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 <21 years of age with FLT3 ITD and/or TKD-mutated AML (determined using institutional assay). Key inclusion and exclusion criteria include patients who are in first or greater relapse or are refractory to induction therapy with no more than 1 attempt at remission induction and (a) fully recovered from the acute toxic effects of all prior therapy, (b) have a Karnofsky (if ≥16 years) or Lansky (if <16 years) score ≥50, and (c) been ≥90 days relapsed since hematopoietic stem cell transplantation with no active graft-versus-host disease, if relevant. Patients will undergo screening, including complete physical exam, subject-reported symptoms, and areas of disease (Figure). Patients will be enrolled in 1 of the 3 following groups: group 1 (2 to <21 years), group 2 (1 to <2 years), and group 3 (6 months to <1 year). Gilteritinib will be administered once daily starting from day 8 through day 21 of a 28-day cycle at the starting dose of 2 mg/kg/day for Group 1 and 1 mg/kg/day for Groups 2 and 3, with escalation to 2 or 3 mg/kg/day (the latter to be evaluated only if there is lack of toxicity or acceptable dose-limiting toxicity [DLT] and lack of sufficient gilteritinib activity observed at 2 mg/kg/day). Patients in all groups will receive FLAG (fludarabine, 30 mg/m ²/day; cytarabine, 2000 mg/m ²/day; granulocyte-colony stimulating factor, 5 μg/kg/day) on days −1 to 5 and prophylactic single intrathecal cytarabine (age-adjusted dose). Patients who complete 2 cycles of treatment will have the option to participate in long-term treatment (LTT) with gilteritinib for ≤2 years. An end of treatment (EOT) visit will occur 7 days after the last dose of gilteritinib or before initiation of another anticancer therapy. A follow-up visit will be performed 28 days after the EOT visit in patients who are ineligible for LTT. Patients eligible for LTT will undergo a follow-up visit 28 days after the LTT EOT visit. Follow-up for survival will be performed every 3 months for ≤2 years from the 28-day follow-up visit.

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.

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