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Clin Cancer Res. 2016 Aug 15;22(16):4014-22. doi: 10.1158/1078-0432.CCR-15-1998. Epub 2016 Feb 26.

A Phase I Study of Quizartinib Combined with Chemotherapy in Relapsed Childhood Leukemia: A Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study.

Author information

1
Cancer and Blood Disorders Center, Seattle Children's Hospital, Seattle, Washington. todd.cooper@seattlechildrens.org.
2
Children's Center for Cancer and Blood Diseases, Children's Hospital of Los Angeles, Los Angeles, California.
3
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.
4
Doernbecher Children's Hospital, Oregon Health & Science University, Portland, Oregon.
5
Children's Hospital of Colorado, Aurora, Colorado.
6
Children's Mercy Hospital and Clinics, Kansas City, Missouri.
7
Maine Children's Cancer Program, Scarborough, Maine.
8
Dana Farber Cancer Institute/Boston Children's Hospital, Boston, Massachusetts.
9
Levine Children's Hospital, Charlotte, North Carolina.
10
Clinical Research and Development, Ambit Biosciences Corporation, San Diego, California.
11
Johns Hopkins University School of Medicine, Baltimore, Maryland.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

PMID:
26920889
DOI:
10.1158/1078-0432.CCR-15-1998
[Indexed for MEDLINE]
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