Gilteritinib vs Midostaurin in FLT3 Mutated Acute Myeloid Leukemia

• ClinicalTrials.gov Identifier: NCT03836209
• Recruitment Status: Recruiting
• First Posted: February 11, 2019
• Last Update Posted: July 5, 2022
• Sponsor: PrECOG, LLC.
• Collaborator: Astellas Pharma Inc
• Information provided by (Responsible Party): PrECOG, LLC.

Tracking Information

• First Submitted Date: February 7, 2019
• First Posted Date: February 11, 2019
• Last Update Posted Date: July 5, 2022
• Actual Study Start Date: December 6, 2019
• Estimated Primary Completion Date: December 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 29, 2021)

FLT3 Mutation Negative Composite Complete Response (CRc) [includes Complete Response (CR) or CR with incomplete hematologic recovery (CRi)] at end of Induction [ Time Frame: 3 months ]

CRc evaluated by polymerase chain reaction (PCR) at the end of Induction

Original Primary Outcome Measures (submitted: February 7, 2019)

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 ]

CRc evaluated by polymerase chain reaction (PCR) after Induction

Current Secondary Outcome Measures (submitted: December 29, 2021)

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

Original Secondary Outcome Measures (submitted: February 7, 2019)

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

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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)

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.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

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].

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Acute Myeloid Leukemia

Intervention

• 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 Name: ASP2215
• 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 Name: 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 (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:

  • Cytosar-U
  • Ara-C
  • Arabinosyl
  • Cytosine Arabinoside

Study Arms

• Experimental: Arm A

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

  Consolidation: High-dose cytarabine and gilteritinib.

  Interventions:

  • Drug: Gilteritinib
  • Drug: Daunorubicin
  • Drug: Cytarabine
• 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.

  Interventions:

  • Drug: Midostaurin
  • Drug: Daunorubicin
  • Drug: Cytarabine

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 7, 2019): 179
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2024
• Estimated Primary Completion Date: December 2022 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 70 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Soumya Chappidi, MS; 267-593-3203; PrE0905@precogllc.org

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03836209
• Other Study ID Numbers: PrE0905
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: Data is proprietary.

• Current Responsible Party: PrECOG, LLC.
• Original Responsible Party: Same as current
• Current Study Sponsor: PrECOG, LLC.
• Original Study Sponsor: Same as current
• Collaborators: Astellas Pharma Inc

Investigators

• Study Chair: Selena Luger, MD; University of Pennsylvania

• PRS Account: PrECOG, LLC.
• Verification Date: June 2022