Pacritinib Shows Promise in Phase 2 Advanced Myelofibrosis Study

A new dose-finding study found a twice-daily 200 mg dose of the JAK2/IRAK1 inhibitor pacrinitib led to a spleen volume response in nearly 1 in 10 patients.

A new study suggests a dose of 200 mg of pacritinib taken twice daily is safe and demonstrates clinical activity in patients with advanced myelofibrosis.

The results of the dose-finding study, published in Blood Advances, helped investigators settle on the appropriate dose for the pivotal phase 3 study.

Pacritinib is a novel therapy that inhibits both Janus kinase 2 (JAK2) and interleukin-1 receptor-associated kinase 1 (IRAK1) and is aimed at patients who are unable to take ruxolitinib (Jakafi). In 2 earlier phase 3 studies (PERSIST-1 and PERSIST-2), the medication showed clinically meaningful spleen volume responses (SVRs), and appeared to have the potential to be effective even in patients with severe thrombocytopenia (platelet counts above 50 x 103/μL). That’s important because the 2 JAK inhibitors currently on the United States market to treat myelofibrosis have not yet been studied in patients who present with severe thrombocytopenia, wrote corresponding author Aaron T. Gerds, MD, of the Cleveland Clinic Taussig Cancer Ins

Though the PERSIST studies showed promising results, they also raised concerns due to high-grade cardiac and bleeding events observed in some study enrollees. As a result, the investigators constructed the new study, dubbed PAC203, as a phase 2 study to ascertain a recommended dosage for phase 3 study.

In PAC203, 161 patients were randomly assigned to 1 of 3 dosage cohorts: 1 group received pacritinib at a dosage of 100 mg once per day; the second group received 100 mg twice daily; the last group received 200 mg twice per day.

Each of the patients enrolled in the study had advanced myelofibrosis and was intolerant of (73%) or resistant to (76%) ruxolitinib. Half of the patients met the criteria for both intolerance and resistance. Forty-four percent of patients had severe thrombocytopenia.

The two metrics chosen to gauge efficacy were 35% or greater SVR, and 50% or greater reduction in the disease’s 7-component total symptom score (TSS) at 24 weeks.

In terms of SVR, 9.3% of patients in the 200 mg/twice daily group met the benchmark response, compared to just 1.8% in the 100 mg/twice daily group and 0% in the 100 mg once-daily group. The median reduction of -10.1% was also greatest in that group.

In terms of TSS, overall rates were similar across all 3 groups, ranging from 7.3% to 7.7%. However, the percent reduction varied across groups, with the highest median reduction in the 200 mg/twice daily group (-27%, versus -16% and -3% in the 100 mg/twice daily and 100 mg/once daily groups, respectively).

Notably, while gastrointestinal adverse events, thrombocytopenia, and anemia were the most common adverse events, there was no excess of grade 3 or higher hemorrhagic or cardiac events in the highest-dose group. The authors said those data suggest the study’s risk minimization measures were successful. Those measures will be carried forward in the phase 3 study, which is ongoing and has been named PACIFICA. That study will compare 200 mg/twice daily of pacritinib with physician’s choice therapy in patients with myelofibrosis and severe thrombocytolpenia.

As that study continues, Gerds and colleagues said the existing data leaves room for optimism.

“Pacritinib remains the only prospectively evaluated therapy supported by clinical data for treating patients with myelofibrosis and severe thrombocytopenia, an area of unmet need and the focus of the current phase 3 trial,” they concluded.


Gerds AT, Savona MR, Scott BL, et al. Determining the recommended dose of pacritinib: results from the PAC203 dose-finding trial in advanced myelofibrosis. Blood Adv. 2020;4(22):5825-5835. doi:10.1182/bloodadvances.2020003314