A Study of ASP2215 in Combination With Induction and Consolidation Chemotherapy in Patients With Newly Diagnosed Acute Myeloid Leukemia.

Study Overview
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Brief Summary
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The purpose of phase 1 part in this study is to determine the maximum tolerated dose (MTD) and/or recommended expansion dose (RED) of ASP2215 concomitant with cytarabine/idarubicin as induction chemotherapy based on the status of the onset of dose-limiting toxicity (DLT) in newly diagnosed Acute Myeloid Leukemia (AML) subjects. Phase 1 part will also evaluate safety and tolerability and characterize the pharmacokinetic (PK) parameters of ASP2215 concomitant with induction and consolidation chemotherapy as well as evaluate the PK parameters of cytarabine concomitant with ASP2215. The purpose of phase 2 part is to evaluate efficacy of ASP2215 in combination with induction therapy. Phase 2 cohort will also evaluate safety and characterize the PK parameters of ASP2215 in combination with induction and consolidation therapy followed by maintenance therapy in newly diagnosed FLT3-mutated AML subjects.

Detailed Description
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This study is composed of Phase 1 part (the dose-evaluation part and the expansion part) and Phase 2 part. In the dose-evaluation part of Phase 1 part, at least 3 subjects will receive ASP2215 at each dose (low, middle, and high) for determination of MTD and/or RED. Treatment of AML in Phase 1 part is composed of 3 periods of therapy: remission induction, consolidation, and maintenance. The decision of whether or not to proceed to the next dose will be made based on the occurrence of DLT during Cycle 1 of the induction period. In the expansion part of Phase 1 part, a maximum of 3 subjects will receive ASP2215 at RED that has been recommended in the dose-evaluation part and the safety will be assessed based on the onset of DLTs during Cycle 1 of the induction and consolidation periods. In Phase 2 part, Subjects will receive ASP2215 at the recommended dose established in Phase 1 part. The target population will be limited to newly diagnosed FLT3-mutated AML.

Official Title
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A Phase 1/2 Study of ASP2215 in Combination With Induction and Consolidation Chemotherapy in Patients With Newly Diagnosed Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia, FLT3-mutated Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: gilteritinib
* Drug: Idarubicin
* Drug: Cytarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: [Phase 1 part] Subject is defined as having previously untreated de novo AML according to the World Health Organization (WHO) criteria (2008) within 28 days prior to study enrollment. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. Subject must meet all of the following criteria in the laboratory test at screening: Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels of ≤ 2.5 × institutional upper limit of normal (ULN) Total serum bilirubin level of ≤ 1.5 × institutional ULN Serum creatinine level of ≤ 1.5 × institutional ULN or an estimated glomerular filtration rate (eGFR) of > 50 mL/min Subject is suitable for oral administration of ASP2215. Female subject falls under the following: Of non-childbearing potential: ・Post-menopausal (defined as at least 1 year with no menses without a medical reason such as drug administration) at screening, or ・Documented surgically sterile or status post-hysterectomy (at least 1 month prior to screening) Of childbearing potential: ・Has a negative result for the pregnancy test at screening, and ・Agrees to use an appropriate contraception starting at screening and throughout the study period and for 60 days after the final study drug administration Female subject agrees not to breastfeed starting at screening and throughout the study period and for 60 days after the final study drug administration. Female subject agrees not to donate ova starting at screening and throughout the study period and for 60 days after the final study drug administration. Male subject and his female spouse/partner who is of childbearing potential agrees to use an appropriate contraception starting at screening and throughout the study period and for 120 days after the final study drug administration. Male subject agrees not to donate sperm starting at screening and throughout the study period and for 120 days after the final study drug administration. Subject agrees not to participate in another interventional study while on study treatment. Subject can be admitted during the induction period. [Phase 2 part] Subject has a diagnosis of previously-untreated de novo acute myeloid leukemia (AML) according to World Health Organization (WHO) classification (2017) documented within 28 days prior to enrollment. Subject is positive for FLT3-ITD and/or TKD mutation in bone marrow or whole blood as determined by the central lab. Registration by the local lab result is not acceptable. Subject has an ECOG performance status (PS) 0 to 1. Subject who has an ECOG PS 2 is eligible only if the primary disease related symptoms such as pneumonia and febrile neutropenia are the cause of PS score. Subject is suitable for oral administration of ASP2215. Female subject is not pregnant and at least 1 of the following conditions apply: Not a woman of childbearing potential (WOCBP) WOCBP who agrees to follow the contraceptive guidance from the time of informed consent through at least 180 days after final study treatment administration. Female subject must agree not to breastfeed starting at screening and throughout the study period, and for 60 days after the final study drug administration. Female subject must not donate ova starting at screening and throughout the study period, and for 180 days after the final study drug administration. Male subject and their 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 120 days after the final study drug administration. Male subject must not donate sperm starting at screening and throughout the study period and for 120 days after the final study drug administration. Male subject with pregnant partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy throughout the study period and for 120 days after the final study treatment administration. Subject agrees not to participate in another interventional study while on treatment. Subject must meet the following criteria as indicated on the clinical laboratory tests: Serum creatinine ≤ 1.5 × institutional upper limit of normal (ULN), or if serum creatinine outside normal range, then glomerular filtration rate (GFR) > 50 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. If liver abnormality by the primary disease is suspected, subject may be pre-registered to initiate the chemotherapy. Prior to registration, AST/ALT values must meet the criteria to continue the study. Serum magnesium ≥ institutional lower limit of normal (LLN). Subject may pre-register without magnesium value, but subject must meet the criteria prior to the full registration on Day 8. Serum potassium ≥ institutional lower limit of normal (LLN). Exclusion Criteria: [Phase 1 part] Subject was diagnosed with acute promyelocytic leukemia (APL). Subject has breakpoint cluster region-abelson (BCR-ABL)-positive leukemia (chronic myelogenous leukemia in blast crisis). Subject has active malignant tumors other than AML or myelodysplastic syndrome (MDS). Subject has received prior AML treatment except for the following: Urgent leukapheresis Hydroxyurea administration for emergency treatment of hyperleukocytosis (≤ 7 days) Administration of retinoic acid before the diagnosis to exclude APL (≤ 7 days) Supportive care using growth factors or cytokines Steroid administration to treat hypersensitivity or blood transfusion reactions Subject has clinically active central nervous system leukemia. Subject has disseminated intravascular coagulation (DIC). Subject has had major surgery within 28 days prior to the first study drug administration. Subject has had radiation therapy within 28 days prior to the first study drug administration. Subject has congestive heart failure of New York Heart Association (NYHA) class 3 or 4, or subject with a past history of congestive heart failure of NYHA class 3 or 4 and in whom echocardiogram (ECHO) or Multiple Gate Acquisition (MUGA) scan performed within 3 months prior to screening or at screening showed a left ventricular ejection fraction (LVEF) of < 45%. Subject has cardiac impairment or a clinically significant cardiac disease, including any one of the following: Complete left bundle branch block Obligate use of a cardiac pacemaker Long QT syndrome at Screening Prolongation of the QTc interval (> 450 ms) on electrocardiogram (ECG) at screening Right bundle branch block + left anterior hemiblock (bifascicular block) Angina pectoris within 3 months prior to study drug administration Acute myocardial infarction within 3 months prior to study drug administration 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 5HT1 or 5HT2B receptors or sigma receptors, with the exception of drugs that are considered absolutely essential for treatment of the subject. Subject has an active uncontrollable infection. Subject is known to have human immunodeficiency virus (HIV) infection. Subject has active hepatitis B or C or other active hepatic disorders. Subject has any condition that, in the investigator's or sub-investigator's opinion, makes the subject unsuitable for study participation. Potassium and magnesium levels of below institutional lower limit of normal in the laboratory test at screening. [Phase 2 part] Subject was diagnosed with acute promyelocytic leukemia (APL). Subject has known BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis). Subject has therapy-related AML. Subject has active malignant tumors other than AML. Subject has received previous therapy for AML, with the exception of the following: Emergency leukapheresis Emergency treatment for hyperleukocytosis with hydroxyurea for ≤ 10 days Preemptive treatment with retinoic acid prior to exclusion of APL ≤ 7 days Growth factor or cytokine support Steroids for the treatment of hypersensitivity or transfusion reactions. Subject has QTcF interval > 450 ms (average of triplicate determinations based on central reading). Subject with long QT syndrome. Subject has clinically active central nervous system leukemia. 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 immediate life-threatening, severe complications of leukemia such as severe uncontrolled bleeding and/or severe disseminated intravascular coagulation Subject is known to have human immunodeficiency virus infection. Subject has active hepatitis B or C. Subject has an uncontrolled infection. An infection controlled with an approved or closely monitored antibiotic/antiviral/antifungal treatment is allowed. 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 of NYHA class 3 or 4 and echocardiogram (ECHO) or Multiple Gate Acquisition (MUGA) scan performed within 3 months prior to screening or at screening showed a left ventricular ejection fraction (LVEF) of < 45%. Subject requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP) 3A. Subject requires treatment with concomitant drugs that target serotonin 5HT2B receptors or sigma nonspecific receptors, with the exception of drugs that are considered absolutely essential for treatment of the subject. 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 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
Maximum Age: 69 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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Dose Evaluation Part<br>In the dose-evaluation part in Phase 1 part, subjects will receive ASP2215 at assigned single dose for determination of MTD and/or RED. Treatment of AML in this study is composed of 3 periods of therapy: remission induction (42-day cycles x 2 at maximum), consolidation (28-day cycles x 3 at maximum), and maintenance (28-day cycles x 26 at maximum). The decision of whether or not to proceed to the next dose will be made based on the occurrence of DLT during Cycle 1 of the induction period. | Drug: gilteritinib<br>* Once-daily oral administration on 14 consecutive days in every cycle in each period.<br>* Other names: ASP2215;Drug: Idarubicin<br>* Induction period: Once-daily intravenous injection of 12 mg/m^2 idarubicin on 3 consecutive days.<br>Drug: Cytarabine<br>* Induction period: Once-daily intravenous injection of 100 mg/m^2 cytarabine on 7 consecutive days. Consolidation period: Twice-daily intravenous injection of 1.5 g/m^2 cytarabine on Days 1, 3, and 5.<br>|
| Experimental: Phase 1 Dose Expansion Part<br>In the dose expansion part in Phase 1 part, subjects will receive ASP2215 at RED that has been determined in the dose-evaluation part, and the safety will be assessed based on the onset of DLTs during Cycle 1 of the induction and consolidation periods. | Drug: gilteritinib<br>* Once-daily oral administration on 14 consecutive days in every cycle in each period.<br>* Other names: ASP2215;Drug: Idarubicin<br>* Induction period: Once-daily intravenous injection of 12 mg/m^2 idarubicin on 3 consecutive days.<br>Drug: Cytarabine<br>* Induction period: Once-daily intravenous injection of 100 mg/m^2 cytarabine on 7 consecutive days. Consolidation period: Twice-daily intravenous injection of 1.5 g/m^2 cytarabine on Days 1, 3, and 5.<br>|
| Experimental: Phase 2 Part<br>Subjects will receive ASP2215 at the recommended dose established in Phase 1 part. | Drug: gilteritinib<br>* Once-daily oral administration on 14 consecutive days in every cycle in each period.<br>* Other names: ASP2215;Drug: Idarubicin<br>* Induction period: Once-daily intravenous injection of 12 mg/m^2 idarubicin on 3 consecutive days.<br>Drug: Cytarabine<br>* Induction period: Once-daily intravenous injection of 100 mg/m^2 cytarabine on 7 consecutive days. Consolidation period: Twice-daily intravenous injection of 1.5 g/m^2 cytarabine on Days 1, 3, and 5.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 part: Maximum tolerated dose (MTD) | MTD is defined as the highest dose of ASP2215 at which the posterior mean of the Dose-Limiting Toxicity (DLT) incidence during Cycle 1 of induction therapy is estimated to be closest to 33%. | Up to 42 days | 
| Phase 1 part: Recommended expansion dose (RED) | The sponsor will decide the RED considering the MTD, safety, pharmacokinetics, and efficacy of ASP2215. The final RED will be decided by the sponsor's responsible person by comprehensively assessing the data obtained from the study, and taking into account the discussion held between the sponsor, the medical expert, the investigator, and the advisor of medical statistics. | Up to 42 days | 
| Phase 1 part: Number of participants with dose limiting toxicities (DLTs) | A DLT is defined as any Grade ≥ 3 non-hematologic or extramedullary toxicity or any events that require dose reduction of ASP2215 that occur during the DLT assessment period, and that is considered to be possibly, probably, or definitely related to induction or consolidation therapies including the study drugs. The DLT assessment period for making a decision of whether or not to proceed to the next dose is defined as the shorter of the following 2 periods: 39 days from the start of the treatment with ASP2215 in the induction period or days between the start of induction therapy and the start of the first consolidation therapy. For safety assessment during the expansion part, the DLT assessment period includes Cycle 1 of consolidation therapy in addition to the period defined above. | Up to 42 days | 
| Phase 1 part: Number of participants with Adverse Events (AEs) | AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA). A treatment-emergent adverse event (TEAE) is defined as an AE observed after starting administration of the investigational product (IP) and within 28 days after the last administration of IP for phase 1 part. An IP-related TEAE is defined as any TEAE with a causal relationship assessed as YES by the investigator. AE is considered serious if the investigator or sponsor view any of the following outcomes: Death, life-threatening, persistent or significant disability/incapacity, congenital anomaly or birth defect, hospitalization, or medically important event. | Up to 9 months | 
| Phase 1 part: Number of participants with laboratory value abnormalities and/or AEs | Number of participants with potentially clinically significant laboratory values. | Up to 9 months | 
| Phase 1 part: Number of participants with vital sign abnormalities and/or AEs | Number of participants with potentially clinically significant vital sign values. | Up to 9 months | 
| Phase 2 part: Complete remission (CR) rate after induction therapy period | CR is defined as a morphologically leukemia-free state at the post-baseline visit, having a neutrophil count of ≥ 1,000/mm^3 and platelet count of ≥ 100,000/mm^3, bone marrow blasts < 5%. There must be no evidence of Auer rods and no evidence of extramedullary leukemia. The blast counts in peripheral blood must be ≤ 2%. | Up to 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 part: Pharmacokinetics of ASP2215 in plasma: Maximum concentration (Cmax) | Cmax will be recorded from the PK plasma samples collected. | Up to 9 months | 
| Phase 1 part: PK of ASP2215 in plasma: Time to attain Cmax (tmax) | tmax will be recorded from the PK plasma samples collected. | Up to 9 months | 
| Phase 1 part: PK of ASP2215 in plasma: Area under plasma concentration-time curve from time 0 to 24 (AUC24) | AUC24 will be recorded from the PK plasma samples collected. | Up to 9 months | 
| Phase 1 part: PK of ASP2215 in plasma: Oral clearance (CL/F) | CL/F will be recorded from the PK plasma samples collected. | Up to 9 months | 
| Phase 1 part: PK of ASP2215 in plasma: AUC from time 0 to last measurable concentration (AUClast) | AUClast will be recorded from the PK plasma samples collected. | Up to 9 months | 
| Phase 1 part: PK of ASP2215 in plasma: Apparent terminal elimination half-life (t1/2) | t1/2 will be recorded from the PK plasma samples collected. | Up to 9 months | 
| Phase 1 part: PK of ASP2215 in plasma: Apparent Volume of Distribution During the Terminal Elimination Phase after Oral Dosing (Vz/F) | Vz/F will be recorded from the PK plasma samples collected. | Up to 9 months | 
| Phase 1 part: PK of ASP2215 in plasma: Plasma trough concentration (Ctrough) | Ctrough will be recorded from the PK plasma samples collected. | Up to 9 months | 
| Phase 1 part: PK of cytarabine in plasma: Ctrough | Ctrough will be recorded from the PK plasma samples collected. | Up to 9 months | 
| Phase 2 part: PK of ASP2215 in plasma: Concentration | Concentration will be recorded from the PK plasma samples collected. | Up to 135 days | 
| Phase 2 part: Duration of overall survival (OS) | OS is defined as the time from the date of first dose of day 1 to the date of death due to any cause. Patients still alive or lost to follow up will be censored at the time they were last known to be alive. | Up to 41 months | 
| Phase 2 part: Duration of event free survival (EFS) | EFS is defined as the time from the date of first dose of study regimen (day 1) until the date of documented relapse, treatment failure or death from any cause, whichever occurs first. For a subject with none of these events, EFS is censored at the date of last disease assessment. | Up to 41 months | 
| Phase 2 part: Duration of relapse free survival (RFS) | RFS is defined as time from the date of achievement of first CRc until relapse or death from any cause, whichever comes first. For a subject who is not known to have relapsed or died, RFS is censored on the date of last relapse-free disease assessment date. | Up to 41 months | 
| Phase 2 part: CR rate after each treatment therapy | CR is defined as a morphologically leukemia-free state at the post-baseline visit, having a neutrophil count of ≥ 1,000/mm^3 and platelet count of ≥ 100,000/mm^3, bone marrow blasts < 5%. There must be no evidence of Auer rods and no evidence of extramedullary leukemia. The blast counts in peripheral blood must be ≤ 2%. | Up to 34 months | 
| Phase 2 part: CR rate without minimal residual disease (MRD) after each treatment therapy | MRD will be measured from bone marrow samples taken at the screening visit, end of treatment/disease progression and from bone marrow samples taken at other time points during the study. | Up to 34 months | 
| Phase 2 part: CR with partial hematological recovery (CRh) rate after each treatment therapy | CRh is defined as a condition at the post baseline visit, having bone marrow blasts < 5%, partial hematologic recovery neutrophil count≥ 500/mm^3 and platelet count ≥ 50,000/mm^3, no evidence of extramedullary leukemia and cannot be classified as CR. The blast counts in peripheral blood must be ≤ 2%. | Up to 34 months | 
| Phase 2 part: Composite CR (CRc) rate after each treatment therapy | CRc is defined as total of CR, CR with incomplete platelet recovery (CRp) and + CR with incomplete hematologic recovery (CRi). CRp is defined as a condition that meets all of the CR criteria at the post-baseline visit, except for the unrecovered platelet count (< 100,000/mm^3). CRi is defined as a condition that meets all of the CR criteria at the post-baseline visit, except for the unrecovered neutrophil count (< 1,000/mm^3; whether or not having unrecovered platelet counts). | Up to 34 months | 
| Phase 2 part: CR/CRh rate after each treatment therapy | CR is defined as a morphologically leukemia-free state at the post-baseline visit, having a neutrophil count of ≥ 1,000/mm^3 and platelet count of ≥ 100,000/mm^3, bone marrow blasts < 5%. There must be no evidence of Auer rods and no evidence of extramedullary leukemia. The blast counts in peripheral blood must be ≤ 2%. CRh is defined as a condition at the post baseline visit, having bone marrow blasts < 5%, partial hematologic recovery neutrophil count≥ 500/mm^3 and platelet count ≥ 50,000/mm^3, no evidence of extramedullary leukemia and cannot be classified as CR. The blast counts in peripheral blood must be ≤ 2%. | Up to 34 months | 
| Phase 2 part: Duration of CR | Duration of CR is defined as the period from the first day of achieving CR to the first day of confirmed relapse. | Up to 41 months | 
| Phase 2 part: Duration of CR/CRh | Duration of CR/CRh is defined as the period from the first day of achieving CR or CRh to the first day of confirmed relapse. | Up to 41 months | 
| Phase 2 part: Duration of CRh | Duration of CRh is defined as the period from the first day of achieving CRh to the first day of confirmed relapse. | Up to 41 months | 
| Phase 2 part: Duration of CRc | Duration of CRc is defined as the period from the first day of achieving CRc to the first day of confirmed relapse. | Up to 41 months | 
| Phase 2 part: Duration of response | Duration of response is defined as the period from the first day of achieving CR, CRp, CRi, or PR to the first day of confirmed relapse. | Up to 41 months | 
| Phase 2 part: Number of participants with AEs | AEs will be coded using MedDRA. A TEAE is defined as an AE observed after starting administration of the IP and within 30 days after the last administration of IP for phase 2 part. An IP-related TEAE is defined as any TEAE with a causal relationship assessed as YES by the investigator. AE is considered serious if the investigator or sponsor view any of the following outcomes: Death, life-threatening, persistent or significant disability/incapacity, congenital anomaly or birth defect, hospitalization, or medically important event. | Up to 35 months | 
| Phase 2 part: Number of participants with laboratory value abnormalities and/or AEs | Number of participants with potentially clinically significant laboratory values. | Up to 35 months | 
| Phase 2 part: Number of participants with vital sign abnormalities and/or AEs | Number of participants with potentially clinically significant vital sign values. | Up to 35 months | 
| Phase 2 part: Number of participants with 12- ECG abnormalities and/or AEs | Number of participants with potentially clinically significant 12-ECG values. | Up to 35 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Idarubicin, Acute Myeloid Leukemia, Cytarabine, ASP2215