Results of PAC203: A Randomized Phase 2 Dose-Finding Study and Determination of the Recommended Dose of Pacritinib

Background: Pacritinib (PAC), an oral JAK2/IRAK 1 inhibitor, has demonstrated clinical benefit in myelofibrosis (MF) patients in two prior Phase 3 studies (PERSIST-1, PERSIST-2). PAC203 is a randomized Phase 2 dose-finding study in patients with MF who were intolerant of or failed to benefit from ruxolitinib. Herein, we describe the results, including pharmacokinetic and pharmacodynamic (PK/PD) analyses, used to identify the recommended dose of PAC for further study. Methods: Patients with DIPSS intermediate-1, -2, or high-risk MF who were intolerant of ruxolitinib (treatment ≥28 days complicated by development of RBC transfusion requirement or grade ≥3 anemia or thrombocytopenia, hematoma, and/or hemorrhage while treated with Results: PAC203 included 164 patients; 161 received treatment. Median age was 69 years; 43% had platelet count The most common treatment-emergent non-hematologic adverse events (AEs) were gastrointestinal, including diarrhea (20.5%; Grade 3: 3.1%) and nausea (20%; Grade 3: 0.6%), distributed similarly across arms. The most common hematologic AEs were thrombocytopenia and anemia, both occurring at higher frequencies at 200 mg BID (32% and 22% respectively); this did not, however, lead to higher rates of Grade 3/4 hemorrhage at higher doses (200 mg BID: 5.6%; 100 mg BID: 0%; 100 mg QD: 5.8%; all Grade 3). Similarly, the highest dose saw no excess in Grade 3/4 cardiac (200 mg BID: 3.7%; 100 mg BID: 7.3%; 100 mg QD: 3.7%; all Grade 3) or infectious (200 mg BID: 15%; 100 mg BID: 11%; 100 mg QD: 12%) AEs. In this cohort of advanced MF patients, there were 7 Grade 5 (fatal) AEs: 2 at 200 mg BID (sepsis, subdural hematoma), 3 at 100 mg BID (disease progression, subdural hematoma, heart failure), and 2 at 100 mg QD (sepsis, tuberculosis). The 200 mg BID arm had the highest observed rates of SVR ≥35% (200 mg BID: 9.3%; 100 mg BID: 1.8%; 100 mg QD: 0.0%; Figure 1) and TSS ≥50% (200 mg BID: 7.4%; 100 mg BID: 5.5%; 100 mg QD: 5.8%). Of the 5 patients with SVR ≥35% at the 200 mg BID dose, 4 had platelet counts Conclusion: PAC 200 mg BID is generally well tolerated and has demonstrated clinical activity, particularly in patients with severe thrombocytopenia (platelet count Download : Download high-res image (36KB) Download : Download full-size image Disclosures Gerds: Celgene Corporation: Consultancy, Research Funding; CTI Biopharma: Consultancy, Research Funding; Pfizer: Consultancy; Sierra Oncology: Research Funding; Incyte: Consultancy, Research Funding; Roche: Research Funding; Imago Biosciences: Research Funding. Savona: AbbVie: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees. Scott: Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Speakers Bureau. Talpaz: Imago BioSciences: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; CTI BioPharma: Research Funding; Samus Therapeutics: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Constellation: Research Funding. Harrison: Incyte: Speakers Bureau; Shire: Speakers Bureau; Gilead: Speakers Bureau; Promedior: Honoraria. Yacoub: Incyte: Consultancy, Speakers Bureau. Vannucchi: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mead: Bristol Myers-Squibb: Consultancy; Novartis: Consultancy, Honoraria, Other: Travel/accommodation expenses, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; CTI: Honoraria, Research Funding; Pfizer: Consultancy. Buckley: CTI BioPharma: Employment, Equity Ownership. Mould: CTI BioPharma: Consultancy. Tyavanagimatt: CTI BioPharma: Employment, Equity Ownership. Smith: CTI BioPharma: Employment, Equity Ownership. Mascarenhas: Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmaessentia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Roche: Consultancy, Research Funding; Merck: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Promedior: Research Funding; Merus: Research Funding.