Phase 2 Study: 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
Condition: Primary Myelofibrosis; Post-Polycythemia Vera Myelofibrosis; Post- Essential Thrombocythemia Myelofibrosis
MeSH terms: Polycythemia Vera; Primary Myelofibrosis; Polycythemia; Thrombocytosis; Thrombocythemia, Essential
Intervention: Pacritinib
Intervention description: Pacritinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 165.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        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% SVR 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 (RBC) 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 (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 2
             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 scan assessments during the
             study

         15. Able to understand and willing to complete symptom assessments using a PRO 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

          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

          9. Treatment with medications that can prolong the QTc interval within the last 2 weeks

         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 (eg, surgery, trauma, or 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 based on the mean of triplicate ECGs or other factors that
             increase the risk for QT interval prolongation (eg, 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