Determining the recommended dose of pacritinib: results from the PAC203 dose-finding trial in advanced myelofibrosis

Abstract

PAC203 is a randomized dose-finding study of pacritinib, an oral JAK2/IRAK1 inhibitor, in patients with advanced myelofibrosis who are intolerant of or resistant to ruxolitinib. Patients were randomized 1:1:1 to pacritinib 100 mg once per day, 100 mg twice per day, or 200 mg twice per day. Enhanced eligibility criteria, monitoring, and dose modifications were implemented to mitigate risk of cardiac and hemorrhagic events. Efficacy was based on ≥35% spleen volume response (SVR) and ≥50% reduction in the 7-component total symptom score (TSS) through week 24. Of 161 patients, 73% were intolerant of and 76% had become resistant to ruxolitinib; 50% met criteria for both. Severe thrombocytopenia (platelet count <50 × 103/μL) was present in 44%. SVR rates were highest with 200 mg twice per day (100 mg once per day, 0%; 100 mg twice per day, 1.8%; 200 mg twice per day, 9.3%), particularly among patients with baseline platelet counts <50 × 103/μL (17%; 4 of 24). Although TSS response rate was similar across doses (100 mg once per day, 7.7%; 100 mg twice per day, 7.3%; 200 mg twice per day, 7.4%), median percent reduction in TSS suggested a dose-response relationship (–3%, −16%, and −27%, respectively). Pharmacokinetic and pharmacodynamic modeling based on all available data showed greatest SVR and TSS reduction at 200 mg twice per day compared with lower doses. Common adverse events were gastrointestinal events, thrombocytopenia, and anemia. There was no excess of grade ≥3 hemorrhagic or cardiac events at 200 mg twice per day. Pacritinib 200 mg twice per day demonstrated clinical activity and an acceptable safety profile and was selected as the recommended dose for a pivotal phase 3 study in patients with myelofibrosis and severe thrombocytopenia. This trial was registered at www.clinicaltrials.gov as #NCT03165734.

Efficacy and tolerability of Janus kinase inhibitors in myelofibrosis: a systematic review and network meta-analysis

“…The PACIFICA study (NCT03165734), which is recruiting patients with MF and severe thrombocytopenia (platelet counts < 50.10 9 /L at baseline), will evaluate pacritinib as first- or second-line treatment after JAK inhibitor versus physician’s choice, that may include low-dose ruxolitinib. The phase 2 PAC203 study has demonstrated that the dose of 200 mg twice daily of pacritinib provided better response than low dosages with no excess of grade 3 events [ 34 ].…”

Next Generation Therapeutics for the Treatment of Myelofibrosis

“…This phase 2 trial demonstrated that 200 mg BID was the most effective dose resulting in SVR 35% rates of 9.3% in this previously JAK inhibitor-treated population. Importantly, in patients with platelets below 50 × 10 9 /L, the SVR 35% rate was 16.7% and when considering only evaluable patients in this subgroup, 30.8% achieve an SVR 35% [ 26 ]. Given promising activity of pacritinib in thrombocytopenic patients, a phase III trial, PACIFICA, is currently accruing MF patients with a platelet count less than 50 × 10 9 /L (NCT03165734) and limited or no prior ruxolitinib exposure and randomizing them to pacritinib 200 mg twice daily versus physician’s choice.…”

JAK Be Nimble: Reviewing the Development of JAK Inhibitors and JAK Inhibitor Combinations for Special Populations of Patients with Myelofibrosis

“…Spleen responses were more common in patients treated with 200 mg BID and symptom responses occurred with similar frequency across all dose levels. [64] Therefore, a dose of 200 mg BID has been selected for a randomized phase 3 study of patients with MF with severe thrombocytopenia, disease-related symptoms, and splenomegaly (PACIFICA; NCT03165734). [65] In this study that aims to enroll 348 patients, participants will be randomized to either pacritinib or physician's choice of a single-agent therapy with a primary endpoint of spleen response at 24 weeks.…”