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.
Keywords:
Acute myeloid leukemia; Chemotherapy; Clinical trials; FLT3; Pacritinib.
Publication types
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Clinical Trial, Phase I
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Antineoplastic Agents / adverse effects
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use*
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Antineoplastic Combined Chemotherapy Protocols / adverse effects
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Bridged-Ring Compounds / adverse effects
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Bridged-Ring Compounds / pharmacokinetics
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Bridged-Ring Compounds / pharmacology
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Bridged-Ring Compounds / therapeutic use*
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Cell Line, Tumor
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Cell Survival / drug effects
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Cytarabine / adverse effects
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Cytarabine / therapeutic use
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Daunorubicin / adverse effects
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Daunorubicin / therapeutic use
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Decitabine / adverse effects
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Decitabine / therapeutic use
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Drug Resistance, Neoplasm / drug effects
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Female
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Humans
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Janus Kinase 2 / antagonists & inhibitors*
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Kaplan-Meier Estimate
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Leukemia, Myeloid, Acute / drug therapy*
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Leukemia, Myeloid, Acute / genetics
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Leukemia, Myeloid, Acute / metabolism
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Leukemia, Myeloid, Acute / mortality
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Male
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Middle Aged
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Mutation
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Pilot Projects
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Protein Kinase Inhibitors / adverse effects
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use*
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Pyrimidines / adverse effects
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology
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Pyrimidines / therapeutic use*
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fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
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fms-Like Tyrosine Kinase 3 / genetics
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fms-Like Tyrosine Kinase 3 / metabolism
Substances
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11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene
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Antineoplastic Agents
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Bridged-Ring Compounds
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Protein Kinase Inhibitors
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Pyrimidines
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Cytarabine
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Decitabine
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FLT3 protein, human
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fms-Like Tyrosine Kinase 3
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JAK2 protein, human
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Janus Kinase 2
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Daunorubicin