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

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.

• Authors: Todd M Cooper, Jeannette Cassar, Elena Eckroth, Jemily Malvar, Richard Sposto, Paul Gaynon, Bill H Chang, Lia Gore, Keith August, Jessica A Pollard, Steven G DuBois, Lewis B Silverman, Javier Oesterheld, Guy Gammon, Daniel Magoon, Colleen Annesley, Patrick A Brown
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 22 Issue 16 Pg. 4014-22 (Aug 15 2016) ISSN: 1557-3265 [Electronic] United States
• PMID: 26920889 (Publication Type: Clinical Trial, Phase I, Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Benzothiazoles
• Phenylurea Compounds
• quizartinib
• fms-Like Tyrosine Kinase 3

Topics

• Adolescent
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Benzothiazoles (administration & dosage)
• Bone Marrow (pathology)
• Child
• Child, Preschool
• Drug Resistance, Neoplasm
• Female
• Gene Expression
• Genotype
• Humans
• Infant
• Leukemia (drug therapy, genetics, pathology)
• Leukemia, Myeloid, Acute (drug therapy, genetics, pathology)
• Male
• Mutation
• Phenylurea Compounds (administration & dosage)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics, pathology)
• Recurrence
• Treatment Outcome
• Young Adult
• fms-Like Tyrosine Kinase 3 (antagonists & inhibitors, genetics)