Clinical cancer research, 2016-08-15, Vol.22 (16), p.4014-4022
To determine a safe and biologically active dose of quizartinib (AC220), a potent and selective class III receptor tyrosine kinase (RTK) FLT3 inhibitor, in combination with salvage chemotherapy in children with relapsed acute leukemia.
Quizartinib was administered orally to children with relapsed AML or MLL-rearranged ALL following 5 days of high-dose cytarabine and etoposide (AE). A 3+3 dose escalation design was used to identify a safe and biologically active dose. Plasma inhibitory assay (PIA) testing was performed weekly to determine biologic activity.
Toxicities were consistent with intensive relapsed leukemia regimens. One of 6 patients experienced a dose-limiting toxicity (DLT) at 40 mg/m(2)/day (elevated lipase) and 1 of 9 had a DLT (hyperbilirubinemia) at the highest tested dose of 60 mg/m(2)/day. Of 17 response evaluable patients, 2 had complete response (CR), 1 complete response without platelet recovery (CRp), 1 complete response with incomplete neutrophil and platelet recovery (CRi), 10 stable disease (SD), and 3 progressive disease (PD). Of 7 FLT3-ITD patients, 1 achieved CR, 1 CRp, 1 Cri, and 4 SD. FLT3-ITD patients, but not FLT3 wild-type (WT) patients, had significantly lower blast counts post-quizartinib. FLT3 phosphorylation was completely inhibited in all patients.
Quizartinib plus intensive chemotherapy is well tolerated at 60 mg/m(2)/day with near complete inhibition of FLT3 phosphorylation in all patients. The favorable toxicity profile, pharmacodynamic activity, and encouraging response rates warrant further testing of quizartinib in children with FLT3-ITD AML. Clin Cancer Res; 22(16); 4014-22. ©2016 AACR.
fms-Like Tyrosine Kinase 3 - antagonists & inhibitors ; Recurrence ; Leukemia - pathology ; Humans ; Antineoplastic Combined Chemotherapy Protocols - adverse effects ; Child, Preschool ; Drug Resistance, Neoplasm ; Infant ; Male ; Young Adult ; fms-Like Tyrosine Kinase 3 - genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy ; Leukemia, Myeloid, Acute - drug therapy ; Female ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology ; Child ; Leukemia - genetics ; Gene Expression ; Leukemia, Myeloid, Acute - pathology ; Leukemia - drug therapy ; Genotype ; Treatment Outcome ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics ; Phenylurea Compounds - administration & dosage ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Bone Marrow - pathology ; Adolescent ; Mutation ; Benzothiazoles - administration & dosage ; Leukemia, Myeloid, Acute - genetics
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