Details

Details

Title A Randomized Controlled Phase 3 Study of Oral Pacritinib versus Best Available Therapy in Patients with Thrombocytopenia and Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis

IRB CTI1Z14

CC 14-954

Hospital Main Campus

Phase Phase 3

Disease Myelofibrosis, Thrombocytopenia

Drug Pacritinib

Description

Description

Primary Objective

To compare the efficacy of two dose-schedule arms(s) of pacritinib (pooled oncedaily [QD] and twice-daily [BID] dosing arms) with that of best available therapy (BAT) in patients with thrombocytopenia and primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), or post-essential thrombocythemia myelofibrosis (PET-MF). The efficacy co-endpoints for this analysis are the proportion of patients achieving a ≥ 35% reduction in spleen volume from baseline to Week 24, as measured by magnetic resonance imaging (MRI) or computed tomography (CT) scan and the proportion of patients achieving a ≥ 50% reduction in total symptom score (TSS) from baseline to Week 24 as measured by the Myeloproliferative Neoplasm Symptom Assessment Form 2.0 (MPN-SAF TSS 2.0).

Secondary Objectives
  1. To compare the efficacy of QD pacritinib with that of BAT, as assessed by the proportion of patients achieving a ≥ 35% reduction in spleen volume from baseline to Week 24 by MRI or CT and the proportion of patients achieving a ≥ 50% reduction in the TSS from baseline to Week 24 on the MPN-SAF TSS 2.0.
  2. To compare the efficacy of BID pacritinib with that of BAT, as assessed by the proportion of patients achieving a ≥ 35% reduction in spleen volume from baseline to Week 24 by MRI or CT and the proportion of patients achieving a ≥ 50% reduction in the TSS from baseline to Week 24 on the MPN-SAF TSS 2.0.
Exploratory Objectives
  1. Overall survival (OS)
  2. Progression-free survival (PFS)
  3. Leukemia-free survival (LFS)
  4. Time to achievement of ≥ 35% reduction in spleen volume from baseline by MRI or CT
  5. Duration of maintenance of ≥ 35% reduction in spleen volume from baseline
  6. Best response in spleen volume by MRI or CT scan
  7. Duration of treatment
  8. Achievement of red blood cell (RBC) transfusion independence (Appendix 1a)
  9. Achievement of reduced RBC transfusion dependence (Appendix 1a)
  10. Clinical improvement in hemoglobin level (Appendix 2)
  11. Frequency of RBC transfusions
  12. Achievement of platelet transfusion independence (Appendix 1b)
  13. Clinical improvement in platelet count (Appendix 2)
  14. Frequency of platelet transfusions
  15. Change in JAK2V617F allele burden
  16. Quality of life, as measured by the EQ-5D-5L (Appendix 3) and European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 version 3.0 (Appendix 4) Pharmacokinetic and Pharmacodynamic Objectives The pharmacokinetic (PK) and pharmacodynamic (PD) objectives are to assess exposure and exposureresponse relationships on the safety and efficacy of pacritinib.
Inclusion Criteria

Inclusion Criteria

  1. Intermediate-1, intermediate -2, or high risk (Passamonti et al. 2010; Appendix 5) PMF, PPV-MF, or PET-MF (Tefferi and Vardiman 2008; Barosi et al. 2008; Appendix 6)
  2. Thrombocytopenia (platelet count ≤ 100,000/μL) at any time after signing informed consent
  3. Informed consent may be signed up to 35 days prior to randomization
  4. Palpable splenomegaly ≥5 cm below the lower costal margin (LCM) in midclavicular line by physical examination
  5. Total Symptom Score (TSS) ≥13 on the MPN-SAF TSS 2.0, not including the inactivity question (Appendix 7)
  6. Age ≥18 years
  7. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 3 (Appendix 8)
  8. Peripheral blast count <10%
  9. 9. Absolute neutrophil count (ANC) >500/μL
  10. Patients who are platelet or RBC transfusion dependent are eligible
  11. Adequate liver and renal function, defined by liver transaminases (AST/SGOT and ALT/SGPT) ≤3 x ULN (AST/ALT ≤5 x ULN if transaminase elevation is related to MF), direct bilirubin ≤4 x ULN, and creatinine ≤2.5 mg/dL
  12. At least 6 months from prior splenic irradiation
  13. At least 12 months from prior 32P therapy
  14. At least 1 week since prior treatment (most recent dose) with a potent cytochrome P450 3A4 (CYP3A4) inhibitor (Appendix 9)
  15. At least 2 weeks since receiving any treatment for PMF, PPV-MF, or PET-MF
  16. If fertile, males and females must agree to use effective birth control methods during the study
  17. Willing to undergo and able to tolerate frequent MRI or CT assessments during the study
  18. Able to understand and willing to complete symptom assessments using a patient-reported outcome Instrument
  19. Able to understand and willing to sign the Informed Consent Form
Exclusion Criteria

Exclusion Criteria

  1. Any gastrointestinal (GI) or metabolic condition that could interfere with absorption of oral medication
  2. Life expectancy less than 6 months
  3. Prior treatment with more than 2 JAK2 inhibitors or with pacritinib
  4. There is no maximum cumulative prior JAK2 inhibitor treatment (approved or investigational)
  5. Completed allogeneic stem cell transplant (ASCT), or are eligible for and willing to complete ASCT
  6. History of splenectomy or planning to undergo splenectomy
  7. 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
  8. Active bleeding requiring hospitalization during the screening period
  9. 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
  10. Inflammatory or chronic functional bowel disorder, such as Crohn disease, inflammatory bowel disease, chronic diarrhea, or constipation
  11. Clinically symptomatic and uncontrolled cardiovascular disease
  12. History of any of the following within 6 months prior to randomization: myocardial infarction, severe/unstable angina, or symptomatic congestive heart failure
  13. New York Heart Association Class III or IV congestive heart failure (Appendix 10)
  14. Patients with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade 2 cardiac arrhythmias may be considered for inclusion, with the approval of the medical monitor, if the arrhythmias are stable, asymptomatic, and unlikely to affect patient safety. Patients will be excluded if they have ongoing cardiac dysrhythmias of CTCAE grade ≥3, corrected QT interval (QTc) prolongation >450ms, or other factors that increase the risk for QT interval prolongation (eg, heart failure, hypokalemia [defined as serum potassium <3.0mEq/L that is persistent and refractory to correction], or family history of long QT interval syndrome).
  15. Erythropoietic agent within 28 days prior to randomization
  16. Thrombopoietic agent within 14 days prior to randomization
  17. Known seropositivity for human immunodeficiency virus (HIV)
  18. Known active hepatitis A, B, or C virus infection
  19. Women who are pregnant or lactating