Clinical Trials /

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

NCT03165734

Description:

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

Related Conditions:
  • Myelofibrosis Transformation in Essential Thrombocythemia
  • Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase
  • Primary Myelofibrosis
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: A Phase 2/3 Study of Pacritinib in Patients With Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis
  • Official Title: A Phase 2/3 Study of Pacritinib 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 Phase 3 Study (PACIFICA):A Randomized, Controlled Phase 3 Study of Pacritinib Versus Physician's Choice in Patients With Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis With Severe Thrombocytopenia (Platelet Count <50,000/μL)

Clinical Trial IDs

  • ORG STUDY ID: PAC203
  • NCT ID: NCT03165734

Conditions

  • Primary Myelofibrosis
  • Post-polycythemia Vera Myelofibrosis
  • Post-essential Thrombocythemia Myelofibrosis

Interventions

DrugSynonymsArms
PacritinibPacritinib 100 mg QD; 100 mg BID; 200 mg BID - Phase 2
Physician's Choice medicationscorticosteroids, hydroxyurea, lenalidomide, low-dose ruxolitinib, thalidomidePacritinib 200 mg BID - Phase 3

Purpose

Phase 3 of this study 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 180 patients in total will be enrolled, randomized 2:1 to either pacritinib (approximately 120 patients) or to P/C therapy (approximately 60 patients) Phase 2 was an open-label, randomized, dose-ranging study designed to identify the most appropriate dosage of pacritinib for future studies based on risk/benefit profile. Patients were randomized 1:1:1 to three dosage arms: 100mg QD, 100mg BID or 200mg BID. A total of 164 patients were randomized in the phase 2 portion of Study PAC203, and 161 (98.2%) patients received any treatment with pacritinib. Condition or disease: Primary Myelofibrosis/Post-Polycythemia Vera Myelofibrosis/ Post-essential Thrombocythemia Myelofibrosis Intervention/treatment: Drug-Pacritinib

Detailed Description

      The Phase 3 portion 1of the study is a randomized, controlled study 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 up to 90 days (from the date of the first dose) of
      prior treatment with a JAK2 inhibitor or are JAK2 inhibitor-naive, and who have severe
      thrombocytopenia (platelet count <50,000/µL). The Phase 3 portion of 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 Phase 2 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, thalidomide, lenalidomide, 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. For the purposes of stratification, thalidomide and lenalidomide will be
      considered as being in the same group. 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, with duration of therapy limited to no more than 90 days from the first day of
      administration. 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 the pacritinib 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, or initiates any
      non-protocol-directed anti-MF treatment. 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.

      The Phase 2 portion of the study was designed to support a pacritinib dosage selection
      decision. Three dosages were evaluated, with patients randomized 1:1:1 to pacritinib 100 mg
      QD, pacritinib 100 mg BID, or pacritinib 200 mg BID. Randomization was stratified by baseline
      platelet count (≤50,000/µL; >50,000/µL and ≤100,000/µL; and >100,000/µL). Assigned treatment
      continued until the patient experienced progressive disease, intolerable AEs, withdrew
      consent, or until the assigned treatment arm was closed. No study treatment crossover was
      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 was approximately 36 months.
      Following the Week 24 assessment, patients who were benefiting from therapy and who have not
      experienced progressive disease were allowed to continue receiving pacritinib at the original
      randomized dose or following the dose recommendations of the Independent Data Monitoring
      Committee (IDMC), and were followed for survival, efficacy and safety for up to 2.5 years.

      The Sponsor collected 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 were collected on Day 1
      (Baseline), Week 12, and Week 24 at 0 hours (predose). DNA samples were also collected for
      analysis of mutations associated with myelofibrosis at baseline and Week 24.
    

Trial Arms

NameTypeDescriptionInterventions
Pacritinib 200 mg BID - Phase 3Active Comparator2:1 to receive pacritinib 200 mg twice daily (BID) orally, at the same time of day, with or without food or the Physician's Choice (P/C) therapy (limited to single drugs from the following list: corticosteroids, hydroxyurea, thalidomide, lenalidomide, or low-dose ruxolitinib). The proposed P/C regimen for a patient must be selected prior to randomization.
  • Pacritinib
  • Physician's Choice medications
Pacritinib 100 mg QD; 100 mg BID; 200 mg BID - Phase 2Experimental1:1:1 to pacritinib 100 mg QD, pacritinib 100 mg BID, or pacritinib 200 mg BID orally, at the same time of day, with or without food
  • Pacritinib

Eligibility Criteria

        Phase 3 Diagnosis and Inclusion Criteria

          1. PMF, PPV-MF, or PET-MF

          2. Average platelet count of <50,000/µL at Screening (based on three measurements taken
             on different days; two measurements must be <50,000/µL, and none can be >60,000/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. Age ≥18 years

          7. Eastern Cooperative Oncology Group performance status 0 to 2

          8. Peripheral blast count of <10% throughout the Screening period and at baseline

          9. Absolute neutrophil count of ≥500/µL

         10. Left ventricular cardiac ejection fraction of ≥50% by echocardiogram or multigated
             acquisition (MUGA) scan

         11. 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

         12. Adequate coagulation defined by prothrombin time/international normalized ratio and
             partial thromboplastin time ≤1.5 × ULN

         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
             patient-reported outcome instrument

         16. 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 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 a JAK2 inhibitor for more than 90 days from the date of first
             administration. The 90-day JAK2 treatment period may overlap with the Screening period
             but may not extend to within 14 days prior to treatment Day 1.

          8. Prior treatment with more than one JAK2 inhibitor

          9. Treatment with an experimental therapy within 28 days prior to treatment Day 1

         10. Systemic treatment with a strong CYP3A4 inhibitor or a strong cytochrome P450 (CYP450)
             inducer within 14 days prior to treatment Day 1

         11. 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)

         12. 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
             [VEGF]) agents, and daily use of COX-1 inhibiting nonsteroidal anti- inflammatory
             drugs (NSAIDs) within 14 days prior to treatment Day 1

         13. Systemic treatment with medications that can prolong the QT interval within 14 days
             prior to treatment Day 1

         14. 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.

         15. 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.

         16. 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

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

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

         19. Active or uncontrolled inflammatory or chronic functional bowel disorder such as
             Crohn's Disease, inflammatory bowel disease, chronic diarrhea, or chronic constipation

         20. 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

         21. 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

         22. Known seropositivity for human immunodeficiency virus

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

         24. Women who are pregnant or lactating

         25. Concurrent enrollment in another interventional trial
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Spleen volume
Time Frame:From baseline to 24 weeks
Safety Issue:
Description:To compare the efficacy of pacritinib with that of physician's choice (P/C) therapy, as assessed by the proportion of patients achieving a ≥35% spleen volume reduction (SVR) as measured by magnetic resonance imaging (MRI, preferred) or computed tomography (CT) scans

Secondary Outcome Measures

Measure:Total Symptom Score (TSS)
Time Frame:Between baseline and Week 24
Safety Issue:
Description:To compare the efficacy of pacritinib with P/C therapy, as assessed by the proportion of patients achieving a ≥50% reduction in Total Symptom Score (TSS)
Measure:Overall Survival (OS)
Time Frame:until 2.5 years after the date of randomization
Safety Issue:
Description:To compare the overall survival (OS) of patients treated with pacritinib versus those treated with P/C
Measure:Patient Global Impression of Change (PGIC) assessed at Week 24
Time Frame:End of Week 12 to 2 years following Week 24 visit
Safety Issue:
Description:To compare the percentage of patients who self-assess as "very much improved" or "much improved" as measured by the Patient Global Impression of Change (PGIC) in patients treated with pacritinib versus those treated with P/C

Details

Phase:Phase 2/Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:CTI BioPharma

Trial Keywords

  • myelofibrosis
  • pacritinib
  • Post-polycythemia Vera Myelofibrosis
  • Post-essential Thrombocythemia Myelofibrosis
  • Ruxolitinib
  • Bone Marrow Disease
  • Hematologic Diseases
  • Blood Platelet Disorders
  • Hemorrhagic Disorders
  • Splenomegaly
  • Anemia
  • Spleen volume
  • Spleen

Last Updated

January 24, 2020