Dose-Finding Study of Pacritinib in Patients With Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis 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). 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. The maximum duration of trial
participation for an individual patient will be approximately 36 months. The Following the
Week 24 assessment, patients who are benefiting from therapy and who have not experienced
progressive disease will be allowed to continue receiving pacritinib at the original
randomized dose or following the dose recommendations of the Independent Data Monitoring
Committee (IDMC), and will be followed for survival, efficacy and safety for up to 2.5 years.

The Sponsor will collect PK samples from all patients in each dosing arm at the end of Week
12 and Week 24 at the following timepoints: 0 hours (predose), 4 hours postdose (±10
minutes), and 8 hours postdose (±15 minutes). In addition, PD samples will be collected on
Day 1 (Baseline), Week 12, and Week 24 at 0 hours (predose). DNA samples will also be
collected for analysis of mutations associated with myelofibrosis at baseline and Week 24.

This study will utilize planned frequent monitoring by an IDMC. The first meeting will occur
once 18 patients have been randomized and will meet approximately quarterly thereafter. To
minimize the patient exposure to minimally effective dosages, an interim analysis of the
primary efficacy and safety data will be performed to allow an earlier decision to
discontinue an arm that is unlikely to achieve at least 10% SVR at Week 24. The interim
analysis will be performed when 6 patients per arm have completed the Week 12 evaluations and
have evaluable spleen volume data by MRI or CT.

IDMC will review efficacy and safety data, including interim analysis, and make
recommendations on:

1. Closing treatment arm(s) and expanding enrollment in remaining treatment arm(s)

2. Pausing enrollment due to cardiac or hemorrhage adverse events

3. Dosage for further clinical studies

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:

1. 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

2. 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%

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. Treatment with anticoagulation or antiplatelet agents, except for aspirin dosages of
≤100 mg per day, within the last 2 weeks

7. Treatment with a strong CYP3A4 inhibitor or a strong cytochrome P450 inducer within
the last 2 weeks

8. Treatment with medications that can prolong the QTc interval within the last 2 weeks

9. Treatment with an experimental therapy within the last 28 days

10. 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)

11. 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.

12. New York Heart Association Class II, III, or IV congestive heart failure

13. 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.

14. 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)

15. Any gastrointestinal or metabolic condition that could interfere with absorption of
oral medication

16. Inflammatory or chronic functional bowel disorder such as Crohn's Disease,
inflammatory bowel disease, chronic diarrhea, or constipation

17. 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

18. 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

19. Known seropositivity for human immunodeficiency virus

20. Known active hepatitis A, B, or C virus infection

21. Women who are pregnant or lactating

22. Concurrent enrollment in another interventional trial