Clinical Trials /

Gilteritinib vs Midostaurin in FLT3 Mutated Acute Myeloid Leukemia

NCT03836209

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Gilteritinib vs Midostaurin in FLT3 Mutated Acute Myeloid Leukemia
  • Official Title: Randomized Trial of Gilteritinib vs Midostaurin in FLT3 Mutated Acute Myeloid Leukemia (AML)

Clinical Trial IDs

  • ORG STUDY ID: PrE0905
  • NCT ID: NCT03836209

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
GilteritinibASP2215Arm A
MidostaurinRYDAPTArm B
DaunorubicinDaunorubicin hydrochloride, Daunomycin, Rubidomycin, CerubidineArm A
CytarabineCytosar-U, Ara-C, Arabinosyl, Cytosine ArabinosideArm A

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm AExperimentalInduction: Daunorubicin, cytarabine and gilteritinib. Depending on response, second cycle of Induction may be given. Consolidation: High-dose cytarabine and gilteritinib.
  • Gilteritinib
  • Daunorubicin
  • Cytarabine
Arm BActive ComparatorInduction: Daunorubicin, cytarabine and midostaurin. Depending on response, second cycle of Induction may be given. Consolidation: High-dose cytarabine and midostaurin.
  • Midostaurin
  • Daunorubicin
  • Cytarabine

Eligibility Criteria

        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.

          -  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.
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:FLT3 Mutation Negative Composite Complete Response (CRc) [includes Complete Response (CR) or CR with incomplete hematologic recovery (CRi)] at end of Induction
Time Frame:40 months
Safety Issue:
Description:CRc evaluated by polymerase chain reaction (PCR) at the end of Induction

Secondary Outcome Measures

Measure:FLT3 mutation negative Complete Response (CR) rate at end of Induction
Time Frame:40 months
Safety Issue:
Description:CR evaluated by FLT3 testing after Induction
Measure:Minimal Residual Disease (MRD)- CRc rate at end of Induction
Time Frame:40 months
Safety Issue:
Description:MRD- CRc evaluated by flow cytometry after Induction
Measure:CRc (CR or CRi) rate at end of Induction
Time Frame:40 months
Safety Issue:
Description:CRc assessed in accordance with 2017 European LeukemiaNet (ELN)
Measure:Event Free Survival (EFS)
Time Frame:68 months
Safety Issue:
Description:EFS assessed in accordance with 2017 ELN
Measure:Overall Survival (OS)
Time Frame:68 months
Safety Issue:
Description:OS assessed in accordance with 2017 ELN
Measure:Number of participants treatment-related adverse events on Arm A (gilteritinib) as assessed by CTCAE v5.0
Time Frame:68 months
Safety Issue:
Description:Number of participants with abnormal laboratory values and/or adverse events
Measure:Number of participants treatment-related adverse events on Arm B (midostaurin) as assessed by CTCAE v5.0
Time Frame:68 months
Safety Issue:
Description:Number of participants with abnormal laboratory values and/or adverse events

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:PrECOG, LLC.

Trial Keywords

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

Last Updated

August 24, 2021