Final Results of A Phase 1 Study Investigating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Quizartinib (AC220) Administered Daily to Patients with Relapsed or Refractory Acute Myeloid Leukemia Irrespective of FLT3-ITD Status
Authors: Cortes Jorge E. , Kantarjian Hagop M. , Foran James M. , Ghirdaladze Darejan , Zodelava Mamia , Borthakur Gautam , Gammon Guy , Trone Denise , Armstrong Robert C , James Joyce , Levis Mark J. 
Published: October 2019

Abstract
Abstract 1507
FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) are associated with early relapse after standard chemotherapy and poor survival. Quizartinib is an oral FLT3 receptor tyrosine kinase (RTK) inhibitor that inhibits both ITD-mutant and wild-type FLT3 and displays efficacy in preclinical models of AML. In this first-in-human study, quizartinib was evaluated in patients with relapsed or refractory AML who were enrolled irrespective of FLT3-ITD status.
Quizartinib was administered orally on an intermittent schedule (ID, 14 days on, 14 days off) at 12–450 mg/day or continuously (CD) at 200 or 300 mg/day. A total of 76 patients (61% male; 90% white; median age 60 years [23–86]) received quizartinib; median number of prior treatments was 3 (0–12), including 16% with a prior hematopoietic stem cell transplant. FLT3-ITD status was 22% positive (+) (n=17), 49% negative (−) (n=37), and 29% indeterminate/not tested (ind) (n=22).
Plasma inhibitory activity assays using plasma samples collected at trough timepoints showed a high degree of FLT3 inhibition at low dose levels (18 mg/day and higher), indicative of potent in vivo FLT3 inhibition. Marked inhibition of FLT3 phosphorylation was also demonstrated in peripheral blood following administration of quizartinib.
Responses were observed in 23/76 patients (30%), with 10 patients (13%) having a best response of any type of complete remission (CR=morphologic leukemia-free state with absolute neutrophil count >1×109/L and platelet count ≥100×109/L, and normal marrow differential with <5% blasts with no Auer rods; CRp=CR with incomplete platelet recovery; CRi=CR with incomplete hematologic recovery). Responses included 2 CR, 3 CRp, 5 CRi, and 13 (17%) partial remissions (PR, same hematologic values as CR but with a decrease of '50% in % blasts in the bone marrow aspirate to 5% to 25%; a value of <5% blasts was considered a PR if Auer rods were present). Responses were observed at doses as low as 18 mg/day ID. Nine of 17 FLT3-ITD(+) patients responded (53%; 1 CR, 1 CRp, 2 CRi, 5 PR) compared to 5/37 FLT3-ITD(−) patients (14%; 2 CRp, 3 PR) and 9/22 with FLT3-ITD(ind) status (41%; 1 CR, 3 CRi, 5 PR). Median duration of response was 13.3 weeks (95% confidence interval [CI]: 11.0, 29.0 weeks): 9.7 weeks for FLT3-ITD(+) patients (95% CI: 4.1, 29); 23.7 weeks for FLT3-ITD(−) patients (95% CI: 11, not reached); and 12.4 weeks for FLT3-ITD(ind) patients(95% CI: 8, 53). Median overall survival was 14.0 weeks (95% CI: 10.9, 18.6 weeks): 18.3 weeks for FLT3-ITD(+) patients (95% CI: 10.6, 27.1); 9.7 weeks for FLT3-ITD(−) patients (95% CI: 5.6, 14.0); and 18.7 weeks for FLT3-ITD(ind) patients (95% CI: 14.0, 21.1).
Quizartinib was generally well tolerated. The most common drug-related AEs (>10% incidence) were nausea (16%), prolonged ECG QT interval (12%), vomiting (11%), and dysgeusia (11%); most were ≤Grade 2. The maximum tolerated dose was 200 mg/day CD. The dose-limiting toxicity was QTcF interval prolongation, which occurred in 38% of subjects at 300 mg/day CD and in 6% at 200 mg/day CD. QTcF interval prolongation was dose dependent, and there were no associated arrhythmias. Grade 3 AEs related to quizartinib occurring in >1 patient were prolonged ECG QT interval (4 patients [5%]), anemia (3 patients [4%]), and fatigue (2 patients [3%]). Two treatment-related Grade 4 AEs (thrombocytopenia and hypoalbuminemia) were reported in 1 patient each (1%).
The encouraging efficacy results in both FLT3-ITD(+) and FLT3 ITD(−) patients and an acceptable safety profile in this high-risk population support continued clinical evaluation of quizartinib with lower doses. A recent 333 patient Phase 2 study in a similar population given quizartinib at 200, 135, or 90 mg/day has been completed, and, considering the clinical activity observed at low doses, quizartinib is also being studied in patients with relapsed or refractory AML at 30 and 60 mg/day.

Disclosures:
Cortes: Novartis: Consultancy. Kantarjian:Ambit Biosciences: Consultancy. Foran:Ambit Biosciences: Consultancy. Ghirdaladze:Ambit Biosciences: Consultancy. Zodelava:Ambit Biosciences: Consultancy. Borthakur:Ambit Biosciences: Consultancy. Gammon:Ambit Biosciences: Employment. Trone:Ambit Biosciences: Employment. Armstrong:Ambit Biosciences: Employment. James:Ambit Biosciences: Employment. Levis:Ambit Biosciences: Consultancy.