A Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation

Leukemia, Acute Myeloid (AML) Clinical Trial

Official title:

A 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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02421939
• Other study ID #: 2215-CL-0301
• Secondary ID: 2015-000140-42
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: October 20, 2015
• Est. completion date: July 31, 2024

Study information

• Verified date: May 2024
• Source: Astellas Pharma Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine the clinical benefit of ASP2215 therapy in participants with FMS-like tyrosine kinase (FLT3) mutated acute myeloid leukemia (AML) who are refractory to or have relapsed after first-line AML therapy as shown with overall survival (OS) compared to salvage chemotherapy, and to determine the efficacy of ASP2215 therapy as assessed by the rate of complete remission and complete remission with partial hematological recovery (CR/CRh) in these participants. This study will also determine the overall efficacy in event-free survival (EFS) and complete remission (CR) rate of ASP2215 compared to salvage chemotherapy.

Description:

Participants considered an adult according to local regulations at the time of signing informed consent may participate in this study. Participants will be randomized in a 2:1 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, a salvage chemotherapy regimen will be pre-selected for each participant; options will include low-dose cytarabine (LoDAC), azacitidine, mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC), or fludarabine, cytarabine, and granulocyte colony-stimulating factor (G-CSF) with idarubicin (FLAG-IDA). The randomization will be stratified by response to first-line therapy and pre-selected salvage chemotherapy. Participants will be administered treatment over continuous 28-day cycles. After treatment discontinuation, participants will have a pre-hematopoietic stem cell transplant (HSCT)/end-of-treatment visit within 7 days after treatment discontinuation, followed by a 30-day follow-up for safety, in which a telephone contact with the participant is sufficient unless any assessment must be repeated for resolution of treatment-related adverse events (AEs). After that, long term follow-up will be done every 3 months up to 3 years from the participant's end-of-treatment visit.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 371
• Est. completion date: July 31, 2024
• Est. primary completion date: September 17, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Participant has a diagnosis of primary acute myeloid leukemia (AML) or AML secondary to myelodysplastic syndrome (MDS) according to WHO classification (2008) as determined by pathology review at the treating institute.
• Participant is refractory to or relapsed after first-line AML therapy (with or without hematopoietic stem cell transplant (HSCT)).
• Refractory to first-line AML therapy is defined as:

1. Participant did not achieve complete remission/complete remission with incomplete hematologic recovery/complete remission with incomplete platelet recovery (CR/CRi/CRp) under initial therapy. A Participant eligible for standard therapy must receive at least one cycle of an anthracycline containing induction block in standard dose for the selected induction regimen. A Participant not eligible for standard therapy must have received at least one 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:

1. Participant must have achieved a CR/CRi/CRp (criteria as defined by [Cheson et al, 2003], see Section 5.3) with first line treatment and has hematologic relapse.

• Participant is positive for FLT3 mutation in bone marrow or whole blood as determined by the central lab. A Participant 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. Participants can be enrolled from a local test result if they have any of the following FLT3 mutations: FLT3 internal tandem duplication (ITD), FLT3 tyrosine kinase domain (TKD)/D835 or FLT3- TKD/I836.
• Participant has an Eastern Cooperative Oncology Group (ECOG) performance status = 2.
• Participant is eligible for pre-selected salvage chemotherapy.
• Participant must meet the following criteria as indicated on the clinical laboratory

tests:

• Serum aspartate aminotransferase and alanine aminotransferase = 2.5 x upper limit of normal (ULN)
• Serum total bilirubin = 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.
• Participant is suitable for oral administration of study drug.
• Female Participant must either:
• Be of non-child bearing potential:

1. post-menopausal (defined as at least 1 year without any menses) prior to Screening, or

2. documented as surgically sterile (at least 1 month prior to Screening)

• Or, if of childbearing potential,

1. Agree not to try to become pregnant during the study and for 180 days after the final study administration

2. And have a negative urine pregnancy test at Screening

3. 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 180 days after the final study drug administration.

• Female Participant must agree not to breastfeed at Screening and throughout the study period and for 60 days after the final study drug administration.
• Female Participant must not donate ova starting at Screening and throughout the study period and for 180 days after the final study drug administration.
• Male Participant 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 Participant must not donate sperm starting at Screening and throughout the study period and 120 days after the final study drug administration.
• Participant agrees not to participate in another interventional study while on treatment.

Exclusion Criteria:

• Participant was diagnosed as acute promyelocytic leukemia (APL).
• Participant has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).
• Participant has AML secondary to prior chemotherapy for other neoplasms (except for MDS).
• Participant is in second or later hematologic relapse or has received salvage therapy for refractory disease
• Participant has clinically active central nervous system leukemia.
• Participant has been diagnosed with another malignancy, unless disease-free for at least 5 years. Participants 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. Participants 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.
• Participant 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).
• Participant has clinically significant abnormality of coagulation profile, such as disseminated intravascular coagulation (DIC).
• Participant has had major surgery within 4 weeks prior to the first study dose.
• Participant has radiation therapy within 4 weeks prior to the first study dose.
• Participant has congestive heart failure New York Heart Association (NYHA) class 3 or 4, or Participant with a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram performed within 3 months prior to study entry results in a left ventricular ejection fraction that is = 45%.
• Participant requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP)3A.
• Participants with mean of triplicate Fridericia-corrected QT interval (QTcF) > 450 ms at Screening based on central reading.
• Participants with Long QT Syndrome at Screening.
• Participants with hypokalemia and hypomagnesemia at Screening (defined as values below lower limit of normal [LLN]).
• Participant 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.
• Participant 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.
• Participant has an active uncontrolled infection.
• Participant is known to have human immunodeficiency virus infection.
• Participant has active hepatitis B or C, or other active hepatic disorder.
• Participant has any condition which makes the Participant unsuitable for study participation.
• Participant has active clinically significant GVHD or is on treatment with systemic corticosteroids for GVHD.
• Participant has an FLT3 mutation other than the following: FLT3-ITD, FLT3-TKD/D835 or FLT3-TKD/I836.

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Acute Myeloid (AML)
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• gilteritinib
tablet, oral
• LoDAC (Low Dose Cytarabine)
subcutaneous (SC) or intravenous (IV) injection
• Azacitidine
SC or IV injection
• MEC (Mitoxantrone, Etoposide, Cytarabine)
IV injection
• FLAG-IDA (Granulocyte-Colony Stimulating Factor (G-CSF), Fludarabine, Cytarabine, Idarubicin)
SC (G-CSF) and IV (Fludarabine, Cytarabine, Idarubicin) injection

Locations

Country	Name	City	State
Belgium	Site BE32002	Yvoir
Canada	Site CA15004	Edmonton	Alberta
Canada	Site CA15001	Hamilton	Ontario
Canada	Site CA15003	Montreal	Quebec
Canada	Site CA15015	Toronto	Ontario
France	Site FR33013	Brest
France	Site FR33002	Le Chesnay Cedex
France	Site FR33010	Lille
France	Site FR33009	Pessac
France	Site FR33014	Rennes
France	Site FR33008	Toulouse
Germany	Site DE49009	Dresden
Germany	Site DE49011	Leipzig
Germany	Site DE49003	Marburg
Germany	Site DE49002	Munchen
Germany	Site DE49010	Tubingen
Israel	Site IL97201	Ashkelon
Israel	Site IL97209	Haifa
Israel	Site IL97203	Jerusalem
Israel	Site IL97210	Jerusalem
Israel	Site IL97206	Petah Tikva
Israel	Site IL97208	Rehovot
Italy	Site IT39005	Bologna
Italy	Site IT39010	Brescia
Italy	Site IT39001	Milan
Italy	Site IT39004	Palermo
Italy	Site IT39011	Pavia
Italy	Site IT39007	Roma
Italy	Site IT39002	Varese
Japan	Site JP81023	Akita
Japan	Site JP81021	Aomori
Japan	Site JP81005	Chuo-ku	Tokyo
Japan	Site JP81009	Isehara	Kanagawa
Japan	Site JP81020	Kawagoe	Saitama
Japan	Site JP81018	Kobe	Hyogo
Japan	Site JP81013	Kumamoto
Japan	Site JP81007	Kurashiki	Okayama
Japan	Site JP81025	Kyoto
Japan	Site JP81008	Nagasaki
Japan	Site JP81002	Nagoya	Aichi
Japan	Site JP81010	Narita	Chiba
Japan	Site JP81024	Okayama
Japan	Site JP81011	Osaka
Japan	Site JP81014	Osakasayama	Osaka
Japan	Site JP81016	Sapporo	Hokkaido
Japan	Site JP81012	Sendai	Miyagi
Japan	Site JP81027	Shimotsuke	Tochigi
Japan	Site JP81004	Shinagawa-ku	Tokyo
Japan	Site JP81022	Shinjuku-ku	Tokyo
Japan	Site JP81017	Tsukuba	Ibaraki
Japan	Site JP81006	Yokohama	Kanagawa
Japan	Site JP81026	Yoshida-gun	Fukui
Korea, Republic of	Site KR82010	Busan
Korea, Republic of	Site KR82009	Goyang
Korea, Republic of	Site KR82003	Jeollanam-do
Korea, Republic of	Site KR82001	Seoul
Korea, Republic of	Site KR82002	Seoul
Korea, Republic of	Site KR82004	Seoul
Korea, Republic of	Site KR82007	Seoul
Korea, Republic of	Site KR82008	Seoul
Korea, Republic of	Site KR82011	Seoul
Korea, Republic of	Site KR82005	Suwon-si	Gyeonggi-do
Poland	Site PL48002	Gdansk
Poland	Site PL48005	Opole
Poland	Site PL48004	Wroclaw
Spain	Site ES34009	Badalona
Spain	Site ES34010	Barcelona
Spain	Site ES34011	Barcelona
Spain	Site ES34012	Barcelona
Spain	Site ES34016	Girona
Spain	Site ES34005	L'Hospitalet de Llobregat
Spain	Site ES34014	Salamanca
Spain	Site ES34017	Valencia
Taiwan	Site TW88604	Kaohsiung
Taiwan	Site TW88606	Kaohsiung
Taiwan	Site TW88608	Taichung
Taiwan	Site TW88609	Taichung City
Taiwan	Site TW88601	Tainan
Taiwan	Site TW88602	Taipei
Taiwan	Site TW88603	Taipei
Taiwan	Site TW88610	Taipei
Taiwan	Site TW88611	Taipei
Taiwan	Site TW88605	Taoyuan
Turkey	Site TR90001	Ankara
Turkey	Site TR90004	Ankara
United Kingdom	Site GB44014	Bournemouth
United Kingdom	Site GB44013	Harrow
United Kingdom	Site GB44003	Manchester
United Kingdom	Site GB44015	Plymouth
United States	Site US10081	Atlanta	Georgia
United States	Site US10005	Baltimore	Maryland
United States	Site US10011	Birmingham	Alabama
United States	Site US10022	Boston	Massachusetts
United States	Site US10034	Boston	Massachusetts
United States	Site US10085	Boston	Massachusetts
United States	Site US10001	Buffalo	New York
United States	Site US10014	Charleston	South Carolina
United States	Site US10006	Chicago	Illinois
United States	Site US10044	Cleveland	Ohio
United States	Site US10084	Columbus	Ohio
United States	Site US10087	Detroit	Michigan
United States	Site US10024	Durham	North Carolina
United States	Site US10045	Gainesville	Florida
United States	Site US10027	Hackensack	New Jersey
United States	Site US10041	Hershey	Pennsylvania
United States	Site US10023	Lebanon	New Hampshire
United States	Site US10012	Los Angeles	California
United States	Site US10074	Louisville	Kentucky
United States	Site US10035	Milwaukee	Wisconsin
United States	Site US10057	Minneapolis	Minnesota
United States	Site US10063	Nashville	Tennessee
United States	Site US10077	New Brunswick	New Jersey
United States	Site US10067	New Haven	Connecticut
United States	Site US10048	New Orleans	Louisiana
United States	Site US10008	New York	New York
United States	Site US10013	New York	New York
United States	Site US10037	New York	New York
United States	Site US10072	New York	New York
United States	Site US10058	Oklahoma City	Oklahoma
United States	Site US10076	Orange	California
United States	Site US10010	Philadelphia	Pennsylvania
United States	Site US10080	Philadelphia	Pennsylvania
United States	Site US10073	San Francisco	California
United States	Site US10046	Syracuse	New York
United States	Site US10075	Westwood	Kansas
United States	Site US10078	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Astellas Pharma Global Development, Inc.

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  France,  Germany,  Israel,  Italy,  Japan,  Korea, Republic of,  Poland,  Spain,  Taiwan,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Duration of Overall Survival (OS)	Overall survival was defined as the time from the date of randomization until the date of death from any cause (death date - randomization date + 1). 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 (date of last contact - randomized date + 1). The date of last contact was the latest date that the participant was known to be alive by the cutoff date. The last contact date was derived for participants alive at the analysis cutoff date. Survival rate and 95% CI were estimated using the Kaplan-Meier method and the Greenwood formula.	From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months
Primary	Percentage of Participants With Complete Remission and Complete Remission With Partial Hematological Recovery (CR/CRh) in the Gilteritinib Arm	The CR/CRh rate was defined as the number of participants who achieved either CR or CRh at any of the postbaseline visits divided by the number of participants in the analysis population.	From randomization until the data cut-off date 04 Aug 2017, the 142 patients included in the primary analysis of CR/CRh rate were followed up at least 112 days
Secondary	Duration of Event-Free Survival (EFS)	EFS was defined as the time from the date of randomization until the date of documented relapse (excluding relapse after PR), treatment failure or death from any cause within 30 days after the last dose of study drug, whichever occurred first (earliest of [relapse date, treatment failure date, death date] - randomization date + 1). If a participant experienced relapse or death within 30 days after the last dose of study drug, the participant was defined as having an EFS event related to either "relapse" or "death", and the event date was the date of relapse or death. For a participant who was not known to have had a relapse or treatment failure or death event, EFS was censored at the date of last relapse-free disease assessment (last relapse-free disease assessment date - randomization date + 1). Data was estimated based on Kaplan-Meier estimates.	From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months
Secondary	Percentage of Participants With Complete Remission (CR) Rate	The CR rate was defined as the number of participants who achieved the best response of CR divided by the number of participants in the analysis population.	From randomization until the data cut-off date of 17 Sep 2018, all participants included in the primary analysis of CR rate were followed up at least 6 months
Secondary	Duration of Leukemia-Free Survival (LFS)	The LFS was defined as the time from the date of first CRc until the date of documented relapse (excluding relapse from PR) or death for participants who achieved CRc (relapse date or death date - first CRc disease assessment date + 1). For a participant who was not known to have relapsed or died, LFS was censored on the date of last relapse-free disease assessment date (last relapse-free disease assessment date - first CRc disease assessment date + 1). For a participant who was not known to have relapsed or died, LFS was censored on the date of last relapse-free disease assessment date (last relapse-free disease assessment date - first CRc disease assessment date + 1).	From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months
Secondary	Duration of Remission	Duration of remission included duration of composite complete remission (CRc), duration of complete remission (CR)/ complete remission with partial hematologic recovery (CRh), duration of CRh, duration of CR and duration of response (CRc + partial remission (PR). The duration of response was defined as the time from the date of either first CRc or PR until the date of documented relapse (i.e., the date of first NR after CRc or PR) for participants who achieved CRc or PR (relapse date - first CRc or PR disease assessment date + 1). Participants who died without report of relapse were considered nonevents and censored at their last relapse-free disease assessment date (last relapse-free disease assessment date - first CRc or PR disease assessment date + 1). Other participants who did not relapse during the study were considered nonevents and censored at the last relapse-free assessment date. Duration of CR was only applicable to participants with best overall response of CR.	From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months
Secondary	Percentage of Participants With Composite Complete Remission (CRc Rate)	CRc rate was defined as the number of participants who achieved the best response of CRc (CR,complete remission with incomplete platelet recovery (CRp) or complete remission with incomplete hematologic recovery (CRi) divided by the number of participants in the analysis population.	From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months
Secondary	Percentage of Participants Who Underwent Hematopoietic Stem Cell Transplant	Transplantation rate is defined as the percentage of participants undergoing Hematopoietic stem cell transplant (HSCT) during the study period.	From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months
Secondary	Change From Baseline in Brief Fatigue Inventory (BFI)	The Brief Fatigue Inventory (BFI) is a screening tool designed to assess the severity and impact of fatigue on daily functioning of participants with cancer during the 24 hours. There are 9 items on the scale. The first three questions ask participants to rate their fatigues on a scale from 0 (no fatigue) - 10 (as bad as you can imagine), with higher scores indicating worse outcome. The remaining six questions ask participants to rate how much fatigue has interfered with their daily activities on a scale from 0 (Does not interfere) to 10 (Completely interferes). A global fatigue score can be obtained by averaging all the items on the BFI. The global BFI score will be calculated only if at least 5 of the 9 items are answered. A higher BFI fatigue score indicates worse outcome.	Baseline and cycle 1, day 8 and cycle 2 day 1 (up to data cut off date of 17 Sep 2018)
Secondary	Percentage of Participants With Complete Remission (CR) With Partial Hematological Recovery (CRh)	CRh rate was defined as the number of participants who achieved CRh at any of the postbaseline visits and did not have a best response of CR divided by the number of participants in the analysis population.	From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months
Secondary	Percentage of Participants Who Achieved Transfusion Conversion and Maintenance	Transfusion conversion & maintenance rate was defined for gilteritinib arm. Participants were classified as transfusion independent if there were no RBC or platelet transfusions within 28 days prior to the first dose to 28 days after the first dose; otherwise they were classified as transfusion dependent at baseline. Participants were considered independent postbaseline if they had 1 consecutive 8 week period without any RBC or platelet transfusion from 29 days after the first dose until the last dose date. For participants who were on treatment = 4 weeks or > 4 weeks but < 12 weeks and there was no RBC or platelet transfusion within postbaseline period, they were considered not evaluable; otherwise, they were considered postbaseline transfusion dependent. Transfusion conversion rate was defined for participants who had evaluable postbaseline transfusion status. Transfusion status (independent vs. dependent) at baseline and postbaseline was reported in a 2 by 2 contingency table.	From randomization until the data cut-off date of 17 Sep 2018, median treatment duration for gilteritinib was (126.00 [4.0, 885.0]) days versus salvage chemotherapy 28.0 [5.0, 217.0] days)
Secondary	Number of Participants With Adverse Events	A treatment-emergent adverse event (TEAE) was defined as an AE observed after starting administration of the study drug (gilteritinib or salvage chemotherapy). If the AE occurred on day 1 and the onset check box was marked "Onset after first dose of study drug" or the onset check box was left blank, then the AE was considered treatment emergent. If the AE occurred on day 1 and the onset check box was marked "Onset before first dose of study drug", then the AE was not considered treatment emergent. Majority of salvage chemotherapy participants finished the study by cycle 2 of treatment, the duration of exposure was longer in the gilteritinib arm compared with the salvage chemotherapy arm (126.00 [4.0, 885.0] days versus 28.0 [5.0, 217.0] days). The NCI-CTCAE is defined as National Cancer Institute-Common Terminology Criteria for Adverse Events.	From first dose of study drug up to 30 days after the last dose of study drug (median treatment duration for gilteritinib was (126.00 [4.0, 885.0]) days versus salvage chemotherapy 28.0 [5.0, 217.0] days)