A phase i study of quizartinib combined with chemotherapy in relapsed childhood leukemia: A Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) study

Todd M. Cooper, Jeannette Cassar, Elena Eckroth, Jemily Malvar, Richard Sposto, Paul Gaynon, Bill 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

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22 Citations (Scopus)

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/m2/day (elevated lipase) and 1 of 9 had a DLT (hyperbilirubinemia) at the highest tested dose of 60mg/m2/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/m2/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.

Original languageEnglish (US)
Pages (from-to)4014-4022
Number of pages9
JournalClinical Cancer Research
Volume22
Issue number16
DOIs
StatePublished - Aug 15 2016

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Lymphoma
Leukemia
Drug Therapy
Therapeutics
Blood Platelets
Phosphorylation
Hyperbilirubinemia
Cytarabine
Receptor Protein-Tyrosine Kinases
Etoposide
quizartinib
Lipase
Neutrophils
Research Design
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

A phase i study of quizartinib combined with chemotherapy in relapsed childhood leukemia : A Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) study. / Cooper, Todd M.; Cassar, Jeannette; Eckroth, Elena; Malvar, Jemily; Sposto, Richard; Gaynon, Paul; Chang, Bill; Gore, Lia; August, Keith; Pollard, Jessica A.; DuBois, Steven G.; Silverman, Lewis B.; Oesterheld, Javier; Gammon, Guy; Magoon, Daniel; Annesley, Colleen; Brown, Patrick A.

In: Clinical Cancer Research, Vol. 22, No. 16, 15.08.2016, p. 4014-4022.

Research output: Contribution to journalArticle

Cooper, TM, Cassar, J, Eckroth, E, Malvar, J, Sposto, R, Gaynon, P, Chang, B, Gore, L, August, K, Pollard, JA, DuBois, SG, Silverman, LB, Oesterheld, J, Gammon, G, Magoon, D, Annesley, C & Brown, PA 2016, 'A phase i study of quizartinib combined with chemotherapy in relapsed childhood leukemia: A Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) study', Clinical Cancer Research, vol. 22, no. 16, pp. 4014-4022. https://doi.org/10.1158/1078-0432.CCR-15-1998
Cooper, Todd M. ; Cassar, Jeannette ; Eckroth, Elena ; Malvar, Jemily ; Sposto, Richard ; Gaynon, Paul ; Chang, Bill ; Gore, Lia ; August, Keith ; Pollard, Jessica A. ; DuBois, Steven G. ; Silverman, Lewis B. ; Oesterheld, Javier ; Gammon, Guy ; Magoon, Daniel ; Annesley, Colleen ; Brown, Patrick A. / A phase i study of quizartinib combined with chemotherapy in relapsed childhood leukemia : A Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) study. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 16. pp. 4014-4022.
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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/m2/day (elevated lipase) and 1 of 9 had a DLT (hyperbilirubinemia) at the highest tested dose of 60mg/m2/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/m2/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.",
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AU - Eckroth, Elena

AU - Malvar, Jemily

AU - Sposto, Richard

AU - Gaynon, Paul

AU - Chang, Bill

AU - Gore, Lia

AU - August, Keith

AU - Pollard, Jessica A.

AU - DuBois, Steven G.

AU - Silverman, Lewis B.

AU - Oesterheld, Javier

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