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

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.

Study Overview

• Status: Completed
• Conditions: Primary Myelofibrosis; Post-Polycythemia Vera Myelofibrosis; Post- Essential Thrombocythemia Myelofibrosis
• Intervention / Treatment: Drug: Pacritinib

• Study Type: Interventional
• Enrollment (Actual): 165
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Amiens, France, 80054
    • Chu Hopital Sud
  • Lille Cedex, France, 59037
    • Centre Hospitalier Regional Universitaire de Lille - Hopital Claude Huriez
  • Nîmes, France, 30029
    • CHU de Nimes - Hopital Universitaire Caremeau
  • Paris, France, 75010
    • Hopital Saint-Louis
  • Pessac, France, 33604
    • CHU Hopitaux de Bordeaux - Hôpital Haut-Lévêque
  • Pierre-Bénite, France, 69495
    • Centre Hospitalier Lyon-Sud
  • Toulouse Cedex, France, 31059
    • Centre Hospitalier Universitaire de Toulouse- Hopital Purpan
• Hungary
  • Budapest, Hungary, 1083
    • SE AOK I. sx. Belgyogyaszati Klinika
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem Klinikai Kozpont
  • Kaposvár, Hungary, 7400
    • Somogy Megyei Kaposi Mór Oktató Kórház
• Italy
  • Firenze, Italy, 50134
    • Azienda Ospedaliero-Universitaria Careggi
  • Meldola, Italy, 47014
    • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
  • Monza, Italy, 20900
    • ASST Monza - Ospedale San Gerardo
• Korea, Republic of
  • Daegu, Korea, Republic of, 42415
    • Yeungnam University Medical Center
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital
  • Seoul, Korea, Republic of, 06591
    • The Catholic University of Korea, Seoul St. Mary's Hospital
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center
• Spain
  • Barcelona, Spain, 08003
    • Hospital Del Mar
  • Barcelona, Spain, 08036
    • Hospital Clinic de Barcelona
  • Madrid, Spain, 28034
    • Hospital Universitario Ramón y Cajal
  • Pamplona, Spain, 31008
    • Clinica Universidad de Navarra
• Sweden
  • Lund, Sweden, 22185
    • Skane University Hospital Lund
  • Örebro, Sweden, 70185
    • Orebro University Hospital
• United Kingdom
  • Glasgow, United Kingdom, G12 0YN
    • Beatson West of Scotland Cancer Center
  • London, United Kingdom, SE1 9RT
    • Guy's and St Thomas' NHS Foundation Trust - Guy's Hospital
  • London, United Kingdom, E1 2ES
    • Barts Health NHS Trust - The Royal London Hospital
  • London, United Kingdom, W12 0HS
    • Imperial College Healthcare NHS Trust - Hammersmith Hospital
  • Manchester, United Kingdom, M20 4BX
    • The Christie NHS Foundation Trust
  • Oxford, United Kingdom, OX3 7LE
    • Oxford University Hospitals NHS Trust - Churchill Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Hospital
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Los Angeles, California, United States, 90033
      • USC Norris Comprehensive Cancer Center
    • Los Angeles, California, United States, 90095
      • UCLA Jonsson Comprehensive Cancer Center
    • Stanford, California, United States, 94305
      • Stanford Cancer Institute
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale School of Medicine
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • Medical Faculty Associates, Inc.
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Florida Cancer Specialists & Research Institute
    • Saint Petersburg, Florida, United States, 33705
      • Florida Cancer Specialists & Research Institute
    • West Palm Beach, Florida, United States, 33401
      • Florida Cancer Specialists & Research Institute
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University Feinberg School of Medicine
    • Chicago, Illinois, United States, 60637
      • The University of Chicago Medical Center
  • Kansas
    • Westwood, Kansas, United States, 66205
      • University of Kansas Cancer Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21229
      • Saint Agnes Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine in St. Louis
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New York
    • New York, New York, United States, 10032
      • Columbia University
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
    • New York, New York, United States, 10021
      • Weill Cornell Medical College
    • Rochester, New York, United States, 14642
      • University of Rochester
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Hospital
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Comprehensive Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio School of Medicine
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah School of Medicine
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pacritinib 100 mg QD	Drug: Pacritinib; Pacritinib
Experimental: Pacritinib 100 mg BID	Drug: Pacritinib; Pacritinib
Experimental: Pacritinib 200 mg BID	Drug: Pacritinib; Pacritinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Spleen Volume Reduction Response (≥ 35%)	Number of patients achieving a ≥ 35% spleen volume reduction (SVR) as measured by magnetic resonance imaging (MRI, preferred) or computed tomography (CT) scans	From Baseline to Weeks 12 and 24
Percent Change in Spleen Volume	Percent change from baseline	From Baseline to Weeks 12 and 24
Total Symptom Score Analysis	Proportion of patients with ≥ 50% reduction in Total Symptom Score from baseline as assessed by the validated PRO instrument MPN-SAF TSS 2.0	From Baseline to Weeks 12 and 24
Patient Global Impression Assessment	Number of patients with improvement in PGIA. The Patient Global Impression Assessment questionnaire was completed at the end of Week 12 and end of Week 24. The scores were summarized by treatment group at each visit.	From Baseline to Weeks 12 and 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Spleen Length Reduction	Rate of reduction in spleen length from baseline	From Baseline to Weeks 24
Frequency of RBC's or Platelet Transfusions	Number of patients	At week 24
Eastern Cooperative Oncology Group Performance Status	0 = Fully active, able to carry on all pre-disease performance without restriction; = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; = Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours; = Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours; = Completely disabled; cannot carry on any selfcare; totally confined to bed or chair; = Dead	At weeks 4, 12, 24, and 30 days post End-of-Treatment visit
Number of Participants With Adverse Events		Randomization through 30 days post End-of-Treatment visit

Collaborators and Investigators

• Sponsor: CTI BioPharma

Publications and helpful links

General Publications

• Verstovsek S, Mesa R, Talpaz M, Kiladjian JJ, Harrison CN, Oh ST, Vannucchi AM, Rampal R, Scott BL, Buckley SA, Craig AR, Roman-Torres K, Mascarenhas JO. Retrospective analysis of pacritinib in patients with myelofibrosis and severe thrombocytopenia. Haematologica. 2022 Jul 1;107(7):1599-1607. doi: 10.3324/haematol.2021.279415.

Study record dates

Study Major Dates

• Study Start (Actual): July 31, 2017
• Primary Completion (Actual): September 4, 2019
• Study Completion (Actual): September 4, 2019

Study Registration Dates

• First Submitted: May 10, 2021
• First Submitted That Met QC Criteria: May 10, 2021
• First Posted (Actual): May 12, 2021

Study Record Updates

• Last Update Posted (Actual): June 1, 2022
• Last Update Submitted That Met QC Criteria: May 5, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Myeloproliferative Disorders; Blood Coagulation Disorders; Blood Platelet Disorders; Bone Marrow Neoplasms; Hematologic Neoplasms; Primary Myelofibrosis; Thrombocytosis; Thrombocythemia, Essential; Polycythemia Vera; Polycythemia
• Other Study ID Numbers: PAC203

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No