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|Ref Type||Journal Article|
|Authors||Altman JK, Foran JM, Pratz KW, Trone D, Cortes JE, Tallman MS|
|Title||Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia.|
|Journal||American journal of hematology|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
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|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|FLT3 exon 14 ins||acute myeloid leukemia||predicted - sensitive||Cytarabine + Daunorubicin + Quizartinib||Phase I||Actionable||In a Phase I trial (QuANTUM-First), the combination therapy, Quizartinib (AC220) with Cytosar-U (cytarabine) and Cerubidine (daunorubicin), resulted in 67% (6/9) of acute myeloid leukemia patients harboring a FLT3-ITD achieving a composite complete response and two patients achieving morphologic leukemia-free state (PMID: 29139135; NCT01390337).||29139135|
|Unknown unknown||acute myeloid leukemia||not applicable||Cytarabine + Daunorubicin + Quizartinib||Phase I||Actionable||In a Phase I trial (QuANTUM-First), the combination therapy, Quizartinib (AC220) with Cytosar-U (cytarabine) and Cerubidine (daunorubicin), resulted in a response in 84% (16/19) of patients with acute myeloid leukemia, including fourteen patients with a composite complete response and two patients achieving morphologic leukemia-free state (PMID: 29139135; NCT01390337).||29139135|