title: A Phase I Study of Quizartinib Combined with Chemotherapy in Relapsed Childhood Leukemia: A Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cancer and Blood Disorders Center, Seattle Children's Hospital, Seattle, Washington. todd.cooper@seattlechildrens.org.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Cooper
authors.affiliation: Children's Center for Cancer and Blood Diseases, Children's Hospital of Los Angeles, Los Angeles, California.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Cassar
authors.affiliation: Children's Center for Cancer and Blood Diseases, Children's Hospital of Los Angeles, Los Angeles, California.
authors.forename: Elena
authors.initials: E
authors.lastname: Eckroth
authors.affiliation: Children's Center for Cancer and Blood Diseases, Children's Hospital of Los Angeles, Los Angeles, California.
authors.forename: Jemily
authors.initials: J
authors.lastname: Malvar
authors.affiliation: Children's Center for Cancer and Blood Diseases, Children's Hospital of Los Angeles, Los Angeles, California. Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Richard
authors.initials: R
authors.lastname: Sposto
authors.affiliation: Children's Center for Cancer and Blood Diseases, Children's Hospital of Los Angeles, Los Angeles, California. Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Paul
authors.initials: P
authors.lastname: Gaynon
authors.affiliation: Doernbecher Children's Hospital, Oregon Health & Science University, Portland, Oregon.
authors.forename: Bill H
authors.initials: BH
authors.lastname: Chang
authors.affiliation: Children's Hospital of Colorado, Aurora, Colorado.
authors.forename: Lia
authors.initials: L
authors.lastname: Gore
authors.affiliation: Children's Mercy Hospital and Clinics, Kansas City, Missouri.
authors.forename: Keith
authors.initials: K
authors.lastname: August
authors.affiliation: Maine Children's Cancer Program, Scarborough, Maine.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Pollard
authors.affiliation: Dana Farber Cancer Institute/Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Steven G
authors.initials: SG
authors.lastname: DuBois
authors.affiliation: Dana Farber Cancer Institute/Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Silverman
authors.affiliation: Levine Children's Hospital, Charlotte, North Carolina.
authors.forename: Javier
authors.initials: J
authors.lastname: Oesterheld
authors.affiliation: Clinical Research and Development, Ambit Biosciences Corporation, San Diego, California.
authors.forename: Guy
authors.initials: G
authors.lastname: Gammon
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Magoon
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Colleen
authors.initials: C
authors.lastname: Annesley
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Brown
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D052160:Benzothiazoles / Q000008:administration & dosage; D001853:Bone Marrow / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D007223:Infant; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008297:Male; D009154:Mutation; D010671:Phenylurea Compounds / Q000008:administration & dosage; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D012008:Recurrence; D016896:Treatment Outcome; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D052160:Benzothiazoles; D010671:Phenylurea Compounds; C544967:quizartinib; D051941:fms-Like Tyrosine Kinase 3