by designated site personnel using single data 
entry.  Concomitant medications entered into the database will be encoded using the World Health 
Organization Drug Reference Dictionary. AEs, coexisting disease, and other data items will be encoded 
using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. 
 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in a database 
system maintained by the central vendor. 
CTI BioPharma Corp. staff or designees will review the data on a periodic basis to ensure validity, 
accuracy and completeness.  Data suspected to be discrepant or incomplete will be questioned using data 
queries.  Data queries resulting from these reviews will be sent to the study sites via the EDC system. The 
staff at the study sites will respond to the queries in the EDC system and these responses will be reviewed 
by CTI BioPharma Corp. staff or designee.   


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11 Statistical Analysis Plan 
 
Statistical analysis of the study data will be the responsibility of CTI BioPharma Corp. Biostatistics 
Department or its designee. This section describes the statistical methodology used in the analysis of the 
primary safety and efficacy endpoints to aid the decision of dosage determination. Other supportive 
analyses will be specified in a separate statistical analysis plan (SAP). The SAP will be finalized before 
the first patient is randomized. 
 
11.1 Variables for the Analysis 
 
Efficacy 
 
 
The primary efficacy variable for dosage selection is the percent reduction in spleen volume from 
baseline as measured by MRI (preferred) or CT at Weeks 12 and 24.  
 
Other supportive measures for evaluation as part of the dose–response relationship include: the 
percentage of patients who achieve at least 35% reduction in spleen volume; % TSS reduction from 
baseline; and the percentage of patients with at least 50% reduction in TSS.  
 
Long term efficacy is evaluated using percent reduction in spleen volume from baseline as measured 
by MRI or CT, percent reduction in TSS from baseline, percent reduction in spleen length by physical 
exam and the patient global impression assessment. 
 
Safety 
 
 
The primary safety measure for dosage selection is the percentage of patients with CTCAE grade ≥3 
cardiac AEs (Standardized MedDRA Query [SMQ]), CTCAE grade ≥3 hemorrhage AEs (SMQ), 
CTCAE grade ≥4 thrombocytopenia toxicity (central laboratory based), or CTCAE grade ≥4 anemia 
toxicity (central laboratory based).  
 
All other safety data including AEs, death, and clinical laboratory measures will be used as supportive 
measures for evaluation of pacritinib dose-safety relationship and for long term safety evaluation. 
 
11.2 Hypotheses 
 
The primary objective of this study is to explore the dose–response relationship for pacritinib among 
primary and secondary MF patients to determine a recommended dosage for further clinical studies. 
There is no formal statistical hypothesis to be tested.  
 
11.3 Analysis Populations 
 
11.3.1 Full Analysis Set 
 
The full analysis set (FAS) is defined as all randomized patients who received at least one dose of study 
treatment. Patients in this population will be analyzed according to the treatment arm to which they were 
assigned at randomization. The FAS will serve as the population for the analyses of efficacy, in keeping 
with the intent-to-treat (ITT) principle. 
 
 
 


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11.3.2 Safety Population 
 
The safety population is defined as all randomized patients who received at least one dose of study 
treatment.  All safety analyses will be performed using the safety population, and patients in this 
population will be analyzed according to the treatment actually received. 
 
11.3.3 Pharmacokinetic/Pharmacodynamic Evaluable Population 
 
The PK/PD evaluable population is defined as all randomized patients who received any dose of study 
treatment and have the necessary baseline and post-baseline measurements to provide interpretable results 
for the specific parameters of interest.  The study pharmacokineticist will review data listings of patient 
dosing and sample records to identify patients with appropriate samples for the analysis. 
 
11.4 Efficacy Analysis 
 
Summary statistics and 95% confidence intervals of the percent change in spleen volume by visit and the 
proportion of patients achieving a ≥35% reduction at Weeks 12 and 24 will be generated for each arm for 
the final locked data.  The same analysis will be repeated for percent change in TSS and the proportion of 
patients achieving a ≥50% reduction in TSS at Weeks 12 and 24.   
In addition, analyses of the dose–response and dose-exposure-response relationship will be performed 
using a modeling approach.  The details of the analysis will be described in the SAP. 
 
11.5 Multiplicity 
 
No formal statistical hypothesis testing will be performed, thus no multiplicity adjustment is needed. 
 
11.6 Safety Analysis 
 
The assessment of safety will be based mainly on the frequency of AEs and the number of laboratory 
values that fall outside of predetermined ranges. 
Treatment-emergent AEs will be coded using MedDRA and summarized by system organ class, preferred 
term, and treatment arm as the number and percentage of patients with an event. AE data for hemorrhagic 
and cardiac events will be identified based on SMQs and analyzed as a SMQ group by treatment arm. 
Incidences of hemorrhagic and cardiac AE data by SMQs over 8-week interval will be summarized by 
treatment arm. The following subsets of treatment-emergent AEs will also be summarized by treatment 
arm: AEs related to study treatment, CTCAE grade 3 or 4 AEs, AEs leading to treatment discontinuation, 
deaths, and SAEs.  
Clinical laboratory data will be summarized with descriptive statistics by treatment and timepoint.  Each 
patient’s data will be classified by the CTCAE grade, where possible, and summarized in shift tables 
comparing the worst post-baseline visit to baseline.  
 
11.7 Determination of Sample Size  
 
The determination of sample size for this dosage finding study was not only driven by a targeted 
predictive probability, but also to ensure adequate precision to evaluate efficacy using percent reduction 
of spleen volume from baseline. Based on past clinical experience (e.g., 10% SVR deemed as the 
minimum clinically meaningful reduction), variance in percent reduction in spleen volume (standard 


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deviation around 20%) from PERSIST-1 and PERSIST-2 studies, and the need for exploratory modeling 
analysis of pacritinib dose–response and dose–exposure-response relationship, a maximum of 30 
evaluable patients per treatment arm are adequate to evaluate efficacy.  
With 50 patients per arm, if the true incidence rate for a specified safety event is 5% among patients per 
each arm, then the chance of observing at least 1 event among 50 patients will be 92%.  At the end of the 
study, for each treatment group, if none of the 50 patients experience an AE, then the true incidence rate 
of the AE is no greater than 3.2% with 80% confidence (no greater than 4.5% with 90% confidence). 
Approximately 150 patients are planned for enrollment (up to 50 patients per arm). 
 
11.8 Interim Analyses 
 
No additional analysis will be performed in this study following the first interim analysis performed on 29 
June 2018.  
 
11.9 Safety Stopping Criteria 
 
In the event of the occurrence of 2 treatment-emergent CTCAE grade ≥4 cardiac AEs or 
2 treatment-emergent CTCAE grade ≥4 hemorrhage AEs in any of the individual treatment arms, study 
enrollment will be suspended until the IDMC has adjudicated the events.  If the IDMC confirms the 
nature and grade of the events together with a relationship to study drug, the IDMC may recommend 
closure of one or more treatment arms.  This recommendation is non-binding.  The FDA and other 
competent authorities will be notified of any IDMC meeting that is convened under these circumstances, 
and the resultant decision will be reported to the FDA within 2 business days. The MHRA will be 
informed via a substantial amendment. After the first IDMC meeting, patients will continue to be enrolled 
into each of the remaining treatment arms to further evaluate safety and efficacy at doses carried forward.  
In the event one or more arms are suspended or terminated for a safety observation, randomization into 
the arm(s) will be halted immediately, however patients who are experiencing benefit, in the opinion of 
the investigator and Sponsor, and who were randomized to an arm that is suspended or terminated, may 
continue treatment. 
 
12 Pharmacokinetic and Pharmacodynamic Analyses 
 
The PK parameters, minimum concentration observed, maximum concentration observed, and area under 
the curve will be determined and summarized using descriptive statistics for each pacritinib dosage arm. 
Exposure-response analyses will be conducted on both safety and efficacy populations in the study.  PD 
samples will be analyzed for biomarkers associated with the JAK/STAT pathway.   
 
13 Independent Data Monitoring Committee 
 
See Section 2.2 for a description of the composition and responsibilities of the IDMC. 
 
14 Study Administration and Investigator Obligations 
 
For studies conducted outside the US under a US Investigational New Drug (IND), the principal 
investigator must comply with US FDA IND regulations and with those of relevant national and local 
health authorities. 
 


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14.1 Study Drug Accountability 
 
CTI BioPharma Corp. will provide pacritinib.  The recipient will acknowledge receipt of the drug by 
returning the appropriate shipping receipt form according to the study-specific pharmacy manual.  
Damaged supplies will be replaced. 
Accurate records of all pacritinib dispensed from and returned to the study site should be recorded by 
using the Drug Inventory Log (refer to study-specific pharmacy manual). 
Pacritinib will be disposed of at the study site according to institutional standard operating procedures 
after study monitors have completed the drug inventory reconciliation.  The method of destruction must 
be documented.  A copy of the destruction certification along with the inventory of destroyed clinical 
material will be provided to CTI BioPharma Corp. 
 
14.2 Informed Consent 
 
CTI BioPharma Corp. will provide a sample informed consent form (ICF) to each site for submission and 
approval by site's Institutional Review Board (IRB), Research Ethics Board (REB), or Independent Ethics 
Committee (IEC).  CTI BioPharma Corp. or its designee must review and approve any proposed 
deviations from the sample ICF. Patients must be re-consented to the most current IRB/REB/IEC 
approved version of the ICF during their participation in the study. The investigator must provide the final 
IRB/REC/IEC approved ICF to CTI BioPharma Corp. for regulatory purposes. 
The patient or the patient’s legally authorized representative must sign the ICF before his or her 
participation in the study.  The source record for each patient shall document that informed consent was 
obtained prior to participation in the study.  A copy of each signed ICF or Addendum to an existing ICF 
must be provided to the patient or the patient’s legally authorized representative.  If applicable, it will be 
provided in a certified translation of the local language. 
All signed consent forms must remain in each patient’s study file and must be available for verification by 
the study monitor, Sponsor representative, or regulatory agency at any time. 
 
14.3 Disclosure of Data 
 
Patient medical information obtained by this study is confidential, and disclosure to third parties other 
than those noted below is prohibited. 
Upon the patient’s permission, medical information may be given to his or her personal physician or other 
appropriate medical personnel responsible for his or her welfare. 
Data generated by this study must be available for inspection upon request by representatives of the US 
FDA, national and local health authorities, CTI BioPharma Corp., its designees and the IRB/REB/IEC for 
each study site, if appropriate. 
 
14.4 Case Report Forms  
 
CTI BioPharma Corp. will provide eCRFs, which should be completed in accordance with instructions 
from CTI BioPharma Corp. 
 
 


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14.5 Study Monitoring 
 
Representatives of CTI BioPharma Corp. or their designee must be allowed to visit all study site locations 
at appropriate intervals to assure compliance with Good Clinical Practice (GCP), satisfactory enrollment 
rate, data recording, and protocol adherence. The frequency of monitoring may vary depending on 
enrollment rate and the quality of data collected. The investigator and staff are expected to cooperate and 
provide all relevant study documentation in detail at each site visit on request for review. The investigator 
agrees to cooperate with the monitor to ensure any problems detected in the course of these monitoring 
visits are resolved. In addition to these visits, CTI BioPharma Corp. or designee may monitor each site by 
phone to keep abreast of patient status and to answer questions. 
In order for the investigator to participate in this study, the study monitor must have direct access to 
source data for verification. This will be done by comparing data from the eCRFs with data from the 
patient’s clinic or hospital records (permission will be sought from the patient as part of the consent 
process).  
In addition, CTI BioPharma Corp. internal auditors and government inspectors may evaluate the study.  
They must be allowed access to eCRFs, source documents, and other study files.  CTI BioPharma Corp. 
audit reports will be kept confidential. 
The investigator should promptly notify CTI BioPharma Corp. of an audit scheduled by any regulatory 
authority, and immediately forward copies of audit reports. 
 
14.6 Record Retention 
 
US FDA regulations (21CFR§312.62[c]) and the International Council on Harmonization (ICH) 
Guideline for GCP (see Section 4.9 of the guideline) require that the principal investigator retain records 
and documents pertaining to the conduct of the study and distribution of investigational drug, including 
eCRFs, consent forms, laboratory test results, radiographic assessments, and medication inventory records 
for 2 years after the last marketing application approval in an ICH region or after at least 2 years have 
elapsed since formal discontinuation of clinical development of the investigational product.  All state and 
local laws for retention of records also apply.  CTI BioPharma Corp. will notify the principal investigator 
of these events. 
No records should be disposed of without the written approval of CTI BioPharma Corp. 
 
15 Ethics 
 
15.1 Good Clinical Practice 
 
The investigator and Sponsor will ensure that this study is conducted in full compliance with Declaration 
of Helsinki, ICH guidelines, US FDA regulations 21 CFR Parts 50, 56, and 312, and with the laws and 
regulations of the country in which the research is conducted, whichever affords the greatest protection to 
the study patient. 
 
15.2 Institutional Review Board/Research Ethics Board/Independent Ethics Committee 
 
The appropriate IRB, REB, or IEC must approve in writing the protocol and ICF for this study in 
accordance with the laws and regulation of the country in which the research is conducted prior to any 
patient being registered in this study. 


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Before the investigational drug will be shipped to the investigator, the investigator must provide CTI 
BioPharma Corp. with a copy of the IRB/REB/IEC approval letter stating that the study protocol and ICF 
have been reviewed and approved.  Original US FDA Form 1572 (for all studies conducted under US 
IND regulations) signed by the principal investigator, and a copy of the curriculum vitae for the principal 
investigator, and a copy of an IRB/REB/IEC approved ICF are also required. 
The investigator must also report all serious and medically significant AEs to the IRB/REB/IEC 
according to the local regulation.  Appendix 10 lists the responsibilities of the investigator. 
 
16 Termination of Study  
CTI BioPharma Corp. will retain the right to terminate the study and remove all the study materials from 
the study site at any time.  Specific instances that may precipitate such termination are as follows: 
 
 
Unsatisfactory enrollment with regard to quality or quantity 
 
Deviations from GCP 
 
Deviation from protocol requirements, without prior approval from CTI BioPharma Corp. 
 
Inaccurate and/or incomplete data recording on a recurrent basis 
 
The incidence and/or severity of adverse drug events in this or other studies indicating a potential 
health hazard caused by the treatment 
 
In terminating the study, CTI BioPharma Corp. and the investigator will assure adequate consideration to 
the protection of the patients’ interest. 
 
17 Study Amendments 
 
Changes in any portion of this protocol must be documented in the form of an amendment from CTI 
BioPharma Corp. and must be approved by the site’s IRB/REB/IEC before the amendment can be 
implemented at the site.  The IRB/REB/IEC chairperson may approve minor changes, or may designate 
one or more regulatory members to approve revisions. In addition, substantial amendments made to this 
protocol will require approval by the appropriate regulatory authority prior to implementation. 
 
18 Use of Information and Publication 
 
CTI BioPharma Corp. recognizes the importance of communicating medical study data and therefore 
encourages their publication in reputable scientific journals and at seminars or conferences.  The Clinical 
Study Agreement will describe the details of the processes of producing and reviewing reports, 
manuscripts, and presentations based on the data from this study. 
 
 


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19 References 
 
Ahmed A, Chang CC.  Chronic idiopathic myelofibrosis: clinicopathologic features, pathogenesis, and 
prognosis.  Arch Pathol Lab Med 2006;130:1133-43. 
Arana-Yi C, Quintas-Cardama A, Giles F, et al.  Advances in the therapy of chronic idiopathic 
myelofibrosis.  Oncologist 2006;11:929-43. 
Barosi G.  Myelofibrosis with myeloid metaplasia: diagnostic definition and prognostic classification for 
clinical studies and treatment guidelines.  J Clin Oncol 1999;17:2954-70. 
Barosi G, Elliott M, Canepa L, et al.  Thalidomide in myelofibrosis with myeloid metaplasia: a pooled-
analysis of individual patient data from five studies.  Leuk Lymphoma 2002;43:2301-7. 
Barosi G, Mesa RA, Thiele J, et al.  Proposed criteria for the diagnosis of post-polycythemia vera and 
post-essential thrombocythemia myelofibrosis: a consensus statement from the international working 
group for myelofibrosis research and treatment.  Leukemia 2008;22:437-8. 
Campbell PJ, Green AR.  The myeloproliferative disorders.  N Engl J Med 2006;355:2452-66. 
Cervantes F, Dupriez B, Pereira A, et al.  New prognostic scoring system for primary myelofibrosis based 
on a study of the International Working Group for Myelofibrosis Research and Treatment.  Blood 
2009;113:2895-901. 
Dupriez B, Morel P, Demory JL, et al.  Prognostic factors in agnogenic myeloid metaplasia: a report on 
195 cases with a new scoring system.  Blood 1996;88:1013-8. 
Gilbert HS.  Long term treatment of myeloproliferative disease with interferon-alpha-2b: feasibility and 
efficacy.  Cancer 1998;83:1205-13. 
Harrison C, Kiladjian J-J, Kathrin H, et al.  JAK inhibition with ruxolitinib versus best available therapy 
for myelofibrosis. N Engl J Med 2012;366:787-98. 
Jakafi [package insert]. Wilmington, DE: Incyte; 2014. Available at:  www.jakafi.com/pdf/prescribing-
information.pdf, accessed 16Dec2015. 
Jakafi [SPC]. Wilmington, DE: Incyte: 2016. Available at: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/002464/WC500133223.pdf 
James C, Ugo V, Le Couedic JP, et al.  A unique clonal JAK2 mutation leading to constitutive signalling 
causes polycythaemia vera.  Nature 2005;434:1144-8. 
le Bousse-Kerdiles MC, Desterke C, Guerton B, et al.  Glivec/STI571 treatment stimulates 
megakaryopoiesis and normalizes PDGF receptor beta kinase expression in thrombocytopenic patients 
with myeloid metaplasia with myelofibrosis.  Blood (ASH Annual Meeting Abstracts) 2005;106:Abstract 
2599. 
Marchetti M, Barosi G, Balestri F, et al.  Low-dose thalidomide ameliorates cytopenias and splenomegaly 
in myelofibrosis with myeloid metaplasia: a phase II trial.  J Clin Oncol 2004;22:424-31. 
Mesa RA, Elliott MA, Schroeder G, Tefferi A.  Durable responses to thalidomide-based drug therapy for 
myelofibrosis with myeloid metaplasia. Mayo Clin Proc 2004;79:883-9. 
Mesa RA, Komrokji RS, Verstovsek S.  Ruxolitinib dose management as a key to long-term treatment 
success.  Int J Hematol 2016;104:420-9. 
Newberry KJ, Patel K, Masarova L, et al. Clonal evolution and outcomes in myelofibrosis after 
ruxolitinib discontinuation. Blood 2017; 130(9): 1125-1131. 


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Ni H, Barosi G, Rondelli D, Hoffman R.  Studies of the site and distribution of CD34+ cells in idiopathic 
myelofibrosis.  Am J Clin Pathol 2005;123:833-9. 
Passamonti F, Rumi E, Caramella M, et al.  A dynamic prognostic model to predict survival in post-
polycythemia vera myelofibrosis.  Blood 2008;111:3383-7. 
Passamonti F, Cervantes F, Vannucchi AM, et al.  A dynamic prognostic model to predict survival in 
primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative 
Neoplasms Research and Treatment).  Blood 2010;115:1703-8. 
Rondelli D, Barosi G, Bacigalupo A, et al.  Allogeneic hematopoietic stem-cell transplantation with 
reduced-intensity conditioning in intermediate- or high-risk patients with myelofibrosis with myeloid 
metaplasia.  Blood 2005;105:4115-9. 
Sacchi S.  The role of alpha-interferon in essential thrombocythaemia, polycythaemia vera and 
myelofibrosis with myeloid metaplasia (MMM): a concise update.  Leuk Lymphoma 1995;19:13-20. 
Strupp C, Germing U, Scherer A, et al.  Thalidomide for the treatment of idiopathic myelofibrosis.  
Eur J Haematol 2004;72:52-7. 
Tefferi A.  Myelofibrosis with myeloid metaplasia.  N Engl J Med. 2000;342:1255-65. 
Tefferi A, Mesa RA, Schroeder G, Hanson CA, Li CY, Dewald GW.  Cytogenetic findings and their 
clinical relevance in myelofibrosis with myeloid metaplasia.  Br J Haematol 2001;113:763-71. 
Tefferi A, Cortes J, Verstovsek S, et al.  Lenalidomide therapy in myelofibrosis with myeloid metaplasia.  
Blood 2006;108:1158-64. 
Tefferi A, Vardiman JW.  Classification and diagnosis of myeloproliferative neoplasms: the 2008 World 
Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 2008;22:14-22. 
Tefferi A, Litzow MR, Pardanani A. Long-term outcome of treatment with ruxolitinib in myelofibrosis. N 
Engl J Med. 2011; 365:1455-1457. 
Verstovsek S, Mesa RA, Gotlib J, et al.  A double-blind, placebo-controlled trial of ruxolitinib for 
myelofibrosis. N Engl J Med. 2012;366:799-807. 


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Appendix 1 - Diagnostic Criteria for Primary Myelofibrosis, Post-Polycythemia Myelofibrosis, and 
Post-Essential Thrombocythemia Myelofibrosis 
 
 
Major Criteria 
Minor/Additional Criteria 
Primary myelofibrosis (PMF) 
 
Diagnosis requires meeting all 
3 major criteria and at least 2 
minor criteria1 
1. Megakaryocyte proliferation and 
atypia3 accompanied by either reticulin 
and/or collagen fibrosis  
or 
In the absence of reticulin fibrosis, the 
megakaryocyte changes must be 
accompanied by increased marrow 
cellularity, granulocytic proliferation and 
often decreased erythropoiesis 
(i.e., pre-fibrotic PMF) 
2. Not meeting WHO criteria for CML, 
PV, MDS, or other myeloid neoplasm 
3. Demonstration of JAK2V617F or 
other clonal marker 
or 
4. No evidence of reactive marrow 
fibrosis 
1. Leukoerythroblastosis 
2. Increased serum LDH 
3. Anemia 
4. Palpable splenomegaly 
Post-polycythemia vera 
myelofibrosis (PPV-MF) 
 
Diagnosis requires meeting both 
major criteria and at least 2 
additional criteria2 
1. Documentation of a previous 
diagnosis of polycythemia vera as 
defined by the WHO criteria1  
2. Bone marrow fibrosis grade 2-3 (on 
0-3 scale)4 or grade 3-4 (on 0-4 scale)5 
1. Anemia6 or sustained loss 
of requirement of either 
phlebotomy (in the 
absence of cytoreductive 
therapy) or cytoreductive 
treatment for 
erythrocytosis 
2. A leukoerythroblastic 
peripheral blood picture 
3. Increasing splenomegaly 
defined as either an 
increase in palpable 
splenomegaly of ≥5cm 
(distance of the tip of the 
spleen from the left costal 
margin) or the appearance 
of a newly palpable 
splenomegaly 
4. Development of ≥1 of 
three constitutional 
symptoms: >10% weight 
loss in 6 months, night 
sweats, and unexplained 
fever (>37.5 degrees C) 


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Major Criteria 
Minor/Additional Criteria 
Post-essential thrombocythemia 
myelofibrosis (PET-MF) 
 
Diagnosis requires meeting both 
major criteria and at least 2 
additional criteria2 
1. Documentation of a previous 
diagnosis of essential 
thrombocythemia as defined by the 
WHO criteria1 
2. Bone marrow fibrosis grade 2-3 (on 
0-3 scale)4 or grade 3-4 (on 0-4 scale)5 
1. Anemia6 and a ≥2 mg ml-1 
decrease from baseline 
hemoglobin level 
2. A leukoerythroblastic 
peripheral blood picture 
3. Increasing splenomegaly 
defined as either an 
increase in palpable 
splenomegaly of ≥5 cm 
(distance of the tip of the 
spleen from the left costal 
margin) or the appearance 
of a newly palpable 
splenomegaly 
4. Increased LDH (above 
reference level) 
5. Development of ≥1 of 
three constitutional 
symptoms: >10% weight 
loss in 6 months, night 
sweats, and unexplained 
fever (>37.5 degrees C) 
Abbreviations: 
WHO - World Health Organization 
CML - chronic myelogenous leukemia 
MDS - myelodysplastic syndrome 
LDH - lactate dehydrogenase 
 
1 
Source: Tefferi A, Vardiman JW.  Classification and diagnosis of myeloproliferative neoplasms: the 2008 World 
Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 2008;22:14-22.  
2 
Source: Barosi G, Mesa RA, Thiele J, et al.  Proposed criteria for the diagnosis of post-polycythemia vera and 
post-essential thrombocythemia myelofibrosis: a consensus statement from the international working group for 
myelofibrosis research and treatment.  Leukemia 2008;22:437-8. 
3 
Small to large megakaryocytes with an aberrant nuclear/cytoplasmic ratio and hyperchromatic and irregularly 
folded nuclei and dense clustering 
4 
Grade 2-3 according to the European classification: diffuse, often coarse fiber network with no evidence of 
collagenization (negative trichrome stain) or diffuse, coarse fiber network with areas of collagenization (positive 
trichrome stain) (see WHO criteria) 
5 
Grade 3-4 according to the standard classification: diffuse and dense increase in reticulin with extensive 
intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis or diffuse and dense 
increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant 
osteosclerosis (see WHO criteria) 
6 
Below the reference range for appropriate age, sex, gender, and altitude considerations 
  
 


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 Appendix 2 - Dynamic International Prognostic Scoring System in Primary Myelofibrosis  
 
Prognostic Variable 
Value 
0 
1 
2 
Age, years 
≤65 
>65 
 
White blood cell count, x 109/L 
≤25 
>25 
 
Hemoglobin, g/dL 
≥10 
 
<10 
Peripheral blood blast, % 
<1 
≥1 
 
Constitutional symptoms, Y/N 
N 
Y 
 
 
Risk Category 
 
Low 
0 
Intermediate-1 
1-2 
Intermediate-2 
3-4 
High 
5-6 
Source:  Passamonti F, Cervantes F, Vannucchi AM, et al.  A dynamic prognostic model to predict survival in primary 
myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and 
Treatment).  Blood 2010;115:1703-8. 


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Appendix 3 - Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score 
Version 2.0 (MPN-SAF TSS 2.0) – 24-Hour Recall Period 
 
This form should be used from study screening to Week 48 
 
Symptom 
0 to 10 Ranking 
Select the one number that describes the worst severity you have experienced with each of the following in the past 
24 hours:  
Tiredness 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Filling up quickly when you eat (Early satiety) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Abdominal discomfort 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Inactivity 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Night sweats 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Itching (pruritus) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Bone pain (diffuse not joint pain or arthritis) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Pain under ribs on the left side 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)  
 
For assessing eligibility, the TSS is the sum of the individual symptom scores for tiredness, early satiety, 
abdominal discomfort, night sweats, pruritis, bone pain, and pain under ribs on the left side.  The 
inactivity symptom score should not be included in the TSS calculation for eligibility.   
Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score version 2.0 (MPN-
SAF TSS 2.0) – 7 day recall period  
This form is used at each visit from Week 48 visit to the end of the study 
 
Symptom 
0 to 10 Ranking 
Select the one number that describes the worst severity you have experienced with each of the following in the past 
7 days:  
Tiredness 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Filling up quickly when you eat (Early satiety) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Abdominal discomfort 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Inactivity 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Night sweats 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Itching (pruritus) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Bone pain (diffuse not joint pain or arthritis) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Pain under ribs on the left side 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)  


CTI BioPharma Corp. 
PAC203 Protocol Amendment 6 
 
Page 74 of 83 
Appendix 4 - Eastern Cooperative Oncology Group Performance Status Scale Grade Description  
 
Grade 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but ambulatory and able to carry 
out work of a light or sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but unable to carry out any work 
activities.  Up and about more than 50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair. 
5 
Dead. 
Source: Oken MM, Creech RH, Tormey DC, et al.  Toxicity and response criteria of the Eastern Cooperative Oncology Group.  
Am J Clin Oncol. 1982;5:649-55.


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PAC203 Protocol Amendment 6 
 
Page 75 of 83 
Appendix 5 - Selected Strong Inhibitors of CYP3A4 
 
boceprevir 
ciprofloxacin 
clarithromycin 
conivaptan 
erythromycin 
fluconazole 
grapefruit 
grapefruit juice 
indinavir 
itraconazole 
ketoconazole 
lopinavir 
mibefradil 
nefazodone  
nelfinavir 
norfloxacin 
posaconazole 
quinidine 
ritonavir 
saquinavir 
Seville oranges 
star fruit 
telaprevir 
telithromycin 
troleandomycin 
voriconazole 
This list is not comprehensive. When considering using an agent that could be a potential CYP3A4 inhibitor, please discuss 
this with the medical monitor. 
Source:  http://medicine.iupui.edu/clinpharm/ddis/table.asp and http://www.pharmacytimescom/issue/pharmacy/2008/2008-
09/2008-09-8687. 
 
Appendix 6 – Selected Strong Inducers of CYP450 
 
carbamazepine 
efavirenz 
nevirapine 
phenobarbital 
phenytoin 
pioglitazone 
rifabutin 
rifampin 
St. John's Wort 
troglitazone 
This list is not comprehensive. When considering using an agent that could be a potential CYP450 inducer, please discuss this 
with the medical monitor. 
Source:  http://medicine.iupui.edu/clinpharm/ddis/table.asp and http://www.pharmacytimescom/issue/pharmacy/2008/2008-
09/2008-09-8687. 


CTI BioPharma Corp. 
PAC203 Protocol Amendment 6 
 
Page 76 of 83 
Appendix 7 - The Stages of Heart Failure, New York Heart Association Classification 
 
To determine the best course of therapy, physicians often assess the stage of heart failure according to the 
New York Heart Association (NYHA) functional classification system.  This system relates symptoms to 
everyday activities and the patient’s quality of life. 
 
Class 
Patient Symptoms 
I (Mild) 
No limitation of physical activity.  Ordinary physical activity does not cause undue fatigue, 
palpitation, or dyspnea (shortness of breath). 
II (Mild) 
Slight limitation of physical activity.  Comfortable at rest, but ordinary physical activity 
results in fatigue, palpitation, or dyspnea. 
III (Moderate) 
Marked limitation of physical activity.  Comfortable at rest, but less-than-ordinary activity 
causes fatigue, palpitation, or dyspnea. 
IV (Severe) 
Unable to carry out any physical activity without discomfort.  Symptoms of cardiac 
insufficiency at rest.  If any physical activity is undertaken, discomfort is increased. 
Source:  Dolgin M, Fox AC, Devereaux RB.  Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. 
9th ed.  Boston: Little Brown and Company; 1994. p. 253-256.
 


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PAC203 Protocol Amendment 6 
 
Page 77 of 83 
Appendix 8 - Medications with Significant Arrhythmogenic Potential 
 
Use of the following drugs is prohibited, due to the potential for QT interval prolongation.a 
Alkylating agent 
Bendamustine (Treanda, Treakisym, Ribomustin, Levact) 
Alpha 1 blocker 
Alfuzosin (Uroxatral) 
Analgesic 
Hydrocodone-ER (Hysingla™ ER, Zohydro ER); Tramadol (Crispin, Ralivia ER, 
Ralivia Flashtab, Tramadolum, Tramal, Tramodol, Tridural, Ultram, Ultram ER, 
Zydol) 
Anesthetic 
Propofol (Diprivan, Propoven); Sevoflurane (Ultane, Sojourn) 
Antianginal 
Bepridil (Removed from Market) (Vascor) 
Antiarrhythmic 
Amiodarone (Cordarone, Pacerone, Nexterone); Disopyramide (Norpace); Dofetilide 
(Tikosyn); Dronedarone (Multaq); Flecainide (Tambocor, Almarytm, Apocard, 
Ecrinal, Flécaine); Ibutilide (Corvert); Procainamide (Pronestyl, Procan); Quinidine 
(Quinaglute, Duraquin, Quinact, Quinidex, Cin-Quin, Quinora); Sotalol (Betapace, 
Sotalex, Sotacor); Pilsicainide (Only on Non-US Market) (Sunrythm) 
Antibiotic 
Azithromycin (Zithromax, Zmax); Bedaquiline (Sirturo); Ciprofloxacin (Cipro, 
Cipro-XR, Neofloxin); Clarithromycin (Biaxin, Prevpac); Delamanid (Only on Non 
US Market) (Deltyba); Erythromycin (E.E.S., Robimycin, EMycin, Erymax, 
Ery-Tab, Eryc Ranbaxy, Erypar, Eryped, Erythrocin Stearate Filmtab, Erythrocot, 
E-Base, Erythroped, Ilosone, MY-E, Pediamycin, Abboticin, Abboticin-ES, Erycin, 
PCE Dispertab, Stiemycine, Acnasol, Tiloryth); Gatifloxacin (Removed from 
Market) (Tequin); Gemifloxacin (Factive); Grepafloxacin (Removed from Market) 
(Raxar); Levofloxacin (Levaquin, Tavanic); Moxifloxacin (Avelox, Avalox, 
Avelon); Norfloxacin (Removed from Market) (Noroxin, Ambigram); Ofloxacin 
(Floxin); Roxithromycin (Only on Non US Market) (Rulide, Xthrocin, Roxl-150, 
Roxo, Surlid, Rulide, Biaxsig, Roxar, Roximycinv, Roxomycin, Rulid, Tirabicin, 
Coroxin); Sparfloxacin (Removed from Market) (Zagam); Telavancin (Vibativ); 
Telithromycin (Ketek); 
Anticancer 
Arsenic trioxide (Trisenox); Capecitabine (Xeloda); Lenvatinib (Lenvima); 
Tamoxifen (Nolvadex [discontinued 6/13], Istubal, Valodex); Vandetanib 
(Caprelsa); Cabozantinib (Cometriq); Epirubicin (Ellence, Pharmorubicin, 
Epirubicin Ebewe); Fluorouracil (5-FU) (Adrucil, Carac, Efudex, Efudix, others); 
Midostaurin (Rydapt); Necitumumab (Portrazza); Tipiracil and Trifluridine 
(Lonsurf) 
Anticoagulant 
Betrixaban (Bevyxxa) 
Anticonvulsant 
Ezogabine (Retigabine) (Potiga, Trobalt); Felbamate (Felbatol) 
Antidepressant 
SNRI: Venlafaxine (Effexor, Efexor) 
SSRI: Citalopram (Celexa, Cipramil); Escitalopram (Cipralex, Lexapro, Nexito, 
Anxiset-E [India], Exodus [Brazil], Esto [Israel], Seroplex, Elicea, Lexamil, Lexam, 
Entact [Greece], Losita [Bangladesh], Reposil [Chile], Animaxen [Colombia], 
Esitalo [Australia], Lexamil [South Africa]) 
Tetracyclic: Mirtazapine (Remeron) 
Tricyclic: Clomipramine (Anafranil); Desipramine (Pertofrane, Norpramine); 
Imipramine (melipramine) (Tofranil); Nortriptyline (Pamelor, Sensoval, Aventyl, 
Norpress, Allegron, Noritren, Nortrilen); Trimipramine (Surmontil, Rhotrimine, 
Stangyl) 
Antiemetic 
Dolasetron (Anzemet); Granisetron (Kytril, Sancuso, Granisol); Ondansetron 
(Zofran, Anset, Ondemet, Zuplenz, Emetron, Ondavell, Emeset, Ondisolv, 


CTI BioPharma Corp. 
PAC203 Protocol Amendment 6 
 
Page 78 of 83 
Use of the following drugs is prohibited, due to the potential for QT interval prolongation.a 
Setronax); Palonosetron (Aloxi); Tropisetron (Only on Non US Market) (Navoban, 
Setrovel) 
Antifungal 
Fluconazole (Diflucan, Trican); Pentamidine (Pentam) 
Antihistamine 
Astemizole (Removed from Market) (Hismanal); Terfenadine (Removed from 
Market) (Seldane) 
Antihypertensive 
Isradipine (Dynacirc); Ketanserin (Only on Non US Market) (Sufrexal); 
Moexipril/HCTZ (Uniretic, Univasc); Nicardipine (Cardene) 
Antilipemic 
Probucol (Removed from Market) (Lorelco) 
Antimalarial 
Artenimol+piperaquine (Only on Non-US Market) (Eurartesim); Chloroquine 
(Aralen); Halofantrine (Only on Non-US Market) (Halfan); Primaquine phosphate 
Antimania 
Lithium (Eskalith, Lithobid) 
Antimycobacterial 
Clofazimine (Only on Non-US Market) (Lamprene) 
Antinausea 
Domperidone (Only on Non-US Market) (Motilium, Motillium, Motinorm Costi, 
Nomit) 
Antineoplastic agent 
Inotuzumab ozogamicin (Besponsa); Oxaliplatin (Eloxatin) 
Antipsychotic 
Cyamemazine (cyamepromazine) (Only on Non-US Market) (Tercian); Haloperidol 
(Haldol [US & UK], Aloperidin, Bioperidolo, Brotopon, Dozic, Duraperidol 
[Germany], Einalon S, Eukystol, Halosten, Keselan, Linton, Peluces, Serenace, 
Serenase, Sigaperidol); Levomepromazine (methotrimeprazine) (Only on Non-US 
Market) (Nosinan, Nozinan, Levoprome); Levosulpiride (Only on Non-US Market) 
(Lesuride, Levazeo, Enliva [with rabeprazole]; Mesoridazine (Removed from 
Market) (Serentil); Perphenazine (Trilafon, Etrafon/Triavil, Decentan); Pimozide 
(Orap); Pipamperone (Only on Non-US Market) (Dipiperon [E.U], Propitan [Japan], 
Dipiperal, Piperonil, Piperonyl); Prothipendyl (Only on Non-US Market) (Dominal, 
Largophren, Timoval, Timovan, Tumovan); Thioridazine (Mellaril, Novoridazine, 
Thioril); Benperidol (Only on Non-US Market) (Anquil, Glianimon) 
Antipsychotic/antiemetic 
Chlorpromazine (Thorazine, Largactil, Megaphen); Droperidol (Inapsine, Droleptan, 
Dridol, Xomolix); Promethazine (Phenergan) 
Antipsychotic, atypical 
Aripiprazole (Abilify, Aripiprex); Asenapine (Saphris, Sycrest); Clozapine (Clozaril, 
Fazaclo, Versacloz); Iloperidone (Fanapt, Fanapta, Zomaril); Melperone (Only on 
Non-US Market) (Bunil, Buronil, Eunerpan); Paliperidone (Invega, Xepilon); 
Pimavanserin (Nuplazid); Risperidone (Risperdal); Sertindole (Only on Non-US 
Market) (Serdolect, Serlect); Sulpiride (Only on Non-US Market) (Dogmatil, 
Dolmatil, Eglonyl, Espiride, Modal, Sulpor); Sultopride (Only on Non-US Market) 
(Barnetil, Barnotil,  Topral); Zotepine (Only on Non-US Market) (Losizopilon, 
Lodopin, Setous and Zoleptil) 
Antiretroviral 
Efavirenz (Sustiva and others) 
Antisense 
oligonucleotide 
Nusinersen (Spinraza) 
Antiviral 
Rilpivirine (Edurant, Complera, Eviplera); Saquinavir (Invirase [combo]) 
Beta-3 adrenergic 
antagonist 
Mirabegron (Myrbetriq) 
Cholinesterase inhibitor 
Donepezil (Aricept) 


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PAC203 Protocol Amendment 6 
 
Page 79 of 83 
Use of the following drugs is prohibited, due to the potential for QT interval prolongation.a 
Cyclin dependent kinase 
inhibitor 
Ribociclib (Kisqali) 
Dopamine 2 and 5HT2a 
antagonist 
Flupentixol (Only on Non-US Market) (Depixol, Fluanxol) 
Dopamine agonist 
Apomorphine (Apokyn, Ixense, Spontane, Uprima) 
Estrogen 
agonist/antagonist 
Toremifene (Fareston) 
GI stimulant 
Cisapride (Removed from Market) (Propulsid) 
Glucosylceramide 
synthase inhibitor 
Eliglustat (Cerdelga) 
Gonadotropin receptor 
agonist/antagonist 
Leuprolide (Lupron, Eligard, Viadur, Carcinil, Enanton, Leuplin, Lucrin, Procren, 
Prostap and others) 
Gonadotropin releasing 
hormone 
agonist/antagonist 
Degarelix (Firmagon, Ferring) 
Histone deacetylase 
inhibitor 
Panobinostat (Farydak); Romidepsin (Istodax); Vorinostat (Zolinza) 
Imaging contrast agent 
Perflutren lipid microspheres (Definity, Optison) 
Imunosuppressant 
Tacrolimus (Prograf, Advagraf, Protopic) 
Kinase inhibitor 
Ceritinib (Zykadia); Crizotinib (Xalkori); Dabrafenib (Tafinlar); Lapatinib (Tykerb, 
Tyverb); Nilotinib (Tasigna); Sunitinib (Sutent); Vemurafenib (Zelboraf) 
Local anesthetic  
Cocaine 
Microtubule inhibitor 
Eribulin mesylate (Halaven) 
Muscle relaxant 
Terodiline (Only on Non-US Market) (Micturin, Mictrol [not bethanechol]); 
Tizanidine (Zanaflex, Sirdalud); Tolterodine (Detrol, Detrusitol) 
Norepinephrine reuptake 
inhibitor 
Atomoxetine (Strattera) 
Opioid agonist 
Levomethadyl acetate (Removed from Market) (Orlaam); Methadone (Dolophine, 
Symoron, Amidone, Methadose, Physeptone, Heptadon) 
Opioid receptor 
modulator 
Buprenorphine (Butrans, Belbuca, Bunavail, Buprenex, Suboxone, Zubsolv) 
Oxytocic 
Oxytocin (Pitocin, Syntocinon) 
Phosphodiesterase 3 
inhibitor 
Anagrelide (Agrylin, Xagrid); Cilostazol (Pletal) 
Phosphodiesterase 5 
inhibitor 
Vardenafil (Levitra) 
Progesterone antagonist 
Mifepristone (Korlym, Mifeprex) 
Proteasome inhibitor 
Bortezomib (Velcade, Bortecad) 
Psychedelic 
Ibogaine (Only on Non-US Market) 
Sedative 
Dexmedetomidine (Precedex, Dexdor, Dexdomitor) 


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PAC203 Protocol Amendment 6 
 
Page 80 of 83 
Use of the following drugs is prohibited, due to the potential for QT interval prolongation.a 
Selective D2, D3 
dopamine antagonist 
Tiapride (Only on Non-US Market) (Tiapridal, Italprid, Sereprile, Tialaread, Tiaryl, 
Tiaprim, Tiaprizal, Sereprid, Tiapridex) 
Somatostatic analog 
Pasireotide (Signifor) 
Sphingosine phospate 
receptor modulator 
Fingolimod (Gilenya) 
Tyrosine kinase inhibitor 
Bosutinib (Bosulif); Dasatinib (Sprycel); Osimertinib (Tagrisso); Pazopanib 
(Votrient); Sorafenib (Nexavar) 
Vasoconstrictor 
Terlipressin (Only on Non US Market) (Teripress, Glypressin, Terlipin, Remestyp, 
Tresil, Teriss and others) 
Vasodilator, Coronary 
Papaverine HCl (Intra-coronary) 
Vesicular monamine 
transporter 2 inhibitor 
Deutetrabenazine (Austedo); Valbenazine (Ingrezza); Tetrabenazine (Nitoman, 
Xenazine) 
Viral protease inhibitor 
Lopinavir and ritonavir (Kaletra, Aluvia) 
Source: CredibleMeds Filtered QT Drug List Rev March 01 2018 (AZCERT.ORG)


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PAC203 Protocol Amendment 6 
 
Page 81 of 83 
Appendix 9 - Common Terminology Criteria for Adverse Events: Diarrhea (Version 4.03) 
 
Definition: A Disorder Characterized by Frequent and Watery Bowel Movements. 
1 
Increase of  <4 stools per day over baseline; mild increase in ostomy output compared to baseline 
2 
Increase of 4 – 6 stools per day over baseline; moderate increase in ostomy output compared to baseline 
3 
Increase of  >7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in 
ostomy output compared to baseline; limiting self-care ADL 
4 
Life-threatening consequences; urgent intervention indicated 
5 
Death 


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PAC203 Protocol Amendment 6 
 
Page 82 of 83 
Appendix 10 - Investigator Responsibilities, Required Documentation, and Signature 
 
CTI BioPharma Corp. will select the investigator(s) on the basis of their expertise in the field of clinical 
studies in hematologic oncology and in the care and treatment of patients with chronic myeloproliferative 
diseases. Investigators will also be selected on the appropriateness of their facility to conduct a research 
study of this nature, and the characteristics of the patient population treated at the institution. The 
investigator will: 
 
 
Obtain Institutional Review Board (IRB), Research Ethics Board (REB), or Independent Ethics 
Committee (IEC) approval of the protocol and amendments to the protocol and Informed Consent 
Form before initiation of the protocol or any amendments for the study, and obtain annual IRB or IEC 
renewal, as required.  
 
Ensure that current FDA and/or ICH-E6 regulations are followed. 
 
Select all patients in accordance with the selection criteria outlined in the study protocol. 
 
Treat and follow patients as described in this research protocol. Complete all electronic case report 
forms (eCRFs) in a timely manner and review eCRFs for accuracy and completeness.  Provide the 
original clinical source documents to verify all data entered on eCRFs or SAE reports and all data that 
document the course of the patient throughout their participation on the study.  Provide a clinical 
summary to the Sponsor's clinical research monitor. 
 
Report all adverse events to CTI BioPharma Corp. or designee, as required by the protocol. 
 
Ensure that the investigational drug is kept in a secured, limited access area and stored under proper 
conditions. Ensure that all investigational drug receipt and dispensing information is recorded and all 
drug can be accounted for at all times. 
 
Before initiation of the study, each participating investigator will submit to CTI: 
- 
FDA Form 1572 and, if applicable, other ministry of health required forms 
- 
Copies of the medical licenses of principal investigators and subinvestigators 
- 
Addresses and descriptions of all clinical laboratory facilities to be used 
- 
Laboratory certification and expiration dates 
- 
Normal ranges and effective dates for all required laboratory tests 
- 
IRB/REB/IEC approval letter referencing the protocol (and amendments, if applicable). 
- 
IRB/REB/IEC Membership List: A list of the IRB/REB/EC members, their respective titles or 
occupations, and their institutional affiliations. 
- 
A sample copy of the IRB/REB/IEC-approved Informed Consent Form 
- 
Curricula vitae: Curricula vitae for the principal investigator and all subinvestigators 
- 
Financial disclosure for the principal investigator and all subinvestigators 
- 
Protocol signature page, signed by the principal investigator 
 
Investigator Statement and Signature: 
 
I attest that I have read this protocol, understand and agree to the provisions of the protocol, and accept the 
responsibilities listed above in my role as principal investigator for the study. 
 
 
 
Principal Investigator Signature 
Date 
 
 
 
Principal Investigator Name, Printed 


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PAC203 Protocol Amendment 6 
 
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Appendix 11 - Patient Global Impression Assessment 
 
Patient Global Impression Assessment 
 
Patient Number: ___________________ 
Today’s date (day/month/year): _____/________/________ 
 
Instructions: Circle the answer that is most appropriate.  
_____________________________________________________________________________________ 
Since the start of the treatment you’ve received in 
this study, your myelofibrosis symptoms are: 
1.  Very much improved 
2.  Much improved 
3.  Minimally improved 
4.  No change 
5.  Minimally worse 
6.  Much worse 
7.  Very much worse 
 
 

SAP_001.pdf: 
 
Confidential 
Property of CTI BioPharma Corp. This document or information within may not be used, divulged, published or 
otherwise disclosed without the written consent of CTI BioPharma Corp. 
 
 
 
 
Study PAC203 
Statistical Analysis Plan 
Version: 3.0 
01November2019 
An Open-Label, Randomized, Phase 2 Dose-Finding Study of Pacritinib in Patients with 
Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential 
Thrombocythemia Myelofibrosis Previously Treated with Ruxolitinib 
 
Prepared by: Tanya Granston, PhD, Manager, Biostatistics 
Modified by:   Karisse Roman-Torres, MSPH, Lead Statistician 
 
Protocol Version: 
 
Amendment 7 
Protocol Version Date: 
19 July 2019 
 
 
 
 
CTI BioPharma Corp. 
3101 Western Avenue, Suite 600 
Seattle, WA 98121 
 


PAC203 Statistical Analysis Plan, Version 3.0 
01November2019 
 
 
CTI BioPharma Corp. 
Confidential 
Page 2 of 30 
Table of Contents 
1. 
Scope ............................................................................................................................................. 7 
2. 
Study Objectives and Hypotheses ................................................................................................. 7 
2.1 
Study Objectives ........................................................................................................................ 7 
2.1.1 
Primary Objective ........................................................................................................... 7 
2.1.2 
Secondary Objectives...................................................................................................... 7 
1.1 
Hypotheses ............................................................................................................................. 8 
3. 
Summary of Study Design ............................................................................................................ 8 
4. 
Randomization and Blinding ........................................................................................................ 8 
5. 
Analysis Populations and Approaches to Analysis ....................................................................... 9 
5.1 
Full Analysis Set ........................................................................................................................ 9 
5.2 
Safety Population ....................................................................................................................... 9 
6. 
General statistical considerations ................................................................................................ 10 
6.1 
Data Analysis Conventions ...................................................................................................... 10 
6.2 
Multiplicity .............................................................................................................................. 10 
7. 
Disposition and enrollment ......................................................................................................... 10 
8. 
Demographics, Baseline Characteristics, and Medical History .................................................. 11 
8.1 
Demographic Variables ........................................................................................................... 11 
8.2 
Baseline Disease Characteristic Variables ............................................................................... 11 
8.3 
Prior Therapy and Concomitant Medications .......................................................................... 12 
8.4 
Prior Ruxolitinib Experience ................................................................................................ 12 
8.5 
Medical History .................................................................................................................... 12 
9. 
Exposure to Study Treatment...................................................................................................... 12 
10. 
Efficacy Variables .................................................................................................................... 13 
10.1 
Spleen volume (SPV) ....................................................................................................... 14 
10.2 
Total Symptom Score (TSS)............................................................................................. 14 
TSS Algorithm ............................................................................................................................ 14 
Handling of Missing TSS Values ............................................................................................... 15 
10.3 
Patient Global Impression Assessment ............................................................................. 15 
10.4 
Spleen Length Reduction.................................................................................................. 15 
10.5 
Transfusions...................................................................................................................... 16 
10.6.1 
Frequency of Red Blood Cell (RBC) Transfusions .......................................................... 16 


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10.6.2 
Frequency of Platelet Transfusions .................................................................................. 16 
10.7 
ECOG Performance Status ............................................................................................... 17 
11 Safety variables ........................................................................................................................... 17 
11.1 Adverse Events ........................................................................................................................ 17 
11.2 Safety Laboratory Assessments ............................................................................................... 18 
11.2.1 
Hematology .......................................................................................................................... 18 
11.2.2 
Coagulation Function ........................................................................................................... 18 
11.2.3 
Chemistry ............................................................................................................................. 18 
11.2.4 
ECG Assessment .................................................................................................................. 19 
11.2.5 
Cardiac Ejection Fraction Assessment ................................................................................. 19 
11.2.6 
Additional safety assessments .............................................................................................. 19 
12 Efficacy Endpoints and Analyses ............................................................................................... 20 
12.1 Primary efficacy endpoints ...................................................................................................... 20 
12.1 1 
Spleen Volume Reduction ................................................................................................ 20 
12.1 2 
Total Symptom Score (TSS) Analysis.............................................................................. 20 
12.1 3 
Patient Global Impression Assessment ............................................................................. 21 
12.2 Exploratory Efficacy Analysis ................................................................................................. 21 
12.2 1 Spleen Length Reduction .............................................................................................. 21 
12.2 2 Transfusions .................................................................................................................. 21 
12.2 3 ECOG Performance Status ........................................................................................... 21 
13 Safety Analyses ........................................................................................................................... 22 
13.1 Adverse Events ........................................................................................................................ 22 
13.2 Clinical Laboratory Measurements .......................................................................................... 23 
13.3 Other Clinical Safety................................................................................................................ 23 
13.3.1 
Electrocardiogram (ECG) .................................................................................................... 23 
13.3.2 
Echocardiogram or Multiple-gated Acquisition Scan .......................................................... 24 
13.3.3 
Vital Sign Measurements ..................................................................................................... 24 
13.3.4 
Physical Examinations ......................................................................................................... 26 
13.3.5 
Supplemental Procedures ..................................................................................................... 26 
13.3.6 
Progressive Disease .............................................................................................................. 26 
13.3.7 
Subgroup Analysis of Safety ................................................................................................ 26 
14 Genetic Background.................................................................................................................... 26 
15 Pharmacokinetic and Pharmacodynamic Analyses .................................................................... 26 


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16 Determination of Sample Size .................................................................................................... 26 
17 Data Handling Rules ................................................................................................................... 27 
17.1 
Definition of Baseline Value ............................................................................................ 27 
17.2 
Partial Current MF Diagnosis Date .................................................................................. 27 
17.3 
Partial or Missing AE Onset and Resolution Dates .......................................................... 27 
17.4 
Partial or Missing Transfusion Dates ............................................................................... 28 
17.5 
Partial or Missing Concomitant Medication and Supplemental Procedure Dates ............ 28 
12.1 
Analysis Windows ............................................................................................................ 29 
12.2 
Laboratory Results Reported as a Range .......................................................................... 30 
13 References ................................................................................................................................... 30 
 


PAC203 Statistical Analysis Plan, Version 3.0 
01November2019 
 
 
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Page 5 of 30 
 
Modification 
 
Rationale 
Restructured the layout of the SAP to include 
separate sections for variables definitions and 
analyses  
Reorganization of this document aimed to 
improve the presentation of the statistical 
analysis information. 
Added data convention 
Added details on the data conventions that 
will be used for data reporting. 
Disposition  
Added details and clarification of data 
summaries 
Updated the Safety Population 
The safety population was modified to define 
the subject’s actual treatment as the initial 
dose taken since per protocol dose could have 
been modified (reduced). 
PK/PD analyses 
These analyses were removed from the 
statistical analysis plan as a separate PK/PD 
analysis plan is available.  
Excluded the Per Protocol Population and 
modified the Full Analysis Population to 
evaluate randomized and treated patients and 
not condition on having available endpoint 
data at Week 24. 
Following a conservative approach in order to 
be more data inclusive these populations were 
modified (excluded) in order to include all 
randomized and treated subjects in the 
analysis. 
Added reporting of the Progressive Disease 
information and Physical Examination 
Data on progressive disease and physical 
examinations were collected throughout the 
study however data reporting was not 
specified in previous SAP versions. 
Excluded  TSS evaluation of treatment effects 
(GEE analysis) and the dose response using 
the moving average.  
The primary aim of this study is to establish 
the optimal dose with no plan for a formal 
statistical hypothesis testing.  GEE analysis is  
not considered integral to evaluate the study 
efficacy objectives 
Excluded ‘30 day Post-EOT’ visit from the 
evaluation of ‘worst’ value at post-baseline 
Safety measures are focused on assessments 
performed while on study treatment or within 
30 days after treatment ended. 
Exclusion of the Interim Analysis  
The implementation of the BPP futility rule in 
PAC203, based on spleen volume reduction 
(SVR), was flawed as assumptions for SVR 
were based on response rates observed in the 
completed Phase 3 studies.  This 
misrepresents the population under study in 
PAC203.  For instance, some patients in the 
PERSIST-2 population had prior JAK 
inhibitor exposure, however all patients 
enrolled in the PAC203 study must have prior 
JAK inhibitor exposure.  
 


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Following mid-year 2018 meetings with the 
FDA and EMA, and in consultation with the 
IDMC, the interim efficacy analysis based on 
a BPP futility rule of SVR was removed so 
that the study objective of identifying an 
optimal dose is informed by efficacy, safety, 
pharmacokinetic and pharmacodynamic data 
from a fully enrolled study. 
Expanded the analysis windows of the SPV, 
TSS and PGIC 
To minimize missing data while keeping 
clinical relevance. 
Expanded the windows of the labs and vital 
signs information 
A modification to the ‘EOT’ and ’30 day-post 
EOT’ analysis windows was made to align the 
safety assessments with the visit schedule as 
specified in the protocol calendar of 
assessments. 
Added ECG categories and plots 
Following the E14 clinical evaluation of 
QT/QTc interval prolongation and 
proarrhythmic safety guidelines  
Added information to the prior and 
concomitant medication definitions section 
Added the definitions for prior and 
concomitant medications and specified reports 
by myelofibrosis indication  
Added ECOG definition and reports 
Added information on the EGOC scale and 
the definition for each category. In addition 
added the summary reports. 
Added PGIC and spleen variables definitions  
These efficacy variables were not defined 
previously in the document however analyses 
of this information was specified in the 
protocol. 
Subgroups of Efficacy  
Clarification of clinically meaningful groups 
Added information on imputation of the 
concomitant medications and transfusions 
Added instruction for handling missing dates 
for prior and concomitant medications as well 
as for transfusions. 


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1. SCOPE 
This document describes the statistical analyses and data presentations to be performed for protocol 
PAC203, “An Open-Label, Randomized, Phase 2 Dose-Finding Study of Pacritinib in Patients with 
Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia 
Myelofibrosis Previously Treated with Ruxolitinib”. 
This statistical analysis plan (SAP) provides a detailed description of the strategy, rationale, and 
statistical techniques to be used to determine the most appropriate dosage of pacritinib for future 
studies. It provides additional details concerning the statistical analyses that were mentioned in the 
protocol. If additional analyses are required to supplement the planned analyses described in this 
SAP, they will be identified as post hoc in the clinical study report.  
2. STUDY OBJECTIVES AND HYPOTHESES 
2.1 
STUDY OBJECTIVES 
2.1.1 Primary Objective 
The primary objective is to determine a recommended dosage of pacritinib for further clinical 
studies.  
2.1.2 Secondary Objectives 
The secondary objectives are as follows:  
 
1. To examine the dose-response relationship for efficacy, as measured by spleen volume 
reduction (SVR) using MRI or CT and total symptom score (TSS) using the 
Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score version 2.0 
(MPN-SAF TSS 2.0; protocol Appendix 3) 
2. To examine the dose-response relationship for safety with a focus on AEs of interest 
3. To further characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of pacritinib 
4. To evaluate the long term efficacy and safety of pacritinib treatment 
 


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1.1 
Hypotheses 
As this study is designed to explore the dose-response relationship for pacritinib among primary and 
secondary myelofibrosis (MF) patients and to determine a recommended dosage for further clinical 
studies, there is no formal statistical hypothesis to be tested. 
3. SUMMARY OF STUDY DESIGN 
This is a dose-finding study in patients with myelofibrosis who were previously treated with 
ruxolitinib, are highly symptomatic (DIPSS risk score of Intermediate-1 to High Risk), and have 
splenomegaly (assessed by physical examination). The study is designed to support a pacritinib 
dosage selection decision, the process of which will be based on pre-specified efficacy and safety 
parameters and assessed by an independent data monitoring committee (IDMC).  
Spleen volume will be measured by MRI or CT at baseline and Weeks 12 and 24. Safety will be 
monitored with physical examinations, clinical laboratory assessments (including hematologic, 
chemistry, and coagulation testing), and cardiac monitoring (including ECG and echocardiogram 
testing); specified study treatment dosage modifications will be followed to address identified 
abnormalities.  Adverse event data will be collected throughout the study. 
Three dosages will be evaluated; pacritinib 100 mg QD, pacritinib 100 mg BID, and pacritinib 200 
mg BID.  During the study, the interim data will be reviewed by the IDMC for the determination of 
dropping treatment arm(s), which will be guided by  
 The results of interim analyses evaluating the Bayesian predictive probability (BPP) of 
clinically meaningful SVR (details in section 7.4), 
 Safety reviews, with occurrence of 2 treatment-emergent CTCAE grade ≥4 cardiac AEs or 2 
treatment emergent CTCAE grade ≥4 hemorrhage AEs in any arm being of particular 
concern, and 
 Other efficacy and safety measures. 
Assigned treatment will continue for 24 weeks unless the patient experiences progressive disease, 
intolerable AEs, or withdraws consent, or until the assigned treatment arm is closed. Once an arm is 
closed, patients in that arm will discontinue the study. No study treatment crossover will be allowed. 
The maximum duration of trial participation for an individual patient will be approximately 3 years. 
4. RANDOMIZATION AND BLINDING 
Initially, eligible patients will be centrally randomized in a 1:1:1 allocation ratio to pacritinib 100 mg 
QD, pacritinib 100 mg BID, or pacritinib 200 mg BID using a central interactive web response 
system (IWRS). If interim analysis indicates that any one of the treatment arm meets the stopping 


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criteria (protocol Sections 11.8 and 11.9) for efficacy or safety and is thus dropped, then the 
randomization will be updated to a 1:1 ratio of the two remaining study arms. In the case of two 
arms being dropped by interim efficacy or safety monitoring, all eligible patients will be enrolled to 
the remaining one active arm until up to 30 evaluable subjects are enrolled in that arm. The dropping 
of a treatment arm is effected in the IWRS by disabling randomization to the relevant treatment arm. 
Thus, the treatment arm being dropped will not be available as an option for treatment assignment at 
randomization. 
The randomization will be stratified by geographic region (North America vs. Europe vs. rest of the 
world (RoW)) and baseline platelet count (≤50,000/µL vs. >50,000/µL to ≤100,000/µL vs. 
>100,000/µL). Permuted blocks of size 3 will be used within each stratum to balance the treatment 
allocation. The treatment codes and descriptions for the treatment arms are: 
 1: PAC 100 mg QD (100 mg of pacritinib once daily) 
 
 
 
 
 
 2: PAC 100 mg BID (100 mg of pacritinib twice daily), and 
 
 
 
 
 3: PAC 200 mg BID (200 mg of pacritinib twice daily). 
This study is an open-label study. A patient’s treatment assignment will be known to all except the 
independent radiographic and cardiology assessors who will remain blinded to patient treatment 
assignment throughout the study. 
5. ANALYSIS POPULATIONS AND APPROACHES TO ANALYSIS 
5.1 
FULL ANALYSIS SET 
The full analysis set (FAS) is defined as all randomized patients who received at least one dose of 
study treatment. Patients in this population will be analyzed according to the treatment arm to which 
they were assigned at randomization. The FAS will serve as the population for the analyses of 
efficacy, in keeping with the intent-to-treat (ITT) principle. Analyses of efficacy will provide an 
indication of potential benefit in the exploration to determine the recommended dose of pacritinib for 
further clinical studies. 
5.2 
SAFETY POPULATION 
The safety population is defined as all randomized patients who received at least one dose of study 
treatment.   
All safety analyses will be performed using the safety population, and patients in this population will 
be analyzed according to the treatment actually received. Treatment actually received will be 


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determined by the treatment initially taken. Safety analyses will provide an indication of potential 
risk in the exploration to determine the recommended dose of pacritinib for further clinical studies. 
6. GENERAL STATISTICAL CONSIDERATIONS 
6.1 
DATA ANALYSIS CONVENTIONS 
All data analysis will be performed by CTI or designee after the study is completed and the database 
has been locked and released.  Statistical programming and analyses will be performed using SAS® 
version 9.4.  Outputs will be provided in both RTF and PDF for tables, listings and figures using 
landscape orientation.  Applicable study data will be listed at minimum by subject, treatment arm, 
and visit (as applicable) based on the analysis population as specified in this plan.   
Summaries for continuous and ordinal variables will include the number of observations (n), 
arithmetic mean, standard deviation (SD), minimum, first quartile (Q1), median, third quartile (Q3), 
and maximum. Summaries of discrete variables will include frequency counts and percentages.  
6.2 
MULTIPLICITY 
No formal statistical hypothesis testing will be performed, thus no multiplicity adjustment is needed. 
7. DISPOSITION AND ENROLLMENT 
Patient disposition will be presented as number and percentages of patients who were screened, 
randomized, completed the study, and discontinued the study.  A completed patient will be one who 
has not been discontinued or withdrew consent from the study.  Disposition will be summarized by 
treatment arm and for all study patients. 
The number and percentage of patients prematurely discontinued from the study and the reasons for 
study discontinuation will be summarized for all randomized patients.  The reasons for study 
termination include: withdrawal by patient, lost to follow-up, death, study termination by sponsor, 
physician decision and other reasons.  In addition, the number of patients who discontinued 
treatment as well as the reasons for treatment discontinuation (adverse event, death, lost to follow-
up, physician decision, study terminated by Sponsor, withdrawal by patient and other reasons) will 
be presented by treatment arm. 
Study enrollment by country and region will be presented by treatment arm. 


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8. DEMOGRAPHICS, BASELINE CHARACTERISTICS, AND MEDICAL HISTORY 
The demographic and baseline characteristics will be analyzed with the following variables in all 
randomized patients. 
8.1 
   DEMOGRAPHIC VARIABLES 
Age, age category (< 65 years vs. ≥ 65 years), gender (female vs. male), race (American Indian or 
Alaska Native vs. Asian vs. Black or African American vs. Native Hawaiian or Other Pacific 
Islander vs. White vs. Other vs. Multiple), ethnicity (Hispanic or Latino vs. Non-Hispanic or Latino), 
height, weight, body mass index, and ECOG performance status (0 vs. 1 vs. 2),. 
8.2 
  BASELINE DISEASE CHARACTERISTIC VARIABLES 
Spleen length by physical exam, baseline platelet count and category (≤ 50,000/µL vs. > 50,000/µL 
to ≤100,000/µL vs. >100,000/µL), baseline hemoglobin and category (< 100 g/L vs. ≥ 100 g/L), 
peripheral blasts percentage and category (< 1% vs. ≥ 1%), white blood cell count and category (≤ 
25x109/L vs. > 25x109/L), current MF diagnosis (PMF vs. PPV MF vs. PET MF), time since current 
MF diagnosis, gene mutation status (JAK2V617F vs. other JAK2 vs. MPL vs. CALR vs. Triple 
Negative vs. Other vs. None), abnormal cytogenetics (Yes vs. No), unfavorable karyotype (Yes vs. 
No), current DIPSS score (1 vs. 2 vs. 3 vs. 4 vs. 5 vs. 6), DIPSS plus score (1 vs. 2 vs. 3 vs. 4 vs. 5 
vs. 6), transfusion history (within 90 days prior to (Informed Consent date through the treatment start 
date + 1)), red blood cell (RBC) transfusion dependence as defined by the Gale criteria (Gale et al. 
2011; Table 1), and platelet transfusion dependence (Table 2). 
Table 1 – Definitions of Red Blood Cell Transfusion Dependence and Independence 
 
RBC Transfusions 
RBC transfusion dependence 
> 2 units/month 
RBC transfusion independence 
None 
Reduced RBC transfusion dependence 
50% decrease 
Gale et al. 2011 
 
Table 2 – Definitions of Platelet Transfusion Dependence and Independence 
 
Platelet Transfusions 
Platelet transfusion dependence 
Any episode of platelet transfusion during the past 
month 
Platelet transfusion independence 
No platelet transfusion during the past month 


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8.3 
PRIOR THERAPY AND CONCOMITANT MEDICATIONS 
Prior therapy is any therapy or medication taken prior to informed consent. Prior therapy includes 
both prior MF and non-MF therapies. Both will be summarized for all enrolled patients by treatment 
and overall. 
A medication will be considered a concomitant medication if it was taken by the patient at any time 
on study (on or after the first day of treatment and within 30 days after the last dose of study drug). 
The following will also be considered concomitant medications:  
 Medications missing both start and stop dates. 
 Medications having a start date prior to the last dose of study drug and missing the stop date. 
Concomitant medications will be summarized by ATC class and preferred term in each treatment 
arm. Prior MF and non-MF therapies or medications will be summarized by Anatomic Therapeutic 
Chemical (ATC) class and preferred term using WHO Drug Dictionary version 01, March 2013. 
8.4 
Prior Ruxolitinib Experience 
The experience of patients with prior ruxolitinib therapy will be summarized as well. Descriptive 
statistics for the following characteristics will be presented by treatment arm and overall: prior 
ruxolitinib treatment experience, ruxolitinib treatment duration, time since last ruxolitinib treatment, 
most recent ruxolitinib total daily dose and dose category (< 10 mg/day vs. ≥ 10 mg/day), highest 
ruxolitinib total daily dose, the lowest hemoglobin at start of and on ruxolitinib therapy, RBC 
transfusion requirements prior to and at the end of ruxolitinib therapy, the lowest platelet count at 
start of and on ruxolitinib therapy, and adverse events experienced, patients with reduction in spleen 
length and volume, and patients with clinically meaningful reduction in symptoms while on 
ruxolitinib therapy. The reasons for discontinuing ruxolitinib therapy will also be summarized. 
8.5 
Medical History 
Medical history is any disease that occurred prior to informed consent. Medical history will be 
summarized by frequency distribution (n and %) of system organ class and preferred term by 
MedDRA dictionary version 16.0 for all enrolled patients. 
9. EXPOSURE TO STUDY TREATMENT 
Exposure to study treatment will be evaluated by the duration of treatment, cumulative dose, actual 
dose intensity, and relative dose intensity in the safety population.  


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Duration of treatment (weeks): is defined as the duration from first day of study treatment to the last 
day of study treatment, i.e., 
 
Descriptive statistics will be provided for duration of treatment by treatment arm. 
Cumulative dose (mg): is defined as the sum of all doses of study treatment taken and descriptive 
statistics will be provided by treatment arm. The counts and percentages of patients with any dose 
modifications will be provided by treatment arm. Reasons for dose modifications will also be 
summarized. 
Actual dose intensity (ADI, mg/day) = (total dose taken in mg) ÷ (duration of treatment in days) and 
descriptive statistics will be provided by treatment arm. 
Relative dose intensity (RDI, %) = (ADI) ÷ (planned daily dose) * 100.  The planned pacritinib dose 
is 100, 200, and 400 mg/day in the pacritinib 100 mg QD, 100 mg BID, and 200 mg BID arms, 
respectively. Descriptive statistics will be provided by treatment arm. 
Study drug modification categories will be defined for drug holds and drug reduction.  Drug holds 
will be identified by those records with dose entered as 0mg.  Drug reduced will be identified by 
evaluating the subject’s initial dose and determining if a reduction occurred at any time during the 
treatment period.   
Finally, reasons for drug modifications will be presented by treatment arm. 
10. 
EFFICACY VARIABLES  
The primary efficacy variable for dosage selection is the percent reduction in spleen volume from 
baseline as measured by MRI or CT at Weeks 12 and 24.  
Other supportive measures for evaluation as part of the dose-response relationship include  
 the percentage of patients who achieve at least 35% reduction in spleen volume 
 % TSS reduction from baseline, and  
 the percentage of patients with at least 50% reduction in TSS.  
 
The planned analyses for the efficacy endpoints of the study are detailed in the subsections below 
and will be performed in the full analysis set. 


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10.1 
Spleen volume (SPV) 
Spleen volume will be measured by MRI (preferred) at baseline and Weeks 12 and 24 or end of 
treatment visit if imaging did not occur at the end of Week 24.  Unscheduled imaging assessments 
may be performed at physician discretion if he/she considers disease-related symptoms to be 
worsening.  Patients who cannot undergo MRI, or for whom MRI is not available will assess spleen 
volume by CT scan.  However, for each patient, the same imagining modality will be used 
throughout the study.  An independent radiologist, blinded to all patient and site identifiers as well as 
treatment assignments, will measure spleen volume.  While images generated as part of unscheduled 
visits may be read locally if treatment discontinuation is being considered, only the scheduled 
centrally read images will be used for the efficacy analysis. 
The percent reduction and the proportion of subjects with a ≥ 35% spleen volume reduction will 
be computed as follows: 
SPV % Reduction  = 
 
Proportion of subject with SPV reduction ≥ 35% = 
 
10.2 
Total Symptom Score (TSS)  
 The MPN-SAF TSS 2.0 is an instrument measuring disease impact among patients with 
Myelofibrosis (MF).  Supportive measures of efficacy are the percent change from baseline in TSS 
as measured by the MPN-SAF TSS 2.0 and the proportion of patients with TSS reduction ≥50% at 
Weeks 12 and 24. Patients will begin reporting symptoms via electronic dairy at least 7 days before 
starting pacritinib treatment and will continue until the Week 48 visit. After Week 48, patients will 
complete a 7-day recall version of the symptom assessment at each study visit. 
TSS Algorithm 
 The daily TSS is the sum of the scores for the following symptoms: tiredness, early satiety, 
abdominal discomfort, night sweats, pruritus, bone pain, and pain under ribs on the left side 
(excludes the inactivity score). 
 The baseline TSS is the mean of the daily TSS over the 7 consecutive days prior to the start 
of treatment. Missing values during these days are handled as described below (section 
7.2.2). 
 Week 24 TSS is the mean of the daily TSS obtained during the 28 consecutive days prior to 
the post-baseline spleen volume scan date (i.e. Week 12 or 24 visit date if scan date is 


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missing).  A similar approach will be performed when defining the TSS values for Weeks 12, 
36 and 48. 
 The percent reduction in TSS from baseline to the Week 12 or 24 visit is computed by:  
TSS % Reduction = 
. 
Handling of Missing TSS Values 
 If any of the seven individual symptoms scores are missing, the TSS for that day will be 
considered as missing. 
 The baseline TSS is set to missing if fewer than 4 daily TSS are available out of the 7 
consecutive days prior to the start of study treatment. 
 The Week 24 TSS is set to missing if fewer than 20 daily TSS are available out of the 28 
consecutive days prior to Week 24 spleen volume scan date (or Week 24 visit date if scan 
date is missing). In sensitivity analyses where Week 24 TSS is derived from the mean of 7 
consecutive days of daily TSS, the Week 24 TSS is set to missing if fewer than 4 daily TSS 
are available out of the 7 consecutive days prior to Week 24 spleen volume scan date (or 
Week 24 visit date if scan date is missing). Missing TSS at other post-baseline time-points is 
similarly handled.  A similar approach will be performed when defining the TSS values for 
Weeks 12, 36 and 48. 
10.3 
Patient Global Impression Assessment 
The self-reported measure Patient Global Impression of Change (PGIC) is a 7 point scale depicting a 
patient’s rating of overall improvement. Patients rate their change as ‘very much improved’, ‘much 
improved’, ‘minimally improved’, ‘no change’, ‘minimally worse’ or ‘very much worse’.  PGIC will 
be collected at the end of Week 12, the end of Week 24 or the end of treatment visit and every 3 
months up to 2.5 years. 
10.4 
Spleen Length Reduction 
Spleen size, assessed by physical examination as the distance below the lower costal margin at the 
midclavicular line, will be evaluated at study visits Week4, Week 12, Week 24 and every 3 months 
thereafter up to 2.5 years.  The percent change from baseline and the proportion of patients with 
>50% spleen length (SPL) reduction at 12 and 24 weeks will be computed as follows: 


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SPL % Reduction  = 
 
Proportion of subject with SPL reduction ≥ 50% = 
 
 
10.5 
Transfusions 
10.6.1 Frequency of Red Blood Cell (RBC) Transfusions 
The frequency of RBC transfusions at baseline is defined as the number of units of RBC transfusions 
per month prior to and including the date of the start of treatment. Since this data comes from two 
different sources, the baseline RBC transfusion frequency is computed as the sum of the number of 
units of RBC transfusions in the 90 days prior to the informed consent date and the number of units 
of RBC transfusions after the informed consent date through to the start of treatment date, divided by 
the number of days from informed consent to the start of treatment plus 90 days, multiplied by a 
conversion factor of 30 days/month. That is, 
 
 
At post-baseline timepoints, the frequency of RBC transfusions is defined as the number of units of 
RBC transfusions per month in the three months (approximately 84 – 90 days) preceding the visit 
date. That is,  
 
 
10.6.2 Frequency of Platelet Transfusions 
The frequency of platelet transfusions at baseline is defined as the number of platelet transfusions 
per month prior to and including the date of the start of treatment. Since this data comes from two 
different sources, the baseline platelet transfusion frequency is computed as the sum of the number 
of transfusions in the 90 days prior to the informed consent date and the number of transfusions after 
the informed consent date through to the start of treatment date, divided by the number of days from 
informed consent to the start of treatment plus 90 days, multiplied by a conversion factor of 30 
days/month. That is,  


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At post-baseline timepoints, frequency of platelet transfusions is defined as the number of platelet 
transfusions in the month (30 days) preceding the visit date. 
 
10.7 ECOG Performance Status 
The ECOG (developed by the Eastern Cooperative Oncology Group) is scale which describes a 
patient’s level of functioning in terms of their ability to care for themselves, daily activity, and 
physical ability (walking, working, etc.).  It is a scale from 0 to 5 defined as: 
GRADE 
ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more 
than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 
11 
SAFETY VARIABLES  
11.1 ADVERSE EVENTS 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment.  All AEs, including serious adverse events (SAEs) will be collected 
during the clinical study from the time the patient signs the informed consent through 30 days 
following the last dose of study treatment.  For screened patients who are not randomized, only 


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SAEs occurring between the time of informed consent and determination of screen failure are to be 
reported.  
A TEAE is defined as an adverse event (AE) occurring after the first dose of study treatment and 
within 30 days after the last study treatment date. In addition, an AE with a missing start date but 
with an end date after the first study drug dose date is also considered a TEAE. An AE occurring 
after the first dose of study drug that also occurred prior to the first dose of study drug is only 
considered a TEAE if the AE worsened in grade after the first dose of study drug. 
Analysis of AEs will be based on Treatment Emergent Adverse Events (TEAEs). 
11.2 SAFETY LABORATORY ASSESSMENTS 
Hematology and coagulation function laboratory measures will be collected via central lab, but in 
addition can be analyzed locally for assessment and management of patients in real time. 
11.2.1 HEMATOLOGY 
Hematology parameters including CBC, differential, platelet count and hemoglobin A1C among 
others will be evaluated at screening, baseline, the end of week 4, the end of Week 12, the end of 
Week 24 or the end of treatment visit, every 3 months during the follow-up period, and 30 days after 
the last dose of study treatment.   
11.2.2 COAGULATION FUNCTION 
Coagulation testing will include PT, INR, PTT and TT at screening, baseline, the end of week 4, the 
end of Week 12, the end of Week 24 or the end of treatment visit, every 3 months during the follow 
up period, and 30 days after the last dose of study treatment.   
11.2.3 CHEMISTRY 
Screening laboratory assessments should be performed at least 1 week after the end of prior therapy.  
Serum chemistry parameters (ALT/SGPT and AST/SGOT, alkaline phosphatase, bilirubin [total, 
direct, and indirect], creatinine, lactate dehydrogenase (LDH), sodium, potassium, chloride, 
bicarbonate, calcium, phosphate, magnesium, blood urea nitrogen (BUN/area), albumin, amylase, 
lipase, glucose, cholesterol, uric acid, and high specificity CRP) will be evaluated by a central 
laboratory at screening, at baseline and whenever is clinically indicated. 
The derived visit window definitions for clinical hematology, chemistry, and coagulation function 
are displayed in Table 5. 


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Table 5. Analysis Window Definitions for Clinical Hematology and Coagulation 
Function Results 
Visit 
Nominal Day 
Range 
Baseline 
1 (first dose date) 
[-14, 1] 
Week 4 
28 
[2, 55] 
Week 12 
84 
[56, 111] 
Week 24 
168 
[112, 195] 
Week 36 
252 
[196, 279] 
Week 48 
336 
[280, 363] 
⁞ 
⁞ 
⁞ 
Week XX 
XX times 7 
[(Week XX-1 upper range + 1, (XX times 7) + 27] 
EOT 
Last dose date 
[Last dose date, Last dose date + 15] 
30 days post EOT 
Last dose date + 30 days 
[Last dose date + 16, ] 
 
 
11.2.4 ECG ASSESSMENT 
All patients will have a 12-lead ECGs collected in triplicate and centrally read by a blinded 
independent cardiologist and QTc intervals, calculated and corrected using the Fredericia method 
(QTcF), at screening, baseline, the end of Week 4, the end of Week 12, the end of Week 24 or the 
end of treatment visit, and every 3 months while in the follow-up period (pre-dose only for the post 
24-week follow-up visit and 30 days after the last dose of study treatment).  Additional ECGs may 
have been collected in the event patient demonstrated QTc prolongation. 
The three QTcF interval measures will be averaged for a summary measure of QTcF interval. 
11.2.5 CARDIAC EJECTION FRACTION ASSESSMENT 
All patients will have ejection fraction (echocardiogram or MUGA scan) at screening, the end of 
Week 4, the end of Week 12, the end of Week 24 or the end of treatment visit, and every 6 months 
while in the follow-up period, and 30 days after the last dose of study treatment.   
11.2.6 ADDITIONAL SAFETY ASSESSMENTS 
 


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11.2.6.1 
Vital signs including pulse, systolic and diastolic blood pressure, respiratory rate, 
temperature, and body weight. 
 
11.2.6.2 
Physical examination, including clinical signs and symptoms, and spleen 
measurement. 
12 
EFFICACY ENPOINTS AND ANALYSES 
12.1 PRIMARY EFFICACY ENDPOINTS 
12.1 1 
Spleen Volume Reduction  
 
The primary efficacy variable for dosage selection is the percent reduction in spleen volume from 
baseline as measured by MRI or CT at Weeks 12 and 24.. 
Descriptive statistics of spleen volume at baseline, Week 12, Week 24, and at End of Treatment will 
be presented by treatment arm. Spleen volume at End of Treatment is defined as the spleen volume 
collected at the end of treatment visit or the last spleen volume measured on treatment if not 
measured at end of treatment. Descriptive statistics of percent reduction in spleen volume at Weeks 
12 and 24 and at End of Treatment will be presented by treatment arm. These descriptive statistics 
include counts, mean, standard deviation, standard error of the mean, median, 25th percentile, 75th 
percentile, minimum, and maximum. As a supportive measure of efficacy, the counts and 
proportions of patients with spleen volume reduction (SVR) ≥35% at Weeks 12 and 24 and at End of 
Treatment will be presented by treatment arm. The exact (Clopper-Pearson) 95% confidence 
intervals (CIs) for the proportions will also be presented. Additional supportive analyses include 
imputing missing Week 24 spleen volume with the previous post-baseline (Week 12) spleen volume, 
if any, and repeating the above analyses. These analyses will be repeated for spleen volume 
measured after Week 24 in long term follow up. 
 
12.1 2 
Total Symptom Score (TSS) Analysis 
Descriptive statistics of individual symptoms and TSS at baseline, every 12 weeks, and at End of 
Treatment will be presented by treatment arm. Descriptive statistics of percent reduction in TSS 
every 12 weeks and at End of Treatment will be presented by treatment arm. The counts and 
proportions (including Clopper-Pearson 95% CIs) of patients with TSS reduction ≥50% every 12 
weeks and at End of Treatment will be presented by treatment arm. Supportive analyses include 
imputing missing Week 24 TSS with the previous post-baseline (Week 12) TSS, if any, and 
repeating the above analyses at Week 24.  


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As an anchor for patient-reported symptom assessment, the patient global impression assessment 
(PGIA) will also be summarized and evaluated for correlation with TSS. There is 1 domain in the 
PGIA instrument with possible scores ranging from 1 (very much improved) to 7 (very much worse).  
12.1 3 
Patient Global Impression Assessment 
The scores for the PGIA will be summarized by treatment arm at each visit at which the patients are 
scheduled to complete the instrument using descriptive statistics. Additionally, the correlation 
between PGIA and TSS and the change in PGIA and change in TSS at each visit assessed will be 
explored. 
12.2 EXPLORATORY EFFICACY ANALYSIS 
12.2 1 
Spleen Length Reduction 
Descriptive statistics of spleen length by physical exam at each visit will be presented by treatment 
arm. Descriptive statistics of percent reduction in spleen length at each post-baseline visit will be 
presented by treatment arm. The counts and proportions (including Clopper-Pearson 95% CIs) of 
patients with spleen length reduction ≥50% at Weeks 12 and 24 will be presented by treatment arm. 
12.2 2 
Transfusions 
The change in the frequency of transfusions will be summarized by treatment arm over time using 
descriptive statistics in patients receiving at least one transfusion at baseline or while on study 
treatment. This summary is dependent on the number of patients who received at least one 
transfusion at baseline or while on study treatment. 
12.2 3 
ECOG Performance Status 
The scores for the ECOG performance status will be summarized by treatment arm at each visit 
using descriptive statistics such as counts and percent.  In addition, the shift from baseline to worst 
ECOG performance status at post-baseline visits will be presented by treatment arm. 
12.1 
Subgroup Analyses of Efficacy 
If there are enough patients per group, subgroup analyses may be evaluated for any potential impact 
of demographics or baseline disease characteristics on the efficacy endpoints. Subgroups may 
include, but are not limited to, baseline hemoglobin (< 100 g/L vs. ≥ 100 g/L), and baseline platelet 
count (≤ 50,000/µL vs. > 50,000/µL). 


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13 SAFETY ANALYSES 
Safety analyses include summaries and graphical presentations of treatment emergent adverse 
events, clinical labs, ECG, vital signs, performance status, and any abnormal findings observed 
during the performance of physical examinations by treatment received after randomization through 
the end of assigned study treatment + 30 days. 
The primary safety measure for dosage selection is the percentage of patients with CTCAE grade 3/4 
cardiac treatment-emergent AEs, CTCAE grade 3/4, hemorrhage treatment-emergent AEs, CTCAE 
grade ≥4 thrombocytopenia toxicity, or CTCAE grade ≥4 anemia toxicity. Cardiac and hemorrhage 
treatment-emergent AEs will be determined using Standardized MedDRA Query (SMQ). See section 
9.1 for more details. Thrombocytopenia and anemia will be determined by central laboratory 
measurement. 
All other safety data including TEAEs, death, and clinical laboratory measures will be used as 
supportive measures for evaluation of pacritinib dose-safety relationship. 
13.1 
ADVERSE EVENTS 
Treatment-emergent AEs (TEAEs) will be summarized by presenting, for each treatment arm, the 
count and percentage of patients having any TEAE, having a TEAE in each body system, and having 
an individual event according to version 16.0 of the MedDRA dictionary. CTCAE (version 4.03) 
grades and relationship to study medication will be summarized as appropriate. For summaries by 
CTCAE grade or relatedness, only the highest CTCAE grade or degree of relatedness of each SOC 
and/or preferred term will be summarized. A patient having the same event more than once will be 
counted only once and by greatest severity or closest relationship. 
In addition, serious TEAEs (SAEs), CTCAE grade 3 or 4 TEAEs, TEAEs leading to study 
medication discontinuation, interruption, or dose reduction, TEAEs with an outcome of death, and 
related TEAEs will be summarized. A listing of all SAEs will be generated. The preferred term of 
TEAEs of all grades, as well as for TEAEs of grade 3 or 4 will also be presented for each treatment 
arm by decreasing frequency in the PAC 200 mg BID arm. 
Cardiac, hemorrhage, skin neoplasms, and hypersensitivity TEAEs as defined by Standardised 
MedDRA Queries (SMQs) will also be summarized by SOC and preferred term. Cardiac TEAEs are 
all the preferred terms in the SMQs of Cardiac Arrhythmias, Cardiac Failure, Ischaemic Heart 
Disease, and Embolic and Thrombotic Events. Hemorrhage TEAEs are all preferred terms in the 
SMQ of Haemorrhages. Skin neoplasm TEAEs are all preferred terms in the SMQ of Skin 
Neoplasms (malignant and unspecified). Hypersensitivity TEAEs are all preferred terms in the SMQ 


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of Hypersensitivity. A listing of time to onset and resolution of these TEAEs will also be presented 
by treatment arm. These will also be presented graphically. 
The counts and percentages for the causes of all deaths will be presented by treatment arm. A listing 
of all deaths, both on and off treatment, will also be generated. On treatment deaths are defined as 
deaths that occur on treatment and within 30 days of treatment discontinuation. 
13.2 
CLINICAL LABORATORY MEASUREMENTS  
The counts and percentages of the shifts in CTCAE grade from baseline to the worst and last post-
baseline grade (not including the 30 post treatment end visit in the evaluation of worst grade at post-
baseline) will be presented for each laboratory measure. Descriptive statistics of change and percent 
change from baseline in laboratory values will be presented by visit. Plots of the  shift from baseline 
to worst post-baseline in selected parameters by treatment arm will be presented. In the case of 
hemoglobin, a parameter that is hugely affected by transfusions, the percent change over time will be 
explored in patients who did not have a transfusion in the 90 days prior to informed consent or on 
study. 
Laboratory results (including serum pregnancy) will be provided in a subject list and include at 
minimum subject id, age, treatment arm, visit, assessment date, laboratory category, laboratory 
parameter, results and lab units. 
 
13.3 
OTHER CLINICAL SAFETY 
13.3.1 ELECTROCARDIOGRAM (ECG) 
The frequency distribution of abnormal QTcF interval measurements on study (after the first study 
drug treatment through the last dose of study drug) will also be summarized. That is, the proportion 
of subjects with the following QTcF intervals will tabulated by timepoint at each visit (including 
worst and last on treatment values) and treatment arm: 
• 
A measured value > 450 ms 
• 
A measured value > 480 ms 
• 
A measured value > 500 ms 
• 
0 - <= 10 ms above baseline  
• 
10 - 20 ms above baseline 


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• 
>= 20 ms above baseline 
• 
30 ms above baseline 
• 
> 60 ms above baseline 
Plots of the shift in QTcF from baseline to highest on treatment will also be presented for each 
treatment group. 
Finally, a plot of the mean change of the QTcF over time will be presented by treatment arm. 
13.3.2  ECHOCARDIOGRAM OR MULTIPLE-GATED ACQUISITION SCAN 
Change in the left ventricular ejection fraction (LVEF) assessed on study (after the first study drug 
treatment through the last dose of study drug) will be summarized. Descriptive statistics of change 
from baseline in LVEF will be presented by treatment arm at each visit, the last post-baseline 
assessment, and the worst post-baseline assessment (not including the 30-day post treatment end 
visit in the evaluation of worst grade at post-baseline).  At these visits and by treatment arm, the 
count and percentage of patients with LVEF values ≤50% will also be presented overall and in 
categories of 50% to 40%, 39% to 20%, and < 20%.  Similarly, the count and percentage of patients 
with decreases in LVEF of ≥10% or more will be presented overall and in categories of 10% to 19% 
and ≥ 20%.  
13.3.3 VITAL SIGN MEASUREMENTS 
Descriptive statistics (mean, median, standard deviation, minimum, and maximum) of the actual 
values and the change from baseline in vital sign measurements, including weight, will be presented 
by visit.  
A table summarizing clinically notable blood pressure and weight measurements which are aligned 
with CTCAE cut-offs, where available, will be displayed.  The proportion of subjects whose worst 
observed values while on study treatment (on or after the first day of treatment) meet the following 
clinically notable criteria will be tabulated by treatment arm: 
 Systolic Blood Pressure 
o < 85 mm Hg 
o ≥ 140 - < 160 mm Hg 
o ≥ 160 mm Hg 


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 Diastolic Blood Pressure 
o < 50 mm Hg 
o ≥ 90 - < 100 mm Hg 
o ≥ 100 mm Hg 
 Weight gain from baseline 
o ≥ 5% - < 10% increase 
o ≥ 10% - < 20% increase 
o ≥ 20% increase 
 Weight loss from baseline 
o ≥ 5% - < 10% decrease 
o ≥ 10% - < 20% decrease 
o ≥ 20% decrease 
The derived visit window definitions for vital signs are displayed in Table 6. 
 
 
Table 6. Analysis Window Definitions for Vital Signs Results 
Visit 
Nominal Day 
Range 
Baseline 
1 (first dose date) 
[-14, 1] 
Week 4 
28 
[2, 55] 
Week 12 
84 
[56, 111] 
Week 24 
168 
[112, 195] 
Week 36 
252 
[196, 279] 
Week 48 
336 
[280, 363] 
⁞ 
⁞ 
⁞ 
Week XX 
XX times 7 
[(Week XX-1 upper range + 1, (XX times 7) + 
27] 
EOT 
Last dose date 
[Last dose date, Last dose date + 15] 
30 days post EOT 
Last dose date + 30 days 
[Last dose date + 16, ] 


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13.3.4 PHYSICAL EXAMINATIONS 
Physical examination information will be provided in a subject listing and include at minimum: 
subject id, treatment arm, visit, assessment date, physical examination, results and clinical findings 
(if applicable). 
13.3.5 SUPPLEMENTAL PROCEDURES 
Procedures received from the first day of treatment to the last day of treatment will be summarized 
by SOC class and preferred term. 
13.3.6 PROGRESSIVE DISEASE  
Progressive disease information will be presented in a subject listing and include at minimum: 
subject id, age, treatment arm, assessment date, splenic progression status, progression date, form of 
splenic progression (increase in splenic volume of >=25% from baseline, splenectomy or other 
splenic surgery, splenic irradiation), leukemic transformation status, transformation date, form of 
leukemic transformation (peripheral blood blast >=20% sustained for 8 weeks, bone marrow blast 
>=20%) and treatment end date.  
13.3.7 SUBGROUP ANALYSIS OF SAFETY 
If there are enough patients per group, treatment-emergent adverse events, including all AEs, grade 
3/4 AEs, and SAEs, and hematology toxicity may also be summarized by subgroups as appropriate. 
Subgroups may include, but are not limited to, baseline platelet count (≤ 50,000/µL vs. > 50,000/µL) 
and baseline hemoglobin (< 100 g/L vs. ≥ 100 g/L). 
14 GENETIC BACKGROUND 
 Details of the genetic background analysis can be found in the DNA analysis plan. 
 
15 PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Details of the PK/PD analysis can be found in the PK/PD analysis plan.  
16 DETERMINATION OF SAMPLE SIZE 
The determination of sample size for this dosage finding study was driven by a targeted predictive 
probability (see Table 3) and to ensure adequate precision to evaluate efficacy using percent 
reduction of spleen volume from baseline. Based on past clinical experience (e.g., ≤10% SVR 


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deemed as the minimally, clinically meaningful reduction), variance in percent reduction in spleen 
volume (standard deviation ≈ 20%) from PERSIST-1 and PERSIST-2 studies, and the need for 
exploratory modeling analysis of pacritinib dose-response and dose-exposure-response relationship, 
a maximum of 30 evaluable patients per treatment arm are adequate to evaluate efficacy. 
As for safety, with a sample size of 30 patients per arm, if the true incidence rate for a specified 
safety event is 5% among patients per each arm, then the chance of observing at least 1 event among 
30 patients will be 78%. At the end of the study, if none of the 30 patients in each treatment arm 
experience an AE, then the true incidence rate of the AE is no greater than 5.2% with 80% 
confidence and no greater than 7.4% with 90% confidence. 
A 15% overage will be built into the study sample size to account for potential drop-outs, thus a 
maximum of 35 patients are planned for enrollment per treatment arm. 
17 DATA HANDLING RULES 
17.1 
Definition of Baseline Value 
The baseline value for safety analyses will be defined as the last assessment prior to the start of 
treatment, unless otherwise specified. 
17.2 
Partial Current MF Diagnosis Date 
For patients who have a partial diagnosis date, the 15th of the month will be used if day is missing, 
and July 15th will be used if both the month and day are missing. 
17.3 
Partial or Missing AE Onset and Resolution Dates 
For AE summaries, the missing day of onset of an adverse event will conservatively be set to: 
 First day of the month that the AE occurred if this is after the date of the start of first 
treatment. 
 One day after the first treatment if this is the same month that the AE occurred. 
 The 15th of the month and year if the AE month and year are before the month and year of 
the first treatment. 
If the onset date of an adverse event is missing both day and month, it will be set to: 
 January 1 of the year of onset, as long as this is after the first study treatment. 
 One day after the first study treatment if this is the same year that the AE occurred. 
 July 1st of the year if the AE year is before the year of the first study treatment. 
If the day of resolution of an adverse event is missing, it will conservatively be set to the last day of 
the month or 30 days after the last dose of study treatment if this day is in the same month and year, 


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whichever is earlier. If the day of resolution of an adverse event is missing both day and month, it 
will conservatively be set to the last day of the year or 30 days after the last dose of study treatment 
if this day is in the same year, whichever is earlier. 
All missing and partial dates will be presented “as is” in listings. 
 
17.4 
Partial or Missing Transfusion Dates 
For transfusion summaries, the missing day of transfusion start date will conservatively be set to: 
 First day of the month that the transfusion occurred if this is after the date of the start of first 
treatment. 
 One day after the first treatment if this is the same month that the transfusion occurred. 
 The 15th of the month and year if the transfusion month and year are before the month and 
year of the first treatment. 
If the onset date of the transfusion is missing both day and month, it will be set to: 
 January 1 of the year of onset, as long as this is after the first study treatment. 
 One day after the first study treatment if this is the same year that the transfusion occurred. 
 July 1st of the year if the transfusion year is before the year of the first study treatment. 
If the day of resolution of transfusion is missing, it will conservatively be set to the last day of the 
month or 30 days after the last dose of study treatment if this day is in the same month and year, 
whichever is earlier. If the day of resolution of transfusion is missing both day and month, it will 
conservatively be set to the last day of the year or 30 days after the last dose of study treatment if 
this day is in the same year, whichever is earlier. 
All missing and partial dates will be presented “as is” in listings. 
 
17.5 
Partial or Missing Concomitant Medication and Supplemental Procedure Dates 
For concomitant medication, when missing the start date information the following imputation will 
be applied: 
Derive data only with the missing day of the month: 
 First day of the month that the CM occurred if this is after the date of the start of first 
treatment. 
 One day after the first treatment if this is the same month that the CM occurred. 
 The 15th of the month and year if the CM month and year are before the month and year of 
the first treatment. 
Derive data if both day and month are missing: 


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 January 1 of the year of onset, as long as this is after the first study treatment. 
 One day after the first study treatment if this is the same year that the AE occurred. 
 July 15th of the year if the CM year is before the year of the first study treatment. 
 
When missing the end date information the following imputation will be applied: 
Derive data only with the missing day of the month: 
 Set as the last day of the month 
Derive data with both missing day and month: 
 set as December 31th 
 
All missing and partial dates will be presented “as is” in listings 
 
 
12.1 
Analysis Windows 
Analysis windows will be defined as follows: 
Endpoint 
Nominal 
Visit 
 
Nominal Study 
Day 
Analysis 
Windows (in 
days) 
Spleen volume (SPV) 
Week 12 
84 
(63 to 105) 
 
Week 24 
168 
(147 to 189) 
 
Week 36 
+3 months 
pos-24 week 
+/- 21 days 
 
… 
 
 
 
 
 
 
Total Symptom Score (TSS) 
Week 12 
84 
(63 to 105) 
 
Week 24 
168 
(147 to 189) 
 
Week 36 
+3 months 
pos-24 week 
+/- 21 days 
 
… 
 
 
 
 
 
 
Patient Global Impression Assessment (PGIC) 
Week 12 
84 
(63 to 105) 
 
Week 24 
168 
(147 to 189) 
 
Week 36 
+3 months 
pos-24 week 
+/- 21 days 
 
… 
 
 
 


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12.2 
Laboratory Results Reported as a Range 
Laboratory results that are reported as less than or greater than a certain value (limit of 
quantification) or as a range of values will be imputed for analysis using the rules described below. 
Myeloblast Percentages 
 Myeloblast results in the hematology data reported as <X% will be imputed with the value 
(X-1)% for analysis. 
 Myeloblast results in the hematology data reported as ≤X% will be imputed with the value 
X% for analysis. 
 Myeloblast results in the hematology data reported as X-Y% will be imputed with the value 
Y% for analysis. 
Other Laboratory Results 
 Laboratory results reported as <X will be imputed with the value (X-1) for analysis. Results 
reported as <X.Y will be imputed by subtracting one from the last significant digit (Y). 
Results reported as <0.1 will be imputed as 0 for analysis as long as the normal range extends 
to 0. 
 Laboratory results reported as >X will be imputed with the value (X+1) for analysis. Results 
reported as >X.Y will be imputed by adding one to the last significant digit (Y). 
13 REFERENCES 
 
1. Dmitrienko A and Wang M. Bayesian predictive approach to interim monitoring in clinical trials. 
Statistics in Medicine 2006;25:2178-95. 
2. Gale RP, Barosi G, Barbui T, et al. What are RBC-transfusion-dependence and -independence? 
Leuk Res. 2011;35:8-11. 
3. Liang K-Y and Zeger SL. Longitudinal data analysis using generalised linear models. Biometrika 
1986;73:13-22. 
4. Vannucchi A, Kantarjian H, Kiladjian, et. al. A pooled analysis of overall survival in 
COMFORT-I and COMFORT-II, 2 randomized phase 3 trials of ruxolitinib for the treatment of 
myelofibrosis. Haematologica 2015;100:1139-1145. 
5. Mesa R, Vannucchi A, Mead A, et. al. Pacritinib versus best available therapy for the treatment 
of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomized, 
phase 3 trial. Lancet 2017; 4(5):e225-e236.