TY - JOUR
T1 - A phase i study of quizartinib combined with chemotherapy in relapsed childhood leukemia
T2 - A Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) study
AU - Cooper, Todd M.
AU - Cassar, Jeannette
AU - Eckroth, Elena
AU - Malvar, Jemily
AU - Sposto, Richard
AU - Gaynon, Paul
AU - Chang, Bill H.
AU - Gore, Lia
AU - August, Keith
AU - Pollard, Jessica A.
AU - DuBois, Steven G.
AU - Silverman, Lewis B.
AU - Oesterheld, Javier
AU - Gammon, Guy
AU - Magoon, Daniel
AU - Annesley, Colleen
AU - Brown, Patrick A.
N1 - Funding Information:
This work was financially supported by grants from the Phase One Foundation to Children's Hospital of Los Angeles, TACL Consortium. Quizartinib was provided by Ambit Biosciences Corporation. The correlative laboratory assays were funded by grants (to P. Brown) from the Leukemia and Lymphoma Society (LLS Scholar in Clinical Research Grant #2365-12) and the American Cancer Society (ACS Research Scholar Grant #120237).
Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/8/15
Y1 - 2016/8/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84982091466&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84982091466&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-15-1998
DO - 10.1158/1078-0432.CCR-15-1998
M3 - Article
C2 - 26920889
AN - SCOPUS:84982091466
SN - 1078-0432
VL - 22
SP - 4014
EP - 4022
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 16
ER -