A Phase I Study Of AC220 (Quizartinib) In Combination With Cytarabine and Etoposide In Relapsed/Refractory Childhood ALL and AML: A Therapeutic Advances In Childhood Leukemia & Lymphoma (TACL) Study

AC220 is a novel class III receptor tyrosine kinase (RTK) inhibitor that is potent and highly selective for mutant and wild type (WT) FLT3 with lower activity against other class III RTKs including KIT, CSF1R, RET and PDGFR. In childhood acute myeloid leukemia (AML), FLT3 internal tandem duplication mutations (FLT3-ITD) confer poor prognosis. In childhood acute lymphoblastic leukemia (ALL), high WT FLT3 expression is seen in the high risk MLL-rearranged subset.

TACL 2009-004 was the first clinical trial using AC220 in children, and the first study overall in combination with intensive chemotherapy. Children > 1 month and ≤ 21 years of age with relapsed/refractory AML or MLL-rearranged ALL (MLL-r ALL) were eligible. A standard 3+3 dose escalation design was utilized to identify a safe and biologically active dose. The three doses tested (25, 40 and 60 mg/m²/day) are significantly lower than those tested in adults. All patients (pts) received intravenous (IV) cytarabine(1 gm/m2/dose every 12 hours) and IV etoposide (150 mg/m2/dose daily) on days 1-5. AC220 was administered once daily as an oral solution on days 7-28. Patients were eligible to receive up to 2 courses of therapy. Plasma inhibitory assay (PIA) testing was performed at trough time points weekly to determine biologic activity of AC220.

Twenty-two pts were enrolled: 18 patients were evaluable for response and 20 were evaluable for toxicity. Four pts (1 ALL, 3 AML (2 FLT3-ITD)) not evaluable for response received < 75% of AC220 and 2 pts without DLTs were not evaluable for toxicity for the same reason. Four pts had relapsed MLL-r ALL, 17 relapsed AML and 1 secondary AML. Of pts with AML, 9 were FLT3-WT, 8 FLT3-ITD+, and one had unknown FLT3 status. The median number of prior regimens was 2 (range 1-10) for ALL and 3 (range 1-5) for AML. No pts with ALL had prior hematopoietic stem cell transplant (HSCT) while 10/18 with AML had prior HSCT. Toxicities were consistent with intensive relapsed leukemia regimens. Across all dose levels, non-hematologic toxicities ≥ grade 3 attributed to AC220 included vomiting (n=1), elevated transaminases (n=1), anorexia (n=2), rash (n=1), hypophosphatemia (n=1), hypoxia (n=1), headache (n=1), and infection (n=2). One of 6 pts experienced a dose-limiting toxicity (DLT) on dose level 2 (40 mg/m²/day) of grade 3 elevated lipase, and 1 of 9 pts experienced DLT of hyperbilirubinemia on dose level 3 (60 mg/m²/day). Near total (>99%) inhibition of FLT3 phosphorylation by PIA was seen in every patient across all dose levels. Therefore, dose escalation past 60 mg/m2/day was not performed and a maximum tolerated dose (MTD) was not reached. Responses are listed in the table below. Of note, 4/6 (67%) FLT3-ITD patients achieved CR or CRi. Both FLT3-ITD pts with SD had significant reduction in marrow blasts without peripheral blood count recovery. Conclusions: AC220 plus intensive chemotherapy is well tolerated at 60 mg/m2/day with near complete inhibition of FLT3 phosphorylation in all pts tested to date. The favorable toxicity profile and encouraging response rates warrant further testing ofAC220 in pediatric pts with FLT3-ITD mutated AML.

Off Label Use: AC220 is not approved for use in pediatric acute leukemia. Gammon:Ambit: Employment.