Claire Harrison, MD
Pacritinib, a JAK2/FLT3 multikinase inhibitor, significantly reduced spleen volume for patients with myeloproliferative neoplasms when compared with non-JAK2 inhibitors, according to top-line findings from the phase III PERSIST-1 trial.
A greater number of patients with primary and secondary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis achieved a 35% or higher reduction in spleen volume from baseline to week 24, when compared with physician-specified best available therapy (excluding a JAK inhibitor), according to a joint announcement by CTI BioPharma Corp and Baxter International Inc, the companies developing and commercializing the drug.
These findings are significant for patients with thrombocytopenia, said Claire Harrison, MD, Consultant Hematologist, Guy's and St. Thomas' NHS Foundation Trust, Guy's Hospital, and one of the principal investigators for PERSIST-1. Thrombocytopenia occurs in about one-third of patients with myelofibrosis and is associated with poor outcomes.
“Despite the introduction of JAK2 inhibitors as effective therapies for patients with myelofibrosis, there remains a treatment gap for patients with disease-related or treatment-emergent thrombocytopenia,” stated Harrison. “The currently approved drug may require dose titration to less effective doses in this patient population, thus limiting our ability to effectively treat them. Results from the PERSIST-1 randomized trial demonstrate that pacritinib could address this unmet medical need."
The PERSIST-1 trial included 327 patients will all levels of blood platelet counts. Pacritinib showed particular benefit for patients with low platelet counts (>100,000 per microliter and >50,000 per microliter). Among the 50 patients who were red blood cell (RBC) transfusion dependent at study entry (≥6 units of RBC over 90 days pre entry), pacritinib therapy resulted in a clinically meaningful percentage of patients becoming transfusion independent.
"PERSIST-1 is the first randomized phase III trial investigating the potential benefit of a JAK2 inhibitor across a patient population with myelofibrosis that is representative of patients that healthcare providers see and treat in clinical practice," James A. Bianco, MD, president and CEO, CTI BioPharma, said in a statement. "We are excited by the clinical profile demonstrated in this randomized trial with respect to benefit–risk especially for a segment of MF patients excluded from other randomized trials with JAK2 inhibitors."
In August 2014, pacritinib was granted Fast Track designation by the FDA for the treatment of intermediate- and high-risk myelofibrosis. Prior to that, a second phase III trial, known as PERSIST-2, was initiated in March 2014 to further investigate the impact pacritinib may have on patients with low platelet counts.
The PERSIST-2 trial will evaluate pacritinib compared to best available therapy, including approved JAK2 inhibitors that are dosed according to product label, in patients with myelofibrosis whose platelet counts are less than or equal to 100,000/uL.
CTI and the FDA reached a Special Protocol Assessment (SPA) for PERSIST-2. It stipulates that co-primary endpoints for the trial are the percentage of patients achieving a 35% or greater reduction in spleen volume from baseline to 24 weeks, and the percentage of patients achieving a Total Symptom Score (TSS) reduction of 50% or greater using six key symptoms as measured by the modified Myeloproliferative Neoplasm Symptom Assessment (MPN-SAF TSS 2.0) diary from baseline to 24 weeks.
Pacritinib has so far proved to be a tolerable drug, with diarrhea, nausea and vomiting observed as the most common adverse events in the phase III PERSIST-1 trial. No grade 4 gastrointestinal adverse events were reported. Three patients discontinued therapy and 9 patients required dose reduction for diarrhea. Preliminary analysis suggests that very few patients discontinued treatment while on pacritinib or required a dose reduction due to treatment-related anemia or thrombocytopenia.
Eligible patients enrolled in the PERSIST-1 study were at least 18 years of age, had adequate white blood cell counts (with low blast counts), liver function, and renal function, and had received no spleen radiation therapy for 6 to 12 months before entering the trial.
Patients were excluded from the trial if they had any prior treatment with a JAK2 inhibitor, a history of spleen removal surgery or allogeneic stem cell transplant, an ongoing gastrointestinal medical condition, cardiovascular disease, or a life expectancy of less than 6 months.
The trial randomized patients to receive pacritinib at 400 mg taken orally once daily or the best available therapy as determined by their physician. Best available therapies included hydroxyurea, glucocorticoids, erythropoietic-stimulating agents, immunomodulatory agents, mercaptopurine, danazol, interferons, cytarabine, melphalan, and other agents.
"These positive top-line results illustrate the potential of this investigational treatment to become a valuable new treatment option for this challenging disease," said David Meek, Head of Oncology at Baxter, in a press release.