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

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ClinicalTrials.gov Identifier: NCT03165734
Recruitment Status : Recruiting
First Posted : May 24, 2017
Last Update Posted : September 25, 2020
Sponsor:
Collaborator:
PSI CRO
Information provided by (Responsible Party):
CTI BioPharma

Brief Summary:

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


Condition or disease Intervention/treatment Phase
Primary Myelofibrosis Post-polycythemia Vera Myelofibrosis Post-essential Thrombocythemia Myelofibrosis Drug: Pacritinib Drug: Physician's Choice medications Phase 3

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 348 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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)(PACIFICA)
Actual Study Start Date : June 26, 2017
Estimated Primary Completion Date : July 31, 2022
Estimated Study Completion Date : December 2, 2022


Arm Intervention/treatment
Experimental: Pacritinib 200 mg BID
To receive pacritinib 200 mg twice daily (BID) orally, at the same time of day, with or without food
Drug: Pacritinib
Oral administration. Supplied in capsules containing 100 mg (as the free base) in red cap/gray body size 0 opaque hard gelatin capsules. The inactive ingredients are microcrystalline cellulose, magnesium stearate, and polyethylene glycol 8000. Each capsule contains 146 mg of pacritinib citrate, which is equivalent to 100 mg pacritinib free base

Active Comparator: Physician's Choice (P/C) therapy
The Physician's Choice (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.
Drug: Physician's Choice medications
Physician's Choice medications will be selected and administered according to the investigator's judgement. Investigators can select individual P/C agents but cannot combine agents or give them sequentially.
Other Names:
  • corticosteroids
  • hydroxyurea
  • danazol
  • low-dose ruxolitinib




Primary Outcome Measures :
  1. Spleen volume [ Time Frame: From baseline to 24 weeks ]
    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 :
  1. Total Symptom Score (TSS) [ Time Frame: Between baseline and Week 24 ]
    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)

  2. Overall Survival (OS) [ Time Frame: until 2.5 years after the date of randomization ]
    To compare the overall survival (OS) of patients treated with pacritinib versus those treated with P/C

  3. Patient Global Impression of Change (PGIC) assessed at Week 24 [ Time Frame: End of Week 12 to 2 years following Week 24 visit ]
    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

  4. To compare the safety of pacritinib versus P/C therapy [ Time Frame: Randomization through 30 after last treatment ]
    Safety will be assessed based on the incidence and severity (according to the Common Terminology Criteria for Adverse Events) of treatment emergent adverse events from the time of randomization until 30 days after completion of treatment with pacritinib and/or physician's choice therapy.


Other Outcome Measures:
  1. SVR of ≥35% [ Time Frame: Up to 24 Weeks ]
    Time to achievement of SVR of ≥35%

  2. Best response in SVR [ Time Frame: At 24 Weeks ]
    Best response in SVR by MRI or CT scan

  3. >25% SVR [ Time Frame: Between baseline and Week 24 ]
    Proportion of patients achieving >25% SVR

  4. Red blood cell (RBC) [ Time Frame: Baseline to End of Treatment ]
    Achievement of red blood cell (RBC) transfusion independence at Weeks 12 and 24

  5. hemoglobin level [ Time Frame: Weeks 12 and 24 ]
    Improvement in hemoglobin level without transfusion at Weeks 12 and 24

  6. platelet count [ Time Frame: Weeks 12 and 24 ]
    Improvement in platelet count at Weeks 12 and 24

  7. platelet transfusions [ Time Frame: Weeks 12 and 24 ]
    Frequency of platelet transfusions at Weeks 12 and 24

  8. PROMIS [ Time Frame: Baseline to Week 24 ]
    Improvement in fatigue as measured by Patient-Reported Outcomes Measurement Information System (PROMIS) v.1.0 - Fatigue from Baseline through Week 24

  9. Leukemia-free survival (LFS) [ Time Frame: Baseline to Week 24 ]
    Leukemia-free survival (LFS) of patients treated with pacritinib versus P/C therapy

  10. The percentage of red blood cell transfusion-independent patients achieving a 1 g/dL and a 2 g/dL increase in hemoglobin [ Time Frame: Baseline to 24 weeks ]
    The percentage of red blood cell transfusion-independent patients at baseline achieving a 1 g/dL and a 2 g/dL increase in hemoglobin at week 24

  11. The percentage of platelet transfusion-independent patients with improvement in grade of thrombocytopenia [ Time Frame: Baseline to 24 weeks ]
    The percentage of platelet transfusion-independent patients at baseline with improvement in grade of thrombocytopenia at week 24

  12. The percentage of transfusion-dependent patients achieving transfusion independence and achieving 50% reduction in transfusion rate [ Time Frame: Baseline to 24 weeks ]
    The percentage of transfusion-dependent patients at baseline achieving transfusion independence and achieving 50% reduction in transfusion rate at week 24

  13. Hemaglobin A1c [ Time Frame: Baseline to Week 24 ]
    Changes in hemoglobin A1c

  14. mutated allelic burden, gene expression, and pharmacodynamic (PD) biomarkers [ Time Frame: Baseline to up to 24 Weeks ]
    Changes in mutated allelic burden, gene expression, and pharmacodynamic (PD) biomarkers



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03165734


Contacts
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Contact: Simran Bedi Singh 206-272-4454 ssingh@ctibiopharma.com
Contact: John Volpone 1-206-272-4652 jvolpone@ctibiopharma.com

Locations
Show Show 140 study locations
Sponsors and Collaborators
CTI BioPharma
PSI CRO
Investigators
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Study Director: Simran Bedi Singh CTI BioPharma
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Responsible Party: CTI BioPharma
ClinicalTrials.gov Identifier: NCT03165734    
Other Study ID Numbers: PAC203/PAC303
PAC303 ( Other Identifier: CTI BioPharma )
First Posted: May 24, 2017    Key Record Dates
Last Update Posted: September 25, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by CTI BioPharma:
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
Additional relevant MeSH terms:
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Polycythemia Vera
Primary Myelofibrosis
Polycythemia
Thrombocytosis
Thrombocythemia, Essential
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Bone Marrow Neoplasms
Hematologic Neoplasms
Neoplasms by Site
Neoplasms
Blood Platelet Disorders
Blood Coagulation Disorders
Hemorrhagic Disorders
Hydroxyurea
Antineoplastic Agents
Antisickling Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors