Preclinical activity and a pilot phase I study of pacritinib, an oral JAK2/FLT3 inhibitor, and chemotherapy in FLT3-ITD-positive AML

• Type of Material: Article
• Authors: Jae Yoon Jeon, Ohio State University; Qiuhong Zhao, Ohio State University; Daelynn R. Buelow, Ohio State University; Mitch Phelps, Ohio State University; Alison R. Walker, Ohio State University; Alice S. Mims, Ohio State University; Sumithira Vasu, Ohio State University; Gregory Behbehani, Ohio State University; James Blachly, Ohio State University; William Blum, Emory University; Rebecca Klisovic, Emory University; John C. Byrd, Ohio State University; Ramiro Garzon, Ohio State University; Sharyn D. Baker, Ohio State University; Bhavana Bhatnagar, Ohio State University
• Language: English
• Date: 2020-04-01
• Publisher: Springer
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © Springer Science+Business Media, LLC, part of Springer Nature 2019.
• Final Published Version (URL): http://dx.doi.org/10.1007/s10637-019-00786-4
• Title of Journal or Parent Work: Investigational New Drugs
• Volume: 38
• Issue: 2
• Start Page: 340
• End Page: 349
• Grant/Funding Information: This work was supported by CTI BioPharma.; It was also supported by the National Institute of Health grants R01 CA138744 to Sharyn D. Baker, R35 CA197734 to John C. Byrd and Cancer Center Support Grant P30 CA021765, funds from The Ohio State University Comprehensive Cancer Center Pelotonia foundation, and Eli Lilly fellowship to Jae Yoon Jeon.
• Keywords: Science & Technology; Pharmacology & Pharmacy; Pacritinib; Clinical trials; Discovery; Chemotherapy; Life Sciences & Biomedicine; Therapy; Myelofibrosis; Mutations; Acute myeloid leukemia; Oncology; FLT3
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Oncology; Health Sciences, Rehabilitation and Therapy; Chemistry, Biochemistry

Abstract

Activating FLT3 internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) associate with inferior outcomes. We determined that pacritinib, a JAK2/FLT3 inhibitor, has in vitro activity against FLT3-ITD and tyrosine kinase domain (TKD) mutations. Therefore, we conducted a phase I study of pacritinib in combination with chemotherapy in AML patients with FLT3 mutations to determine the pharmacokinetics and preliminary toxicity and clinical activity. Pacritinib was administered at a dose of 100 mg or 200 mg twice daily following a 3 + 3 dose-escalation in combination with cytarabine and daunorubicin (cohort A) or with decitabine induction (cohort B). A total of thirteen patients were enrolled (five in cohort A; eight in cohort B). Dose limiting toxicities include hemolytic anemia and grade 3 QTc prolongation in two patients who received 100 mg. Complete remission was achieved in two patients in cohort A, one of whom had a minor D835Y clone at baseline. One patient in cohort B achieved morphologic leukemia free state. Seven patients (two in cohort A; five in cohort B) had stable disease. In conclusion, pacritinib, an inhibitor of FLT3-ITD and resistant-conferring TKD mutations, was well tolerated and demonstrated preliminary anti-leukemic activity in combination with chemotherapy in patients with FLT3 mutations.