A Study of ASP2215 Versus Salvage Chemotherapy In Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FLT3 Mutation

Study Overview
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Brief Summary
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The purpose of this study is to determine the clinical benefit of ASP2215 therapy in participants with FMS-like tyrosine kinase (FLT3) mutated AML who are refractory to or have relapsed after first-line AML therapy as shown with overall survival (OS) compared to salvage chemotherapy. In addition, this study will evaluate safety as well as determine the overall efficacy in event-free survival (EFS) and complete remission (CR) rate of ASP2215 compared to salvage chemotherapy.

Detailed Description
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Participants considered an adult according to local regulations at the time of signing informed consent will be randomized in a 1:1 ratio to receive ASP2215 or salvage chemotherapy. Participants will enter the screening period up to 14 days prior to the start of treatment. Prior to randomization, the investigator will preselect a salvage chemotherapy regimen for each participant; options will include low-dose cytarabine (LoDAC), mitoxantrone, etoposide and intermediate-dose cytarabine (MEC) or fludarabine, high-dose cytarabine and granulocyte colony-stimulating factor (FLAG). The randomization will be stratified by response to first-line therapy and preselected salvage chemotherapy. Participants will be administered treatment over continuous 28-day cycles. Among the participants, approximately 20 Chinese participants who are randomized into the ASP2215 arm will be allocated to the pharmacokinetic (PK) cohort. Participants in the PK cohort will be requested to be hospitalized from the date of randomization (Day 1) to at least the completion of all the assessments planned on Day 2. All participants in the PK cohort will undergo blood sampling for PK measurement of ASP2215. Participants in PK cohort will be administered the study drug in the same manner and undergo the same efficacy and safety assessments as other participants except for blood sampling for additional PK measurements.

Official Title
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Phase 3 Open-label, Multicenter, Randomized Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FLT3 Mutation

Conditions
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Acute Myeloid Leukemia With FMS-like Tyrosine Kinase (FLT3) Mutation

Intervention / Treatment
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* Drug: gilteritinib
* Drug: LoDAC (Low Dose Cytarabine)
* Drug: MEC (Mitoxantrone, Etoposide, Cytarabine)
* Drug: FLAG (Granulocyte colony-stimulating factor (G-CSF), Fludarabine, Cytarabine)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has a diagnosis of primary AML or AML secondary to myelodysplastic syndrome (MDS) according to World Health Organization (WHO) classification as determined by pathology review at the treating institution. Subject is refractory to or relapsed after first-line AML therapy (with or without HSCT) Refractory to first-line AML therapy is defined as: a. Subject did not achieve CR/CRi/CRp under initial therapy. A subject eligible for standard therapy must receive at least 1 cycle of an anthracycline containing induction block in standard dose for the selected induction regimen. A subject not eligible for standard therapy must have received at least 1 complete block of induction therapy seen as the optimum choice of therapy to induce remission for this subject. Untreated first hematologic relapse is defined as: Subject must have achieved a CR/CRi/CRp with first-line treatment and has hematologic relapse. Subject is positive for FLT3 mutation in bone marrow or whole blood as determined by the central lab. A subject with rapidly proliferative disease and unable to wait for the central lab results can be enrolled based on a local test performed after completion of the last interventional treatment. Subjects can be enrolled from a local test result if the subjects have any of the following FLT3 mutations: FLT3-internal tandem duplication (ITD), FLT3-tyrosine kinase domain (TKD)/D835 or FLT3-TKD/I836. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Subject is eligible for preselected salvage chemotherapy. Subject must meet the following criteria as indicated on the clinical laboratory tests: Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN) Serum total bilirubin (TBL) ≤ 1.5 x ULN Serum creatinine ≤ 1.5 x ULN or an estimated glomerular filtration rate of > 50 mL/min as calculated by the Modification of Diet in Renal Disease equation. Subject is suitable for oral administration of study drug. Subject agrees not to participate in another interventional study while on treatment. Inclusion Criteria for COE: Subject is eligible for the COE if they continue to meet all inclusion criteria from the main protocol in addition to the following when the subject is evaluated for eligibility to participate in the COE portion of the study: Subject has received study treatment of either LoDAC, MEC or FLAG and has no response or progressive disease. Subject have not received other antileukemic therapy after EOT (hydroxyurea is allowed for the control of peripheral leukemic blasts in subjects with leukocytosis). Subject agrees not to participate in another interventional study while on treatment. Exclusion Criteria: Subject was diagnosed as acute promyelocytic leukemia. Subject has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis). Subject has AML secondary to prior chemotherapy for other neoplasms (except for MDS). Subject is in second or later hematologic relapse or has received salvage therapy for refractory disease. Subject has clinically active central nervous system leukemia.. Subject has been diagnosed with another malignancy, unless disease-free for at least 5 years. Subjects with treated nonmelanoma skin cancer, in situ carcinoma or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed. Subjects with organ-confined prostate cancer with no evidence of recurrent or progressive disease are eligible if hormonal therapy has been initiated or the malignancy has been surgically removed or treated with definitive radiotherapy. Subject has received prior treatment with ASP2215 or other FLT3 inhibitors (with the exception of sorafenib and midostaurin used in first-line therapy regimen as part of induction, consolidation and/or maintenance). Subject has clinically significant abnormality of coagulation profile, such as disseminated intravascular coagulation. Subject has had major surgery within 4 weeks prior to the first study dose. Subject has radiation therapy within 4 weeks prior to the first study dose. Subject has congestive heart failure New York Heart Association (NYHA) class 3 or 4 or subject with a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram (ECHO) performed within 1 month prior to study entry results in a left ventricular ejection fraction (LVEF) that is ≥ 45%. Subject with mean of triplicate Fridericia-corrected QT interval (QTcF) > 450 ms at Screening based on central reading. Subject with Long QT Syndrome at Screening. Subject with hypokalemia and hypomagnesemia at Screening (defined as values below lower limit of normal [LLN]). Subject requires treatment with concomitant drugs that are strong inducers of CYP3A. Subject requires treatment with concomitant drugs that are strong inhibitors or inducers of 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) receptors or sigma nonspecific receptor with the exception of drugs that are considered absolutely essential for the care of the subject. Subject has an active uncontrolled infection. Subject is known to have human immunodeficiency virus infection. Subject has active hepatitis B or C or other active hepatic disorder. Subject has any condition which makes the subject unsuitable for study participation. Subject has active clinically significant (graft-versus-host disease) GVHD or is on treatment with systemic corticosteroids for GVHD. Subject has an FLT3 mutation other than the following: FLT3-ITD, FLT3-TKD/D835 or FLT3-TKD/I836. Exclusion Criteria for COE: Subject will be excluded from participation in the COE if they meet any of the exclusion criteria listed in the main protocol or when the subject is evaluated for eligibility to participate in the COE portion of the study.

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ASP2215<br>ASP2215 will be administered orally once daily. | Drug: gilteritinib<br>* oral<br>* Other names: ASP2215;|
| Active Comparator: Salvage chemotherapy<br>Options for salvage chemotherapy are limited to the following: Low-dose Cytarabine (LoDAC) will be administered twice daily by subcutaneous or intravenous injection for 10 days. Mitoxantrone, Etoposide, Cytarabine (MEC Induction Chemotherapy) will each be administered intravenously for 5 days (days 1 through 5). Granulocyte colony-stimulating factor (G-CSF) will be administered intravenously for 5 days (days 1 through 5) and also recommended 7 days after completing chemotherapy, Fludarabine and Cytarabine administered intravenously for 5 days (days 2 through 6) (FLAG Induction Chemotherapy). Based on the outcome of interim analysis, participants will be evaluated for eligibility for crossover extension (COE). In COE participants will be administered ASP2215 orally once daily. | Drug: LoDAC (Low Dose Cytarabine)<br>* subcutaneous (SC) or intravenous (IV) injection<br>Drug: MEC (Mitoxantrone, Etoposide, Cytarabine)<br>* intravenous<br>Drug: FLAG (Granulocyte colony-stimulating factor (G-CSF), Fludarabine, Cytarabine)<br>* intravenous<br>|
| Experimental: ASP2215 PK in Chinese population<br>PK samples will be collected after single and multiple doses in Chinese subjects. | Drug: gilteritinib<br>* oral<br>* Other names: ASP2215;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival (OS) is defined as the time from the date of randomization until the date of death from any cause. For a participant who is not known to have died by the end of study follow-up, OS is censored at the date of last contact. | up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival | Event-free survival (EFS) is defined as the time from the date of randomization until the date of documented relapse (including relapse after complete remission (CR), complete remission with incomplete platelet recovery (CRp) and complete remission with incomplete hematologic recovery (CRi)), treatment failure or death whichever occurs first. | up to 3 years | 
| Complete remission | For participants to be classified as being in CR, the participants must have bone marrow regenerating normal hematopoietic cells and achieve a morphologic leukemia-free state and must have an absolute neutrophil count (ANC) greater than 1 x 10^9/L and platelet count ≥ 100 x 10^9/L and normal marrow differential with less than 5% blasts, and will be red blood cell (RBC) and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). There should be no evidence of extramedullary leukemia. | up to 3 years | 
| Leukemia-free survival | Leukemia-free survival (LFS) is defined as the time from the date of first composite complete remission (CRc) until the date of documented relapse or death for participants who achieve CRc. For a participant who is not known to have relapsed or died, LFS is censored on the date of last relapse-free disease assessment date. | up to 3 years | 
| Duration of composite complete remission (CRc) | Duration of CRc is defined as the time from the date of first CRc until the date of documented relapse for participants who achieve CRc. | up to 3 years | 
| Duration of complete remission (CR) | Duration of CR is defined as the time from the date of first CR until the date of documented relapse for participants who achieve CR. | up to 3 years | 
| Duration of complete remission with incomplete platelet recovery (CRp) | Duration of CRp is defined as the time from the date of first CRp until the date of documented relapse for participants who achieve CRp. | up to 3 years | 
| Duration of complete remission with incomplete hematologic recovery (CRi) | Duration of CRi is defined as the time from the date of first CRi until the date of documented relapse for participants who achieve CRi. | up to 3 years | 
| Composite complete remission rate | CRc rate is defined as the remission rate of all CR, CRp and CRi (i.e., CR + CRp + CRi) | up to 3 years | 
| Transplantation rate | Transplantation rate is defined as the percentage of participants undergoing hematopoietic stem cell transplant (HSCT). | up to 3 years | 
| Brief Fatigue Inventory | Brief Fatigue Inventory (BFI) will assess the severity of fatigue and the impact of fatigue on daily functioning in participants with fatigue due to cancer and cancer treatment. The BFI short form has 9 items and a 24-hour recall. A global fatigue score is computed by averaging the 9 items. | up to 3 years | 
| Safety assessed by adverse events | An adverse event (AE) is defined as any untoward medical occurrence in a participant administered a study drug or has undergone study procedures and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a medicinal investigational) product, whether or not related to the medicinal (investigational) product. | up to 3 years | 
| Safety assessed by laboratory test: chemistry | To assess chemistry as a criteria of safety variables | up to 3 years | 
| Safety assessed by laboratory test: hematology | To assess hematology as a criteria of safety variables | up to 3 years | 
| Safety assessed by laboratory test: coagulation | To assess coagulation as a criteria of safety variables | up to 3 years | 
| Safety assessed by laboratory test: urinalysis | To assess urinalysis as a criteria of safety variable | up to 3 years | 
| Number of participants with vital signs abnormalities and/or adverse events | Number of participants with potentially clinically significant vital sign values | up to 3 years | 
| Safety assessed by electrocardiograms | Electrocardiograms (ECGs) will be obtained after the participant has rested quietly and is awake in a fully supine position (or semi-recumbent, if supine not tolerated) for 10 minutes before the first ECG from a triplicate. | up to 3 years | 
| Pharmacokinetics (PK) of ASP2215: Area under the concentration curve at 24 hours (AUC24) | AUC24 will be derived from the PK blood samples collected. | Cycle 1 Day 1: predose and up to 24 hours post-dose; Cycle 1 Day 15: predose and up to 24 hours post-dose. A cycle is 28 days. | 
| PK of ASP2215: Maximum concentration (Cmax) | Cmax will be derived from the PK blood samples collected. | Cycle 1 Day 1: predose and up to 24 hours post-dose; Cycle 1 Day 15: predose and up to 24 hours post-dose. A cycle is 28 days. | 
| PK of ASP2215: Observed trough concentration (Ctrough) | Ctrough will be derived from the PK blood samples collected. | Cycle 1 Day 1: predose and up to 24 hours post-dose; Cycle 1 Day 8: predose; Cycle 1 Day 15: predose and up to 24 hours post-dose; Day 1 predose of each subsequent cycle. A cycle is 28 days. | 
| PK of ASP2215: Time after dosing when Cmax occurs (tmax) | tmax will be derived from the PK blood samples collected. | Cycle 1 Day 1: predose and up to 24 hours post-dose; Cycle 1 Day 15: predose and up to 24 hours post-dose. A cycle is 28 days. | 
| ASP2215 concentration in blood | Blood samples will be taken to measure the concentration of the drug | Cycle 1 Day 1, Cycle 1 Day 8, Cycle 1 Day 15: predose; Day 1 predose of each subsequent cycle. A cycle is 28 days. | 
| Safety assessed by Eastern Cooperative Oncology Group (ECOG) performance scores | ECOG performance status measured on 6 point scale to assess participant's performance status. 0=Fully active, able to carry on all pre-disease activities without restriction; 1=Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature; 2= Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours; 3=Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4=Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair; 5=Dead. 0=Best status; 5=Worst status. | up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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gilteritinib, Acute Myeloid Leukemia (AML), ASP2215