Final Results of a Phase 2 Open-Label, Monotherapy Efficacy and Safety Study of Quizartinib (AC220) in Patients ≥ 60 Years of Age with FLT3 ITD Positive or Negative Relapsed/Refractory Acute Myeloid Leukemia
Authors: Cortes Jorge E. , Perl Alexander E , Dombret Hervé , Kayser Sabine , Steffen Björn , Rousselot Philippe , Martinelli Giovanni , Estey Elihu H. , Burnett Alan K , Gammon Guy , Trone Denise , Leo Eugen , Levis Mark J. 
Published: October 2019

Abstract
Abstract 48
FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) in acute myeloid leukemia (AML) are associated with early relapse after standard chemotherapy and poor survival. Quizartinib (AC220) is an oral FLT3 receptor tyrosine kinase inhibitor that is active against both ITD mutant and wild type FLT3, and has shown promising activity in a Phase 1 study of patients (pts) with AML. This Phase 2 study was conducted to assess the efficacy and safety of quizartinib monotherapy in FLT3-ITD positive (+) and FLT3-ITD negative (-) pts with a total of 333 pts included in two cohorts. Cohort 1 included pts aged ≥ 60 yrs with AML relapsed in <1 yr or refractory to 1st-line chemotherapy. A total of 134 pts were included in this cohort and constitute the basis for this analysis.
Data through 31 January 2012 from 134 pts in this cohort were analyzed. These pts included 92 (69%) who were FLT3 ITD(+), 41 (31%) who were FLT3-ITD(-), and 1 (1%) whose FLT3-ITD status was unknown. Half the 92 FLT3-ITD(+) pts and 46% of the 41 FLT3-ITD(-) pts were male. The FLT3-ITD(+) pts had a median age of 70 yrs (range 54 to 85 yrs), and the FLT3-ITD(-) pts had a median age of 69 yrs (range 60 to 78 yrs). Pts received quizartinib at a starting dose of 90 mg/day (females) or 135 mg/day (males and 1 female), and were treated continuously during 28-day cycles.
The composite complete remission (CRc) rate included complete remission (CR), complete remission with incomplete platelet recovery (CRp), and complete remission with incomplete hematologic recovery (CRi). For FLT3-ITD(+) pts the CRc rate was 54% (0 CR, 3% CRp, and 51% CRi), with a median duration of response of 12.7 weeks and median overall survival of 25.3 weeks. Of those refractory to their last AML therapy, 39% achieved a CRc with quizartinib. For FLT3-ITD(-) pts the CRc rate was 32% (2% CR, 2% CRp, and 27% CRi), with a median duration of response of 22.1 weeks and median overall survival of 19.0 weeks. Of those refractory to their last AML therapy, 44% achieved a CRc with quizartinib.
Efficacy Results in Relapsed/Refractory AML Pts ≥ 60 Yrs FLT3-ITD(+) (N = 92) FLT3-ITD(−) (N = 41) Cumulative CRc, n (%) 50 (54) 13 (32) CRc + PR, n (%) 66 (72) 17 (41) Prior nonresponders achieving CRc to quizartinib, n (%) 12/31 (39) 8/18 (44) Subjects discontinuing quizartinib because of HSCT, n (%) 9 (10) 1 (2) Median CRc duration, weeks 12.7 22.1 Median overall survival, weeks 25.3 19.0 CRc = composite complete remission; HSCT = hematopoietic stem cell transplantation; PR = partial remission.
The most common (≥20%) treatment-related adverse events (AEs) were nausea (40%), fatigue (31%), anemia (28%), QT interval prolongation (25%), diarrhea (23%), vomiting (23%), dysgeusia (22%), and febrile neutropenia (20%). The most common (≥10%) Grade 3 or 4 treatment-related AEs were anemia (25%), febrile neutropenia (20%), QT interval prolongation (13%), and thrombocytopenia (12%). An AE of QT interval prolongation occurred in 33/134 pts (25%) and was Grade 3 or 4 in 17 pts (13%). There was 1 occurrence of Grade 4 QT prolongation with torsade de pointes. QT interval prolongations were transient, and none were fatal. A total of 17 pts (13%) experienced a treatment-related AE resulting in discontinuation of quizartinib.
The final data from this Phase 2 study for elderly relapsed/refractory AML pts with few other available therapy options confirm the high degree of activity of quizartinib monotherapy in FLT3-ITD(+) pts and also suggest activity in FLT3-ITD(-) pts. These data represent the highest level of single agent activity observed to date for FLT3-targeted therapy in elderly pts with relapsed/refractory FLT3-ITD(+) AML. Of clinical significance in this elderly population, a number of pts refractory to prior therapy responded to quizartinib, with some pts (8%) able to bridge to potentially curative hematopoietic stem cell transplantation. Safety findings were manageable, and were primarily myelosuppression and QT prolongation that was mitigated with dose modifications.
Results from the total study population will be presented. Further Phase 1 and 2 studies investigating lower doses of quizartinib as monotherapy and in combination with other agents in FLT3-ITD(+) and FLT3-ITD(-) AML are being planned/ongoing.

Disclosures:
Cortes: Novartis: Consultancy. Perl:Ambit Biosciences: Consultancy. Dombret:Celgene: Consultancy. Steffen:Novartis: Travel/accommodations/meeting expenses Other. Rousselot:Ambit Biosciences: Consultancy. Martinelli:BMS, Novartis; Pfizer, Roche: Consultancy. Estey:Ambit Biosciences: Consultancy. Burnett:Ambit Biosciences: Consultancy. Gammon:Ambit Biosciences: Employment. Trone:Ambit Biosciences: Employment. Leo:Ambit Biosciences: Employment. Levis:Ambit Biosciences: Consultancy.