Gilteritinib vs Midostaurin in FLT3 Mutated Acute Myeloid Leukemia

NCT ID: NCT03836209

Last Updated: 2025-06-15

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 181 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-12-06
• Study Completion Date: 2026-12-31

Brief Summary

Eligible untreated patients with FLT3 acute myeloid leukemia (AML) between the ages of 18 and 70 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 combination chemotherapy for FLT3 AML.

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 the first cycle of 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 if patient receives Consolidation, after the first cycle of Consolidation.

Conditions

Acute Myeloid Leukemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm A

Induction: Daunorubicin, cytarabine and gilteritinib. Depending on response, second cycle of Induction may be given.

Consolidation: High-dose cytarabine and gilteritinib.

Group Type: EXPERIMENTAL

Gilteritinib

Intervention Type: DRUG

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)

Daunorubicin

Intervention Type: DRUG

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

Cytarabine

Intervention Type: DRUG

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 (recommend 1.5 g/m² for age ≥ 55 or patients with decreased creatinine clearance) every 12 hours IV Days 1,3,5 or Days 1-3 for 6 doses for up to 4 cycles

Arm B

Induction: Daunorubicin, cytarabine and midostaurin. Depending on response, second cycle of Induction may be given.

Consolidation: High-dose cytarabine and midostaurin.

Group Type: ACTIVE_COMPARATOR

Midostaurin

Intervention Type: DRUG

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)

Daunorubicin

Intervention Type: DRUG

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

Cytarabine

Intervention Type: DRUG

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 (recommend 1.5 g/m² for age ≥ 55 or patients with decreased creatinine clearance) every 12 hours IV Days 1,3,5 or Days 1-3 for 6 doses for up to 4 cycles

Interventions

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)

Intervention Type: 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)

Intervention Type: 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

Intervention Type: 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 (recommend 1.5 g/m² for age ≥ 55 or patients with decreased creatinine clearance) every 12 hours IV Days 1,3,5 or Days 1-3 for 6 doses for up to 4 cycles

Intervention Type: DRUG

Other Intervention Names

ASP2215; RYDAPT; Daunorubicin hydrochloride; Daunomycin; Rubidomycin; Cerubidine; Cytosar-U; Ara-C; Arabinosyl; Cytosine Arabinoside

Eligibility Criteria

Exclusion Criteria

• 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).
• Initiation of standard of care 7+3 induction chemotherapy using same regimen and doses as defined in protocol while awaiting prescreening test results
• Patient may not have received 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.

° Prophylaxis with intrathecal chemotherapy is allowed prior to or during induction/consolidation.

• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-3.
• Patient must be age ≥ 18 years to ≤ 70 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 treatment 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 treatment 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 and P-gp.
• 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Astellas Pharma Inc

INDUSTRY

Sponsor Role: collaborator

PrECOG, LLC.

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Selena Luger, MD

Role: STUDY_CHAIR

University of Pennsylvania

Locations

HonorHealth Research Institute

Scottsdale, Arizona, United States

University of California, San Francisco-Fresno (University Oncology Associates)

Clovis, California, United States

UCLA

Los Angeles, California, United States

Kaiser Permanente Oakland

Oakland, California, United States

UC Irvine Health

Orange, California, United States

Kaiser Permanente Roseville

Roseville, California, United States

Kaiser Permanente Santa Clara

Santa Clara, California, United States

Mayo Clinic- Jacksonville, FL

Jacksonville, Florida, United States

Augusta University Medical Center

Augusta, Georgia, United States

University of Chicago Medical Center

Chicago, Illinois, United States

Northwestern University Feinberg School of Medicine

Chicago, Illinois, United States

Franciscan Health Indianapolis

Indianapolis, Indiana, United States

University of Kentucky Markey Cancer Center

Lexington, Kentucky, United States

Ochsner Clinic Foundation

New Orleans, Louisiana, United States

Johns Hopkins University

Baltimore, Maryland, United States

Tufts Medical Center

Boston, Massachusetts, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

St. Joseph's Mercy Hospital

Ann Arbor, Michigan, United States

Mayo Clinic- Rochester, MN

Rochester, Minnesota, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

Atlantic Health Systems/Morristown Medical Center

Morristown, New Jersey, United States

Northwell Health

Lake Success, New York, United States

Mount Sinai

New York, New York, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Weill Cornell Medicine New York Presbyterian Hospital

New York, New York, United States

University of Rochester Medical Center

Rochester, New York, United States

SUNY Upstate Medical University

Syracuse, New York, United States

East Carolina University

Greenville, North Carolina, United States

University of Cincinnati Medical Center

Cincinnati, Ohio, United States

University Hospitals Cleveland Medical Center

Cleveland, Ohio, United States

University of Oklahoma Stephenson Cancer Center

Oklahoma City, Oklahoma, United States

Geisinger Medical Center

Danville, Pennsylvania, United States

Penn State Milton S. Hershey Medical Center

Hershey, Pennsylvania, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

Thomas Jefferson University

Philadelphia, Pennsylvania, United States

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States

Vanderbilt University

Nashville, Tennessee, United States

LDS Hospital

Salt Lake City, Utah, United States

MultiCare

Spokane, Washington, United States

West Virginia University

Morgantown, West Virginia, United States

University of Wisconsin Clinical Science Center

Madison, Wisconsin, United States

Marshfield Medical Center

Marshfield, Wisconsin, United States

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

UW Cancer Center at ProHealth Care

Waukesha, Wisconsin, United States

Countries

United States

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

PrE0905

Identifier Type: -

Identifier Source: org_study_id