Clinical trial NCT04884191: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Primary Myelofibrosis
Post-Polycythemia Vera Myelofibrosis
Post- Essential Thrombocythemia Myelofibrosis
Lead sponsor: CTI BioPharma
Sponsor class: INDUSTRY
First posted: 2021-05-12
Enrollment: 165
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Spleen Volume Reduction Response (≥ 35%)
timeFrame: From Baseline to Weeks 12 and 24
measure: Percent Change in Spleen Volume
timeFrame: From Baseline to Weeks 12 and 24
measure: Total Symptom Score Analysis
timeFrame: From Baseline to Weeks 12 and 24
measure: Patient Global Impression Assessment
timeFrame: From Baseline to Weeks 12 and 24
Secondary outcomes:
measure: Spleen Length Reduction
timeFrame: From Baseline to Weeks 24
measure: Frequency of RBC's or Platelet Transfusions
timeFrame: At week 24
measure: Eastern Cooperative Oncology Group Performance Status
timeFrame: At weeks 4, 12, 24, and 30 days post End-of-Treatment visit
measure: Number of Participants With Adverse Events
timeFrame: Randomization through 30 days post End-of-Treatment visit
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Hospital
state: Arizona
city: Duarte
country: United States
facility: City of Hope
state: California
city: Los Angeles
country: United States
facility: USC Norris Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: UCLA Jonsson Comprehensive Cancer Center
state: California
city: Stanford
country: United States
facility: Stanford Cancer Institute
state: California
city: New Haven
country: United States
facility: Yale School of Medicine
state: Connecticut
city: Washington
country: United States
facility: Medical Faculty Associates, Inc.
state: District of Columbia
city: Fort Myers
country: United States
facility: Florida Cancer Specialists & Research Institute
state: Florida
city: Saint Petersburg
country: United States
facility: Florida Cancer Specialists & Research Institute
state: Florida
city: West Palm Beach
country: United States
facility: Florida Cancer Specialists & Research Institute
state: Florida
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine
state: Illinois
city: Chicago
country: United States
facility: The University of Chicago Medical Center
state: Illinois
city: Westwood
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: New Orleans
country: United States
facility: Ochsner Medical Center
state: Louisiana
city: Baltimore
country: United States
facility: Saint Agnes Hospital
state: Maryland
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine in St. Louis
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Durham
country: United States
facility: Duke University Hospital
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Comprehensive Cancer Center
state: Ohio
city: Nashville
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio School of Medicine
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah School of Medicine
state: Utah
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Amiens
country: France
facility: CHU Hopital Sud
city: Lille Cedex
country: France
facility: Centre Hospitalier Regional Universitaire de Lille - Hopital Claude Huriez
city: Nîmes
country: France
facility: CHU de Nimes - Hopital Universitaire Caremeau
city: Paris
country: France
facility: Hôpital Saint-Louis
city: Pessac
country: France
facility: CHU Hopitaux de Bordeaux - Hôpital Haut-Lévêque
city: Pierre-Bénite
country: France
facility: Centre Hospitalier Lyon-Sud
city: Toulouse Cedex
country: France
facility: Centre Hospitalier Universitaire de Toulouse- Hôpital Purpan
city: Budapest
country: Hungary
facility: SE AOK I. sx. Belgyogyaszati Klinika
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Klinikai Központ
city: Kaposvár
country: Hungary
facility: Somogy Megyei Kaposi Mór Oktató Kórház
city: Firenze
country: Italy
facility: Azienda Ospedaliero-Universitaria Careggi
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura Dei Tumori
city: Monza
country: Italy
facility: ASST Monza - Ospedale San Gerardo
city: Daegu
country: Korea, Republic of
facility: Yeungnam University Medical Center
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St. Mary's Hospital
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Pamplona
country: Spain
facility: Clínica Universidad de Navarra
city: Lund
country: Sweden
facility: Skane University Hospital Lund
city: Örebro
country: Sweden
facility: Orebro University Hospital
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Center
city: London
country: United Kingdom
facility: Barts Health NHS Trust - The Royal London Hospital
city: London
country: United Kingdom
facility: Guy's and St Thomas' NHS Foundation Trust - Guy's Hospital
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust - Hammersmith Hospital
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Trust - Churchill Hospital
Study officials:
References:
citation: 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.