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A Phase 2/3 Study of Pacritinib in Patients With Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis (PACIFICA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03165734
Recruitment Status : Recruiting
First Posted : May 24, 2017
Last Update Posted : March 6, 2020
Sponsor:
Collaborator:
The Physicians' Services Incorporated Foundation
Information provided by (Responsible Party):
CTI BioPharma

Tracking Information
First Submitted Date  ICMJE May 17, 2017
First Posted Date  ICMJE May 24, 2017
Last Update Posted Date March 6, 2020
Actual Study Start Date  ICMJE June 26, 2017
Estimated Primary Completion Date July 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 24, 2020)
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
Original Primary Outcome Measures  ICMJE
 (submitted: May 23, 2017)
Spleen volume [ Time Frame: 24 weeks ]
The primary efficacy variable for dosage selection is the percent reduction in spleen volume from baseline as measured by MRI or CT. For evaluation as part of the dose-response relationship will include the percentage of patients who achieve at least 35% reduction in spleen volume
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 24, 2020)
  • 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)
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: May 23, 2017)
Percentage of patients with CTCAE grade ≥3 cardiac AEs, CTCAE grade ≥3 hemorrhage AEs, CTCAE grade ≥4 thrombocytopenia toxicity, or CTCAE grade ≥4 anemia toxicity [ Time Frame: Day 0 through the patient's last day of study participation, approximately 8 months ]
The safety population is defined as all randomized patients who received at least one dose of study treatment. For screened patients who are not randomized, only SAEs occurring between the time of informed consent and determination of screen failure are to be reported.
Current Other Pre-specified Outcome Measures
 (submitted: January 24, 2020)
  • SVR of ≥35% [ Time Frame: Up to 24 Weeks ]
    Time to achievement of SVR of ≥35%
  • Best response in SVR [ Time Frame: At 24 Weeks ]
    Best response in SVR by MRI or CT scan
  • >25% SVR [ Time Frame: Between baseline and Week 24 ]
    Proportion of patients achieving >25% SVR
  • Red blood cell (RBC) [ Time Frame: Baseline to End of Treatment ]
    Achievement of red blood cell (RBC) transfusion independence at Weeks 12 and 24
  • hemoglobin level [ Time Frame: Weeks 12 and 24 ]
    Improvement in hemoglobin level without transfusion at Weeks 12 and 24
  • platelet count [ Time Frame: Weeks 12 and 24 ]
    Improvement in platelet count at Weeks 12 and 24
  • platelet transfusions [ Time Frame: Weeks 12 and 24 ]
    Frequency of platelet transfusions at Weeks 12 and 24
  • 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
  • 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
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase 2/3 Study of Pacritinib in Patients With Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis
Official Title  ICMJE 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)
Brief Summary

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Primary Myelofibrosis
  • Post-polycythemia Vera Myelofibrosis
  • Post-essential Thrombocythemia Myelofibrosis
Intervention  ICMJE
  • 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
  • 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
    • lenalidomide
    • low-dose ruxolitinib
    • thalidomide
Study Arms  ICMJE
  • Active Comparator: Pacritinib 200 mg BID - Phase 3
    2:1 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.
    Interventions:
    • Drug: Pacritinib
    • Drug: Physician's Choice medications
  • Experimental: Pacritinib 100 mg QD; 100 mg BID; 200 mg BID - Phase 2
    1:1:1 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
    Intervention: Drug: Pacritinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 24, 2020)
180
Original Estimated Enrollment  ICMJE
 (submitted: May 23, 2017)
105
Estimated Study Completion Date  ICMJE December 2, 2022
Estimated Primary Completion Date July 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Sirin Artan Kahrs, MD 206-272-4386 sartankahrs@ctibiopharma.com
Listed Location Countries  ICMJE Canada,   France,   Hungary,   Israel,   Italy,   Korea, Republic of,   Spain,   Sweden,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03165734
Other Study ID Numbers  ICMJE PAC203
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party CTI BioPharma
Study Sponsor  ICMJE CTI BioPharma
Collaborators  ICMJE The Physicians' Services Incorporated Foundation
Investigators  ICMJE
Study Director: Simran Singh Sponsor GmbH
PRS Account CTI BioPharma
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP