Phase 2 Open-Label, AC220 Monotherapy Efficacy (ACE) Study in Patients With Acute Myeloid Leukemia (AML) With and Without FLT3-ITD Activating Mutations
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 333
- 试验地点
- 85
- 主要终点
- Derived Disease Assessment Based on Local Morphology Including All On-Treatment Data (Safety Population, FLT3-ITD [+] Participants)
研究概览
简要总结
AC220 will be administered as a once daily oral solution given continuously as 28-day treatment cycles, without any rest periods, until disease progression, relapse, intolerance to the drug, or elective allogeneic hematopoietic stem cell transplantation (HSCT).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Males and females age ≥18 years in second relapse or refractory.
- •Males and females age ≥60 years in first relapse or refractory.
- •Must have baseline bone marrow sample taken.
- •Morphologically documented primary AML or AML secondary to myelodysplastic syndrome (MDS with ≥20% bone marrow or peripheral blasts), as defined by the World Health Organization (WHO) criteria, confirmed by pathology review at treating institution.
- •Able to swallow the liquid study drug.
- •Eastern Cooperative Oncology Group performance status of 0 to 2
- •In the absence of rapidly progressing disease, the interval from prior treatment to time of AC220 administration will be at least 2 weeks for cytotoxic agents or at least 5 half-lives for noncytotoxic agents. The use of chemotherapeutic or antileukemic agents other than hydroxyurea is not permitted during the study with the possible exception of intrathecal (IT) therapy at the discretion of the Investigator and with the agreement of the Sponsor.
- •Persistent chronic clinically significant non-hematological toxicities from prior treatment must be ≤Grade
- •Prior therapy with FLT3 inhibitors is permitted, except previous treatment with AC
- •Serum creatinine ≤1.5 × upper limit of normal (ULN) and glomerular filtration rate (GFR) > 30 mL/min
- •Serum potassium, magnesium, and calcium levels should be at least within institutional normal limits.
- •Total serum bilirubin ≤1.5 × ULN
- •Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤2.5 × ULN
- •Females of childbearing potential must have a negative pregnancy test (urine β-hCG).
- •Females of childbearing potential and sexually mature males must agree to use a medically accepted method of contraception throughout the study.
- •Written informed consent must be provided.
排除标准
- •Patients over the age of 85 years except at the discretion of the Investigator and with agreement of the Sponsor.
- •Diagnosis of acute promyelocytic leukemia
- •Diagnosis of chronic myelogenous leukemia (CML) in blast crisis
- •AML in relapse or refractory after 3 or more previous lines of chemotherapy (and/or HSCT) treatment
- •AML or antecedent MDS secondary to prior chemotherapy
- •Persistent clinically significant non-hematological toxicity that is Grade >1 by NCI CTCAE v4 from prior chemotherapy
- •Patients who have had HSCT and are within 100 days of transplant and/or are still taking immunosuppressive drugs and/or have clinically significant graft-versus-host disease requiring treatment and/or have >Grade 1 persistent non hematological toxicity related to the transplant
- •Clinically active central nervous system (CNS) leukemia. Patients with CNS leukemia, which is controlled, but who are still receiving IT therapy at study entry may be considered eligible and continue receive IT therapy at the discretion of the Investigator and with agreement of the Sponsor.
- •Patients who have previously received AC220
- •Disseminated intravascular coagulation (DIC) (diagnosis by laboratory or clinical assessment)
- •Major surgery within 4 weeks prior to enrollment in the study
- •Radiation therapy within 4 weeks prior to, or concurrent with study
- •Use of concomitant drugs that prolong the time between the start of the Q wave and the end of the T wave (QT)/corrected interval between the Q wave and T wave (QTc) interval and/or are CYP3A4 inhibitors are prohibited with the exception of antibiotics, antifungals, and other antimicrobials that are used as standard of care to prevent or treat infections and other such drugs that are considered absolutely essential for the care of the patient.
- •Uncontrolled or significant cardiovascular disease
- •Women who are pregnant, lactating, or unwilling to use contraception if of childbearing potential
- •Men who are unwilling to use contraception if their partners are of childbearing potential
- •Active, uncontrolled infection
- •Human immunodeficiency virus positivity
- •Active hepatitis B or C or other active liver disease
- •History of cancer, except Stage 1 cervix or nonmelanotic skin cancer, with the possible exception of patients in complete remission
研究组 & 干预措施
Cohort 1; ≥60 years of age
Participants ≥60 years of age who were relapsed after one first-line chemotherapy regimen (with or without consolidation) and after first complete remission <12 months or are primary refractory to first-line chemotherapy received a starting dose of 200 mg/day quizartinib.
Exploratory: FLT3-ITD (+) and FLT3-ITD (-) Confirmatory: FLT3-ITD (+) and FLT3-ITD (-)
After an amendment, male participants received a starting dose of 135 mg/day quizartinib and all females received a starting dose of 90 mg/day.
干预措施: Compound AC220 (Drug)
Cohort 2; ≥18 years of age
Participants ≥18 years of age (including participants ≥60 years of age) who were relapsed or refractory after one second-line (salvage) regimen or after hematopoietic stem cell transplant (HSCT) received a starting dose of 200 mg/day quizartinib.
Exploratory: FLT3-ITD (+) and FLT3-ITD (-) Confirmatory: FLT3-ITD (+) and FLT3-ITD (-)
After an amendment, male participants received a starting dose of 135 mg/day quizartinib and all females received a starting dose of 90 mg/day.
干预措施: Compound AC220 (Drug)
结局指标
主要结局
Derived Disease Assessment Based on Local Morphology Including All On-Treatment Data (Safety Population, FLT3-ITD [+] Participants)
时间窗: Within the first 3 cycles of treatment (84 days)
Derived disease assessment based on local morphology of bone marrow disease performed by each local site pathologist, including all on-treatment data (Safety Population, FLT3-ITD\[+\] Participants) Modified from Cheson et al, abbreviations include the following: CR=complete remission; CRc=composite complete remission (CR+CRp+CRi); CRi=complete remission with incomplete hematological recovery, includes participants who met CRia criteria plus participants who met CRib criteria; CRia=all criteria specified for CR are met except for incomplete hematological recovery with residual neutropenia \<1 x 10\^9/L with or without complete platelet recovery. Red blood cell and platelet transfusion independence is not required; CRib=All criteria for CR or CRp are met, except for recent red blood cell or platelet transfusion; CRp=complete remission with incomplete platelet recovery; NR=no response; PR=partial remission.
Derived Disease Assessment Based on Local Morphology Including All On-Treatment Data (Safety Population, FLT3-ITD [-] Participants)
时间窗: Within the first 3 cycles of treatment (84 days)
Derived disease assessment based on local morphology of bone marrow disease performed by each local site pathologist, including all on-treatment data (Safety Population, FLT3-ITD\[-\] Participants) Modified from Cheson et al, abbreviations include the following: CR=complete remission; CRc=composite complete remission (CR+CRp+CRi); CRi=complete remission with incomplete hematological recovery, includes participants who met CRia criteria plus participants who met CRib criteria; CRia=all criteria specified for CR are met except for incomplete hematological recovery with residual neutropenia \<1 x 10\^9/L with or without complete platelet recovery. Red blood cell and platelet transfusion independence is not required; CRib=All criteria for CR or CRp are met, except for recent red blood cell or platelet transfusion; CRp=complete remission with incomplete platelet recovery; NR=no response; PR=partial remission.
Number of Participants With Composite Complete Remission (CRc), Categorised by FLT3-ITD Status
时间窗: within 28 months
CRc is defined as composite complete remission (CR+CRp+CRi) - CR = complete remission; CRp = complete remission with incomplete platelet recovery; CRi = complete remission with incomplete hematological recovery, includes participants who met CRia criteria plus participants who met CRib criteria; CRia = all criteria specified for CR are met except for incomplete hematological recovery with residual neutropenia \<1 x 10\^9/L with or without complete platelet recovery. Red blood cell and platelet transfusion independence is not required; CRib = all criteria for CR or CRp are met, except for recent red blood cell or platelet transfusion.
次要结局
- Median Duration of Leukemia-free Survival in FLT3-ITD (+) Participants(From the time CRc was achieved until disease progression or death, up to approximately 3 years post treatment)
- Duration of Composite Complete Remission in FLT3-ITD (+) Participants Who Achieved CRc Based on All On-Treatment Data(From time at which CRc was achieved until disease progression or death, up to approximately 3 years post treatment)
- Duration of Composite Complete Remission in FLT3-ITD (-) Participants Who Achieved CRc Based on All On-Treatment Data(From time at which CRc was achieved until disease progression or death, up to approximately 3 years post treatment)
- Duration of Any Response in FLT3-ITD (+) Participants(From the time of any response until disease progression or death, up to approximately 3 years post treatment)
- Duration of Any Response in FLT3-ITD (-) Participants(From the time of any response until disease progression or death, up to approximately 3 years post treatment)
- Median Duration of Leukemia-free Survival in FLT3-ITD (-) Participants(From the time CRc was achieved until disease progression or death, up to approximately 3 years post treatment)
- Median Duration of Overall Survival in FLT3-ITD (+) Participants(Time from first dose to death from any cause, up to 3 years post treatment)
- Median Duration of Overall Survival in FLT3-ITD (-) Participants(Time from first dose to death from any cause, up to approximately 3 years post treatment)
- Early Treatment-related Death(Within first 3 cycles of treatment (84 days))