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

Author:

Gerds Aaron T.1ORCID,Savona Michael R.2ORCID,Scott Bart L.3,Talpaz Moshe4,Egyed Miklos5ORCID,Harrison Claire N.6,Yacoub Abdulraheem7ORCID,Vannucchi Alessandro8ORCID,Mead Adam J.9ORCID,Kiladjian Jean-Jacques10,O’Sullivan Jennifer9,García-Gutiérrez Valentin11,Bose Prithviraj12,Rampal Raajit K.13,Miller Carole B.14,Palmer Jeanne15,Oh Stephen T.16ORCID,Buckley Sarah A.17,Mould Diane R.18,Ito Kaori18,Tyavanagimatt Shanthakumar17,Smith Jennifer A.17,Roman-Torres Karisse17,Devineni Sri17,Craig Adam R.17,Mascarenhas John O.19ORCID

Affiliation:

1. Cleveland Clinic Taussig Cancer Institute, Cleveland OH;

2. Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN;

3. Fred Hutchinson Cancer Research Center, Seattle, WA;

4. Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI;

5. Kaposi Mor Hospital, Kaposvar, Hungary;

6. Haematology, Guy’s and St Thomas’ National Health Service Foundation Trust, London, United Kingdom;

7. The University of Kansas Cancer Center, Kansas City, KS;

8. University of Florence, Azienda Ospedaliera-Universitaria Careggi, Florence, Italy;

9. National Institute for Health Research Oxford Biomedical Research Centre, Medical Research Center (MRC) Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom;

10. Hôpital Saint-Louis et Université Paris Diderot, Paris, France;

11. Ramón y Cajal Health Research Institute, University Hospital Ramón y Cajal, Madrid, Spain;

12. University of Texas MD Anderson Cancer Center, Houston, TX;

13. Memorial Sloan Kettering Cancer Center, New York, NY;

14. Saint Agnes Cancer Institute, Baltimore, MD;

15. Mayo Clinic, Phoenix, AZ;

16. Washington University School of Medicine, St. Louis, MO;

17. CTI BioPharma Inc, Seattle, WA;

18. Projections Research Inc, Phoenixville, PA; and

19. Ichan School of Medicine at Mount Sinai, New York, NY

Abstract

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.

Publisher

American Society of Hematology

Subject

Hematology

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3