ASH 2017 | Gilteritinib in combination with induction and consolidation chemotherapy in newly diagnosed AML patients

In July 2017, the AML Global Portal (AGP) reported on published data from the phase I/II dose-escalation Chrysalis study, which demonstrated that single agent gilteritinib, a potent, oral Fms-like Tyrosine Kinase 3 (FLT3)/AXL inhibitor, had a favorable safety profile and was effective in patients with relapsed/refractory Acute Myeloid Leukemia (AML) with FLT3 mutations. More results from this study are reported here.¹

Keith Pratz, MD, from the John Hopkins University, Baltimore, presented at the 59th American Society of Hematology (ASH) Annual Meeting, Atlanta, GA, preliminary data from the phase I dose-escalation/expansion study (NCT02236013), which evaluated the safety and anti-tumor activity of gilteritinib in combination with intensive chemotherapy in adult patients with newly diagnosed AML with or without FLT3 mutations.²

As of October 2017, 50 AML patients with a median age of 59 years (range, 23–77 years) were enrolled in this study. FLT3 mutation status was available for 48 patients; 47.9% (23/48) were positive for FLT3 mutation (FLT3^mut+) and 52% (25/48) were negative (FLT3^mut-).

Dose-escalation of gilteritinib occurred sequentially and patients (n = 17) were administered one of three dose-levels oral of gilteritinib of either 40, 80, or 120 mg/day on Days 1–14 or 4–7 (due to DLTs) of induction therapy. During induction, patients were administered up to two cycles of cytarabine (100 mg/m²/day, Days 1–7) and idarubicin (12 mg/m²/day, Days 1–3). During consolidation, patients were administered cytarabine (1.5 g/m² every 12 hours, Days 1, 3, and 5) and once-daily gilteritinib (Days 1–14) at the induction dose for up to three cycles.Patients in the expansion cohort (n = 33) of this study were administered gilteritinib at the recommended dose +-+established at the dose-escalation stage of the study.

The primary endpoints of the study were safety and Maximum Tolerated Dose (MTD) of gilteritinib when combined with 7+3 induction and high-dose cytarabine (HiDAC) consolidation.

Key findings in patients (n = 44) evaluable for response:

• Safety

  • Dose Limiting Toxicities (DLTs) of prolonged neutropenia/ thrombocytopenia and decreased ejection fraction occurred in two patients respectively in the 40 mg/day cohort
  • MTD: not reached
  • Recommended expansion dose: 120 mg/day gilteritinib
  • Grade ≥ 3 treatment-related Adverse Effects (AEs) occurred in ≥ 10% of patients including febrile neutropenia (36.7%), thrombocytopenia (18.4%), neutropenia (16.3%), decreased platelet count (12.2%), sepsis (10.2%) and decreased white blood cell count (10.2%)
  • Serious treatment-emergent AEs related to gilteritinib occurring in > 1 patient were febrile neutropenia (n = 8), sepsis (n = 2), small intestinal obstruction (n = 2), lung infection (n = 2) and decreased ejection fraction (n = 2)
  • There were no deaths from the treatment-emergent AEs

• Efficacy

  • Composite Complete Remission (CRc) rate in FLT3^mut+ (n = 21) and FLT3^mut- (n = 23) patients: 100 % vs 60.9% respectively
  • Median OS and duration of response: not reached

In an interview with the AGP, Keith Pratz noted that the responses observed in patients treated in this phase I trial has been “good so far”. He further concluded that in patients with newly diagnosed AML, gilteritinib in combination with intensive chemotherapy was “well tolerated” with an MTD at ≥ 120 mg/day. Additionally, a higher response for this combination regimen was seen in FLT3^mut+ AML patients. 

Keith Pratz added that although gilteritinib at doses of 120 mg /day was potent, it was not as robust as that observed with the same dose administered as monotherapy. Evaluation of a dose-escalation cohort of 200 mg/day gilteritinib is ongoing.