This study (study ID PAC203 North America; PAC303 ex-North America) is evaluating 200 mg BID
of pacritinib compared to physician's choice (P/C) therapy in patients with MF and severe
thrombocytopenia (platelet count <50,000/μL). Approximately 348 patients in total will be
enrolled, randomized 2:1 to either pacritinib (approximately 232 patients) or to P/C therapy
(approximately 116 patients)
Condition or disease: Primary Myelofibrosis/Post-Polycythemia Vera Myelofibrosis/
Post-essential Thrombocythemia Myelofibrosis
Intervention/treatment: Drug-Pacritinib
The study is a randomized, controlled phase 3 study comparing the efficacy of pacritinib with
P/C therapy in patients with PMF, PPV-MF, or PET-MF (Dynamic International Prognostic Scoring
System [DIPSS] risk score of Intermediate-1 to High-Risk), who have had had no or limited
exposure to any JAK2 inhibitor or are JAK2 inhibitor-naive, and who have severe
thrombocytopenia (platelet count <50,000/µL). This study was designed to use the pacritinib
200 mg BID dose, which was determined to be the optimal dose based on dose- and
exposure-response analyses conducted using all available data, including the dosing data from
the previous portion of this study. Patients will be randomized 2:1 to receive pacritinib 200
mg BID or the P/C therapy (limited to single drugs from the following list: corticosteroids,
hydroxyurea, danazol, or low-dose ruxolitinib). The proposed P/C regimen for a patient must
be selected prior to randomization. Randomization will be stratified by prior JAK2 inhibitor
therapy (yes/no) and P/C therapy selected prior to randomization. Prior JAK2 inhibitor
therapy will be defined as any duration of treatment with a JAK2 inhibitor, such as
ruxolitinib, fedratinib, or momelotinib. To be eligible, patients are not allowed to have
been treated with more than one JAK2 inhibitor. Assigned treatment will continue until the
patient experiences progressive disease or intolerable AEs, withdraws consent, or initiates
new MF-directed therapy. No study treatment crossover will be allowed at any time. All
patients should complete all visit procedures through Week 24, including patients who stop
treatment or have protocol-defined progressive disease prior to Week 24, unless the patient
withdraws consent for study procedures, dies, undergoes splenic irradiation or splenectomy,
initiates any non-protocol-directed anti-MF treatment, or the study is terminated. In
addition to the above, patients will be considered to have discontinued treatment if
pacritinib or P/C therapy is held for >28 consecutive days due to treatment toxicity, or if
treatment is discontinued for lack of efficacy, or at the request of the principal
investigator or the patient. Following the Week 24 assessment, patients who are benefiting
from therapy will be allowed to continue receiving the assigned treatment (pacritinib or P/C)
until the patient experiences progressive disease, intolerable AEs, withdraws consent, or
initiates new MF-directed therapy. All randomized patients will be followed for survival for
2.5 years from the date of randomization unless consent for follow-up is withdrawn.
Diagnosis and Inclusion Criteria
1. PMF, PPV-MF, or PET-MF (Tefferi and Vandiman 2008)
2. Average platelet count of <50,000/µL at Screening (Day -35 to Day -3) based on two
measurements taken on different days; both measurements must be <50,000/µL
3. DIPSS Intermediate-1, Intermediate-2, or High risk (Passamonti et al 2010)
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 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. If the patient has received prior JAK2 inhibitor treatment, this treatment must meet
at least one of the following criteria:
1. Prior treatment with any JAK2 inhibitor, irrespective of dose, with a duration of
90 days or less. The 90-day period starts on the date of first administration of
JAK2 inhibitor therapy and continues for 90 calendar days, regardless of whether
therapy is administered continuously or intermittently during that interval.
2. Prior treatment with ruxolitinib, at no more than 10 mg total daily dose on any
day, with a duration of 180 days or less. The 180-day period starts on the date
of first ruxolitinib administration and continues for 180 calendar days,
regardless of whether therapy is administered continuously or intermittently
during that interval.The patient may not have received >10 mg of ruxolitinib on
any day during that interval
7. Age ≥18 years
8. Eastern Cooperative Oncology Group performance status 0 to 2
9. Peripheral blast count of <10% throughout the Screening period and at baseline
10. Absolute neutrophil count of ≥500/µL
11. Left ventricular cardiac ejection fraction of ≥50% by echocardiogram or multigated
acquisition (MUGA) scan
12. 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
13. Adequate coagulation defined by prothrombin time/international normalized ratio and
partial thromboplastin time ≤1.5 × ULN
14. If fertile, willing to use effective birth control methods during the study
15. Willing to undergo and able to tolerate frequent MRI or CT scan assessments during the
study
16. Able to understand and willing to complete symptom assessments using a
patient-reported outcome instrument
17. Provision of signed 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 other approved available therapy including 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 any MF-directed therapy within 14 days prior to treatment Day 1
7. Any prior treatment with more than one JAK2 inhibitor
8. Treatment with an experimental therapy within 28 days prior to treatment Day 1
9. Systemic treatment with a strong CYP3A4 inhibitor or a strong cytochrome P450 (CYP450)
inducer within 14 days prior to treatment Day 1. Shorter washout periods may be
permitted with approval of the Medical Monitor, provided that the washout period is at
least five half-lives of the drug prior to treatment Day 1
10. Significant recent bleeding history defined as National Cancer Institute Common
Terminology Criteria for Adverse Events (CTCAE) grade ≥2 within 3 months prior to
treatment Day 1, unless precipitated by an inciting event (e.g., surgery, trauma, or
injury)
11. Systemic treatment with medications that increase the risk of bleeding, including
anticoagulants, antiplatelet agents (except for aspirin dosages of ≤100 mg per day),
anti-vascular endothelial growth factor (anti-vascular endothelial growth factor
[anti-VEGF]) agents, and daily use of cyclooxygenase-1 (COX-1) inhibiting nonsteroidal
anti- inflammatory drugs (NSAIDs) within 14 days prior to treatment Day 1
12. Systemic treatment with medications that can prolong the QT interval within 14 days
prior to treatment Day 1. Shorter washout periods may be permitted with approval of
the Medical Monitor, provided that the washout period is at least five half-lives of
the drug prior to treatment Day 1
13. Any history of CTCAE grade ≥2 non-dysrhythmia cardiac conditions within 6 months prior
to treatment Day 1. Patients with asymptomatic grade 2 non- dysrhythmia cardiovascular
conditions may be considered for inclusion, with the approval of the Medical Monitor,
if stable and unlikely to affect patient safety.
14. Any history of CTCAE grade ≥2 cardiac dysrhythmias within 6 months prior to treatment
Day 1. 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. QT corrected by the Fridericia method (QTcF) 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], or history of long QT interval syndrome
16. New York Heart Association Class II, III, or IV congestive heart failure
17. Any active gastrointestinal or metabolic condition that could interfere with
absorption of oral medication
18. Active or uncontrolled inflammatory or chronic functional bowel disorder such as
Crohn's Disease, inflammatory bowel disease, chronic diarrhea, or chronic constipation
19. Other malignancy within 3 years prior to treatment Day 1, other than curatively
treated basal cell or squamous cell skin or corneal cancer; curatively treated
carcinoma in situ of the cervix; organ-confined prostate cancer with prostate-specific
antigen (PSA) <20 ng/mL and National Comprehensive Cancer Network risk of Very Low,
Low, or Favorable Intermediate; curatively treated non-metastatic prostate cancer with
negative PSA; or in situ breast carcinoma after complete surgical resection
20. Uncontrolled intercurrent illness, including, but not limited to, ongoing active
infection, psychiatric illness, or social situation that, in the judgment of the
treating physician, would limit compliance with study requirements
21. Known seropositivity for human immunodeficiency virus
22. Known active hepatitis A, B, or C virus infection
23. Women who are pregnant or lactating
24. Concurrent enrollment in another interventional trial
