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
- 进行中（未招募）
- 入组人数
- 276
- 试验地点
- 89
- 主要终点
- 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 AML who were refractory to or had relapse after first-line AML therapy as shown with overall survival (OS) compared to salvage chemotherapy. In addition, this study evaluated safety as well as 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 were randomized in a 1:1 ratio and received ASP2215 or salvage chemotherapy. Participants entered the screening period up to 14 days prior to the start of treatment. Prior to randomization, the investigator preselected a salvage chemotherapy regimen for each participant; options included low-dose cytarabine (LoDAC), mitoxantrone, etoposide and intermediate-dose cytarabine (MEC) or fludarabine, high-dose cytarabine and granulocyte colony-stimulating factor (FLAG). The randomization was stratified by response to first-line therapy and preselected salvage chemotherapy. Participants were administered treatment over continuous 28-day cycles.
Among the participants, approximately 20 Chinese participants who were randomized into the ASP2215 arm were allocated to the pharmacokinetic (PK) cohort. Participants in the PK cohort were requested to be hospitalized from the date of randomization (Day 1) to at least the completion of all the assessments planned on Day 2. All participants in the PK cohort underwent blood sampling for PK measurement of ASP2215. Participants in PK cohort were administered the study drug in the same manner and underwent the same efficacy and safety assessments as other participants except for blood sampling for additional PK measurements.
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 AML or AML secondary to myelodysplastic syndrome (MDS) according to World Health Organization (WHO) classification as determined by pathology review at the treating institution.
- •Participant is refractory to or relapsed after first-line AML therapy (with or without HSCT)
- •Refractory to first-line AML therapy is defined as:
- •a. Participant did not achieve CR/CRi/CRp under initial therapy. A participant eligible for standard therapy must receive at least 1 cycle of an anthracycline containing induction block in standard dose for the selected induction regimen. A participant not eligible for standard therapy must have received at least 1 complete block of induction therapy seen as the optimum choice of therapy to induce remission for this participant.
- •Untreated first hematologic relapse is defined as:
- •Participant must have achieved a CR/CRi/CRp 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 the participants 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 preselected salvage chemotherapy.
- •Participant must meet the following criteria as indicated on the clinical laboratory tests:
- •Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN)
- •Serum total bilirubin (TBL) ≤ 1.5 x ULN
- •Serum creatinine ≤ 1.5 x ULN or an estimated glomerular filtration rate of > 50 mL/min as calculated by the Modification of Diet in Renal Disease equation.
- •Participant is suitable for oral administration of study drug.
- •Participant agrees not to participate in another interventional study while on treatment.
- •Inclusion Criteria for COE:
- •Participant is eligible for the COE if they continue to meet all inclusion criteria from the main protocol in addition to the following when the participant is evaluated for eligibility to participate in the COE portion of the study:
- •Participant has received study treatment of either LoDAC, MEC or FLAG and has no response or progressive disease.
- •Participant have not received other antileukemic therapy after EOT (hydroxyurea is allowed for the control of peripheral leukemic blasts in participants with leukocytosis).
- •Participant agrees not to participate in another interventional study while on treatment.
排除标准
- •Participant was diagnosed as acute promyelocytic leukemia.
- •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.
- •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 (ECHO) performed within 1 month prior to study entry results in a left ventricular ejection fraction (LVEF) that is ≥ 45%.
- •Participant with mean of triplicate Fridericia-corrected QT interval (QTcF) > 450 ms at Screening based on central reading.
- •Participant with Long QT Syndrome at Screening.
- •Participant with hypokalemia and hypomagnesemia at Screening (defined as values below lower limit of normal [LLN]).
- •Participant requires treatment with concomitant drugs that are strong inducers of CYP3A.
- •Participant 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 participant.
- •Participant requires treatment with concomitant drugs that target serotonin 5-hydroxytryptamine receptor 1 (5HT1R) or 5-hydroxytryptamine receptor 2B (5HT2BR) receptors or sigma nonspecific receptor with the exception of drugs that are considered absolutely essential for the care of the participant.
- •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 (graft-versus-host disease) 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/I
- •Exclusion Criteria for COE:
- •Participant will be excluded from participation in the COE if they meet any of the exclusion criteria listed in the main protocol or when the participant is evaluated for eligibility to participate in the COE portion of the study.
研究组 & 干预措施
Gilteritinib
Participants received 120 milligrams (mg) gilteritinib (3 tablets of 40 mg) orally, once a day in continuous 28-day cycles until treatment discontinuation criteria were met. Participants who met the treatment discontinuation criteria, entered the long-term follow-up period. Participants remained in the long-term follow-up period for up to 3 years from the participant's end of treatment visit or until discontinuation from the study.
干预措施: Gilteritinib (Drug)
Salvage chemotherapy
Participants received salvage chemotherapy in continuous 28-day cycles per institutional guidelines:LoDAC:20mg cytarabine twice daily SC/IV for 10 days. MEC:mitoxantrone 6 milligrams per square meter(mg/m^2)/day IV for 5 days (days 1 to 5), etoposide 100mg/m^2/day IV for 5 days (days 1 to 5), cytarabine 1000mg/m^2/day IV for 5 days (days 1 to 5). FLAG: granulocyte colony-stimulating factor (G-CSF) 300 micrograms per square meter (μg/m^2) per day SC/IV for 5 days (days 1 to 5), fludarabine 30mg/m^2/day IV for 5 days (days 2 to 6), cytarabine 2000mg/m^2/day IV for 5 days (days 2 to 6). Participants meeting treatment discontinuation criteria, entered long-term follow-up, for up to 3 years from end of treatment visit/until study discontinuation. Based on interim analysis outcome, at investigators discretion, treatment period participants had option to enter crossover extension to receive 120mg gilteritinib, orally, once daily in continuous 28-day cycles until treatment discontinuation.
干预措施: Cytarabine (Drug)
Salvage chemotherapy
Participants received salvage chemotherapy in continuous 28-day cycles per institutional guidelines:LoDAC:20mg cytarabine twice daily SC/IV for 10 days. MEC:mitoxantrone 6 milligrams per square meter(mg/m^2)/day IV for 5 days (days 1 to 5), etoposide 100mg/m^2/day IV for 5 days (days 1 to 5), cytarabine 1000mg/m^2/day IV for 5 days (days 1 to 5). FLAG: granulocyte colony-stimulating factor (G-CSF) 300 micrograms per square meter (μg/m^2) per day SC/IV for 5 days (days 1 to 5), fludarabine 30mg/m^2/day IV for 5 days (days 2 to 6), cytarabine 2000mg/m^2/day IV for 5 days (days 2 to 6). Participants meeting treatment discontinuation criteria, entered long-term follow-up, for up to 3 years from end of treatment visit/until study discontinuation. Based on interim analysis outcome, at investigators discretion, treatment period participants had option to enter crossover extension to receive 120mg gilteritinib, orally, once daily in continuous 28-day cycles until treatment discontinuation.
干预措施: G-CSF (Drug)
Salvage chemotherapy
Participants received salvage chemotherapy in continuous 28-day cycles per institutional guidelines:LoDAC:20mg cytarabine twice daily SC/IV for 10 days. MEC:mitoxantrone 6 milligrams per square meter(mg/m^2)/day IV for 5 days (days 1 to 5), etoposide 100mg/m^2/day IV for 5 days (days 1 to 5), cytarabine 1000mg/m^2/day IV for 5 days (days 1 to 5). FLAG: granulocyte colony-stimulating factor (G-CSF) 300 micrograms per square meter (μg/m^2) per day SC/IV for 5 days (days 1 to 5), fludarabine 30mg/m^2/day IV for 5 days (days 2 to 6), cytarabine 2000mg/m^2/day IV for 5 days (days 2 to 6). Participants meeting treatment discontinuation criteria, entered long-term follow-up, for up to 3 years from end of treatment visit/until study discontinuation. Based on interim analysis outcome, at investigators discretion, treatment period participants had option to enter crossover extension to receive 120mg gilteritinib, orally, once daily in continuous 28-day cycles until treatment discontinuation.
干预措施: Fludarabine (Drug)
Salvage chemotherapy
Participants received salvage chemotherapy in continuous 28-day cycles per institutional guidelines:LoDAC:20mg cytarabine twice daily SC/IV for 10 days. MEC:mitoxantrone 6 milligrams per square meter(mg/m^2)/day IV for 5 days (days 1 to 5), etoposide 100mg/m^2/day IV for 5 days (days 1 to 5), cytarabine 1000mg/m^2/day IV for 5 days (days 1 to 5). FLAG: granulocyte colony-stimulating factor (G-CSF) 300 micrograms per square meter (μg/m^2) per day SC/IV for 5 days (days 1 to 5), fludarabine 30mg/m^2/day IV for 5 days (days 2 to 6), cytarabine 2000mg/m^2/day IV for 5 days (days 2 to 6). Participants meeting treatment discontinuation criteria, entered long-term follow-up, for up to 3 years from end of treatment visit/until study discontinuation. Based on interim analysis outcome, at investigators discretion, treatment period participants had option to enter crossover extension to receive 120mg gilteritinib, orally, once daily in continuous 28-day cycles until treatment discontinuation.
干预措施: Etoposide (Drug)
Salvage chemotherapy
Participants received salvage chemotherapy in continuous 28-day cycles per institutional guidelines:LoDAC:20mg cytarabine twice daily SC/IV for 10 days. MEC:mitoxantrone 6 milligrams per square meter(mg/m^2)/day IV for 5 days (days 1 to 5), etoposide 100mg/m^2/day IV for 5 days (days 1 to 5), cytarabine 1000mg/m^2/day IV for 5 days (days 1 to 5). FLAG: granulocyte colony-stimulating factor (G-CSF) 300 micrograms per square meter (μg/m^2) per day SC/IV for 5 days (days 1 to 5), fludarabine 30mg/m^2/day IV for 5 days (days 2 to 6), cytarabine 2000mg/m^2/day IV for 5 days (days 2 to 6). Participants meeting treatment discontinuation criteria, entered long-term follow-up, for up to 3 years from end of treatment visit/until study discontinuation. Based on interim analysis outcome, at investigators discretion, treatment period participants had option to enter crossover extension to receive 120mg gilteritinib, orally, once daily in continuous 28-day cycles until treatment discontinuation.
干预措施: Mitoxantrone (Drug)
结局指标
主要结局
Overall Survival (OS)
时间窗: From the date of randomization up to the date of death (up to approximatley 74 months)
OS was defined as the time from the date of randomization to the date of death due to any cause. Participants who were still alive or lost to follow up were censored at the time they were last known to be alive. Kaplan-Meier (KM) estimates was used for analysis.
次要结局
- PK of Gilteritinib: Observed Trough Concentration (Ctrough)(Predose on C1D15)
- Event-Free Survival (EFS)(From the date of randomization up to the date of documented relapse, treatment failure or death from any cause, off-treatment relapse and start of new AML therapy (up to approximately 74 months))
- Complete Remission (CR) Rate(From the date of randomization up to approximately 74 months)
- Duration of CR(From date of achieving CR until date of confirmed relapse (maximum duration was 53.4 months ))
- Duration of Composite Complete Remission (CRc)(From date of achieving CRc until date of confirmed relapse (maximum duration was 60 months))
- Percentage of Participants With Transplantation Rate(Baseline up to approximately 74 months)
- Duration of CR/Complete Remission With Partial Hematologic Recovery (CRh)(From date of achieving CR/CRh until date of confirmed relapse (maximum duration was 58.1 months))
- Duration Of Response (DOR)(From date of achieving CRc/PR until date of confirmed relapse (maximum duration was 52.1 months))
- CR/CRh Rate(From the date of randomization up to approximately 74 months)
- Best Response Rate(From the date of randomization up to approximately 74 months)
- Leukemia-Fee Survival (LFS)(From first day of achieving first CRc to the first day of confirmed relapse/death (maximum duration was 60.0 months))
- Composite Complete Remission (CRc)(From the date of randomization up to approximately 74 months)
- Time to CRc(From randomization until date of first CRc (up to approximately 74 months))
- Time to CR(From randomization until date of first CR (up to approximately 74 months))
- Time to Response(From randomization until date of first CRc or PR (up to approximately 74 months))
- Time to CR/CRh(From randomization until date of first CR/CRh (up to approximately 74 months))
- Percentage of Participants With Transfusion Conversion and Transfusion Maintenance(Baseline up to approximately 74 months)
- Change From Baseline in Brief Fatigue Inventory (BFI)(Baseline, End of treatment (63 months))
- Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores(Baseline, end of treatment visit (63 months))
- PK of Gilteritinib in Chinese PK Cohort: Maximum Concentration (Cmax)(C1D1: predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hour post dose, C1D15: predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hour post dose)
- Ctrough Concentration of Gilteritinib(Predose C1D8, C1D15, Day 1 of each cycle from C2 to C65, C67D1,C68D1,C69D1,C70D1)
- Number of Participants With Treatment Emergent Adverse Events (TEAEs)(From the date of first dose up to approximately 74 months)
- Pharmacokinetics (PK) of Gilteritinib in Chinese PK Cohort: Area Under the Concentration Curve at 24 Hours (AUC24)(Cycle 1 Day 1(C1D1): predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hour post dose, Cycle 1 Day 15(C1D15): predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hour post dose)
- PK of Gilteritinib in Chinese PK Cohort: Time to Maximum Concentration (Tmax)(C1D1: predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hours (+/- 20 minutes) post dose, C1D15: predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hours (+/- 20 minutes) post dose)