A Phase I Study of Quizartinib Combined With Chemotherapy in Relapsed Childhood Leukemia: A Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study
Mené sur 17 patients pédiatriques atteints d'une leucémie aiguë récidivante, cet essai de phase I évalue la dose maximale tolérée et l'activité antitumorale du quizartinib en combinaison avec une chimiothérapie de sauvetage
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 60 mg/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.