General AML,   FLT3

Quizartinib plus chemotherapy for newly diagnosed AML

Jessica K. Altman from Northwestern University, Chicago, IL, and colleagues published in American Journal of Hematology, results  from the phase I  sequential group dose-escalation study (NCT01390337), which evaluated the safety and tolerability of quizartinib, a selective and highly potent Fms Like Tyrosine 3 (FLT3) kinase inhibitor, in combination with induction and consolidation chemotherapy in patients with newly diagnosed Acute Myeloid Leukemia (AML).

In total, 19 newly diagnosed AML patients with a median age of 43 years irrespective of their FLT3 mutation status were enrolled between November 2011 and July 2013. Dose-escalation of quizartinib occurred sequentially and patients were administered one of three quizartinib dose levels (DL) consisting of oral quizartinib at either 60 mg/d, Days 4–10 of induction (DL1, n = 6), 60 mg/d Days 4–17 of induction (DL2, n = 7) or 40 mg/d Days 4–1 of induction7 (DL-1, n = 6).  During induction patients were administered cytarabine (200mg/m2/day, Days 1–7) and daunorubicin (60 mg/m2/day, Days 1–3). High-Dose cytarabine (HiDAC) consolidation therapy was used in this study.

The primary objectives of the study were to determine the Dose Limiting Toxicities (DLTs), Maximum Tolerated Dose (MTD), Recommended phase II/III dose and safety.

Key findings:
  • Ten patients completed induction and consolidation treatment
  • Safety
    • DLTs
      • No DLTs were observed at DL1
      • Two patients treated at DL2 experienced a DLT of grade 4 pericardial effusion and febrile neutropenia/ decreased platelet count/ grade 3 QT prolongation respectively
      • One patient at DL-1 experienced a DLT of grade 3 pericarditis
    • MTD; DL-1 (quizartinib at 40 mg/d, Days 4–17)
    • Most common treatment-emergent Adverse Events (AEs) include nausea (79%), diarrhea (63%), constipation (58%), neutropenia (53%), vomiting (47%), hypokalemia (53%) and febrile neutropenia (47%)
    • Most common grade 3–4 AEs occurring in 79% of patients include febrile neutropenia (47%), neutropenia (42%), thrombocytopenia (32%), anemia (26%) and leukopenia (16%)
    • In one patient treated at the MTD, ECQ QT prolongation occurred
  • Efficacy
    • Overall Response Rate; 84% (16/19)
    • Composite Complete Response (CRc); 74% (14/19)
    • Two patients achieved morphologic leukemia-free state

Key limitations of this study includes the small sample size of the patient population. Additionally, the authors noted that enrollment was limited to 19 patients because the study was terminated early, which limited the planned readouts on safety, pharmacodynamics and preliminary efficacy.

Irrespective of the above limitations, the authors concluded that the findings of this study provide a strong evidence that “quizartinib can be safely administered in combination with standard induction and consolidation chemotherapy”. Additionally, early evidence of anti-leukemic activity of this combination regimen was observed and the authors suggested that this supports further clinical evaluation in patients with newly diagnosed AML.

Currently, quizartinib 40 mg versus placebo in combination with standard induction and consolidation salvage chemotherapy is being evaluated in the phase III QuANTUM-R study (NCT02039726) in Relapsed or Refractory (R/R) FLT3 mutated AML patients, with the primary outcome being Overall Survival (OS).

Abstract

Novel therapies have potential to improve outcomes in patients with acute myeloid leukemia (AML) harboring FLT3-ITD mutations that have high risk of relapse and poor survival following standard of care (SOC) cytarabine/anthracycline-based induction/consolidation chemotherapy. Quizartinib is a selective and highly potent FLT3 inhibitor that has shown strong single-agent activity in relapsed or refractory (R/R) AML. This phase 1, open-label, sequential group dose-escalation trial (NCT 01390337) is the first evaluating safety and tolerability of quizartinib in combination with SOC chemotherapy in newly diagnosed AML (ndAML). Nineteen patients unselected for FLT3 mutational status received one of three quizartinib dihydrochloride dose levels (DL): 60 mg/d for 7 days (DL1; n=6), 60 mg/d for 14 days (DL2; n=7), and 40 mg/d for 14 days (DL-1; n=6); administered orally starting on day 4 of chemotherapy. Median age was 43.8 years. Ten patients completed induction and consolidation. Three patients experienced dose-limiting toxicities (DLTs): 2 at DL2 (1 pericardial effusion; 1 febrile neutropenia, decreased platelet count, and QT prolongation); 1 at DL-1 (pericarditis). Maximum tolerated dose (MTD) was identified as DL-1. Most common grade 3/4 adverse events were febrile neutropenia (47%), neutropenia (42%), thrombocytopenia (32%), and anemia (26%). There were no apparent additional toxicities with addition of quizartinib to chemotherapy although grade ≤1 QT prolongation was observed at MTD. Sixteen patients (84%) achieved a response; 14 (74%) composite complete response; 2 (11%) morphologic leukemia-free state. The phase 3 QuANTUM-First trial (NCT02668653) is further evaluating the effect of quizartinib plus SOC chemotherapy in ndAML FLT3-ITD mutated patients.

References
  1. Altman J. et al. Phase 1 Study of Quizartinib in Combination With Induction and Consolidation Chemotherapy in Patients With Newly Diagnosed Acute Myeloid Leukemia. Am J Hematol. 2017 Nov 15. DOI: 10.1002/ajh.24974. [Epub ahead of print]