We hypothesize that pacritinib leads to modification of the myelofibrosis (MF) disease phenotype, especially related to BM fibrosis and cytopenias; due potentially to its dual effect as an inhibitor of the JAK and NFκB pathways, through its targets JAK2 and IRAK1 respectively, leading to a decrease of inflammatory cytokines and/or effects on stem/progenitor populations restoring hematopoiesis New evidence suggests that blocking simultaneously the JAK/STAT and NF-κB pathways might have a beneficial effect on aspects that only inhibition of the JAK pathway cannot achieve: partial recovery of BM histology and
PACRIMYEL is a multicenter, open-label, single arm, phase II, exploratory study including patients with MF and platelet count between 50 - 120 x 109/L. Clinic visits will occur on weeks 4, 8, 12, 24, 36 and 52 during the first year and every 12 weeks during the second year of the treatment, and pacritinib will be dispensed at every visit to the clinic.
Bone fibrosis will be assessed by biopsy and MRI imaging \[mDixon Quant "(Philips), IDEAL IQ (General Electric) or qDixon (Siemens)\] on weeks 24 and 52 after the first dose of study treatment. Splenomegaly and SVR (Splenic Volume Reduction) will be assessed by physical exam and MRI imaging on weeks 24 and 52 after the first dose of study treatment if splenomegaly at diagnosis. Same MRI to evaluate BM imaging will be used to measure spleen volume. Additionally, spleen size will be assessed by physical exam during the routine clinic visits. All patients should complete all efficacy assessments through Week 52, including patients who stop study treatment or have protocol-defined progressive disease prior to Week 24 and 52, unless the patient withdraws consent or dies. For patients who discontinue treatment before disease assessments on week 24 and week 52 for other reasons different than protocol-based progression of the disease (i.e. toxicity), and with no recent disease / fibrosis assessment (last BM biopsy \> 12 weeks), disease and fibrosis assessments will be performed by the end of treatment visit. The trial includes the assessment of safety (AEs, comorbidities) throughout the study period at every visit.
Patient-reported symptoms through MPN-SAF TSS 2.0 will be collected screening, baseline (C1D1), and on Week 12, Week 24, Week 36, Week 52 and in 12-weeks intervals during the second year. Blood samples for translational research will be collected at screening and at week 24 for determination of cytokines.
Signed written and voluntary informed consent.
Age ≥18 years
Patients with a confirmed diagnosis of myelofibrosis, either primary myelofibrosis (PMF) or post polycythemia vera (PPV-MF) or post essential thrombocythemia (PET-MF).
Patients with thrombocytopenia, delimited by platelets counts between 50 - 120 x 109/L.
Life expectancy <6 months.
Splenic irradiation within the last 6 months.
Previously treated with pacritinib.
Concurrent enrollment in another interventional trial.
Single group
Pacritinib
DrugAll patients enrolled will receive pacritinib 200 mg twice a day (BID). The maximum daily dose will be 400 mg of pacritinib. Pacritinib dose may be reduced by one level to 100 mg BID (200 mg total daily dose), or by two levels to 100 mg once daily (QD) for management of AEs. The treatment will be continued until progressive disease, unacceptable toxic effects, the patient no longer derives benefit from treatment, patients consent withdrawal or death, whichever occurs first.
Decrease in reticulin fibrosis in bone marrow (BM)
Measured in BM biopsy. Percentage of patients who experience a decrease of ≥1 grade in reticulin fibrosis from baseline to week 52. Definition of BM fibrosis grade will follow the European consensus that ranges from 0 (scattered, less fibrotic) to 3 (difuse and dense reticulin, more fibrotic). Patients will be classified as improvement (fibrosis decrease ≥1 grade), no change, or worsening (fibrosis increase \> 1 grade).
Improvement in BM fat fraction (FF)
measured by quantitative quantitative Dixon Quant MRI or equivalent. Changes in the bone marrow associated with MF, such as replacement of the bone marrow fat by fibrosis or elevated numbers of hematopoietic cells, reduce the abundance of fat. Here we will report the percentage of patient who had an improvement in the FF (increase from baseline at week 52).
red blood cell (RBC) transfusion independence
Percentage of patients who achieved no need of RBC transfusions during at least 12 week. RBC transfusion independence will be reported in subgroup of patients with the changes in the Bone Marrow (by MRI and/or BM biopsy) over the first 24 and 52 weeks of treatment.
Improvement in hemoglobin level
Percentage of patients who improve their hemoglobin levels without transfusion. Improvement was defined as a ≥ 1.5 g/dL increase in hemoglobin from baseline. Changes in hemoglobin level without transfusion will be reported in subgroup of patients with the changes in the Bone Marrow (by MRI and/or BM biopsy) over the first 24 and 52 weeks of treatment.
Improvement in platelet counts
increase of platelet count (without transfusions) in comparison to baseline of above 75 x 109/L (if platelet count was between 50 - 75 109/L at baseline) or above 100 x 109/L (if platelet count was between 75 - 100 x 109/L at baseline). Alternatively, the proportion of patients who increase platelet counts ≥25% above baseline will be measured.
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Grupo Español de Enfermedades Mieloproliferativas Crónicas PH Negativas
Lead sponsor
Swedish Orphan Biovitrum
Collaborator
MFAR Clinical Research S.L.
Collaborator
