FDA Approval Sought for Pacritinib to Treat Myelofibrosis With Severe Thrombocytopenia


A rolling submission of a new drug application (NDA) for the JAK2/FLT3 inhibitor pacritinib has been initiated for patients with myelofibrosis and severe thrombocytopenia defined as platelet counts of less than 50,000 μL.

A rolling submission of a new drug application (NDA) for the JAK2/FLT3 inhibitor pacritinib has been initiated for patients with myelofibrosis and severe thrombocytopenia defined as platelet counts of less than 50,000 μL, according to a statement from CTI BioPharma, Corp.1

The application is based on available information from the phase 3 PERSIST-1 (NCT01773187) and PERSIST-2 trials (NCT02055781), as well as data from the phase 2 PAC203 trial.

“Today we are pleased to announce the start of a rolling NDA submission that seeks to address the important unmet medical need of [patients with] myelofibrosis with severe thrombocytopenia, a population that includes both frontline treatment-naïve patients and patients with prior exposure to JAK2 inhibitors,” said Adam R. Craig, MD, PhD, president and chief executive officer of CTI Biopharma.1 “We have started pre-commercial activities and are planning for a commercial launch in 2021, subject to priority review.”

In the PERSIST-1 trial, 327 participants were randomized in a 2:1 fashion to receive either pacritinib at a daily dose of 400 mg or physician’s choice of best available therapy, with the exception of ruxolitinib (Jakafi). In the control arm, the most commonly used therapies included hydroxycarbamide (55.7%) and a watch-and-wait approach (25.5%).2

Participants had either primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocytopenia myelofibrosis. No platelet level was required for enrollment. Notably, 32% of patients had platelet levels under 100,000 μL, while 16% had counts below 50,000 μL. The primary objective of PERSIST-1 was spleen volume reduction of 35% or greater.

The median duration of treatment in the investigational arm was 16.2 months versus 5.9 months in the control arm. Additionally, 79% of those on the control arm crossed over to the experimental arm.

After 24 weeks of follow-up, results demonstrated that spleen volume was reduced by 35% or greater in 19.1% of those who received pacritinib versus 4.7% of those who received best available therapy (P =.0003).

In the open-label PERSIST-2 trial, patients with myelofibrosis who had platelet counts of 100,000 μL or less were randomized 1:1:1 to receive either pacritinib at 400 mg once daily, pacritinib at 200 mg twice daily, or best available therapy; in this trial, patients could receive ruxolitinib.

A total of 311 patients were included in the study and 48% (n = 149) had previously received ruxolitinib.3 In the intention-to-treat efficacy population, 75 patients received pacritinib once daily, 74 received the agent twice daily, and 72 received best available therapy. Results showed that more patients who received pacritinib achieved a 35% or greater spleen volume reduction compared with those who received best available treatment, at 18% versus 3%, respectively (P =.001). Pacritinib also resulted in a 50% or greater reduction in total symptom score compared with the control, although this was not determined to be statistically significant (25% vs 14%, respectively; P =.08).

The JAK2/FLT3 inhibitor, when given at a twice-daily dose, resulted in significant improvements with regard to greater spleen volume reduction (22% vs 3% with best available therapy; P =.001) and reduction in total symptom score (32% vs 14%; P =.01). Additionally, improvement in hemoglobin and reduction in transfusion burden was also most significant at this dose level.

With regard to safety, the most common toxicities that were grade 3 or 4 in severity across the arms included thrombocytopenia (31% once daily, 32% twice daily, 18% best available therapy) and anemia (27%, 22%, and 14%, respectively).

In February 2016, PERSIST-2 was placed on clinical hold by the FDA, along with other trials evaluating the agent. The hold followed reports of patient deaths associated with intracranial hemorrhage, cardiac failure, and cardiac arrest reported in this trial. To adequately address the hold, the company provided the FDA with the final clinical study reports from PERSIST-1 and PERSIST-2; they also launched the PAC203 trial. The following year, in January 2017, the regulatory agency decided to lift the clinical hold on trials examining pacritinib.

In the PAC203 trial, investigators set out to evaluate the safety and efficacy of the JAK2/FLT3 inhibitor in patients with primary myelofibrosis who had received previous treatment with ruxolitinib. In the trial, participants were given pacritinib at 1 of the following doses: 100 mg once daily, 100 mg twice daily, or 200 mg twice daily.

Results from the trial demonstrated that the 200 mg twice daily dose of pacritinib resulted in the greatest efficacy for this patient population versus the lower doses examined.4 Moreover, spleen volume responses were reported in those with severe thrombocytopenia, which was defined as platelet counts under 50,000 μL. Pacritinib was also found to be well tolerated at the higher dose; no excess in high-grade cardiac or bleeding effects were observed with the 200-mg dose versus the other doses evaluated.

The phase 3 PACIFICA trial is also ongoing, according to CTI Biopharma Corp, and it is expected to be completed as part of a post-marketing commitment. This trial will evaluate the efficacy of pacritinib versus physician’s choice in patients with myelofibrosis and severe thrombocytopenia.5 About 348 patients are expected to enroll on the trial. Participants will be randomized 2:1 to either pacritinib of physician’s choice of treatment.

The primary objective of the trial is spleen volume. Secondary end points of the trial include total symptom score, overall survival, patient global impression change, and safety. To participate in the trial, patients must have an average platelet count of less than 50,000 μL at baseline, Dynamic International Prognostic Scoring System intermediate-1, -2, or high-risk disease, and palpable splenomegaly of 5 cm or more below the lower costal margin in the midclavicular line.


1. CTI Biopharma initiates rolling submission of new drug application (NDA) for pacritinib in myelofibrosis patients with severe thrombocytopenia. News release. CTI Biopharma Corp. October 13, 2020. Accessed October 13, 2020. https://prn.to/2SUT6Og.

2, 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). J Clin Oncol. 2015;(suppl 33):LBA7006. https://bit.ly/2SgFNHL.

3, Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol. 2018;4(5):652-659. doi:10.1001/jamaoncol.2017.5818

4, Gerds AT, Savona MR, Scott BL, et al. Results of PAC203: a randomized phase 2 dose-finding study and determination of the recommended dose of pacritinib in patients with myelofibrosis. Accessed October 1, 2020. https://bit.ly/2Sn3MVD.

5. Harrison CN, Gerds AT, Kiladjian J-J, et al. Pacifica: a randomized, controlled phase 3 study of pacritinib vs. physician’s choice in patients with primary myelofibrosis, post polycythemia vera myelofibrosis, or post essential thrombocytopenia myelofibrosis with severe thrombocytopenia (platelet count <50,000/mL). Blood. 2019;134(suppl 1):4175. doi:10.1182/blood-2019-129245

This article was originally published on OncLive as, "FDA Approval Sought for Pacritinib in Myelofibrosis With Severe Thrombocytopenia."

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