Gilteritinib vs Midostaurin in FLT3 Mutated Acute Myeloid Leukemia

NCT03836209 | Active Not Recruiting Phase 2 Results DMC FDA Drug

• 1 other identifier: PrE0905
• Study Type: interventional
• Target: 181
• Locations: 1 country
• Sites: 44

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.

Conditions

Acute Myeloid Leukemia

Keywords

Gilteritinib; Midostaurin; Daunorubicin; Cytarabine; FLT3; FLT3 Mutation; FLT3 Internal Tandem Duplication (ITD); FLT3 ITD; FLT3 Tyrosine Kinase Domain (TKD); FLT3 TKD

Outcome Measures

Primary Outcomes (1)

• FLT3 Mutation Negative Composite Complete Response (CRc) [Includes Complete Response (CR) or CR With Incomplete Hematologic Recovery (CRi)] at End of Induction

  FLT3 mutation negative (evaluated by polymerase chain reaction \[PCR\]) Composite Complete Response (CRc) \[includes CR and CRi\] rate after induction treatment and complete MRD assessment. The cut points used for FLT3 mutation negative are 1% (equivalent to 10-2) for FLT3-TKD and 10-4 for FLT3-ITD.

  3 months

Secondary Outcomes (6)

• FLT3 Mutation Negative Complete Response (CR) Rate at End of Induction

  3 months

• Minimal Residual Disease (MRD)- CRc Rate at End of Induction

  3 months

• CRc (CR or CRi) Rate at End of Induction

  3 months

• Event Free Survival (EFS)

  68 months

• Overall Survival (OS)

  68 months

Study Arms (2)

Arm A

EXPERIMENTAL

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

Drug: Gilteritinib; Drug: Daunorubicin; Drug: Cytarabine

Arm B

ACTIVE COMPARATOR

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

Drug: Midostaurin; Drug: Daunorubicin; Drug: Cytarabine

Interventions

Gilteritinib 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)

Also known as: ASP2215

Arm A

Midostaurin 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)

Also known as: RYDAPT

Arm B

Daunorubicin 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

Also known as: Daunorubicin hydrochloride, Daunomycin, Rubidomycin, Cerubidine

Arm A; Arm B

Cytarabine 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

Also known as: Cytosar-U, Ara-C, Arabinosyl, Cytosine Arabinoside

Arm A; Arm B

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

Registration 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. Randomization Eligibility Criteria: * Patient must have previously untreated FLT3 mutated Non M3 AML (FLT3-TKD or FLT3-ITD allowed). ° Standard of care induction 7+3 chemotherapy may start prior to randomization using same regimen and doses as defined in the protocol while awaiting prescreening test results. * 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). * 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.

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• PrECOG, LLC.: lead
• Astellas Pharma Inc: collaborator

Study Sites (44)

HonorHealth Research Institute

Scottsdale, Arizona, 85258, United States

Location

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

Clovis, California, 93611, United States

Location

UCLA

Los Angeles, California, 90095, United States

Location

Kaiser Permanente Oakland

Oakland, California, 94611, United States

Location

UC Irvine Health

Orange, California, 92868, United States

Location

Kaiser Permanente Roseville

Roseville, California, 95661, United States

Location

Kaiser Permanente Santa Clara

Santa Clara, California, 94115, United States

Location

Mayo Clinic- Jacksonville, FL

Jacksonville, Florida, 32224, United States

Location

Augusta University Medical Center

Augusta, Georgia, 30912, United States

Location

University of Chicago Medical Center

Chicago, Illinois, 60451, United States

Location

Northwestern University Feinberg School of Medicine

Chicago, Illinois, 60611, United States

Location

Franciscan Health Indianapolis

Indianapolis, Indiana, 46237, United States

Location

University of Kentucky Markey Cancer Center

Lexington, Kentucky, 40536, United States

Location

Ochsner Clinic Foundation

New Orleans, Louisiana, 70121, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

Tufts Medical Center

Boston, Massachusetts, 02111, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

St. Joseph's Mercy Hospital

Ann Arbor, Michigan, 48106, United States

Location

Mayo Clinic- Rochester, MN

Rochester, Minnesota, 55905, United States

Location

University of Nebraska Medical Center

Omaha, Nebraska, 68105, United States

Location

Atlantic Health Systems/Morristown Medical Center

Morristown, New Jersey, 07962, United States

Location

Northwell Health

Lake Success, New York, 11042, United States

Location

Mount Sinai

New York, New York, 10029, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Weill Cornell Medicine New York Presbyterian Hospital

New York, New York, 10065, United States

Location

University of Rochester Medical Center

Rochester, New York, 14642, United States

Location

SUNY Upstate Medical University

Syracuse, New York, 13210, United States

Location

East Carolina University

Greenville, North Carolina, 27834, United States

Location

University of Cincinnati Medical Center

Cincinnati, Ohio, 45267, United States

Location

University Hospitals Cleveland Medical Center

Cleveland, Ohio, 44106, United States

Location

University of Oklahoma Stephenson Cancer Center

Oklahoma City, Oklahoma, 73104, United States

Location

Geisinger Medical Center

Danville, Pennsylvania, 17822, United States

Location

Penn State Milton S. Hershey Medical Center

Hershey, Pennsylvania, 17033, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Thomas Jefferson University

Philadelphia, Pennsylvania, 19107, United States

Location

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15232, United States

Location

Vanderbilt University

Nashville, Tennessee, 37232, United States

Location

LDS Hospital

Salt Lake City, Utah, 84143, United States

Location

MultiCare

Spokane, Washington, 99218, United States

Location

West Virginia University

Morgantown, West Virginia, 26506, United States

Location

University of Wisconsin Clinical Science Center

Madison, Wisconsin, 53792, United States

Location

Marshfield Medical Center

Marshfield, Wisconsin, 54449, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

UW Cancer Center at ProHealth Care

Waukesha, Wisconsin, 53188, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

gilteritinib; midostaurin; Daunorubicin; Cytarabine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Results Point of Contact

• Title: Li Chen, MS; Statistician
• Organization: PrECOG

Li Chen <lic@ds.dfci.harvard.edu>

857-284-3670

Study Officials

• Selena Luger, MD

  University of Pennsylvania

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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) \[positive vs negative\].

Study Record Dates

• First Submitted: February 7, 2019
• First Posted: February 11, 2019
• Study Start: December 6, 2019
• Primary Completion: October 17, 2023
• Study Completion (Estimated): December 1, 2026
• Last Updated: June 15, 2025
• Results First Posted: February 28, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (44)