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

Phase 2

Completed

• Conditions: Primary Myelofibrosis; Post- Essential Thrombocythemia Myelofibrosis; Post-Polycythemia Vera Myelofibrosis
• Interventions: Drug: Pacritinib

• Registration Number: NCT04884191
• Lead Sponsor: CTI BioPharma

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2017-07-31
• Primary Completion: 2019-09-04
• Study Completion: 2019-09-04
• Study First Submitted: 2021-05-10
• Study First Submitted QC: 2021-05-10
• Study First Posted: 2021-05-12
• Results First Submitted: 2021-08-23
• Status Verified: 2022-05
• Results First Submitted QC: 2022-05-05
• Last Update Submitted: 2022-05-05
• Results First Posted: 2022-06-01
• Last Update Posted: 2022-06-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 165

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Pacritinib 200 mg BID	Pacritinib	-
Pacritinib 100 mg QD	Pacritinib	-
Pacritinib 100 mg BID	Pacritinib	-

Primary Outcome Measures

Name	Time	Method
Spleen Volume Reduction Response (≥ 35%)	From Baseline to Weeks 12 and 24	Number of patients achieving a ≥ 35% spleen volume reduction (SVR) as measured by magnetic resonance imaging (MRI, preferred) or computed tomography (CT) scans
Total Symptom Score Analysis	From Baseline to Weeks 12 and 24	Proportion of patients with ≥ 50% reduction in Total Symptom Score from baseline as assessed by the validated PRO instrument MPN-SAF TSS 2.0
Percent Change in Spleen Volume	From Baseline to Weeks 12 and 24	Percent change from baseline
Patient Global Impression Assessment	From Baseline to Weeks 12 and 24	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.

Secondary Outcome Measures

Name	Time	Method
Spleen Length Reduction	From Baseline to Weeks 24	Rate of reduction in spleen length from baseline
Frequency of RBC's or Platelet Transfusions	At week 24	Number of patients
Number of Participants With Adverse Events	Randomization through 30 days post End-of-Treatment visit
Eastern Cooperative Oncology Group Performance Status	At weeks 4, 12, 24, and 30 days post End-of-Treatment visit	0 = Fully active, able to carry on all pre-disease performance without restriction; 1. = 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; 2. = Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours; 3. = Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours; 4. = Completely disabled; cannot carry on any selfcare; totally confined to bed or chair; 5. = Dead

Trial Locations

Locations (60)

University of Kansas Cancer Center; 🇺🇸 Westwood, Kansas, United States

UCLA Jonsson Comprehensive Cancer Center; 🇺🇸 Los Angeles, California, United States

City of Hope; 🇺🇸 Duarte, California, United States

Medical Faculty Associates, Inc.; 🇺🇸 Washington, District of Columbia, United States

The University of Chicago Medical Center; 🇺🇸 Chicago, Illinois, United States

Memorial Sloan-Kettering Cancer Center; 🇺🇸 New York, New York, United States

The Ohio State University Comprehensive Cancer Center; 🇺🇸 Columbus, Ohio, United States

Centre Hospitalier Regional Universitaire de Lille - Hopital Claude Huriez; 🇫🇷 Lille Cedex, France

CHU de Nimes - Hopital Universitaire Caremeau; 🇫🇷 Nîmes, France

Hôpital Saint-Louis; 🇫🇷 Paris, France

Debreceni Egyetem Klinikai Központ; 🇭🇺 Debrecen, Hungary

Azienda Ospedaliero-Universitaria Careggi; 🇮🇹 Firenze, Italy

Istituto Scientifico Romagnolo per lo Studio e la Cura Dei Tumori; 🇮🇹 Meldola, Italy

Severance Hospital; 🇰🇷 Seoul, Korea, Republic of

Samsung Medical Center; 🇰🇷 Seoul, Korea, Republic of

The Catholic University of Korea, Seoul St. Mary's Hospital; 🇰🇷 Seoul, Korea, Republic of

Hospital del Mar; 🇪🇸 Barcelona, Spain

Hospital Clínic de Barcelona; 🇪🇸 Barcelona, Spain

Clínica Universidad de Navarra; 🇪🇸 Pamplona, Spain

Hospital Universitario Ramón y Cajal; 🇪🇸 Madrid, Spain

Skane University Hospital Lund; 🇸🇪 Lund, Sweden

Orebro University Hospital; 🇸🇪 Örebro, Sweden

Beatson West of Scotland Cancer Center; 🇬🇧 Glasgow, United Kingdom

Guy's and St Thomas' NHS Foundation Trust - Guy's Hospital; 🇬🇧 London, United Kingdom

Barts Health NHS Trust - The Royal London Hospital; 🇬🇧 London, United Kingdom

The Christie NHS Foundation Trust; 🇬🇧 Manchester, United Kingdom

Oxford University Hospitals NHS Trust - Churchill Hospital; 🇬🇧 Oxford, United Kingdom

Duke University Hospital; 🇺🇸 Durham, North Carolina, United States

University of Texas Health Science Center at San Antonio School of Medicine; 🇺🇸 San Antonio, Texas, United States

Icahn School of Medicine at Mount Sinai; 🇺🇸 New York, New York, United States

Vanderbilt-Ingram Cancer Center; 🇺🇸 Nashville, Tennessee, United States

University of Utah School of Medicine; 🇺🇸 Salt Lake City, Utah, United States

Weill Cornell Medical College; 🇺🇸 New York, New York, United States

Tennessee Oncology; 🇺🇸 Nashville, Tennessee, United States

USC Norris Comprehensive Cancer Center; 🇺🇸 Los Angeles, California, United States

Florida Cancer Specialists & Research Institute; 🇺🇸 West Palm Beach, Florida, United States

Stanford Cancer Institute; 🇺🇸 Stanford, California, United States

Saint Agnes Hospital; 🇺🇸 Baltimore, Maryland, United States

Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Washington University School of Medicine in St. Louis; 🇺🇸 Saint Louis, Missouri, United States

Columbia University; 🇺🇸 New York, New York, United States

University of Rochester; 🇺🇸 Rochester, New York, United States

Cleveland Clinic; 🇺🇸 Cleveland, Ohio, United States

The University of Texas MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

Fred Hutchinson Cancer Research Center; 🇺🇸 Seattle, Washington, United States

CHU Hopital Sud; 🇫🇷 Amiens, France

Centre Hospitalier Universitaire de Toulouse- Hôpital Purpan; 🇫🇷 Toulouse Cedex, France

CHU Hopitaux de Bordeaux - Hôpital Haut-Lévêque; 🇫🇷 Pessac, France

Centre Hospitalier Lyon-Sud; 🇫🇷 Pierre-Bénite, France

ASST Monza - Ospedale San Gerardo; 🇮🇹 Monza, Italy

Yeungnam University Medical Center; 🇰🇷 Daegu, Korea, Republic of

Imperial College Healthcare NHS Trust - Hammersmith Hospital; 🇬🇧 London, United Kingdom

Northwestern University Feinberg School of Medicine; 🇺🇸 Chicago, Illinois, United States

University of Michigan Comprehensive Cancer Center; 🇺🇸 Ann Arbor, Michigan, United States

Yale School of Medicine; 🇺🇸 New Haven, Connecticut, United States

Hackensack University Medical Center; 🇺🇸 Hackensack, New Jersey, United States

Somogy Megyei Kaposi Mór Oktató Kórház; 🇭🇺 Kaposvár, Hungary

Mayo Clinic Hospital; 🇺🇸 Phoenix, Arizona, United States

SE AOK I. sx. Belgyogyaszati Klinika; 🇭🇺 Budapest, Hungary

Ochsner Medical Center; 🇺🇸 New Orleans, Louisiana, United States