Gilteritinib vs Midostaurin in FLT3 Mutated Acute Myeloid Leukemia

Sponsor

PrECOG, LLC. (Other)

Overall Status

Recruiting

CT.gov ID

NCT03836209

Collaborator

Astellas Pharma Inc (Industry)

179

Enrollment

Locations

Arms

59.9

Anticipated Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: Gilteritinib Drug: Midostaurin Drug: Daunorubicin Drug: Cytarabine	Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

179 participants

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].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

Official Title:

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

Actual Study Start Date :

Dec 6, 2019

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Dec 1, 2024

Arms and Interventions

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: 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
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: 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 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

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:

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

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: 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

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

Other Names:

Cytosar-U

Ara-C

Arabinosyl

Cytosine Arabinoside

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

FLT3 mutation negative Complete Response (CR) rate at end of Induction [3 months]
CR evaluated by FLT3 testing after Induction
Minimal Residual Disease (MRD)- CRc rate at end of Induction [3 months]
MRD- CRc evaluated by flow cytometry after Induction
CRc (CR or CRi) rate at end of Induction [3 months]
CRc assessed in accordance with 2017 European LeukemiaNet (ELN)
Event Free Survival (EFS) [68 months]
EFS assessed in accordance with 2017 ELN
Overall Survival (OS) [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 [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 [10 months]
Number of participants with abnormal laboratory values and/or adverse events

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	HonorHealth Research Institute	Scottsdale	Arizona	United States	85258
2	University of California, San Francisco-Fresno (University Oncology Associates)	Clovis	California	United States	93611
3	UCLA	Los Angeles	California	United States	90095
4	Kaiser Permanente Oakland	Oakland	California	United States	94611
5	UC Irvine Health	Orange	California	United States	92868
6	Kaiser Permanente Roseville	Roseville	California	United States	95661
7	Kaiser Permanente Santa Clara	Santa Clara	California	United States	94115
8	Mayo Clinic- Jacksonville, FL	Jacksonville	Florida	United States	32224
9	Augusta University Medical Center	Augusta	Georgia	United States	30912
10	University of Chicago Medical Center	Chicago	Illinois	United States	60451
11	Northwestern University Feinberg School of Medicine	Chicago	Illinois	United States	60611
12	Franciscan Health Indianapolis	Indianapolis	Indiana	United States	46237
13	University of Kentucky Markey Cancer Center	Lexington	Kentucky	United States	40536
14	Ochsner Clinic Foundation	New Orleans	Louisiana	United States	70121
15	Johns Hopkins University	Baltimore	Maryland	United States	21287
16	Tufts Medical Center	Boston	Massachusetts	United States	02111
17	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
18	St. Joseph's Mercy Hospital	Ann Arbor	Michigan	United States	48106
19	Mayo Clinic- Rochester, MN	Rochester	Minnesota	United States	55905
20	University of Nebraska Medical Center	Omaha	Nebraska	United States	68105
21	Atlantic Health Systems/Morristown Medical Center	Morristown	New Jersey	United States	07962
22	Northwell Health	Lake Success	New York	United States	11042
23	Mount Sinai	New York	New York	United States	10029
24	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
25	Weill Cornell Medicine New York Presbyterian Hospital	New York	New York	United States	10065
26	University of Rochester Medical Center	Rochester	New York	United States	14642
27	SUNY Upstate Medical University	Syracuse	New York	United States	13210
28	East Carolina University	Greenville	North Carolina	United States	27834
29	University of Cincinnati Medical Center	Cincinnati	Ohio	United States	45267
30	University Hospitals Cleveland Medical Center	Cleveland	Ohio	United States	44106
31	University of Oklahoma Stephenson Cancer Center	Oklahoma City	Oklahoma	United States	73104
32	Geisinger Medical Center	Danville	Pennsylvania	United States	17822
33	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033
34	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
35	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107
36	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15232
37	Vanderbilt University	Nashville	Tennessee	United States	37232
38	LDS Hospital	Salt Lake City	Utah	United States	84143
39	University of Vermont Medical Center	Burlington	Vermont	United States	05401
40	MultiCare	Spokane	Washington	United States	99218
41	West Virginia University	Morgantown	West Virginia	United States	26506
42	University of Wisconsin Clinical Science Center	Madison	Wisconsin	United States	53792
43	Marshfield Medical Center	Marshfield	Wisconsin	United States	54449
44	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
45	UW Cancer Center at ProHealth Care	Waukesha	Wisconsin	United States	53188