The FDA has placed a full clinical hold on myelofibrosis trials exploring the JAK2/FLT3 inhibitor pacritinib, following reports of patient deaths related to intracranial hemorrhage, cardiac failure and cardiac arrest in the phase 3 PERSIST-2 trial. The full hold was announced by CTI BioPharma last week.
To rectify the hold, the FDA recommended that CTI BioPharma should conduct additional dose exploration studies for pacritinib in patients with myelofibrosis. Moreover, the agency asked the company to amend existing protocols, revise consent forms and investigator brochures and submit final data from the PERSIST-2 trial and the earlier phase 3 PERSIST-1 study for further review.
“All clinical investigators worldwide have been delivered a notice of the full clinical hold,” CTI BioPharma wrote in a statement. “Under the full clinical hold, all patients currently on pacritinib must discontinue pacritinib immediately and no patients can be enrolled or start pacritinib as initial or crossover treatment.”
In the open-label PERSIST-2 trial, patients with myelofibrosis and platelet counts less than or equal to 100,000/μL were randomized in a two-to-one ratio to pacritinib or best available therapy, which could include Jakafi (ruxolitinib), which became the first drug specifically approved for patients with myelofibrosis in 2011. The trial had already reached its accrual goal at the time of the clinical hold.
Prior to the hold, pacritinib had demonstrated promising data in the PERSIST-1 trial, which was presented at the 2015 meeting of the American Society of Clinical Oncology. In this study, the agent demonstrated improvements in spleen volume and symptom control versus best available therapy for patients with myelofibrosis.
Findings from the PERSIST-1 trial had been submitted to the FDA; however, following the clinical hold, CTI BioPharma announced that it had withdrawn its new drug application. In August 2014, pacritinib was granted a fast track designation for the treatment of intermediate and high-risk myelofibrosis.
In the PERSIST-1 trial, 327 patients were randomized two-to-one to receive 400 mg pacritinib daily versus physician’s choice of best available therapy, excluding Jakafi. The most frequently used treatments in the control arm were hydroxycarbamide (55.7 percent) and a watch-and-wait strategy (25.5 percent).
Patients with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythema-myelofibrosis were eligible for the trial. There was no required platelet level for enrollment, with 32 percent of patients having platelet levels less than 100,000/μL and 16 percent having platelet counts less than 50,000/μL. The primary endpoint of the study was spleen volume reduction of at least 35 percent.
The median duration of treatment was 16.2 months with pacritinib compared with 5.9 months in the control arm. Overall, 79 percent of those in the control arm crossed over to receive pacritinib. After 24 weeks of follow-up, the spleen volume was reduced by at least 35 percent for 19.1 percent of patients treated with pacritinib versus 4.7 percent of those in the best available therapy arm.
In those with platelets less than 100,000/μL, spleen volume reduction was seen in 16.7 percent of patients treated with pacritinib versus 0 with best available therapy. In those with platelet counts less than 50,000/μL, 22.9 percent of patients treated with pacritinib experienced spleen volume reduction versus none in the control arm.
Additionally, more patients treated with pacritinib experienced a reduction of at least 50 percent in total symptom score at 24 weeks using the Myeloproliferative Neoplasm Symptom Assessment. Overall, 24.5 percent of patients in the pacritinib arm experienced a symptom score reduction versus 9.9 percent in the control group.
Among patients who were dependent upon red blood cell transfusions, 25 percent in the pacritinib arm became independent during the trial compared with none of those on best available therapy.
The most common adverse events (AEs) for pacritinib were diarrhea, nausea and vomiting. There was a low incidence of grade 3 AEs. In the pacritinib arm, three patients discontinued therapy and 13 required dose interruptions for diarrhea. There were no grade 4 gastrointestinal events reported.
The most common all-grade AEs for pacritinib versus best available therapy, respectively, were diarrhea (53.2 percent vs 12.3 percent), nausea (26.8 percent vs 6.6 percent), anemia (22.3 percent vs 19.8 percent), thrombocytopenia (16.8 percent vs 13.2 percent) and vomiting (15.9 percent vs 5.7 percent).
In the United States, CTI BioPharma and Baxalta are jointly developing pacritinib, following a license agreement in November 2013. Outside of the United States, Baxter has exclusive rights for pacritinib. At this point, the future remains unclear for the medication.