Approximately one third of patients with AML have a particular change in their leukemia cells
(called a mutation) in a gene called FLT3. The presence of a FLT3 mutation can be used to
direct treatment options.
This is an open-label phase II study. Patients will receive standard chemotherapy of
daunorubicin and cytarabine during Induction and high-dose cytarabine during Consolidation.
Patients will be randomized to gilteritinib or midostaurin. After approximately 90 patient's
complete treatment, a review of the effectiveness of gliteritinib compared to midostaurin
will be done. If gilteritinib is not as effective as midostaurin, the study may be stopped.
Bone marrow aspirate and biopsy will be done on Day 21 after start of Induction and after
Induction to assess response. Patients with a complete response may proceed to consolidation
chemotherapy. Another bone marrow aspirate and biopsy will be done after consolidation is
Mandatory prescreening bone marrow and/or blood samples are required for FLT3 testing. Any
left-over samples will be requested for future research (optional).
Mandatory bone marrow samples for research are required after Induction and Consolidation.
Optional blood samples for patients who receive gilteritinib are also requested for future
- Any patient undergoing bone marrow biopsy with suspicion of or known diagnosis of
acute myeloid leukemia (AML) will be asked to sign a Prescreening Consent to allow for
centralized testing of bone marrow/peripheral blood samples.
- Patient must have previously untreated FLT3 mutated Non M3 AML (FLT3-TKD or FLT3-ITD
- Patient must have had no prior systemic therapy for AML, except as noted below:
- Hydroxyurea and emergent leukapheresis or preemptive treatment with retinoic acid
prior to exclusion of Acute Promyelocytic Leukemia (APL) allowed.
- Prior therapy for myelodysplastic syndrome (MDS) or myeloproliferative neoplasms
(MPN) (e.g., thalidomide or lenalidomide, interferon, jakafi, cytokines,
5-azacytidine or decitabine, histone deacetylase inhibitors).
- Patient may not have hypomethylating agent within 21 days.
- Patient may not have M3 AML.
- Patient may not have AML with known Core Binding Factor -t(8;21), inv(16), t(16;16).
- Patient may not have known active Central Nervous System (CNS) leukemia.
- Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of
- Patient must be age ≥ 18 years to ≤ 65 years.
- Patient must be able to understand and willing to sign Institutional Review Board
(IRB)-approved informed consent.
- Patient must be willing to provide mandatory bone marrow and blood samples for
- Patient must have adequate organ function as measured by the following criteria,
obtained ≤ 48 hours prior to randomization except ECG and left ventricular ejection
fraction (LVEF) which can be done ≤ 2 weeks prior to randomization:
- Serum creatinine ≤ 1.5x institutional upper limit of normal (ULN), or if serum
creatinine outside normal range, then glomerular filtration rate (GFR) >40 mL/min
as measured by Cockcroft-Gault formula.
- Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 3x ULN,
unless secondary to leukemia.
- Serum total or direct bilirubin <2 mg/dL, unless due to Gilbert's, hemolysis or
- Fridericia-Corrected QT Interval (QTcF) interval ≤ 500 msec (using Friderica's
- Left Ventricular Ejection Fraction >45%.
- The patient may not be known to have hypokalemia and/or hypomagnesemia that does not
respond to supplementation.
- A female patient is eligible to participate if she is not pregnant and at least one of
the following conditions apply:
- Not a woman of childbearing potential (WOCBP) OR
- WOCBP who agrees to follow the contraceptive guidance throughout the treatment
period and for at least 180 days after the final study drug administration.
- Female patient must agree not to breastfeed or donate ova starting at screening and
throughout the study period, and for at least 180 days after the final study drug
- A male patient must agree not to donate sperm starting at screening and throughout the
study period, and for at least 120 days after the final study drug administration.
- A male patient with female partner(s) of child-bearing potential must agree to use
contraception during the treatment period, and for at least 120 days after the final
study drug administration.
- Male patient with a pregnant or breastfeeding partner(s) must agree to remain
abstinent or use a condom for the duration of the pregnancy or time partner is
breastfeeding throughout the treatment period, and for at least 120 days after the
final study drug administration.
- Patient may not have another malignancy that could interfere with the evaluation of
safety or efficacy of this combination.
- Patient may not have a history of Long QT Syndrome.
- Patient may not have evidence of uncontrolled angina, severe uncontrolled ventricular
arrhythmias, electrocardiographic evidence of acute ischemia, or congestive heart
failure (CHF) New York Heart Association (NYHA) Class 3 or 4. Patient may also not
have a history of CHF NYHA Class 3 or 4 in the past, unless a prescreening
echocardiogram (ECHO) or multigated acquisition scan (MUGA) performed within 2 weeks
prior to study entry with results of left ventricular ejection fraction >45%.
- Patient may not have had major surgery or radiation therapy within 4 weeks of
- Patient may not require treatment with concomitant drugs that are strong inducers of
CYP3A with the exception of drugs considered essential for the care of the patient.
- Patient with a known allergy to any of the study medications, their analogues, or
excipients in the various formulations of any agent are not eligible.
- Patient with known gastrointestinal (GI) disease or prior GI procedure that could
interfere with the oral absorption or tolerance of gilteritinib or midostaurin
including difficulty swallowing are not eligible.
- Patient with any serious medical or psychiatric illness that could, in the
investigator's opinion, potentially interfere with the completion of the treatment
according to the protocol are not eligible.
- Patient may not participate in any other therapeutic clinical trials, including those
with other investigational agents not included in this trial during treatment on this
study without prior approval from PrECOG.