Gilteritinib vs Midostaurin in FLT3 Mutated Acute Myeloid Leukemia

Acute Myeloid Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03836209
• Other study ID #: PrE0905
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: December 6, 2019
• Est. completion date: December 2024

Study information

• Verified date: February 2024
• Source: PrECOG, LLC.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 181
• Est. completion date: December 2024
• Est. primary completion date: October 17, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

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)
• 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)
• 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
• 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

Locations

Country	Name	City	State
United States	St. Joseph's Mercy Hospital	Ann Arbor	Michigan
United States	Augusta University Medical Center	Augusta	Georgia
United States	Johns Hopkins University	Baltimore	Maryland
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	Northwestern University Feinberg School of Medicine	Chicago	Illinois
United States	University of Chicago Medical Center	Chicago	Illinois
United States	University of Cincinnati Medical Center	Cincinnati	Ohio
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	University of California, San Francisco-Fresno (University Oncology Associates)	Clovis	California
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	East Carolina University	Greenville	North Carolina
United States	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Franciscan Health Indianapolis	Indianapolis	Indiana
United States	Mayo Clinic- Jacksonville, FL	Jacksonville	Florida
United States	Northwell Health	Lake Success	New York
United States	University of Kentucky Markey Cancer Center	Lexington	Kentucky
United States	UCLA	Los Angeles	California
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	West Virginia University	Morgantown	West Virginia
United States	Atlantic Health Systems/Morristown Medical Center	Morristown	New Jersey
United States	Vanderbilt University	Nashville	Tennessee
United States	Ochsner Clinic Foundation	New Orleans	Louisiana
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Mount Sinai	New York	New York
United States	Weill Cornell Medicine New York Presbyterian Hospital	New York	New York
United States	Kaiser Permanente Oakland	Oakland	California
United States	University of Oklahoma Stephenson Cancer Center	Oklahoma City	Oklahoma
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	UC Irvine Health	Orange	California
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Mayo Clinic- Rochester, MN	Rochester	Minnesota
United States	University of Rochester Medical Center	Rochester	New York
United States	Kaiser Permanente Roseville	Roseville	California
United States	LDS Hospital	Salt Lake City	Utah
United States	Kaiser Permanente Santa Clara	Santa Clara	California
United States	HonorHealth Research Institute	Scottsdale	Arizona
United States	MultiCare	Spokane	Washington
United States	SUNY Upstate Medical University	Syracuse	New York
United States	UW Cancer Center at ProHealth Care	Waukesha	Wisconsin

Sponsors (2)

Lead Sponsor	Collaborator
PrECOG, LLC.	Astellas Pharma Inc

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	FLT3 mutation negative Complete Response (CR) rate at end of Induction	CR evaluated by FLT3 testing after Induction	3 months
Secondary	Minimal Residual Disease (MRD)- CRc rate at end of Induction	MRD- CRc evaluated by flow cytometry after Induction	3 months
Secondary	CRc (CR or CRi) rate at end of Induction	CRc assessed in accordance with 2017 European LeukemiaNet (ELN)	3 months
Secondary	Event Free Survival (EFS)	EFS assessed in accordance with 2017 ELN	68 months
Secondary	Overall Survival (OS)	OS assessed in accordance with 2017 ELN	68 months
Secondary	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
Secondary	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