title: Phase 1/2 study of pacritinib, a next generation JAK2/FLT3 inhibitor, in myelofibrosis or other myeloid malignancies.
abstract: Pacritinib (SB1518) is a highly selective kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CFS1R. This multicenter phase 1/2 study evaluated the maximum tolerated dose (MTD), safety, and clinical activity of pacritinib in patients with myelofibrosis (MF) and other advanced myeloid malignancies.
  
  
  
  In the phase 1 dose-escalation part of the study, 43 adults with advanced myeloid malignancies received pacritinib 100 to 600 mg once daily (QD). In the phase 2 part of the study, 31 adults with refractory or intermediate- or high-risk newly diagnosed MF and any degree of cytopenia received pacritinib 400 mg QD. The primary endpoint is a ≥35% reduction in spleen volume at week 24 as determined by magnetic resonance imaging.
  
  
  
  Five patients (11.6%) experienced a dose-limiting toxicity during cycle 1 of phase 1. The clinical benefit rate was 86.0% (13 patients achieving clinical improvement and 24 patients having stable disease). The MTD was established at 500 mg QD, and the recommended phase 2 dose was 400 mg QD. In phase 2, the primary endpoint was achieved by 23.5% of evaluable patients (4/17), with 47.4% (9/19) achieving a ≥50% spleen length reduction at week 24 as measured by physical examination. At week 24, 38.9% of evaluable patients (7/18) achieved a ≥50% decrease in MF Quality of Life and Symptom Assessment total score. Gastrointestinal toxicities were the most common adverse events and were predominantly grade 1/2 in severity. Grade 3/4 anemia was reported in 5/31 patients and grade 3/4 thrombocytopenia was reported in 3/31 patients. The most frequent AEs considered to be treatment related were diarrhea (28/31), nausea (15/31), vomiting (9/31), and fatigue (4/31). Grade 3 treatment-related AEs were reported in seven patients (22.6%), four of whom had diarrhea. No grade 4/5 treatment-related AEs were reported. No leukopenia, neutropenia, or lymphopenia were reported.
  
  
  
  Pacritinib was well tolerated and demonstrated clinical activity in MF. The study suggests that pacritinib has unique characteristics, namely a lack of substantial myelosuppression and manageable side effects, making it an attractive target for further evaluation in MF.
  
  
  
  Retrospectively registered at www.clinicaltrials.gov (# NCT00719836 ) on July 20, 2008.
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 428, Houston, TX, 77030, USA. sverstov@mdanderson.org.
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
authors.affiliation: Hematology/Oncology, University of Chicago Medical Center, Chicago, IL, USA.
authors.forename: Olatoyosi
authors.initials: O
authors.lastname: Odenike
authors.affiliation: CTI BioPharma Corp., Seattle, WA, USA.
authors.forename: Jack W
authors.initials: JW
authors.lastname: Singer
authors.affiliation: CTI BioPharma Corp., Seattle, WA, USA.
authors.forename: Tanya
authors.initials: T
authors.lastname: Granston
authors.affiliation: CTI BioPharma Corp., Seattle, WA, USA.
authors.forename: Suliman
authors.initials: S
authors.lastname: Al-Fayoumi
authors.affiliation: Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA, USA.
authors.forename: H Joachim
authors.initials: HJ
authors.lastname: Deeg
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001952:Bridged-Ring Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009196:Myeloproliferative Disorders / Q000150:complications / Q000188:drug therapy; D009929:Organ Size / Q000187:drug effects; D055728:Primary Myelofibrosis / Q000150:complications / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors
chemical_list: C561234:11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene; D001952:Bridged-Ring Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: FMS-like tyrosine kinase 3 inhibitors; Janus kinase 2 inhibitors; Myelofibrosis; Myeloid malignancies; Myelosuppression; Pacritinib; Pharmacokinetics; Quality of Life; Splenomegaly