Results of the PERSIST-1 phase III study of pacritinib (PAC) versus best available therapy (BAT) in primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), or post-essential thrombocythemia-myelofibrosis (PET-MF).

Abstract

LBA7006 Background: PAC is a potent JAK2 inhibitor without significant JAK1 inhibition with minimal myelosuppression in early-phase studies in MF. Methods: The efficacy and safety of daily oral PAC was compared to BAT (2:1 randomization stratified for risk and platelet count). The 10 endpoint was the proportion of ITT patients (pts) achieving ≥ 35% spleen volume reduction (SVR) at week (wk) 24 by centrally reviewed MRI or CT. Secondary endpoints included the proportion achieving ≥ 50% reduction in total symptom score (TSS) at wk 24 using the MPN Symptom Assessment Form. Results: Patients:327 were enrolled (PAC:220, BAT:107), 62% with 10 MF. Median time from diagnosis was 1.12 years (PAC 0.99, BAT 1.60): 32% and 15% had a platelet counts < 100,000/µL or <50,000/ µL; 75% were JAK2V617F positive. Efficacy: The median duration of treatment was 16.2 months PAC and 5.9 months BAT. Sixty-two percent of BAT patients received active disease directed therapy. The SVR rates at week 24 were 19.1% for PAC vs. 4.7% for BAT (p=0.0003) in ITT and 25% vs. 5.9% (p=0.0001) in the evaluable population. 79% of BAT patients crossed over to PAC; 21% had achieved a >35% reduction in spleen volume at data cutoff. TSS composite V1 + V2 response rates were 24.5%for PAC vs. 6.5% for BAT (p<0.0001) by ITT, and were 40.9% vs. 9.9% in evaluable pts (p<0.0001). Efficacy with baseline cytopenias: In pts with <100,000 and <50,000 platelets/μ/L, the SVR rates were 16.7% for PAC vs. 0% for BAT (p=0.009), and 22.9% vs. 0% (p=0.045) by ITT and 23.5% vs. 0% (p=0.007) and 33.3% vs. 0% (p=0.037) in evaluable pts. In RBC transfusion dependent pts, 25.7% of PAC pts became RBC independent vs. 0% of BAT pts (p=0.043). Safety: The most common adverse events (AE) for PAC were diarrhea, nausea, and vomiting; (grade 3 were <5%, <1%, <1% respectively). Hematologic AEs were similar between PAC and BAT. Conclusions: This study demonstrated PAC was well tolerated and induced significant and sustained SVR and symptom control even in patients with severe thrombocytopenia. PAC therapy resulted in RBC transfusion independence in a significant proportion of pts. Clinical trial information: NCT01773187.

Primary analysis of a phase II open-label trial of INCB039110, a selective JAK1 inhibitor, in patients with myelofibrosis

“…15 In PERSIST-1, a phase III study of pacritinib versus best available therapy (excluding ruxolitinib) in patients with intermediate-or high-risk myelofibrosis, 24.5% of patients in the pacritinib arm (6.5% for best available therapy) achieved a ≥50% reduction in TSS (assessed with the Myeloproliferative Neoplasm Symptom Assessment Form) at week 24. 16 The proportions of patients with this degree of symptom response in JAKARTA, PERSIST-1, and the current study were smaller than the corresponding proportion seen with ruxolitinib in the COMFORT-I study (45.9% versus 5.3% with placebo). 11 The degree of symptom response was also high in a phase I/II trial of the JAK1/JAK2 inhibitor momelotinib, in which 60% to 100% of patients experienced ≥50% reductions in some individual symptoms at 3 and 6 months; however, TSS was not assessed.…”

“…Notably, INCB039110 overall was less effective in providing spleen size reductions than ruxolitinib and some JAK2 inhibitors tested in phase III clinical trials. 11,12,15,16 Few patients in our study experienced ≥35% spleen volume reduction; however, among patients who remained on treatment, the proportion achieving ≥35% spleen volume reduction increased from week 12 to 24. Additionally, more than half of the patients treated with 200 mg twice daily and nearly half of those treated with 600 mg once daily experienced a ≥10% spleen volume reduction at week 24, which was associated with clinically meaningful symptom improvement in patients treated with ruxolitinib in COMFORT-I.…”

A Comprehensive Review of Pacritinib in Myelofibrosis

“…Importantly, no minimum baseline platelet count was required for trial eligibility. Recently reported results show that pacritinib met its primary endpoint in the PERSIST-1 study 57 . Patients were randomized 2:1 to pacritinib (n = 220) versus BAT (n = 107).…”

“…PERSIST-1 (NCT01773187) is comparing the efficacy and safety of oral pacritinib 400 mg q.d. with BAT in patients with intermediate-1– or intermediate-2–risk MF, high-risk PMF, post-PV MF, or post-ET MF 57 . Primary and secondary efficacy outcomes include ≥ 35% reduction in spleen volume as assessed by MRI or CT scan and ≥ 50% improvement in MF symptoms from baseline to week 24.…”

New Strategies in Myeloproliferative Neoplasms: The Evolving Genetic and Therapeutic Landscape

“…PERSIST-1 and PERSIST-2 are phase 3 trials investigating pacritinib’s efficacy compared to BAT in MF patients with baseline thrombocytopenia. Preliminary data from PERSIST-1 show anemia responses and good tolerance in patients with baseline thrombocytopenia <50,000/uL (83). Spleen volume reduction ≥ 35% at week 24 was 19% in the pacritinib arm and 5% in the BAT arm.…”