Final results from the PERSIST-2 trial suggest pacritinib can be more effective than best available therapy (BAT) for patients with myelofibrosis and thrombocytopenia, and the drug has no significant effect on survival.
Patients who received pacritinib were more likely to experience at least a 35% reduction in spleen volume and a 50% reduction in total symptom score (TSS).
In addition, there was no significant difference in survival between patients who received pacritinib and those who received BAT.
Interim results from PERSIST-2 had indicated that pacritinib negatively impacted survival, which was consistent with results from PERSIST-1. Because of this, the US Food and Drug Administration placed pacritinib trials on clinical hold in February 2016. The hold was lifted in January 2017.
The final results from PERSIST-2 were published in JAMA Oncology. The study was sponsored by CTI BioPharma Corp.
In this phase 3 study, researchers compared 2 dosing schedules of pacritinib to BAT. The study enrolled patients with previously treated or untreated myelofibrosis (intermediate-1/2 or high-risk) and thrombocytopenia (platelet counts ≤ 100 x 109/L).
There were 311 patients randomized to receive pacritinib once daily (n=104), pacritinib twice daily (n=107), or BAT (n=100). Patients in the BAT arm received ruxolitinib (n=44), hydroxyurea (n=19), prednisone and/or prednisolone (n=13), as well as “watchful waiting” (n=19).
Patients could crossover from BAT to pacritinib after week 24 or for progression of splenomegaly. Fifty patients in the BAT arm did cross over.
All patients had discontinued treatment at a median of 23 weeks (pacritinib once daily), 25 weeks (twice daily), and 21 weeks (BAT) from the start of treatment.
Common reasons for discontinuation (in the once daily, twice daily, and BAT arms, respectively) were the clinical hold (59%, 71%, and 27%), adverse events (14%, 9%, and 4%), physician decision (5%, 3%, and 41%), progressive disease (5%, 7%, and 11%), and death (5%, 2%, and 5%).
The intention-to-treat efficacy population included 75 patients in the once-daily arm, 74 in the twice-daily arm, and 72 in the BAT arm. The researchers said baseline characteristics were balanced across the arms.
The co-primary endpoints were the rate of patients achieving a spleen volume reduction (SVR) of 35% or more and a 50% or more reduction in TSS at week 24.
Eighteen percent of patients in the combined pacritinib arms and 3% of patients in the BAT arm achieved an SVR of 35% or more (P=0.001). Fifteen percent of patients in the pacritinib once-daily arm and 22% of patients in the twice-daily arm achieved this endpoint (P values of 0.02 and 0.001, respectively, for comparison with BAT).
Twenty-five percent of patients in the combined pacritinib arms and 14% in the BAT arm had at least a 50% reduction in TSS (P=0.079). Seventeen percent of patients in the pacritinib once-daily arm and 32% of patients in the twice-daily arm achieved this endpoint (P values of 0.65 and 0.01, respectively, for comparison with BAT).
“Pacritinib was shown to reduce both spleen volume and total symptom score, 2 very important clinical measures in myelofibrosis patients with thrombocytopenia, including those patients who received prior treatment with ruxolitinib,” said study author John Mascarenhas, MD, of Icahn School of Medicine at Mount Sinai in New York, New York.
When the clinical hold was placed, there was no significant difference in overall survival between the 3 treatment arms.
The rates of death were 14% (n=14) in the pacritinib once-daily arm, 9% (n=10) in the twice-daily arm, and 14% (n=14) in the BAT arm. For patients in the BAT arm, the death rate was lower for those who crossed over to pacritinib (8%, n=4) than for those who did not (20%, n=10).
The hazard ratios for death were 1.18 in the once-daily pacritinib arm and 0.68 in the twice-daily pacritinib arm.
Dr Mascarenhas said pacritinib had “a generally manageable safety profile.”
Common adverse events—in the once daily, twice daily, and BAT arms, respectively—included:
- Diarrhea—67%, 48%, and 15%
- Nausea—38%, 32%, and 11%
- Thrombocytopenia—33%, 34%, and 23%
- Anemia—28%, 24%, and 15%
- Vomiting—21%, 19%, and 5%
- Fatigue—17%, 17%, and 16%
- Peripheral edema—13%, 2%, and 15%
- Dizziness—14%, 15%, and 5%
- Abdominal pain—19%, 9%, and 19%
- Pyrexia—11%, 15%, and 3%.
Grade 3/4 events—in the once daily, twice daily, and BAT arms, respectively—included:
- Thrombocytopenia—31%, 32%, and 18%
- Anemia—27%, 22%, and 14%
- Neutropenia—9%, 7%, and 5%
- Pneumonia—4%, 7%, and 3%
- Fatigue—7%, 3%, and 5%
- Diarrhea—5%, 4%, and 0%
- Epistaxis—2%, 5%, and 1%.
Serious adverse events—in the once daily, twice daily, and BAT arms, respectively—included:
- Anemia—5%, 8%, and 3%
- Thrombocytopenia—2%, 6%, and 2%
- Pneumonia—5%, 6%, and 4%
- Acute renal failure—5%, 2%, and 2%
- Congestive heart failure—1%, 4%, and 2%
- Atrial fibrillation—3%, 0%, and 3%
- Cardiac arrest—2%, 0%, and 0%
- Epistaxis—2%, 2%, and 1%
- Subdural hematoma—2%, 0%, and 0%.