Pacritinib Shows Mixed Results for Advanced Myelofibrosis

Srdan Verstovsek, MD, PhD

Treatment with pacritinib significantly reduced spleen volume but failed to improve total symptom score (TSS) compared with best available therapy for thrombocytopenic patients with high-risk myelofibrosis, according to topline findings for the coprimary endpoints of the phase III PERSIST-2 trial that were announced by the developer of the JAK2 inhibitor, CTI BioPharma.

In the randomized trial, 311 patients with platelet counts of ≤100,000/μL were treated with pacritinib or best available therapy, which may have included ruxolitinib (Jakafi). Efficacy was assessable for 221 patients with at least 24 weeks of follow-up, in which pacritinib showed a statistically significant ≥35% reduction in spleen volume versus best available therapy (P <.01); however, a 50% reduction in TSS was not seen with pacritinib (P = .0791).

Despite missing the coprimary endpoint of TSS, principal investigator Srdan Verstovsek, MD, PhD, labeled the results encouraging, due to the high unmet need for this population of patients. "Data from the PERSIST-2 prospective randomized, controlled trial is encouraging because we need an effective therapy to treat the most challenging patients with low platelet counts we see in our practice," he said in a statement.

"Unlike patients with myelofibrosis who have normal baseline platelet counts where median survival is reported at 88 months, we recently reported from our institution's experience that patients with severe thrombocytopenia had a median survival of about 14 months," Verstovsek, director, Clinical Research Center for MPNs at the University of Texas MD Anderson Cancer Center, said in a statement. "These patients represent up to 30% of all myelofibrosis patients and an unmet medical need."

In the study, patients were randomized to receive best available therapy or pacritinib at either 200 mg twice daily or 400 mg once daily. MRI or CT scans were used to measure spleen volume reduction from baseline to week 24. TSS was measured using a self-reported assessment of 7 key symptoms, as measured by modified Myeloproliferative Neoplasm Symptom Assessment (MPN-SAF TSS 2.0).

The most common adverse events (AEs) reported in the PERSIST-2 trial were diarrhea, nausea, and vomiting. Additionally, the company noted that cardiac and bleeding AEs were similar between the pacritinib and best available therapy arms. Moreover, the company noted that mortality rates were similar in each group.

Prior to the hold, pacritinib had demonstrated promising data in the phase III PERSIST-1 trial, which was presented at the 2015 ASCO Annual Meeting. In this study, the JAK2 inhibitor demonstrated improvements in spleen volume and TSS versus best available therapy for patients with myelofibrosis. Findings from the PERSIST-1 trial had been submitted to the FDA; however, following the clinical hold, CTI BioPharma announced that it had withdrawn its new drug application.

In the PERSIST-1 trial, platelet levels were not specified as an enrollment criterion, with 32% of patients having platelet levels <100,000/μL and 16% having platelet counts <50,000/μL. After 24 weeks of follow-up, the spleen volume was reduced by ≥35% for 19.1% of patients treated with pacritinib versus 4.7% of those in the best available therapy, which did not include ruxolitinib (P = .0003). Additionally, 24.5% of patients had a reduction in TSS with pacritinib versus 9.9% in the control group (P <.0001).

In those with platelets <100,000/μL, spleen volume reduction was seen in 16.7% of patients treated with pacritinib versus 0% with best available therapy (P = .0086). In those with platelet counts <50,000/μL, 22.9% of patients treated with pacritinib experienced spleen volume reduction versus none in the control arm.

The most common all-grade AEs for pacritinib versus best available therapy, respectively, were diarrhea (53.2% vs 12.3%), nausea (26.8% vs 6.6%), anemia (22.3% vs 19.8%), thrombocytopenia (16.8% vs 13.2%), and vomiting (15.9% vs 5.7%).

"Having analyzed data from two phase III trials with the only JAK inhibitor to be studied in severely thrombocytopenic patients, including patients on JAK2 therapy or those who failed prior JAK2, we are encouraged by pacritinib's clinical profile in this difficult-to-treat group of patients with myelofibrosis," James A. Bianco, MD, president and chief executive officer, CTI BioPharma, said in a statement.

Additional assessments and full data analysis are still ongoing for the PERSIST-2 study. The company plans to submit data from the study for presentation at an upcoming medical meeting.

Mesa RA, Egyed M, Szoke A, et al. 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). Presented at: 2015 ASCO Annual Meeting; May 29-June 2, 2015; Chicago, IL. Abstract LBA7006.

The FDA placed the PERSIST-2 trial on a full clinical hold in February 2016, following reports of deaths related to intracranial hemorrhage, cardiac failure, and cardiac arrest. All patients were required to discontinue therapy under the hold. Out of the 311 patients enrolled, 221 had received treatment for ≥24 weeks, which was required for primary endpoint assessment.