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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 371
- 试验地点
- 126
- 主要终点
- Duration of Overall Survival (OS)
研究概览
简要总结
The purpose of this study was to determine the clinical benefit of ASP2215 therapy in participants with FMS-like tyrosine kinase (FLT3) mutated acute myeloid leukemia (AML) who were refractory to or had relapsed after first-line AML therapy as shown with overall survival (OS) compared to salvage chemotherapy, and determined 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 also determined the overall efficacy in event-free survival (EFS) and complete remission (CR) rate of ASP2215 compared to salvage chemotherapy.
详细描述
Participants considered an adult according to local regulations at the time of signing informed consent participated in this study. Participants were randomized in a 2:1 ratio to receive ASP2215 or salvage chemotherapy. Participants entered the screening period up to 14 days prior to the start of treatment. Prior to randomization, a salvage chemotherapy regimen was pre-selected for each participant; options included 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 was stratified by response to first-line therapy and pre-selected salvage chemotherapy. Participants were administered treatment over continuous 28-day cycles. After treatment discontinuation, participants had 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 was sufficient unless any assessment had to be repeated for resolution of treatment-related adverse events (AEs). After that, long term follow-up was done every 3 months up to 3 years from the participant's end-of-treatment visit.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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:
- •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/I
- •Participant has an Eastern Cooperative Oncology Group (ECOG) performance status ≤
- •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:
- •post-menopausal (defined as at least 1 year without any menses) prior to Screening, or
- •documented as surgically sterile (at least 1 month prior to Screening)
- •Or, if of childbearing potential,
- •Agree not to try to become pregnant during the study and for 180 days after the final study administration
- •And have a negative urine pregnancy test at Screening
- •And, if heterosexually active, agree to consistently use highly effective contraception per locally accepted standards in addition to a barrier method starting at Screening and throughout the study period and for 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.
排除标准
- •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.
研究组 & 干预措施
Gilteritinib
Participants received 120 mg dose (3 tablets of 40 mg) orally once a day in continuous 28-day cycles, at least 2 hours after or 1 hour before food. Gilteritinib treatment continued until participants met one of the treatment discontinuation criteria.
干预措施: gilteritinib (Drug)
Salvage Chemotherapy
Participants received chemotherapy in 28-day cycles. Participants on Low-Dose Cytarabine (LoDAC) received 20 mg of cytarabine twice daily by subcutaneous (SC) or intravenous (IV) injection for 10 days. Participants on azacitidine received 75 mg/m^2 daily by SC or IV injection for 7 days. Participants on LoDAC or azacitidine treatment continued until they met discontinuation criteria. Participants on MEC chemotherapy received mitoxantrone 8 mg/m^2 daily by IV for 5 days, etoposide 100 mg/m^2 daily by IV for 5 days and cytarabine 1000 mg/m^2 daily by IV for 5 days (days 1-5). Participants on FLAG-IDA chemotherapy received G-CSF 300 μg/m^2 daily by SC/IV for 5 days (days 1-5), fludarabine 30 mg/m^2 daily by IV for 5 days (days 2-6), cytarabine 2000 mg/m^2 daily by IV for 5 days (days 2-6) and idarubicin 10 mg/m^2 daily by IV for 3 days (days 2-4). Participants receiving MEC or FLAG-IDA received 1 cycle of therapy and were assessed for response on or after day 15.
干预措施: LoDAC (Low Dose Cytarabine) (Drug)
Salvage Chemotherapy
Participants received chemotherapy in 28-day cycles. Participants on Low-Dose Cytarabine (LoDAC) received 20 mg of cytarabine twice daily by subcutaneous (SC) or intravenous (IV) injection for 10 days. Participants on azacitidine received 75 mg/m^2 daily by SC or IV injection for 7 days. Participants on LoDAC or azacitidine treatment continued until they met discontinuation criteria. Participants on MEC chemotherapy received mitoxantrone 8 mg/m^2 daily by IV for 5 days, etoposide 100 mg/m^2 daily by IV for 5 days and cytarabine 1000 mg/m^2 daily by IV for 5 days (days 1-5). Participants on FLAG-IDA chemotherapy received G-CSF 300 μg/m^2 daily by SC/IV for 5 days (days 1-5), fludarabine 30 mg/m^2 daily by IV for 5 days (days 2-6), cytarabine 2000 mg/m^2 daily by IV for 5 days (days 2-6) and idarubicin 10 mg/m^2 daily by IV for 3 days (days 2-4). Participants receiving MEC or FLAG-IDA received 1 cycle of therapy and were assessed for response on or after day 15.
干预措施: Azacitidine (Drug)
Salvage Chemotherapy
Participants received chemotherapy in 28-day cycles. Participants on Low-Dose Cytarabine (LoDAC) received 20 mg of cytarabine twice daily by subcutaneous (SC) or intravenous (IV) injection for 10 days. Participants on azacitidine received 75 mg/m^2 daily by SC or IV injection for 7 days. Participants on LoDAC or azacitidine treatment continued until they met discontinuation criteria. Participants on MEC chemotherapy received mitoxantrone 8 mg/m^2 daily by IV for 5 days, etoposide 100 mg/m^2 daily by IV for 5 days and cytarabine 1000 mg/m^2 daily by IV for 5 days (days 1-5). Participants on FLAG-IDA chemotherapy received G-CSF 300 μg/m^2 daily by SC/IV for 5 days (days 1-5), fludarabine 30 mg/m^2 daily by IV for 5 days (days 2-6), cytarabine 2000 mg/m^2 daily by IV for 5 days (days 2-6) and idarubicin 10 mg/m^2 daily by IV for 3 days (days 2-4). Participants receiving MEC or FLAG-IDA received 1 cycle of therapy and were assessed for response on or after day 15.
干预措施: MEC (Mitoxantrone, Etoposide, Cytarabine) (Drug)
Salvage Chemotherapy
Participants received chemotherapy in 28-day cycles. Participants on Low-Dose Cytarabine (LoDAC) received 20 mg of cytarabine twice daily by subcutaneous (SC) or intravenous (IV) injection for 10 days. Participants on azacitidine received 75 mg/m^2 daily by SC or IV injection for 7 days. Participants on LoDAC or azacitidine treatment continued until they met discontinuation criteria. Participants on MEC chemotherapy received mitoxantrone 8 mg/m^2 daily by IV for 5 days, etoposide 100 mg/m^2 daily by IV for 5 days and cytarabine 1000 mg/m^2 daily by IV for 5 days (days 1-5). Participants on FLAG-IDA chemotherapy received G-CSF 300 μg/m^2 daily by SC/IV for 5 days (days 1-5), fludarabine 30 mg/m^2 daily by IV for 5 days (days 2-6), cytarabine 2000 mg/m^2 daily by IV for 5 days (days 2-6) and idarubicin 10 mg/m^2 daily by IV for 3 days (days 2-4). Participants receiving MEC or FLAG-IDA received 1 cycle of therapy and were assessed for response on or after day 15.
干预措施: FLAG-IDA (Granulocyte-Colony Stimulating Factor (G-CSF), Fludarabine, Cytarabine, Idarubicin) (Drug)
结局指标
主要结局
Duration of Overall Survival (OS)
时间窗: From randomization to until the date of death from any cause (median time of follow-up for OS was 17.8 months)
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. 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.
Percentage of Participants With Complete Remission and Complete Remission With Partial Hematological Recovery (CR/CRh) in the Gilteritinib Arm
时间窗: From the date of randomization up to at least 112 days
The CR/CRh rate was defined as the number of participants who achieved either CR or CRh divided by the number of participants in the analysis population. CR: For participants to be classified as being in CR at, they must have had bone marrow regenerating normal hematopoietic cells and achieved a morphologic leukemia-free state and must had an ANC ≥ 1 x 10\^9/L and platelet count ≥ 100 x 10\^9/L and normal marrow differential with \< 5% blasts, and they were RBC and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). There was no evidence of extramedullary leukemia. CRh: Participants were classified as CRh if they had marrow blasts \< 5%, partial hematologic recovery ANC ≥ 0.5 x 10\^9/L and platelets ≥ 50 x 10\^9/L, no evidence of extramedullary leukemia and could not be classified as CR.
次要结局
- Duration of Leukemia-Free Survival (LFS)(From the date of first CRc until the date of documented relapse or death for participants who achieved CRc (median time of follow-up was 17.8 months))
- Duration of Event-Free Survival (EFS)(From the date of randomization until the date of documented relapse, treatment failure or death from any cause (median time of follow-up was 17.8 months))
- Percentage of Participants With Complete Remission (CR) Rate(From the date of randomization up to at least 6 months)
- Duration of Remission(From the date of first response until the date of documented relapse for participants who achieved CRc or PR (median time of follow-up was 17.8 months))
- Percentage of Participants With Composite Complete Remission (CRc Rate)(From the date of randomization up to at least 6 months)
- Change From Baseline in Brief Fatigue Inventory (BFI)(Baseline, Cycle 1 Day 8 and Cycle 2 Day 1)
- Percentage of Participants With Complete Remission (CR) With Partial Hematological Recovery (CRh)(From the date of randomization up to at least 6 months)
- Percentage of Participants Who Underwent Hematopoietic Stem Cell Transplant(From the date of randomization until end of study (median time of follow-up was 17.8 months))
- Percentage of Participants Who Achieved Transfusion Conversion and Maintenance(From 29 days post first dose of study drug until last dose(median treatment duration was (126.00 [4.0, 885.0]))
- Number of Participants With Treatment Emergent 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))