A Study of ASP2215 (Gilteritinib) by Itself, ASP2215 Combined With Azacitidine or Azacitidine by Itself to Treat Adult Patients Who Have Recently Been Diagnosed With Acute Myeloid Leukemia With a FLT3 Gene Mutation and Who Cannot Receive Standard Chemotherapy

Phase 3

Completed

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

Interventions: Drug: gilteritinib
Drug: azacitidine

Registration Number: NCT02752035

Lead Sponsor: Astellas Pharma Global Development, Inc.

Brief Summary: This was a clinical study for adult participants who were recently diagnosed with acute myeloid leukemia or AML. AML is a type of cancer. It is when bone marrow makes white blood cells that are not normal. These are called leukemia cells. Some participants with AML have a mutation, or change, in the FLT3 gene. This gene helps leukemia cells make a protein called FLT3. This protein causes the leukemia cells to grow faster.

For participants with AML who could not receive standard chemotherapy, azacitidine (also known as Vidaza®) was a current standard of care treatment option in the United States. This clinical study tested an experimental medicine called ASP2215, also known as gilteritinib. Gilteritinib worked by stopping the leukemia cells from making the FLT3 protein. This helped stop the leukemia cells from growing faster.

This study compared two different treatments. Participants were assigned to one of these two groups by chance: a medicine called azacitidine, also known as Vidaza®, or an experimental medicine gilteritinib in combination with azacitidine. There was a twice as much chance to receive both medicines combined than azacitidine alone. The clinical study may help show which treatment helps patients live longer.

Detailed Description: Participants considered an adult according to local regulation at the time of obtaining informed consent participated in the study.

Safety Cohort Prior to initiation of the randomized trial, 15 participants were enrolled to evaluate the safety and tolerability of ASP2215 given with azacitidine therapy in the study population.

Randomized Trial Approximately 250 participants were randomized in a 2:1 ratio to receive ASP2215 plus azacitidine (Arm AC) or azacitidine only (Arm C). Participants entered the screening period up to 14 days prior to the start of treatment. Participants administered treatment over 28-day cycles.

Earlier protocol versions included a 1:1:1 randomization ratio to receive Arm A: ASP2215, Arm AC: ASP2215 + azacitidine or Arm C: azacitidine. Participants previously randomized to Arm A continued following treatment and assessments as outlined in the protocol.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 183

Inclusion Criteria

Subject is considered an adult according to local regulation at the time of obtaining informed consent.
Subject has a diagnosis of previously-untreated AML according to World Health Organization (WHO) classification [Swerdlow et al, 2008] as determined by pathology review at the treating institution.
Subject is positive for FLT3 mutation (internal tandem duplication [ITD] or tyrosine kinase domain [TKD] [D835/I836] mutation) (or for Korea only: ITD alone or ITD with concurrent TKD activating mutation) in bone marrow or whole blood as determined by central laboratory. Note: Only requirement of FLT3 mutation assessment by central laboratory is only applicable to the randomization portion of the study.
Subject is ineligible for intensive induction chemotherapy by meeting at least 1 of the following criteria:
- Subject is ≥ 65 years of age and ineligible for intensive induction chemotherapy.
- Subject is ≥ 18 to 64 years of age and has any of the following comorbidities: [Ex-US Only]: Congestive heart failure (New York Heart Association {NYHA} class ≤ 3) or ejection fraction (Ef) ≤ 50%; [US Only]: Severe cardiac disorder e.g. congestive heart failure (New York Heart Association [NYHA] class ≤ 3) requiring treatment, ejection fraction ≤ 50%, or chronic stable angina; [Ex-US Only]: Creatinine > 2 mg/dL (177 µmol/L), dialysis or prior renal transplant; [US Only]: Creatinine clearance < 45 mL/min; ECOG performance status ≥ 2;
- [Ex-US Only]: Known pulmonary disease with decreased diffusion capacity of lung for carbon monoxide (DLCO) and/or requiring oxygen ≤ 2 liters per minute; [US Only] Severe pulmonary disorder (e.g., diffusion capacity of lung for carbon monoxide [DLCO] ≤ 65% or forced expiratory volume in the first second [FEV1] ≤ 65%); Prior or current malignancy that does not require concurrent treatment; Subject has received a cumulative anthracycline dose above 400 mg/m2 of doxorubicin (or cumulative maximum dose of another anthracycline). Any other comorbidity incompatible with intensive chemotherapy must be reviewed and approved by the Medical Monitor during screening and before randomization.
Subject must meet the following criteria as indicated on the clinical laboratory tests:
- Serum AST and ALT ≤ 3.0 x Institutional upper limit of normal (ULN)
- Serum total bilirubin ≤ 1.5 x Institutional ULN
- Serum potassium ≥ Institutional lower limit of normal (LLN)
- Serum magnesium ≥ Institutional LLN Repletion of potassium and magnesium levels during the screening period is allowed.
Subject is suitable for oral administration of study drug.
Female subject is eligible to participate if female subject is not pregnant and at least one of the following conditions applies:
- Not a woman of childbearing potential (WOCBP); OR
- WOCBP agrees to follow the contraceptive guidance starting at screening and continue throughout the study period, and for at least 180 days after the final study drug 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 with female partners of childbearing potential must agree to use contraception as detailed in Contraception Requirements, 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.
Subject agrees not to participate in another interventional study while on treatment.

Exclusion Criteria

Subject was diagnosed as acute promyelocytic leukemia (APL).
Subject has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).
Subject has received previous therapy for AML, with the exception of the following:
- Emergency leukapheresis
- Hydroxyurea
- Preemptive treatment with retinoic acid prior to exclusion of APL ≤ 7 days
- Growth factor or cytokine support
- Steroids
Subject has clinically active central nervous system leukemia.
Subject has been diagnosed with another malignancy that requires concurrent treatment (with the exception of hormone therapy limited to those therapies that prevent recurrence and/or spread of cancer) or hepatic malignancy regardless of need for treatment.
Subject requires treatment with concomitant drugs that are strong inducers of cytochrome P450 CYP3A/P-glycoprotein (P-gp).
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 2B (5HT2BR) or sigma nonspecific receptor with the exception of drugs that are considered absolutely essential for the care of the subject.
Subject has congestive heart failure classified as New York Heart Association Class IV.
Subject with mean Fridericia-corrected QT interval (QTcF) > 480 ms at screening based on central reading.
Subject with a history of Long QT Syndrome at screening.
[Ex-US Only]: Subject has known pulmonary function tests with diffusion capacity of lung for carbon monoxide (DLCO) ≤ 50%, forced expiratory volume in the first second (FEV1) ≤ 60%, dyspnea at rest or requiring oxygen or any pleural neoplasm (Transient use of supplemental oxygen is allowed.)
Subject has active hepatitis B or C or other active hepatic disorder.
- Subjects with positive hepatitis B surface antigen (HBsAg) or detectable hepatitis B DNA are not eligible.
- Subjects with negative HBsAg, positive hepatitis B core antibody and negative hepatitis B surface antibody will be eligible if hepatitis B DNA is undetectable.
- Subjects with antibodies to hepatitis C virus will be eligible if hepatitis C RNA is undetectable
Subject has any condition which makes the subject unsuitable for study participation, including any contraindications of azacitidine.
Subject has a known or suspected hypersensitivity to ASP2215, azacitidine or any components of the formulations used.
[US Only]: Subject is ≥ 65 to 74 years of age, suitable for and willing to receive intensive induction chemotherapy.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Safety Cohort: Gilteritinib + Azacitidine (AZA)	gilteritinib	Participants received 80 mg (2 tablets of 40 mg) of gilteritinib orally once daily for continuous 28-day cycles and 75 mg/m\^2 of AZA daily via subcutaneous injection or intravenous infusion for 7 days of each 28-day treatment cycle. Depending on the safety cohort data ,the decision to initiate the randomized trial at the targeted dose was made. After the end of treatment period, participants were followed up for 30- day follow up period. Participants were allowed to enter the long-term follow-up period of up to 3 years for collection of subsequent AML treatment, EQ-5D-5L, remission status and survival (cause of death and date of death). Participants in long-term follow-up who were no longer receiving treatment were followed every 3 months for survival until the implementation of the final protocol version 13.0, at which time they were discontinued from the study, as further survival data were no longer needed.
Safety Cohort: Gilteritinib + Azacitidine (AZA)	azacitidine	Participants received 80 mg (2 tablets of 40 mg) of gilteritinib orally once daily for continuous 28-day cycles and 75 mg/m\^2 of AZA daily via subcutaneous injection or intravenous infusion for 7 days of each 28-day treatment cycle. Depending on the safety cohort data ,the decision to initiate the randomized trial at the targeted dose was made. After the end of treatment period, participants were followed up for 30- day follow up period. Participants were allowed to enter the long-term follow-up period of up to 3 years for collection of subsequent AML treatment, EQ-5D-5L, remission status and survival (cause of death and date of death). Participants in long-term follow-up who were no longer receiving treatment were followed every 3 months for survival until the implementation of the final protocol version 13.0, at which time they were discontinued from the study, as further survival data were no longer needed.
Randomized Cohort: Gilteritinib + AZA	gilteritinib	Participants received 120 mg(3 tablets of 40 mg)of gilteritinib orally once daily for continuous 28-day cycles in combination with 75mg/m\^2 of AZA daily via subcutaneous injection or IV infusion for 7days of each 28-day treatment cycle until the participant no longer received clinical benefit from therapy in the opinion of the investigator,unacceptable toxicity occurred,or the participant met another treatment discontinuation criterion.After the end of treatment period,participants were followed up for 30-day follow up period.Participants were allowed to enter the long-term follow-up period of up to 3 years for collection of subsequent AML treatment,EQ-5D-5L,remission status and survival (cause and date of death).Participants in long-term follow-up who were no longer receiving treatment were followed every 3months for survival until the implementation of the final protocol version 13.0, at which time they were discontinued from the study,as further survival data were no longer needed.
Randomized Cohort: AZA	gilteritinib	Participants received 75 mg/m\^2 of AZA daily via subcutaneous injection or intravenous infusion for 7 days of each 28-day treatment cycle until the participant no longer received clinical benefit from therapy in the opinion of the investigator, unacceptable toxicity occurred or the participant met another treatment discontinuation criterion. After the end of treatment period, participants were followed up for 30- day follow up period. Participants were allowed to enter the long-term follow-up period of up to 3 years for collection of subsequent AML treatment, EQ-5D-5L, remission status and survival (cause of death and date of death). Participants in long-term follow-up who were no longer receiving treatment were followed every 3 months for survival until the implementation of the final protocol version 13.0, at which time they were discontinued from the study, as further survival data were no longer needed.
Randomized Cohort: AZA	azacitidine	Participants received 75 mg/m\^2 of AZA daily via subcutaneous injection or intravenous infusion for 7 days of each 28-day treatment cycle until the participant no longer received clinical benefit from therapy in the opinion of the investigator, unacceptable toxicity occurred or the participant met another treatment discontinuation criterion. After the end of treatment period, participants were followed up for 30- day follow up period. Participants were allowed to enter the long-term follow-up period of up to 3 years for collection of subsequent AML treatment, EQ-5D-5L, remission status and survival (cause of death and date of death). Participants in long-term follow-up who were no longer receiving treatment were followed every 3 months for survival until the implementation of the final protocol version 13.0, at which time they were discontinued from the study, as further survival data were no longer needed.
Randomized Cohort: Gilteritinib	azacitidine	Participants received 120 mg (3 tablets of 40 mg) of gilteritinib orally once daily for continuous 28-day cycles until the participant no longer received clinical benefit from therapy in the opinion of the investigator, unacceptable toxicity occurred or the participant met another treatment discontinuation criterion. However, randomization to this arm was removed in protocol version 7.0. Participants previously randomized to this arm continued following treatment and assessments as outlined in the protocol.

Primary Outcome Measures

Name	Time	Method
Overall Survival (OS)	From the date of randomization until the date of death from any cause ( maximum duration up to 79 months)	OS was defined as the time from the date of randomization until the date of death from any cause. For a participant who was not known to have died by the end of study follow-up, OS was censored at the date of last contact. Kaplan-Meier (KM) estimates was used for analysis.

Secondary Outcome Measures

Name	Time	Method
Event-free Survival (EFS)	From the date of randomization until the date of documented relapse from CR, treatment failure or death from any cause, whichever occurred first (up to 39.7 months)	EFS: time from the date of randomization until the date of documented relapse from Complete Remission (CR), treatment failure(failing to achieve CR within 6 cycles of treatment) or death from any cause, whichever occurred first. CR: bone marrow(BM) regenerating normal hematopoietic cells, morphologically leukemia-free state, absolute neutrophil count (ANC) ≥1 × 10\^9/L, platelet count ≥100 × 10\^9/L, normal marrow differential with \<5% myeloblast counts, missing/≤2% peripheral blood blast counts and being red blood cell (RBC) and platelet transfusion independent (1 week without RBC and platelet transfusion prior to the disease assessment). No evidence of extramedullary leukemia and Auer rods. Relapse: reappearance of leukemic blasts \>2% in the peripheral blood/≥ 5% myeloblasts in the BM unattributable to any other cause/new/reappearance of extramedullary leukemia.
Percentage of Participants With Best Response	From the date of randomization until the date of death from any cause (up to 57 months)	Best response for a participant was defined as the best measured response (in the order of CR, CR with Incomplete Platelet Recovery (CRp), CR with Incomplete Hematologic Recovery (CRi), and treatment failure) from all post-baseline visits. CR: BM regenerating normal hematopoietic cells, morphologically leukemia-free state, ANC ≥1 × 10\^9/L, platelet count ≥100 × 10\^9/L, normal marrow differential with \<5% myeloblast counts, missing/≤2% peripheral blood blast counts and being RBC and platelet transfusion independent (1 week without RBC and platelet transfusion prior to the disease assessment). No evidence of extramedullary leukemia and Auer rods. CRp: achieved CR except incomplete platelet recovery (\< 100 × 10\^9/L). CRi: achieved CR except incomplete hematological recovery with residual neutropenia \< 1 x 10\^9/L with or without complete platelet recovery. RBC and platelet transfusion independence not required.
Completed Remission (CR) Rate	From the date of randomization until the date of death from any cause (approximately 49.7 months)	CR rate: number of participants who achieved the best response of CR divided by the number of participants in the analysis population. Participants with unknown or missing response, or who provided no information on response at the end of treatment were included in the denominator when calculating rates. CR: BM regenerating normal hematopoietic cells, morphologically leukemia-free state, ANC ≥1 × 10\^9/L, platelet count ≥100 × 10\^9/L, normal marrow differential with \<5% myeloblast counts, missing/≤2% peripheral blood blast counts and being RBC and platelet transfusion independent(1 week without RBC and platelet transfusion prior to the disease assessment). No evidence of extramedullary leukemia and Auer rods.
CRc Rate	From the date of randomization until the date of death from any cause (approximately 54.5 months)	CRc rate was defined as participants with best response of (CR + CRp + CRi) divided by the number of participants in the analysis population. Participants were classified as: CR: BM regenerating normal hematopoietic cells, morphologically leukemia-free state, ANC ≥1 × 10\^9/L, platelet count ≥100 × 10\^9/L, normal marrow differential with \<5% myeloblast counts, missing/≤2% peripheral blood blast counts and being RBC and platelet transfusion independent (1 week without RBC and platelet transfusion prior to the disease assessment). No evidence of extramedullary leukemia and Auer rods. CRp: achieved CR except incomplete platelet recovery (\< 100 × 10\^9/L). CRi: achieved CR except incomplete hematological recovery with residual neutropenia \< 1 x 10\^9/L with or without complete platelet recovery. RBC and platelet transfusion independence not required. Percentage of participants with CRc was reported.
Complete Remission With Partial Hematologic Recovery (CRh)	From the date of randomization until the date of death from any cause (up to 49.7 months)	CRh was defined as the response at a post baseline visit as CRh having bone marrow myeloblast count \< 5%, partial hematologic recovery ANC ≥ 0.5 x 10\^9/L and platelets ≥ 50 x 10\^9/L, no evidence of extramedullary leukemia and cannot be classified as CR. The blast counts in peripheral blood must be ≤ 2% or missing. CR: BM regenerating normal hematopoietic cells, morphologically leukemia-free state, ANC ≥1 × 10\^9/L, platelet count ≥100 × 10\^9/L, normal marrow differential with \<5% myeloblast counts, missing/≤2% peripheral blood blast counts and being RBC and platelet transfusion independent (1 week without RBC and platelet transfusion prior to the disease assessment). No evidence of extramedullary leukemia and Auer rods. Percentage of participants with CRh was reported.
CR/CRh Rate	From the date of randomization until the date of death from any cause (up to 49.7 months)	CR/CRh rate: number of participants who achieved CR or CRh divided by the number of participants in the analysis population. CR/CRh: CR/CRh if it fulfilled criteria for CR or CRh at the visit. CR: BM regenerating normal hematopoietic cells, morphologically leukemia-free state, ANC ≥1 × 10\^9/L, platelet count ≥100 × 10\^9/L, normal marrow differential with \<5% myeloblast counts, missing/≤2% peripheral blood blast counts and being RBC and platelet transfusion independent (1 week without RBC and platelet transfusion prior to the disease assessment). No evidence of extramedullary leukemia and Auer rods. CRh: response at a post baseline visit as CRh having bone marrow myeloblast count \< 5%, partial hematologic recovery ANC ≥ 0.5 x 10\^9/L and platelets ≥ 50 x 10\^9/L, no evidence of extramedullary leukemia and cannot be classified as CR. The blast counts in peripheral blood must be ≤ 2% or missing. Percentage of participants with CR/CRh was reported.
Percentage of Participants With Transfusion Conversion Rate	From baseline up to 57 months	Transfusion conversion rate was defined as the number of participants who were transfusion dependent at baseline period but became transfusion independent at post-baseline period divided by the total number of participants who were transfusion dependent at baseline period.
Percentage of Participants With Transfusion Maintenance Rate	From baseline up to 57 months	Transfusion maintenance rate was defined as the number of participants who were transfusion independent at baseline period and remained transfusion independent post-baseline period divided by the total number of participants who were transfusion independent at baseline period.
Leukemia-free Survival (LFS)	From first day of achieving first CRc to the first day of confirmed relapse/death (up to 54.5 months)	LFS: time from the date of first CRc (CR + CRp + CRi) until the date of documented relapse (excluding relapse from PR) or death for participants who achieved CRc. CR: BM regenerating normal hematopoietic cells, morphologically leukemia-free state, ANC ≥1 × 10\^9/L, platelet count ≥100 × 10\^9/L, normal marrow differential with \<5% myeloblast counts, missing/≤2% peripheral blood blast counts and being RBC and platelet transfusion independent (1 week without RBC and platelet transfusion prior to the disease assessment). No evidence of extramedullary leukemia and Auer rods. CRp: achieved CR except incomplete platelet recovery (\< 100 × 10\^9/L). CRi: achieved CR except incomplete hematological recovery with residual neutropenia \< 1 x 10\^9/L with or without complete platelet recovery. RBC and platelet transfusion independence not required. CRc: fulfilled criteria for CR, CRp or CRi. Based on KM estimates.
Duration of Remission	From first day of achieving first response to the first day of confirmed relapse/death (up to 56.4 months)	Duration of remission included CRc, CR, CRh, CR/CRh, and response duration \[CRc + PR\]. Duration of CRc, CR, CRh: the time from the date of first CRc until the date of first documented relapse for participants who achieved CRc, CR, and CRh, respectively. CR/CRh: fulfilled criteria for CR or CRh at the visit. CRh: marrow blasts \<5%, ANC ≥0.5×10\^9/L, platelets ≥50×10\^9/L, not meeting CR criteria. PR: If marrow myeloblasts between \<5% and 25% and ≤2% or missing peripheral blood blast and a decrease from baseline of at least 50% in the marrow myeloblasts and no evidence of extramedullary leukemia, the response was classified as PR. If marrow myeloblasts \<5% and ≤2% or missing peripheral blood blast and no evidence of extramedullary leukemia, the response was classified as PR even with Auer rods.
Change From Baseline in Brief Fatigue Inventory (BFI)	From baseline to 31 months	The BFI was a tool to assess fatigue severity and impact on daily function in cancer participants over 24 hours. It included 9 items. A global fatigue score was computed by averaging the scores of the 9 items measured on the numeric rating scale. Scores were calculated if ≥5 of 9 items were answered. A higher score indicates a higher degree of fatigue. The first 3 rate fatigue from 0 (no fatigue) to 10 (worst imaginable), with higher scores indicating worse outcomes. The remaining 6 assess how fatigue interferes with daily activities from 0 (no interference) to 10 (completely interferes). A global fatigue score (0-10) was the average of all items, with higher scores indicating worse fatigue. Overall BFI score is reported.
Number of Participants With Treatment Emergent Adverse Events (TEAEs)	From first dose up to end of study duration (101 months)	An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE could therefore be any unfavorable \& unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. TEAE was defined as an adverse event observed after starting administration of the study drug until 30 days from the last study treatment
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores	From baseline to end of treatment (up to 57 months)	ECOG performance scores at each assessment time were be provided by treatment group. Negative change scores indicated an improvement and positive scores indicate a decline in performance. The grades were defined as follows: 0: Fully active, able to carry on all pre-disease performance without restriction. 1. 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. 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.

Trial Locations

Locations (111): UCLA David Geffen School of Medicine
🇺🇸
Los Angeles, California, United States
University of California, Irvine Medical Center
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Orange, California, United States
Robert H. Lurie Comprehensive Cancer Center
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Chicago, Illinois, United States
Rush University Medical Center
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Chicago, Illinois, United States
St. Louis University Cancer Center - Hematology/Oncology
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St Louis, Missouri, United States
Hackensack University Medical Center - John Theurer Cancer Center
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Hackensack, New Jersey, United States
Hematology-Oncology Associates of Northern NJ
🇺🇸
Morristown, New Jersey, United States
Roswell Park Cancer Institute
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Buffalo, New York, United States
Memorial Sloan-Kettering Cancer Center
🇺🇸
New York, New York, United States
Weill Cornell Medical College-New York Presbyterian Hospital
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New York, New York, United States
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UCLA David Geffen School of Medicine
🇺🇸Los Angeles, California, United States