FDA Places Pacritinib on Full Clinical Hold

The FDA has placed a full clinical hold on trials exploring pacritinib, following reports of patient deaths related to intracranial hemorrhage, cardiac failure, and cardiac arrest in the phase III PERSIST-2 trial, according to a statement from CTI BioPharma, the developer of the JAK2/FLT3 inhibitor.

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 III 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 ≤100,000/μL were randomized in a 2:1 ratio to pacritinib or best available therapy, which could include ruxolitinib (Jakafi), 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 ASCO Annual Meeting. In this study, the tyrosine kinase inhibitor 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trial had been submitted to the FDA; however, following the clinical hold, CTI BioPharma announced that it had withdrawn its new drug application.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 2:1 to receive 400 mg pacritinib daily versus physician’s choice of best available therapy, excluding ruxolitinib. The most frequently used treatments in the control arm were hydroxycarbamide (55.7%) and a watch-and-wait strategy (25.5%).

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% of patients having platelet levels <100,000/μL and 16% having platelet counts <50,000/μL. The primary endpoint of the study was spleen volume reduction ≥35%.

The median duration of treatment was 16.2 months with pacritinib compared with 5.9 months in the control arm. Overall, 79% of those in the control arm crossed over to receive pacritinib. After 24 weeks of follow-up, the spleen volume was reduced by ≥35% for 19.1% of patients treated with pacritinib versus 4.7% of those in the best available therapy arm (P = .0003).

In those with platelets <100,000/μL, spleen volume reduction was seen in 16.7% of patients treated with pacritinib versus 0% with best available therapy (P = .0086). In those with platelet counts <50,000/μL, 22.9% of patients treated with pacritinib experienced spleen volume reduction versus none in the control arm.

Additionally, more patients treated with pacritinib experienced a ≥50% reduction in total symptom score at 24 weeks using the Myeloproliferative Neoplasm Symptom Assessment. Overall, 24.5% of patients in the pacritinib arm experienced a symptom score reduction versus 9.9% in the control group (P <.0001).

Among patients who were dependent upon red blood cell transfusions, 25% in the pacritinib arm became independent during the trial compared with none of those on best available therapy (P <.05).

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, 3 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% vs 12.3%), nausea (26.8% vs 6.6%), anemia (22.3% vs 19.8%), thrombocytopenia (16.8% vs 13.2%), and vomiting (15.9% vs 5.7%).

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.

Mesa RA, Egyed M, Szoke A, et al. 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). Presented at: 2015 ASCO Annual Meeting; May 29-June 2, 2015; Chicago, IL. Abstract LBA7006.