Pacritinib NDA Submission Planned for Myelofibrosis With Severe Thrombocytopenia


An agreement has been reached to submit a new drug application for the potential accelerated approval of the JAK2/FLT3 inhibitor pacritinib for use in patients with myelofibrosis and severe thrombocytopenia.

An agreement has been reached to submit a new drug application (NDA) for the potential accelerated approval of the JAK2/FLT3 inhibitor pacritinib for use in patients with myelofibrosis and severe thrombocytopenia, according to an announcement from CTI Biopharma Corp., the drug developer.1

The application will be based on findings from the phase 3 PERSIST-1 (NCT01773187) and PERSIST-2 trials (NCT02055781), along with data from the phase 2 PAC203 dose-ranging trial. The FDA has agreed to a rolling NDA submission that is anticipated to be put into effect in the near future, with the completion of the submission expected in the first quarter of 2021.

The ongoing phase 3 PACIFICA trial is expected to be completed as a post-marketing commitment, according to CTI Biopharma Corp.

“Since the completion of the PAC203 phase 2 dose-ranging trial, we have been working collaboratively with the FDA to identify an expeditious approval pathway for pacritinib in [patients with] myelofibrosis with severe thrombocytopenia, a patient population with an important unmet medical need due to reduced survival and limited therapeutic options,” Adam R. Craig, MD, PhD, president and chief executive officer of CTI Biopharma, stated in a press release.

“During a recent pre-NDA meeting, we identified a data package from the PERSIST-1, PERSIST-2, and PAC203 phase 2 trials that will serve as the basis for an accelerated approval application,” Craig added. “In particular, we discussed risk mitigation measures to address the FDA’s prior concerns regarding safety.”

In the open-label PERSIST-2 trial, patients with myelofibrosis and platelet counts of 100,000/μL or less were randomized in a 2:1 fashion to pacritinib or best available therapy, which could include ruxolitinib. The trial had reached its accrual goal, but then was put on a clinical hold by the FDA in February 2016, along with all other studies examining the agent.

The decision followed reports of patient deaths related to intracranial hemorrhage, cardiac failure, and cardiac arrest in PERSIST-2. To rectify the hold, the company supplied the regulatory agency with the final clinical study reports from both the PERSIST-1 and PERSIST-2 trials and initiated the PAC203 trial. In January 2017, the FDA lifted the its clinical hold on trials exploring pacritinib.

In the PAC203 trial, investigators examined the safety and efficacy of pacritinib in patients with primary myelofibrosis who received prior treatment with ruxolitinib (Jakafi). Patients received pacritinib at either 100 mg once daily, 100 mg twice daily, or 200 mg twice daily.

Results from the trial showed that the greatest efficacy achieved with the JAK2/FLT3 inhibitor was at the dose of 200 mg twice daily compared with the lower doses.2 Spleen volume responses were observed in patients with severe thrombocytopenia, defined as platelet counts less than 50,000/μL). The agent was also found to be well tolerated at this dose, with no excess in high-grade cardiac or bleeding toxicities compared with the other doses examined.

In the PERSIST-1 trial, a total of 327 patients were randomized 2:1 to receive a daily dose of pacritinib at 400 mg or physician’s choice of best available therapy, excluding ruxolitinib. The most commonly used treatments in the control arm included hydroxycarbamide (55.7%) and a watch-and-wait strategy (25.5%).3

The trial included participants with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis. No platelet level was required for enrollment. Thirty-two percent of patients had platelet levels less than 100,000/μL and 16% had counts under 50,000/μL. The primary end point of the trial was spleen volume reduction of 35% or greater.

The median duration of treatment in the pacritinib and control arms was 16.2 months and 5.9 months, respectively. Seventy-nine percent of patients in the control arm crossed over to pacritinib. Results showed that after 24 weeks of follow-up, spleen volume was reduced by 35% or more in more patients who received pacritinib versus best available therapy, at 19.1% and 4.7%, respectively (P =.0003).

In the randomized, phase 3 PACIFICA trial, investigators are examining the efficacy of pacritinib versus the physician’s choice of therapy as treatment of patients with myelofibrosis and severe thrombocytopenia.4 Approximately 348 patients are anticipated for enrollment and they will undergo randomization in a 2:1 fashion.

The primary end point of the trial is spleen volume, while key secondary end points comprised total symptom score, overall survival, patient global impression of change, and safety of pacritinib. To be eligible for enrollment, patients had to have an average platelet count of less than 50,000/μL at baseline, a 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.

"In myelofibrosis patients, severe thrombocytopenia occurs as a result of disease or drug-related toxicity from current therapies. There is no approved drug that specifically addresses the unmet need of the myelofibrosis patients who have severe thrombocytopenia,” added Craig. “Pacritinib has demonstrated clinical benefit in treating these patients in multiple trials and now has the potential to become a new treatment option for treatment-naïve and second-line myelofibrosis patients in 2021.”


  1. CTI BioPharma to submit a new drug application (NDA) for the accelerated approval of pacritinib for the treatment of myelofibrosis patients with severe thrombocytopenia. News release. CTI BioPharma Corp. September 29, 2020. October 1, 2020.
  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.
  3. 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.
  4. 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
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