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

Summary

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.

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References

  1. 1.

    Larrosa-Garcia M, Baer MR (2017) FLT3 inhibitors in acute myeloid leukemia: current status and future directions. Mol Cancer Ther 16(6):991–1001

    CAS  Article  Google Scholar 

  2. 2.

    Annesley CE, Brown P (2014) The biology and targeting of FLT3 in pediatric leukemia. Front Oncol 4:263

    Article  Google Scholar 

  3. 3.

    Daver N, Cortes J, Ravandi F, Patel KP, Burger JA, Konopleva M, Kantarjian H (2015) Secondary mutations as mediators of resistance to targeted therapy in leukemia. Blood 125(21):3236–3245

    CAS  Article  Google Scholar 

  4. 4.

    Lim SH, Dubielecka PM, Raghunathan VM (2017) Molecular targeting in acute myeloid leukemia. J Transl Med 15(1):183

    Article  Google Scholar 

  5. 5.

    Mesa RA, Vannucchi AM, Mead A, Egyed M, Szoke A, Suvorov A, Jakucs J, Perkins A, Prasad R, Mayer J, Demeter J, Ganly P, Singer JW, Zhou H, Dean JP, te Boekhorst PA, Nangalia J, Kiladjian JJ, Harrison CN (2017) Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial. Lancet Haematol 4(5):e225–e236

    Article  Google Scholar 

  6. 6.

    Mascarenhas J, Hoffman R, Talpaz M, Gerds AT, Stein B, Gupta V, Szoke A, Drummond M, Pristupa A, Granston T, Daly R, al-Fayoumi S, Callahan JA, Singer JW, Gotlib J, Jamieson C, Harrison C, Mesa R, Verstovsek S (2018) Pacritinib vs best available therapy, including Ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol 4(5):652–659

    Article  Google Scholar 

  7. 7.

    Hosseini MM et al (2018) Inhibition of interleukin-1 receptor-associated kinase-1 is a therapeutic strategy for acute myeloid leukemia subtypes. Leukemia 32(11):2374–2387

    CAS  Article  Google Scholar 

  8. 8.

    William AD, Lee AC, Blanchard S, Poulsen A, Teo EL, Nagaraj H, Tan E, Chen D, Williams M, Sun ET, Goh KC, Ong WC, Goh SK, Hart S, Jayaraman R, Pasha MK, Ethirajulu K, Wood JM, Dymock BW (2011) 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) inhibitor for the treatment of myelofibrosis and lymphoma. J Med Chem 54(13):4638–4658

    CAS  Article  Google Scholar 

  9. 9.

    Hart S, Goh KC, Novotny-Diermayr V, Tan YC, Madan B, Amalini C, Ong LC, Kheng B, Cheong A, Zhou J, Chng WJ, Wood JM (2011) Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia. Blood Cancer J 1(11):e44

    CAS  Article  Google Scholar 

  10. 10.

    Zimmerman EI, Turner DC, Buaboonnam J, Hu S, Orwick S, Roberts MS, Janke LJ, Ramachandran A, Stewart CF, Inaba H, Baker SD (2013) Crenolanib is active against models of drug-resistant FLT3-ITD-positive acute myeloid leukemia. Blood 122(22):3607–3615

    CAS  Article  Google Scholar 

  11. 11.

    Jarusiewicz JA, Jeon JY, Connelly MC, Chen Y, Yang L, Baker SD, Guy RK (2017) Discovery of a Diaminopyrimidine FLT3 inhibitor active against acute myeloid leukemia. ACS Omega 2(5):1985–2009

    CAS  Article  Google Scholar 

  12. 12.

    Wisniewski JR et al (2015) Absolute proteome analysis of colorectal mucosa, adenoma, and Cancer reveals drastic changes in fatty acid metabolism and plasma membrane transporters. J Proteome Res 14(9):4005–4018

    CAS  Article  Google Scholar 

  13. 13.

    Baker SD, Zimmerman EI, Wang YD, Orwick S, Zatechka DS, Buaboonnam J, Neale GA, Olsen SR, Enemark EJ, Shurtleff S, Rubnitz JE, Mullighan CG, Inaba H (2013) 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 19(20):5758–5768

    CAS  Article  Google Scholar 

  14. 14.

    Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Löwenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD, International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia (2003) 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 21(24):4642–4649

    Article  Google Scholar 

  15. 15.

    Smith CC, Wang Q, Chin CS, Salerno S, Damon LE, Levis MJ, Perl AE, Travers KJ, Wang S, Hunt JP, Zarrinkar PP, Schadt EE, Kasarskis A, Kuriyan J, Shah NP (2012) Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature 485(7397):260–263

    CAS  Article  Google Scholar 

  16. 16.

    Patel JP, Gönen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, van Vlierberghe P, Dolgalev I, Thomas S, Aminova O, Huberman K, Cheng J, Viale A, Socci ND, Heguy A, Cherry A, Vance G, Higgins RR, Ketterling RP, Gallagher RE, Litzow M, van den Brink M, Lazarus HM, Rowe JM, Luger S, Ferrando A, Paietta E, Tallman MS, Melnick A, Abdel-Wahab O, Levine RL (2012) Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 366(12):1079–1089

    CAS  Article  Google Scholar 

  17. 17.

    Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, Potter NE, Heuser M, Thol F, Bolli N, Gundem G, van Loo P, Martincorena I, Ganly P, Mudie L, McLaren S, O'Meara S, Raine K, Jones DR, Teague JW, Butler AP, Greaves MF, Ganser A, Döhner K, Schlenk RF, Döhner H, Campbell PJ (2016) Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med 374(23):2209–2221

    CAS  Article  Google Scholar 

  18. 18.

    McMahon CM et al (2017) Mechanisms of acquired resistance to gilteritinib therapy in relapsed and refractory FLT3-mutated acute myeloid leukemia. Blood 130

  19. 19.

    Shih AH, Meydan C, Shank K, Garrett-Bakelman FE, Ward PS, Intlekofer AM, Nazir A, Stein EM, Knapp K, Glass J, Travins J, Straley K, Gliser C, Mason CE, Yen K, Thompson CB, Melnick A, Levine RL (2017) Combination targeted therapy to disrupt aberrant oncogenic signaling and reverse epigenetic dysfunction in IDH2- and TET2-mutant acute myeloid leukemia. Cancer Discov 7(5):494–505

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge CTI BioPharma for providing the drug and financial support for the trial and the service provided by The Ohio State University Comprehensive Cancer Center Shared Resources and Cores.

Funding

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.

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Correspondence to Bhavana Bhatnagar.

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Research support was provided by CTI BioPharma to Bhavana Bhatnagar, and all other authors declare that they have no conflict of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Jeon, J.Y., Zhao, Q., Buelow, D.R. et al. Preclinical activity and a pilot phase I study of pacritinib, an oral JAK2/FLT3 inhibitor, and chemotherapy in FLT3-ITD-positive AML. Invest New Drugs 38, 340–349 (2020). https://doi.org/10.1007/s10637-019-00786-4

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Keywords

  • Acute myeloid leukemia
  • Pacritinib
  • FLT3
  • Clinical trials
  • Chemotherapy