Preclinical Activity and a Pilot Phase I Study of Pacritinib, an Oral JAK2/FLT3 Inhibitor, and Chemotherapy in FLT3-ITD-positive AML

Overview

Journal Invest New Drugs

Publisher Springer

Specialty Oncology

Date 2019 May 19

PMID 31102119

Citations 20

Authors

Jae Yoon Jeon

Qiuhong Zhao

Daelynn R Buelow

Mitch Phelps

Alison R Walker

Alice S Mims

Sumithira Vasu

Gregory Behbehani

James Blachly

William Blum

Rebecca B Klisovic

John C Byrd

Ramiro Garzon

Sharyn D Baker

Bhavana Bhatnagar

Affiliations

Soon will be listed here.

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.

Citing Articles

Dual inhibition of the TrkA and JAK2 pathways using entrectinib and pacritinib suppresses the growth and metastasis of HER2-positive and triple-negative breast cancers.

Regua A, Bindal S, Najjar M, Zhuang C, Khan M, Arrigo A Cancer Lett. 2024; 597:217023.

PMID: 38852701 PMC: 11533721. DOI: 10.1016/j.canlet.2024.217023.

Structure-Based Optimization of Pyrazinamide-Containing Macrocyclic Derivatives as Fms-like Tyrosine Kinase 3 (FLT3) Inhibitors to Overcome Clinical Mutations.

Zheng X, Chen Z, Guo M, Liang H, Song X, Liu Y ACS Pharmacol Transl Sci. 2024; 7(5):1485-1506.

PMID: 38751627 PMC: 11092118. DOI: 10.1021/acsptsci.4c00071.

FLT3 and IRAK4 Inhibitor Emavusertib in Combination with BH3-Mimetics in the Treatment of Acute Myeloid Leukemia.

Seipel K, Mandhair H, Bacher U, Pabst T Curr Issues Mol Biol. 2024; 46(4):2946-2960.

PMID: 38666914 PMC: 11049208. DOI: 10.3390/cimb46040184.

Potential applications of JAK inhibitors, clinically approved drugs against autoimmune diseases, in cancer therapy.

Wei X, Liu Y Front Pharmacol. 2024; 14:1326281.

PMID: 38235120 PMC: 10792058. DOI: 10.3389/fphar.2023.1326281.

Efficacy analysis of different FLT3 inhibitors in patients with relapsed/refractory acute myeloid leukemia and high-risk myelodysplastic syndrome.

Swaminathan M, Aly M, Khan A, Share B, Dhillon V, Lalo E EJHaem. 2023; 4(1):165-173.

PMID: 36819163 PMC: 9928788. DOI: 10.1002/jha2.616.

References

Larrosa-Garcia M, Baer M . FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions. Mol Cancer Ther. 2017; 16(6):991-1001. PMC: 5600895. DOI: 10.1158/1535-7163.MCT-16-0876. View

Baker S, Zimmerman E, Wang Y, Orwick S, Zatechka D, Buaboonnam J . Emergence of polyclonal FLT3 tyrosine kinase domain mutations during sequential therapy with sorafenib and sunitinib in FLT3-ITD-positive acute myeloid leukemia. Clin Cancer Res. 2013; 19(20):5758-68. PMC: 3878304. DOI: 10.1158/1078-0432.CCR-13-1323. View

Lim S, Dubielecka P, Raghunathan V . Molecular targeting in acute myeloid leukemia. J Transl Med. 2017; 15(1):183. PMC: 5576374. DOI: 10.1186/s12967-017-1281-x. View

Smith C, Wang Q, Chin C, Salerno S, Damon L, Levis M . Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature. 2012; 485(7397):260-3. PMC: 3390926. DOI: 10.1038/nature11016. View

William A, Lee A, Blanchard S, Poulsen A, Teo E, Nagaraj H . Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3).... J Med Chem. 2011; 54(13):4638-58. DOI: 10.1021/jm200326p. View

Annesley C, Brown P . The Biology and Targeting of FLT3 in Pediatric Leukemia. Front Oncol. 2014; 4:263. PMC: 4172015. DOI: 10.3389/fonc.2014.00263. View

Zimmerman E, Turner D, Buaboonnam J, Hu S, Orwick S, Roberts M . Crenolanib is active against models of drug-resistant FLT3-ITD-positive acute myeloid leukemia. Blood. 2013; 122(22):3607-15. PMC: 3837509. DOI: 10.1182/blood-2013-07-513044. View

Jarusiewicz J, Jeon J, Connelly M, Chen Y, Yang L, Baker S . Discovery of a Diaminopyrimidine FLT3 Inhibitor Active against Acute Myeloid Leukemia. ACS Omega. 2017; 2(5):1985-2009. PMC: 5452050. DOI: 10.1021/acsomega.7b00144. View

Daver N, Cortes J, Ravandi F, Patel K, Burger J, Konopleva M . Secondary mutations as mediators of resistance to targeted therapy in leukemia. Blood. 2015; 125(21):3236-45. PMC: 4440880. DOI: 10.1182/blood-2014-10-605808. View

10.

Hart S, Goh K, Novotny-Diermayr V, Tan Y, Madan B, Amalini C . Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia. Blood Cancer J. 2012; 1(11):e44. PMC: 3256753. DOI: 10.1038/bcj.2011.43. View

11.

Patel J, Gonen M, Figueroa M, Fernandez H, Sun Z, Racevskis J . Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012; 366(12):1079-89. PMC: 3545649. DOI: 10.1056/NEJMoa1112304. View

12.

Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik V, Paschka P, Roberts N . Genomic Classification and Prognosis in Acute Myeloid Leukemia. N Engl J Med. 2016; 374(23):2209-2221. PMC: 4979995. DOI: 10.1056/NEJMoa1516192. View

13.

Cheson B, Bennett J, Kopecky K, Buchner T, Willman C, Estey E . Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003; 21(24):4642-9. DOI: 10.1200/JCO.2003.04.036. View

14.

Hosseini M, Kurtz S, Abdelhamed S, Mahmood S, Davare M, Kaempf A . Inhibition of interleukin-1 receptor-associated kinase-1 is a therapeutic strategy for acute myeloid leukemia subtypes. Leukemia. 2018; 32(11):2374-2387. PMC: 6558520. DOI: 10.1038/s41375-018-0112-2. View

15.

Mascarenhas J, Hoffman R, Talpaz M, Gerds A, Stein B, Gupta V . Pacritinib vs Best Available Therapy, Including Ruxolitinib, in Patients With Myelofibrosis: A Randomized Clinical Trial. JAMA Oncol. 2018; 4(5):652-659. PMC: 5885169. DOI: 10.1001/jamaoncol.2017.5818. View

16.

Wisniewski J, Dus-Szachniewicz K, Ostasiewicz P, Ziolkowski P, Rakus D, Mann M . Absolute Proteome Analysis of Colorectal Mucosa, Adenoma, and Cancer Reveals Drastic Changes in Fatty Acid Metabolism and Plasma Membrane Transporters. J Proteome Res. 2015; 14(9):4005-18. DOI: 10.1021/acs.jproteome.5b00523. View

17.

Mesa R, Vannucchi A, Mead A, Egyed M, Szoke A, Suvorov A . Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial. Lancet Haematol. 2017; 4(5):e225-e236. PMC: 8209752. DOI: 10.1016/S2352-3026(17)30027-3. View

18.

Shih A, Meydan C, Shank K, Garrett-Bakelman F, Ward P, Intlekofer A . Combination Targeted Therapy to Disrupt Aberrant Oncogenic Signaling and Reverse Epigenetic Dysfunction in - and -Mutant Acute Myeloid Leukemia. Cancer Discov. 2017; 7(5):494-505. PMC: 5413413. DOI: 10.1158/2159-8290.CD-16-1049. View