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Purpose

Eligible untreated patients with FLT3 acute myeloid leukemia (AML) between the ages of 18 and 65 will be randomized to receive gilteritinib or midostaurin during induction and consolidation. Patients will also receive standard chemotherapy of daunorubicin and cytarabine during induction and high-dose cytarabine during consolidation. Gilteritinib, is an oral drug that works by stopping the leukemia cells from making the FLT3 protein. This may help stop the leukemia cells from growing faster and thus may help make chemotherapy more effective. Gilteritinib has been approved by the Food and Drug Administration (FDA) for patients who have relapsed or refractory AML with a FLT3 mutation but is not approved by the FDA for newly diagnosed FLT3 AML, and its use in this setting is considered investigational. Midostaurin is an oral drug that works by blocking several proteins on cancer cells, including FLT3 that can help leukemia cells grow. Blocking this pathway can cause death to the leukemic cells. Midostaurin is approved by the FDA for the treatment of FLT3 AML. The purpose of this study is to compare the effectiveness of gilteritinib to midostaurin in patients receiving standard combination chemotherapy for FLT3 AML.

Condition

Eligibility

Eligible Ages
Between 18 Years and 65 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Criteria


Preregistration Criteria:

- 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.

Eligibility Criteria:

- Patient must have previously untreated FLT3 mutated Non M3 AML (FLT3-TKD or FLT3-ITD
allowed).

- 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
0-3.

- 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
research.

- 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
leukemic infiltration.

- Fridericia-Corrected QT Interval (QTcF) interval ≤ 500 msec (using Friderica's
correction).

- 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
administration.

- 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
registration.

- 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.

Study Design

Phase
Phase 2
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Intervention Model Description
Open-Label, Randomized trial of Daunorubicin/Cytarabine and High Dose Cytarabine + Gilteritinib vs Midostaurin for Induction and Consolidation. FLT3 mutated patients will be stratified based on TKD vs ITD. Patients who are FLT3 ITD will be further stratified by Signal Ratio (high vs. low of FLT3 Wild Type) and Nucleophosmin 1-Mutated (NPM1) [positive vs negative].
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Arm A
Induction: Daunorubicin, cytarabine and gilteritinib. Depending on response, second cycle of Induction may be given. Consolidation: High-dose cytarabine for up to 4 cycles.
  • Drug: Gilteritinib
    Induction: 120 mg orally daily x 14 days starting on day 8 Consolidation: 120 mg orally daily x 14 days starting on day 8 of each cycle (up to 4 cycles)
    Other names:
    • ASP2215
  • Drug: Daunorubicin
    First Induction: Daunorubicin 90 mg/m²/day IV Days 1,2,3 Second Induction, if needed: Daunorubicin 45 mg/m²/day IV Days 1,2,3
    Other names:
    • Daunorubicin hydrochloride
    • Daunomycin
    • Rubidomycin
    • Cerubidine
  • Drug: Cytarabine
    Induction: Cytarabine 100 mg/m²/day continuous infusion x 7 days starting Day 1 Second Induction, if needed: Cytarabine 100 mg/m²/day continuous infusion x 7 days starting Day 1 Consolidation: Cytarabine 3 g/m² (1.5 g/m² for age ≥ 55) every 12 hours IV Days 1,3,5 for 6 doses for up to 4 cycles
    Other names:
    • Cytosar-U
    • Ara-C
    • Arabinosyl
    • Cytosine Arabinoside
Active Comparator
Arm B
Induction: Daunorubicin, cytarabine and midostaurin. Depending on response, second cycle of Induction may be given. Consolidation: High-dose cytarabine for up to 4 cycles.
  • Drug: Midostaurin
    Induction: 50 mg orally twice daily x 14 days beginning on day 8 Consolidation: 50 mg orally twice daily x 14 days beginning on day 8 of each cycle (up to 4 cycles)
    Other names:
    • RYDAPT
  • Drug: Daunorubicin
    First Induction: Daunorubicin 90 mg/m²/day IV Days 1,2,3 Second Induction, if needed: Daunorubicin 45 mg/m²/day IV Days 1,2,3
    Other names:
    • Daunorubicin hydrochloride
    • Daunomycin
    • Rubidomycin
    • Cerubidine
  • Drug: Cytarabine
    Induction: Cytarabine 100 mg/m²/day continuous infusion x 7 days starting Day 1 Second Induction, if needed: Cytarabine 100 mg/m²/day continuous infusion x 7 days starting Day 1 Consolidation: Cytarabine 3 g/m² (1.5 g/m² for age ≥ 55) every 12 hours IV Days 1,3,5 for 6 doses for up to 4 cycles
    Other names:
    • Cytosar-U
    • Ara-C
    • Arabinosyl
    • Cytosine Arabinoside

Recruiting Locations

UK Center for Clinical and Translational Science and nearby locations

University of Kentucky Markey Cancer Center
Lexington, Kentucky 40536
Contact:
Corisa Logan
859-323-5785
corisa.logan@uky.edu

More Details

NCT ID
NCT03836209
Status
Recruiting
Sponsor
PrECOG, LLC.

Study Contact

Lauren Reilly, BS
267-239-7265
PrE0905@precogllc.org

Detailed Description

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 complete. 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.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.