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Results from the PAC203 phase II trial: pacritinib dose recommendation in thrombocytopenic patients with MF

Patients with myelofibrosis (MF), who are intolerant or do no longer respond to the standard of care ruxolitinib, have limited treatment options with challenging management and an approximate median overall survival of 13 months.1 In this setting, one of the alternative regimens under investigation is pacritinib, a Janus kinase 2 (JAK2) and interleukin-1 receptor-associated kinase 1 (IRAK1) inhibitor.1 Pacritinib has shown clinical superiority to best available therapy in two earlier phase III clinical trials (PERSIST-1 and PERSIST-2), when treating JAK inhibitor-naïve patients with primary MF and thrombocytopenia.2

During the 61st American Society of Hematology  Annual Meeting & Exposition (ASH 2019), Aaron Gerds presented an oral abstract2 on the results from the phase II part of the PACIFICA trial, PAC203. This study compared the efficacy and safety of different pacritinib dosing schedules in patients with MF, who no longer benefitted or were intolerant to JAK inhibitors. The current article is based on data presented at the ASH and may supersede the data in the published abstract.

Study design

  • Global, multicenter, open label, randomized phase II trial
  • N = 150 patients with MF who were ruxolitinib-intolerant or had failed ruxolitinib treatment, were randomized 1:1:1 to:
    • Pacritinib 100 mg once daily
    • Pacritinib 100 mg twice daily or;
    • Pacritinib 200 mg twice daily
  • Primary endpoint: safety and efficacy across dosing arms at week 24. Efficacy was assessed as a spleen volume response (SVR) ≥ 35% (SVR35), and as total symptom score reduction ≥ 50% (TSS50) from baseline
  • Intolerance to ruxolitinib was defined as ruxolitinib treatment for ≥ 28 days with the development of red cell transfusion requirement or Grade ≥ 3 anemia, thrombocytopenia or hemorrhage while on < 20 mg twice daily
  • Failure to benefit from ruxolitinib was defined as ruxolitinib treatment for ≥ 3 months with < 10% SVR or < 30% decrease in spleen length or regrowth to these parameters
  • Baseline patient characteristics across all dosing arms are shown in Table 1

Table 1. Baseline characteristics of patients in the PAC203 phase II trial2


All doses

(N = 161)

Median age (years)


Median platelets (/μL)


Hemoglobin < 10 (g/dL)


Peripheral blasts ≥ 1%


Median ruxolitinib duration (years)


Ruxolitinib exposure

Treatment failure







Molecular risk (n = 110)

High molecular risk

TP53 mutation




Average mutations per patient



  • Pacritinib at 200 mg twice daily showed the best efficacy, in terms of SVR35 and TSS50 reduction. The efficacy results for each dosing level are shown below in Table 2
  • Overall, symptom reduction was more pronounced in cytokine-related symptoms (night sweats, itching, bone pain) compared to spleen related symptoms (satiety, abdominal discomfort, left rib pain)

Table 2. Efficacy results reported at week 24 of the PAC203 phase II trial2

IQR, interquartile range; PLT, platelet counts; SVR, spleen volume response; TSS, total symptom score

Dose group

Patients with ≥ 35% SVR

Patients with ≥ 50% TSS reduction

Median TSS reduction (IQR)

100 mg once daily (n/N)

0% (0/52)

7.7% (4/52)

−3% (−30% to 29%)

100 mg twice daily (n/N)

1.8% (1/55)

7.3% (4/55)

−16% (−44% to 1%)

200 mg twice daily (n/N):

All patients

Patients with PLT < 50,000/μL


9.3% (5/54)

17.0% (4/24)


7.4% (4/54)


−27% (−39% to 1%)


  • The most common (> 12%) treatment-emergent adverse events (TEAEs) reported during phase II of the PAC203 trial are shown in Table 3
    • Thrombocytopenia and anemia were the most common hematological TEAEs with dose-dependent increasing incidence. However, it is worth mentioning that platelet counts were relatively stable over the entire study duration
    • The most common non-hematological TEAEs were of gastrointestinal nature, including diarrhea and nausea

Table 3. Most common treatment-related adverse events (> 12%) reported in the PAC203 phase II trial2

TEAEs, treatment-emergent adverse events

TEAEs > 12%

100 mg once daily

(N = 52)

100 mg twice daily

(N = 55)

200 mg twice daily

(N = 54)

















Abdominal pain












Peripheral edema




Decreased appetite




  • Due to the association of pacritinib and high-grade cardiac and hemorrhagic adverse events, previous phase III studies (PERSIST-1 and PERSIST-2) were put on a temporary clinical hold. Therefore, the investigators carefully analysed these TEAEs in PAC203. The rates of these TEAEs are depicted in Table 4

Table 4. Key safety results from the PAC203 phase II trial2

TEAEs, treatment-emergent adverse events


100 mg once daily

(N = 52)

100 mg twice daily

(N = 55)

200 mg twice daily

(N = 54)

Cardiac TEAEs Grade 3 (n)

5.8% (3)

5.5% (3)

3.7% (2)

Cardiac TEAEs Grade 4 (n)

0 (0)

0 (0)

0 (0)

Cardiac TEAEs Grade 5 (n)

0 (0)

1.8% (1)

0 (0)

Hemorrhagic TEAEs Grade 3 (n)

7.7% (4)

0 (0)

5.6% (3)

Hemorrhagic TEAEs Grade 4 (n)

0 (0)

0 (0)

0 (0)

Hemorrhagic TEAEs Grade 5 (n)

0 (0)

1.8% (1)

1.9% (1)

Patients with ≥ 1 Grade 3–4 TEAEs (n)

59.6% (31)

60.0% (33)

74.1% (40)

Patients with ≥ 1 serious TEAE (n)

36.5% (19)

36.4% (20)

46.3% (25)

Patients with ≥ 1 TEAE leading to discontinuation (n)

13.5% (7)

21.8% (12)

16.7% (9)

Fatal TEAEs (n)

7.7% (4)

5.5% (3)

5.6% (3)


Pacritinib showed the best efficacy at 200 mg twice daily when treating patients with MF who were ruxolitinib intolerant or did no longer respond to ruxolitinib. At that dosing level, pacritinib led to a clinically meaningful SVR and a reduction in total symptom score in patients with severe thrombocytopenia. Pacritinib was tolerable at all dose levels with only few high-grade cardiac and hemorrhagic TEAEs that were a significant concern in earlier studies. In conclusion, these early results from the PAC203 phase II trial indicate that pacritinib at 200 mg twice daily could be considered as a new treatment option for MF patients who cannot be treated with ruxolitinib. Results from the phase III stage of PAC203 (PACIFICA) that will compare pacritinib (200 mg twice daily) with best available therapy will provide further insights into these preliminary findings.

  1. Kuykendall AT, Shah S, Talati C, et al. Between a rux and a hard place: evaluating salvage treatment and outcomes in myelofibrosis after ruxolitinib discontinuation. Ann Hematol. 2018;97(3):435-441. DOI: 10.1007/s00277-017-3194-4
  2. Gerds TA, Savona MR, Scott BL, et al. Results of PAC203: a randomized phase 2 dose-finding study and determination of the recommended dose of pacritinib. Oral Abstract Session #634. 61st American Society of Hematology (ASH) Annual Meeting & Exposition; Nov 13, 2019; Orlando, Florida, US.