Gilteritinib vs Midostaurin in FLT3 Mutated Acute Myeloid Leukemia

Randomized Trial of Gilteritinib vs Midostaurin in FLT3 Mutated Acute Myeloid Leukemia (AML)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Gilteritinib; Drug: Daunorubicin; Drug: Cytarabine; Drug: Midostaurin

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.

• Study Type: Interventional
• Enrollment (Actual): 181
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • HonorHealth Research Institute
  • California
    • Clovis, California, United States, 93611
      • University of California, San Francisco-Fresno (University Oncology Associates)
    • Los Angeles, California, United States, 90095
      • UCLA
    • Oakland, California, United States, 94611
      • Kaiser Permanente Oakland
    • Orange, California, United States, 92868
      • UC Irvine Health
    • Roseville, California, United States, 95661
      • Kaiser Permanente Roseville
    • Santa Clara, California, United States, 94115
      • Kaiser Permanente Santa Clara
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic- Jacksonville, FL
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Augusta University Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University Feinberg School of Medicine
    • Chicago, Illinois, United States, 60451
      • University of Chicago Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46237
      • Franciscan Health Indianapolis
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Markey Cancer Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Clinic Foundation
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • St. Joseph's Mercy Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic- Rochester, MN
  • Nebraska
    • Omaha, Nebraska, United States, 68105
      • University of Nebraska Medical Center
  • New Jersey
    • Morristown, New Jersey, United States, 07962
      • Atlantic Health Systems/Morristown Medical Center
  • New York
    • Lake Success, New York, United States, 11042
      • Northwell Health
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10029
      • Mount Sinai
    • New York, New York, United States, 10065
      • Weill Cornell Medicine New York Presbyterian Hospital
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University
  • North Carolina
    • Greenville, North Carolina, United States, 27834
      • East Carolina University
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati Medical Center
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Stephenson Cancer Center
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822
      • Geisinger Medical Center
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University
  • Utah
    • Salt Lake City, Utah, United States, 84143
      • LDS Hospital
  • Washington
    • Spokane, Washington, United States, 99218
      • MultiCare
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University Of Wisconsin Clinical Science Center
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Medical Center
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College Of Wisconsin
    • Waukesha, Wisconsin, United States, 53188
      • UW Cancer Center at ProHealth Care

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A; Induction: Daunorubicin, cytarabine and gilteritinib. Depending on response, second cycle of Induction may be given. Consolidation: High-dose cytarabine and gilteritinib.	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: Cerubidine; Rubidomycin; Daunomycin; Daunorubicin hydrochloride; 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; Other Names: Ara-C; Cytosar-U; Cytosine Arabinoside; Arabinosyl
Active Comparator: Arm B; Induction: Daunorubicin, cytarabine and midostaurin. Depending on response, second cycle of Induction may be given. Consolidation: High-dose cytarabine and midostaurin.	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: Cerubidine; Rubidomycin; Daunomycin; Daunorubicin hydrochloride; 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; Other Names: Ara-C; Cytosar-U; Cytosine Arabinoside; Arabinosyl; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
FLT3 Mutation Negative Composite Complete Response (CRc) [includes Complete Response (CR) or CR with incomplete hematologic recovery (CRi)] at end of Induction	CRc evaluated by polymerase chain reaction (PCR) at the end of Induction	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
FLT3 mutation negative Complete Response (CR) rate at end of Induction	CR evaluated by FLT3 testing after Induction	3 months
Minimal Residual Disease (MRD)- CRc rate at end of Induction	MRD- CRc evaluated by flow cytometry after Induction	3 months
CRc (CR or CRi) rate at end of Induction	CRc assessed in accordance with 2017 European LeukemiaNet (ELN)	3 months
Event Free Survival (EFS)	EFS assessed in accordance with 2017 ELN	68 months
Overall Survival (OS)	OS assessed in accordance with 2017 ELN	68 months
Number of participants treatment-related adverse events on Arm A (gilteritinib) as assessed by CTCAE v5.0	Number of participants with abnormal laboratory values and/or adverse events	10 months
Number of participants treatment-related adverse events on Arm B (midostaurin) as assessed by CTCAE v5.0	Number of participants with abnormal laboratory values and/or adverse events	10 months

Collaborators and Investigators

• Sponsor: PrECOG, LLC.
• Collaborators: Astellas Pharma Inc
• Investigators: Study Chair: Selena Luger, MD, University of Pennsylvania

Study record dates

Study Major Dates

• Study Start (Actual): December 6, 2019
• Primary Completion (Actual): October 17, 2023
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: February 7, 2019
• First Submitted That Met QC Criteria: February 7, 2019
• First Posted (Actual): February 11, 2019

Study Record Updates

• Last Update Posted (Estimated): February 22, 2024
• Last Update Submitted That Met QC Criteria: February 21, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Cytarabine; FLT3 Mutation; FLT3; Gilteritinib; Midostaurin; Daunorubicin; FLT3 Internal Tandem Duplication (ITD); FLT3 ITD; FLT3 Tyrosine Kinase Domain (TKD); FLT3 TKD
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Protein Kinase Inhibitors; Antibiotics, Antineoplastic; Cytarabine; Daunorubicin; Midostaurin
• Other Study ID Numbers: PrE0905

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data is proprietary.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No