A Phase 3 Study of Pacritinib in Patients With Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis

Diagnosis and Inclusion Criteria

Primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF (as defined by Tefferi and Vardiman 2008
Platelet count of <50,000/μL at Screening (Day -35 to Day -3)
Dynamic International Prognostic Scoring System Intermediate-1, Intermediate-2, or High-Risk (Passamonti et al 2010
Palpable splenomegaly ≥5 cm below the lower costal margin (LCM) in the midclavicular line as assessed by physical examination
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.The TSS criteria need only to be met on a single day.
Age ≥18 years
Eastern Cooperative Oncology Group performance status 0 to 2
Peripheral blast count of <10% throughout the Screening period prior to randomization
Absolute neutrophil count of ≥500/µL
Left ventricular cardiac ejection fraction of ≥50% by echocardiogram or multigated acquisition scan
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), total bilirubin ≤4 x ULN (in cases where total bilirubin is elevated, direct bilirubin ≤4 × ULN, is required) and creatinine ≤2.5 mg/dL
Adequate coagulation defined by prothrombin time/international normalized ratio and partial thromboplastin time ≤1.5 × ULN
If fertile, willing to use effective birth control methods during the study
Willing to undergo and able to tolerate frequent MRI or CT scan assessments during the study
Able to understand and willing to complete symptom assessments using a patient-reported outcome instrument
Provision of signed informed consent

Exclusion Criteria

Life expectancy <6 months
Completed allogeneic stem cell transplant (allo-SCT) or are eligible for and willing to complete other approved available therapy including allogeneic stem cell
History of splenectomy or planning to undergo splenectomy
Splenic irradiation within the last 6 months
Previously treated with pacritinib
Treatment with any MF-directed therapy within 14 days prior to treatment Day 1
Prior treatment with more than one JAK2 inhibitor

Prior treatment with with ruxolitinib, if BOTH of the following conditions are met:

i. exposure to higher-dose ruxolitinib (>10 mg daily) within 120 days prior to treatment Day 1 AND ii. total duration of treatment with higher-dose ruxolitinib (>10 mg daily) was >90 days, from first to last exposure (i.e., this 90-day period starts on the date of first administration of ruxolitinib at a total daily dose of >10 mg and continues for 90 calendar days, regardless of whether higher-dose ruxolitinib is administered continuously or intermittently).

Prior treatment with any JAK2 inhibitor other than ruxolitinib, irrespective of dose, with a duration of >90 days. 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.
Treatment with an experimental therapy within 28 days prior to treatment Day 1
Systemic treatment with a strong cytochrome P450 3A4 inhibitor or a strong cytochrome P450 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
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 (eg, surgery, trauma, or injury)
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-VEGF) agents, and daily use of cyclooxygenase-1 (COX-1) inhibiting non-steroidal anti-inflammatory drugs (NSAIDs) within 14 days prior to treatment Day 1
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
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.
Any history of CTCAE grade ≥2 cardiac dysrhythmias within 6 months prior to treatment Day 1. Patients with non-corrected QT interval 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.
QT corrected by the Fridericia method (QTcF) prolongation >450 ms or other factors that increase the risk for QT interval prolongation (eg, hypokalemia [defined as serum potassium <3.0 mEq/L that is persistent and refractory to correction], or history of long QT interval syndrome).
New York Heart Association Class II, III, or IV congestive heart failure
Any active gastrointestinal or metabolic condition that could interfere with absorption of oral medication
Active or uncontrolled inflammatory or chronic functional bowel disorder such as Crohn's Disease, inflammatory bowel disease, chronic diarrhea, or chronic constipation
Other malignancy within 3 years prior to treatment Day 1. The following patients may be eligible despite having had a malignancy within the prior 3 years: patients with curatively treated squamous or basal cell carcinoma of the skin; patients with curatively treated non-invasive cancers; patients with 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; and patients with curatively treated non-metastatic prostate cancer with negative PSA.
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
Known seropositivity for human immunodeficiency (HIV) virus. For patients in France, Czech Republic, and Italy only: testing for HIV is required during Screening.
Known active hepatitis A, B, or C virus infection. For patients in France, Czech Republic and Italy only: testing for hepatitis B and C is required during Screening.
Women who are pregnant or lactating
Concurrent enrollment in another interventional trial
Severe thrombocytopenia due to vitamin B12 deficiency, folate deficiency, or viral infection in the opinion of the investigator
Known hypersensitivity to pacritinib or any of the following inactive ingredients: microcrystalline cellulose, polyethylene glycol, and magnesium stearate; any contraindication to the "physician's choice" medicinal product selected by the investigator to be used as the comparator or to loperamide or equivalent antidiarrheal medication
Persons deprived of their liberty by a judicial or administrative decision
Persons subject to legal protection measures or unable to express their consent
Temporarily incapacitated persons