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.

Conflict of interest statement

Conflict-of-interest disclosure: A.T.G. served on advisory boards for Kartos Therapeutics, CTI BioPharma, Promedior, Galecto, and PharmaEssentia. M.R.S. received research funding from Astex, Incyte, Takeda, and TG Therapeutics, has equity in Karyopharm, served on advisory boards and DSMBs for AbbVie, Bristol Myers Squibb, Celgene, Karyopharm, Ryvu, Sierra Oncology Takeda, and TG Therapeutics, and has consulted for Karyopharm and Ryvu. B.L.S. has consulted for Incyte, Celgene/Bristol Myers Squibb, and CTI BioPharma, has received funding from Celgene/Bristol Myers Squibb, and Incyte, and has served on the speaker’s bureau for Alexion and Agios. M.T. served on advisory boards for Bristol Myers Squibb, CTI BioPharma, Imago, Novartis, and Takeda. M.E. served on the board for AOP. C.N.H. has consulted for Novartis, AstraZeneca, CTI BioPharma, Roche, AOP, Sierra Oncology, Promedior, Constellation, Celgene/Bristol Myers Squibb, and Imago and is on the speaker’s bureau for Novartis and Janssen. A.Y. received honoraria from Incyte, Novartis, and Agios. A.V. served on the speaker’s bureau for Novartis, Bristol Myers Squibb-Celgene, Takeda, and AOP and on the advisory board for Novartis, Bristol Myers Squibb/Celgene, Incyte, CTI BioPharma, and AbbVie. A.J.M. has consulted for Novartis, Bristol Myers Squibb/Celgene, and AbbVie, has received research funding from Novartis, Bristol Myers Squibb/Celgene, and CTI BioPharma, has received honoraria from Novartis and CTI BioPharma, and has served on the speaker’s bureau for Novartis. J.-J.K. has served on advisory boards for Novartis, CTI BioPharma, AOP, Celgene, and AbbVie. V.G.-G. has received honoraria from and served on advisory committees for Novartis, Pfizer, and Celgene/Bristol Myers Squibb. P.B. has received honoraria from Incyte, Celgene/Bristol Myers Squibb, CTI BioPharma, and Kartos Therapeutics, and research funding from Incyte, Celgene/Bristol Myers Squibb, CTI BioPharma, Kartos, Constellation, Blueprint Medicines, Astellas, Pfizer, NS Pharma, and Promedior. R.K.R. has consulted for Constellation, Incyte, Celgene, Promedior, CTI, Jazz Pharmaceuticals, Blueprint, Stemline, and Galecto and received research funding from Incyte, Stemline, and Constellation. C.B.M. has received honoraria from Incyte and Bristol Myers Squibb, has served on the speaker’s bureau for Incyte and Bristol Myers Squibb, has served on advisory boards for Incyte and CTI BioPharma, and has received institutional research support from Incyte, Bristol Myers Squibb, and CTI BioPharma. S.T.O. has served as a consultant for and served on advisory boards for Incyte, Gilead Sciences, Novartis, Celgene/Bristol Myers Squibb, Blueprint Medicines, Kartos Therapeutics, Disc Medicine, PharmaEssentia, and CTI BioPharma. D.R.M. and K.I. have consulted for CTI BioPharma. J.O.M. has received institutional research funding from Incyte, CTI BioPharma, Janssen, PharmaEssentia, Novartis, Merck, Arog, Merus, Promedior, Kartos, Forbius and Roche and has received consulting fees from Incyte, Geron, Kartos, Celgene, Promedior, Prelude, and Galecto. The remaining authors declare no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Patient disposition. Outcomes for all screened and randomized patients are shown. BID, twice per day; QD, once per day.

Figure 2.

Spleen volume and TSS reduction in evaluable patients. Waterfall plots for SVR (A) and TSS (B) reduction from baseline to week 24. TSS is the 7-component version of the Total Symptom Score (inclusive of “tiredness”).

Figure 3.

Change in individual symptom scores per MPN-SAF TSS 2.0 between baseline and week 24 by dosing arm. Median percent change in individual symptom scores show greatest improvement on the 200 mg twice per day dose for the majority of abdominal- and cytokine-related symptoms. Abd, abdominal; MPN-SAF TSS, Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score.

Figure 4.

PGIC assessment (evaluable population) at week 24 by dosing arm. Number of patients with any improvement in disease symptoms was greatest at 200 mg twice per day (n = 18) compared with lower doses (100 mg once per day, n = 10; 100 mg twice per day, n = 13).

Figure 5.

Changes in hematologic parameters. (A) Median percent change in platelet counts on study treatment by dosing arm. (B) Median number of RBC transfusions per month among patients who received RBC transfusions before study treatment by dosing arm.

Figure 6.

Dose-response modeling. Modeling based on efficacy data from previous phase 3 (PERSIST-1 and PERSIST-2) studies as well as the PAC203 phase 2 study. Increasing doses are associated with better responses for both spleen volume and symptom score reduction.