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Ref Type Journal Article
PMID (31102119)
Authors Jeon JY, Zhao Q, Buelow DR, Phelps M, Walker AR, Mims AS, Vasu S, Behbehani G, Blachly J, Blum W, Klisovic RB, Byrd JC, Garzon R, Baker SD, Bhatnagar B
Title Preclinical activity and a pilot phase I study of pacritinib, an oral JAK2/FLT3 inhibitor, and chemotherapy in FLT3-ITD-positive AML.
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Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FLT3 exon 14 ins acute myeloid leukemia predicted - sensitive Cytarabine + Daunorubicin + Pacritinib Phase I Actionable In a Phase I trial, treatment with Vonjo (pacritinib) in combination with Cytosar-U (cytarabine) and Cerubidine (daunorubicin) resulted in 2 complete responses and 2 stable disease in 4 evaluable patients with acute myeloid leukemia harboring a FLT3-ITD mutation and resulted in a median overall survival of 292 days and a response rate of 23.1% when combined with either the combination of Cytosar-U (cytarabine) and Cerubidine (daunorubicin) or Dacogen (decitabine) (PMID: 31102119; NCT02323607). 31102119
FLT3 exon 14 ins FLT3 D835H hematologic cancer sensitive Pacritinib Preclinical - Cell culture Actionable In a preclinical study, Vonjo (pacritinib) inhibited viability in a transformed cell line expressing a FLT3-ITD mutation and FLT3 D835H in culture (PMID: 31102119). 31102119
FLT3 exon 14 ins acute myeloid leukemia predicted - sensitive Decitabine + Pacritinib Phase I Actionable In a Phase I trial, treatment with Vonjo (pacritinib) in combination with Dacogen (decitabine) resulted in morphologic leukemia free state in 1 patient and stable disease in 5 of 8 patients with acute myeloid leukemia harboring a FLT3-ITD mutation, and resulted in a median overall survival of 292 days and a response rate of 23.1% when combined with either the combination of Cytosar-U (cytarabine) and Cerubidine (daunorubicin) or Dacogen (decitabine) (PMID: 31102119; NCT02323607). 31102119
FLT3 exon 14 ins hematologic cancer sensitive Pacritinib Preclinical - Cell culture Actionable In a preclinical study, Vonjo (pacritinib) inhibited kinase activity, phosphorylation of Flt3 and Stat5, and viability in a transformed cell line expressing a FLT3-ITD mutation in culture (PMID: 31102119). 31102119
FLT3 D835H hematologic cancer sensitive Pacritinib Preclinical - Cell culture Actionable In a preclinical study, Vonjo (pacritinib) inhibited viability in a transformed cell line expressing FLT3 D835H in culture (PMID: 31102119). 31102119
FLT3 exon 14 ins acute myeloid leukemia predicted - sensitive Pacritinib Preclinical - Cell culture Actionable In a preclinical study, Vonjo (pacritinib) inhibited viability in acute myeloid leukemia cell lines harboring a FLT3-ITD mutation in culture (PMID: 31102119). 31102119
FLT3 exon 14 ins FLT3 D835Y hematologic cancer conflicting Pacritinib Preclinical - Cell culture Actionable In a preclinical study, Vonjo (pacritinib) inhibited phosphorylation of Flt3 and Stat5 and viability in a transformed cell line expressing a FLT3-ITD mutation and FLT3 D835Y in culture (PMID: 31102119). 31102119
FLT3 exon 14 ins FLT3 D835Y acute myeloid leukemia sensitive Pacritinib Preclinical - Cell culture Actionable In a preclinical study, Vonjo (pacritinib) inhibited viability in an acute myeloid leukemia cell line harboring a FLT3-ITD mutation and FLT3 D835Y in culture (PMID: 31102119). 31102119
FLT3 exon 14 ins FLT3 F691L hematologic cancer conflicting Pacritinib Preclinical - Cell culture Actionable In a preclinical study, Vonjo (pacritinib) inhibited phosphorylation of Flt3 and Stat5 and viability in a transformed cell line expressing a FLT3-ITD mutation and FLT3 F691L in culture (PMID: 31102119). 31102119
FLT3 D835Y hematologic cancer sensitive Pacritinib Preclinical - Cell culture Actionable In a preclinical study, Vonjo (pacritinib) inhibited kinase activity and viability in a transformed cell line expressing FLT3 D835Y in culture (PMID: 31102119). 31102119