A Study of ASP2215 (Gilteritinib), Administered as Maintenance Therapy Following Induction/Consolidation Therapy for Subjects With FMS-like Tyrosine Kinase 3 (FLT3/ITD) Acute Myeloid Leukemia (AML) in First Complete Remission

Study Overview
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Brief Summary
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The purpose of this study was to compare relapse-free survival (RFS) between participants with FMS-like tyrosine kinase 3 (FLT3) / internal tandem duplication (ITD) acute myeloid leukemia (AML) in first complete remission (CR1) and who were randomized to receive gilteritinib or placebo beginning after completion of induction/consolidation chemotherapy for a two-year period.

Detailed Description
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Participants in CR1 were approached for this study after induction/consolidation therapy was complete and a decision not to proceed with transplantation was made or a suitable donor could not be identified. Participants were randomized in a 2:1 ratio to receive gilteritinib or placebo. Participants entered the screening period up to 14 days prior to the start of treatment. Participants were administered treatment over continuous 28-day cycles. Gilteritinib or placebo was given daily for up to 2 years. After treatment discontinuation, participants had a 30-day follow-up visit for safety, after which the participants entered the long-term follow up period for collection of subsequent AML treatment, remission status, and survival (cause of death and date of death). Final database lock will occur when last subject last follow-up visit is reached, per protocol. Study drug was not provided during the follow-up period.

Official Title
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A Phase 2 Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of the FLT3 Inhibitor Gilteritinib (ASP2215) Administered as Maintenance Therapy Following Induction/Consolidation Therapy for Subjects With FLT3/ITD AML in First Complete Remission

Conditions
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Acute Myeloid Leukemia (AML), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase (FLT3) / Internal Tandem Duplication (ITD) Mutation

Intervention / Treatment
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* Drug: Gilteritinib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is considered an adult according to local regulation at the time of obtaining consent form (ICF). Subject consents to allow access to subject's diagnostic bone marrow aspirate or peripheral blood sample and/or the DNA derived from that sample, if available, that may be used to validate a companion diagnostic test for gilteritinib. Subject has confirmed morphologically documented AML, excluding acute promyelocytic leukemia (APL), in CR1 (including CRp and CRi). For the purposes of enrollment, CR will be defined as < 5% blasts in the bone marrow with no morphologic characteristics of acute leukemia (e.g., Auer rods) in the bone marrow with no evidence of extramedullary disease such as central nervous system involvement or granulocytic sarcoma. Subject will not proceed with transplantation as either a decision not to proceed with transplantation has been made either on the recommendation of the treating physician or by the patient or a suitable donor could not be identified. Subject is < 2 months from the start of the last cycle of consolidation and should have completed the recommended number of consolidations per local practice. Subject has had no use of investigational agents, with the exception of FLT3 inhibiting agents during induction and/or consolidation therapy, within the prior 4 weeks. Subject has had presence of the FLT3/ITD activating mutation in the bone marrow or peripheral blood as determined by the local institution at diagnosis. Subject has an ECOG performance status 0 to 2. Subject must meet the following criteria as indicated on the clinical laboratory tests: Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN), or if serum creatinine outside normal range, then glomerular filtration rate (GFR) > 40 mL/min/1.73m^2 as calculated with the 4-parameter Modification of Diet in Renal Disease (MDRD) equation. Serum total bilirubin ≤ 2.5 mg/dL (43 μmol/L), except for subjects with Gilbert's syndrome. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x ULN. Serum potassium and serum magnesium ≥ institutional lower limit of normal (LLN). Absolute neutrophil count (ANC) ≥ 500/μl and platelets ≥ 20000/μl (unsupported by transfusions). Subject is suitable for oral administration of study drug. Female subject must either: Be of nonchildbearing potential: Postmenopausal (defined as at least 1 year without any menses) prior to screening, or Documented surgically sterile or status posthysterectomy (at least 1 month prior to screening) Or, if of childbearing potential, Agree not to try to become pregnant during the study and for 6 months after the final study drug administration And have a negative urine or serum pregnancy test at screening And, if heterosexually active, agree to consistently use highly effective contraception per locally accepted standards (in addition to a barrier method) starting at screening and throughout the study period and for 6 months after the final study drug administration. Female subject must agree not to breastfeed starting at screening and throughout the study period, and for 2 months and 1 week after the final study drug administration. Female subject must not donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration. Male subject and subject's female partners who are of childbearing potential must be using highly effective contraception per locally accepted standards (in addition to a barrier method) starting at screening and continue throughout the study period and for 4 months and 1 week after the final study drug administration. Male subject must not donate sperm starting at screening and throughout the study period and for 4 months and 1 week after the final study drug administration. Subject agrees not to participate in another interventional study while on treatment. Exclusion Criteria: Subject has had prior allogeneic transplant. Subject has QTcF interval > 450 msec (average of triplicate determinations based on central reading). Subject with Long QT Syndrome. Subject with hypokalemia and hypomagnesemia at screening (defined as values below LLN). Subject has clinically active central nervous system leukemia. Subject is known to have human immunodeficiency virus infection. Subject has active hepatitis B or C. Subject has an uncontrolled infection. If a bacterial or viral infection is present, the subject must be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to randomization. If a fungal infection is present, the subject must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection for 1 week prior to randomization. Subject has progressing infection defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection. Subject has uncontrolled angina, severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of acute ischemia, congestive heart failure New York Heart Association (NYHA) class 3 or 4 or subject has a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multigated acquisition (MUGA) scan performed within 1 month prior to study entry results in a left ventricular ejection fraction that is ≥ 45%. Subject requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP) 3A. Subject requires treatment with concomitant drugs that are strong inhibitors or inducers of P-glycoprotein (P-gp) with the exception of drugs that are considered absolutely essential for the care of the subject. Subject requires treatment with concomitant drugs that target serotonin 5-hydroxytryptamine receptor 1 (5HT1R) or 5-hydroxytryptamine receptor 2B (5HT2BR) or sigma nonspecific receptor with the exception of drugs that are considered absolutely essential for the care of the subject. Subject has a serious medical or psychiatric illness likely to interfere with participation in this clinical study. Subject has prior malignancies, except resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent ≥ 5 years previously will be allowed. Cancer treated with curative intent < 5 years previously will not be allowed. Subject has any condition which makes the subject unsuitable for study participation.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gilteritinib<br>Participants received gilteritinib 120 mg (three tablets of 40 mg) orally, once daily (QD) for up to 2 years or until a protocol-specified discontinuation criterion was met. | Drug: Gilteritinib<br>* Oral tablet<br>* Other names: ASP2215;|
| Placebo Comparator: Placebo<br>Participants received gilteritinib matching placebo orally, QD for up to 2 years or until a protocol-specified discontinuation criterion was met. | Drug: Placebo<br>* Oral tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse-free Survival (RFS) Per Independent Review Committee (IRC) Adjudication | RFS was defined as the time from the date of randomization until the date of documented relapse or death from any cause, whichever occurred first. Relapse after complete remission (CR) [including complete remission with incomplete platelet recovery (CRp) and Complete remission with incomplete hematologic recovery (CRi)], was defined as bone marrow blasts 5% or higher (not attributable to regenerating bone marrow), any circulating blasts, any extra-medullary blast foci as per Revised International Working Group (IWG) criteria. Participants were classified as: CRi, if they fulfilled all the criteria for CR except for incomplete hematological recovery with residual neutropenia < 1 × 10^9/L with or without complete platelet recovery. RBC and platelet transfusion independence was not required. CRp, if they achieved CR except for incomplete platelet recovery (< 100 × 10^9/L). RFS was estimated using Kaplan-Meier estimates. hazard ratio (HR), cox proportional hazards model (CHM) | From the date of randomization until the date of documented relapse, or death; (Median time on study drug was 427 days for gilteritinib group and 212 days for placebo group) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was defined as the time from the date of randomization until the date of death from any cause. OS was estimated using Kaplan-Meiers method. | From the date of randomization until the date of death from any cause; (Median time on study drug was 427 days for gilteritinib group and 212 days for placebo group) | 
| Event-Free Survival (EFS) | EFS was defined as the time from the date of randomization until the date of documented relapse or discontinuation of the treatment, or initiation of other anti-leukemic treatment or death from any cause, whichever occurred first. Relapse after CR (including CRp and CRi), was defined as bone marrow blasts 5% or higher (not attributable to regenerating bone marrow), any circulating blasts, any extra-medullary blast foci as per Revised IWG criteria. Participants were classified as: CRi, if they fulfilled all the criteria for CR except for incomplete hematological recovery with residual neutropenia < 1 × 10^9/L with or without complete platelet recovery. RBC and platelet transfusion independence was not required. CRp, if they achieved CR except for incomplete platelet recovery (< 100 × 10^9/L). EFS was estimated using Kaplan-Meier's method. | From date of randomization until the date of documented relapse or discontinuation of the treatment, or initiation of other anti-leukemic treatment or death from any cause; (Median time on study drug was 427 days for gilteritinib and 212 days for Placebo) | 
| Change From Baseline in Quantitative Minimal Residual Disease Measured as Log10-transformed Overall FLT3/ITD Mutation Ratio at Months 3, 6, 12, 24/End of Treatment (EoT) | MRD was measured from bone marrow samples. FLT3/ITD mutation ratio was measured in relation to total FLT3. For a participant with multiple ITD mutations, the overall FLT3/ITD mutation ratio was calculated from the sum of all ITD mutations. Absence of Minimal Residual Disease (MRD) is defined as log10-transformed overall FLT3/ITD mutation ratio ≤ -4. | Baseline and months 3, 6, 12, 24/EoT | 
| Number of Participants With Adverse Events (AE) | AE:any untoward medical occurrence in participants administered study treatment (ST)/had undergone study procedures & did not necessarily have a causal relationship with treatment. Abnormalities was defined as AE only if met 1 of the criteria:Induced clinical signs/symptoms, required active intervention, required interruption or discontinuation of ST, abnormality or investigational value was clinically significant. Serious AE:resulted in death, was life threatening, persistent or significant disability/incapacity or substantial disruption of ability to conduct normal life functions, congenital anomaly/birth defect, required hospitalization or prolongation of hospitalization, other medically important events. Treatment-emergent AE:recorded on treatment ≤ 30 days from last ST. Relapse: defined in Outcome Measure #1. Grades(Gr) based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) (Gr 1=mild, Gr 2=moderate, Gr 3 =severe, Gr 4 =life threatening, Gr 5 =death). | From first dose date up to 30 days after last dose or data cut-off date 25-May 2021 (Maximum treatment duration was 744 days) | 
| Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Score | ECOG performance status was measured on an 6 point scale. 0-Fully active, able to carry on all pre-disease performance without restriction. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. Dead. Number of participants with ECOG PS was reported. ECOG PS grades with zero participants were not reported. | Months 1, 2, 3, 4, 5, 6, 8, 10. 12, 14, 16, 18, 20, 22 and 24/EoT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute myeloid leukemia, First Complete Remission, gilteritinib, FLT3/ITD, AML, ASP2215