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(2): 340-349, 2020 04.
Article
em En
| MEDLINE
| ID: mdl-31102119
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
/
Hidrocarbonetos Aromáticos com Pontes
/
Leucemia Mieloide Aguda
/
Inibidores de Proteínas Quinases
/
Tirosina Quinase 3 Semelhante a fms
/
Janus Quinase 2
/
Antineoplásicos
Idioma:
En
Revista:
Invest New Drugs
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos