A Phase 1, Dose-Escalation Study of Gilteritinib Combined with Chemotherapy in Patients Aged 6 Months to <21 Years with FLT3 Internal Tandem Duplication-Positive Relapsed or Refractory AML

Background : Acute myeloid leukemia (AML) accounts for ~18% of all childhood leukemias (Puumala SE, et al. Pediatr Blood Cancer. 2013;60(5):728-733). Gilteritinib, an oral FMS-like tyrosine kinase 3 (FLT3) inhibitor, has demonstrated efficacy with favorable tolerability in clinical trials of adults with FLT3-mutated relapsed or refractory (R/R) AML, including internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations (Perl AE, et al. N Engl J Med. 2019;381(18):1728-1740), leading to approval for the treatment of adults with R/R AML in the United States and many other countries/regions. Since the clinical progression of FLT3 ITD AML appears to be similar in children and adults, it is expected that the clinical benefit of gilteritinib in pediatric patients with FLT3 ITD R/R AML should be similar to that demonstrated in adults. We describe an ongoing phase 1, multicenter, open-label, single-arm, dose-escalation study (ClinicalTrials.gov identifier: NCT04240002) investigating the combination of gilteritinib with chemotherapy in children, adolescents, and young adults with FLT3 ITD R/R AML, which will inform the dose for the phase 2 dose-expansion portion of the study. Study Design and Methods : This phase 1 dose-escalation study will enroll patients 6 months to Study End Points : The primary end point is identification of the maximum tolerated dose and/or recommended phase 2 dose based on the DLT observed in treatment cycle 1 and biologic activity according to plasma inhibitory activity (PIA). The secondary end points are inhibition of phosphorylated FLT3, gilteritinib pharmacokinetics, safety, tolerability, toxicity, event-free survival, overall survival, minimal residual disease assessment, and acceptability and palatability assessment of the formulation. The exploratory end points are correlation of clinical responses to gilteritinib with FLT3 PIA levels, correlation of FLT3 PIA levels and clinical responses to gilteritinib therapy with FLT3 ligand levels before and after exposure to FLAG chemotherapy, and mechanisms of innate and acquired resistance to gilteritinib. All data will be summarized with descriptive statistics for continuous end points and frequency/percentage for categorical end points. Figure 1 Figure 1. Disclosures Connor: Astellas Pharma Inc.: Research Funding. Fan: Astellas Pharma Global Development: Current Employment. Gill: Astellas Pharma Global Development: Current Employment. Hill: Astellas Pharma Global Development: Current Employment; Ligacept, LLC: Current holder of individual stocks in a privately-held company, Other: Stockholder. Philipose: Astellas Pharma Global Development: Current Employment. Delgado: Astellas Pharma Global Development: Current Employment. Tiu: Astellas Pharma, Inc.: Current Employment. Reinhardt: Abbvie: Other: Advisory board; Eusa: Other: Advisory board; Astellas Pharma Inc.: Research Funding; Janssen: Other: Advisory board; BluebirdBio: Other: Advisory board; BMS: Other: Advisory board; Novartis: Other: Advisory board; JAZZ: Other: Advisory board. OffLabel Disclosure: New Indication