Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia

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 5 6), 60 mg/d for 14 days (DL2; n 5 7), and 40 mg/d for 14 days (DL-1; n 5 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. | I N TR ODU C TI ONOne of the most common molecular alterations observed in patients with ndAML is internal tandem duplication (ITD) mutation of the FLT3 receptor, a driver mutation for disease progression that occurs in approximately 25% of cases. 1-6 FLT3-ITD mutation identifies a high-risk population of AML patients with an increased risk of early relapse, increased mortality following SOC chemotherapy, and a high need for improved treatment wileyonlinelibrary.com/journal/ajh

Allogeneic Transplantation in First Remission Improves Outcomes Irrespective of FLT3 -ITD Allelic Ratio in FLT3 -ITD–Positive Acute Myelogenous Leukemia

“…It is also plausible that the addition of FLT3 inhibitors to induction and/or consolidation therapy prior to stem cell transplantation will yield a potential benefit of reducing early relapses and increasing the likelihood of proceeding with HSCT. Recent studies with improved CR rates and prolonged CR duration when FLT3 inhibitors are used in combination with hypomethylating agents(35) or chemotherapy(40–42) is promising that more patients can be brought to allogeneic HSCT without early relapse while logistics of allogeneic HSCT like donor identification process is ongoing. We believe that it is worth investigating the feasibility of using new generation FLT3 inhibitors incorporated into leukemia treatment before HSCT, to conditioning regimen as a part of HSCT and then in post-transplant maintenance after HSCT, in FLT3-ITD mut patients.…”

<p>Profile of Quizartinib for the Treatment of Adult Patients with Relapsed/Refractory FLT3-ITD-Positive Acute Myeloid Leukemia: Evidence to Date</p>

“…In the phase 1 dose escalation study of quizartinib with induction chemotherapy, 40 mg per day of quizartinib given on days 4-17 with standard 7+3 induction chemotherapy was identified as the maximal tolerated dose. 76 Preliminary efficacy from the trial showed a 74% (14/19) CRc, and the phase 3 randomized QuANTUM-First trial is ongoing to evaluate efficacy. 77 The results of induction chemotherapy trials with more potent second-generation FLT3 inhibitors such as quizartinib will be interesting to compare with results from the midostaurin RATIFY trial since many have speculated that some of midostaurin's clinical success is partly attributable to off-target effects.…”

Acute myeloid leukemia: advancing clinical trials and promising therapeutics

“…In an attempt to improve the response rate and more importantly the duration of response AC220 has been combined with intensive chemotherapy (anthracycline and cytarabine in the “3+7” regimen) in patients ages 18–60 years(77). Initial data from this study demonstrated that quizartinib could be safely administered with induction or consolidation chemotherapy in younger AML patients.…”