Clinical trial NCT03836209: Gilteritinib vs Midostaurin in FLT3 Mutated Acute Myeloid Leukemia
Official title: Randomized Trial of Gilteritinib vs Midostaurin in FLT3 Mutated Acute Myeloid Leukemia (AML)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
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
Lead sponsor: PrECOG, LLC.
Sponsor class: OTHER
Collaborators: name: Astellas Pharma Inc
First posted: 2019-02-11
Enrollment: 181
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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) \[positive vs negative\].
Primary purpose: TREATMENT

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.

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 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.

Primary outcomes:
measure: FLT3 Mutation Negative Composite Complete Response (CRc) [Includes Complete Response (CR) or CR With Incomplete Hematologic Recovery (CRi)] at End of Induction
timeFrame: 3 months
Secondary outcomes:
measure: FLT3 Mutation Negative Complete Response (CR) Rate at End of Induction
timeFrame: 3 months
measure: Minimal Residual Disease (MRD)- CRc Rate at End of Induction
timeFrame: 3 months
measure: CRc (CR or CRi) Rate at End of Induction
timeFrame: 3 months
measure: Event Free Survival (EFS)
timeFrame: 68 months
measure: Overall Survival (OS)
timeFrame: 68 months
measure: Number of Participants Treatment-related Adverse Events as Assessed by CTCAE v5.0
timeFrame: 10 months
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: HonorHealth Research Institute
state: Arizona
city: Clovis
country: United States
facility: University of California, San Francisco-Fresno (University Oncology Associates)
state: California
city: Los Angeles
country: United States
facility: UCLA
state: California
city: Oakland
country: United States
facility: Kaiser Permanente Oakland
state: California
city: Orange
country: United States
facility: UC Irvine Health
state: California
city: Roseville
country: United States
facility: Kaiser Permanente Roseville
state: California
city: Santa Clara
country: United States
facility: Kaiser Permanente Santa Clara
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic- Jacksonville, FL
state: Florida
city: Augusta
country: United States
facility: Augusta University Medical Center
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine
state: Illinois
city: Indianapolis
country: United States
facility: Franciscan Health Indianapolis
state: Indiana
city: Lexington
country: United States
facility: University of Kentucky Markey Cancer Center
state: Kentucky
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: St. Joseph's Mercy Hospital
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic- Rochester, MN
state: Minnesota
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Morristown
country: United States
facility: Atlantic Health Systems/Morristown Medical Center
state: New Jersey
city: Lake Success
country: United States
facility: Northwell Health
state: New York
city: New York
country: United States
facility: Mount Sinai
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medicine New York Presbyterian Hospital
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Greenville
country: United States
facility: East Carolina University
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Stephenson Cancer Center
state: Oklahoma
city: Danville
country: United States
facility: Geisinger Medical Center
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State Milton S. Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Salt Lake City
country: United States
facility: LDS Hospital
state: Utah
city: Spokane
country: United States
facility: MultiCare
state: Washington
city: Morgantown
country: United States
facility: West Virginia University
state: West Virginia
city: Madison
country: United States
facility: University of Wisconsin Clinical Science Center
state: Wisconsin
city: Marshfield
country: United States
facility: Marshfield Medical Center
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Waukesha
country: United States
facility: UW Cancer Center at ProHealth Care
state: Wisconsin
Study officials:
affiliation: University of Pennsylvania
name: Selena Luger, MD
role: STUDY_CHAIR
References: