Phase 1 Study of Venetoclax/Azacitidine or Venetoclax in Combination With Ziftomenib or Standard Induction Cytarabine/Daunorubicin (7+3) Chemotherapy in Combination With Ziftomenib for the Treatment of Patients With Acute Myeloid Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 420
- 试验地点
- 87
- 主要终点
- Rate of dose limiting toxicities (DLTs) per dose level (Part 1a only)
研究概览
简要总结
Ziftomenib is an investigational drug in development for the treatment of patients with acute myeloid leukemia (AML) with certain genetic alterations.
This protocol has 3 separate arms that will investigate the benefits and risks of adding ziftomenib to standard-of-care (SOC) drug treatments in patients who have AML with certain genetic mutations. Both newly diagnosed and relapsed refractory patients with AML will be assigned to different cohorts based on specific study criteria and physician discretion.
The purpose of this study is to assess the safety, tolerability, and early signs of efficacy of ziftomenib in combination with SOC drugs to treat AML.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must have a documented NPM1 mutation or KMT2A rearrangement and have either newly diagnosed or relapsed/refractory AML
- •Those intending treatment with intensive chemotherapy in Arm C should be NPM1-m and FLT3-ITD+ with an allelic ratio ≥0.05 and eligible for FLT3-targeted treatment
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
- •Adequate liver, renal, and cardiac function according to protocol defined criteria
- •A female of childbearing potential must agree to use adequate contraception as well as a double barrier method from the time of screening through 180 days following the last dose of study intervention. A male of childbearing potential must agree to use abstinence or use a double barrier method of contraception from the time of screening through 180 days following the last dose of study intervention
- •Female patients of childbearing potential who receive quizartinib in Arm C should use a highly effective method of contraception during quizartinib treatment and for 7 months after the last dose
排除标准
- •Diagnosis of either acute promyelocytic leukemia or blast phase chronic myeloid leukemia
- •Known history of BCR-ABL alteration
- •Advanced malignant hepatic tumor
- •Administration of live attenuated vaccines within 14 days prior to, during, or after treatment until B-cell recovery
- •Active central nervous system (CNS) involvement by AML.
- •Clinical signs/symptoms of leukostasis or WBC > 25,000 / microliter. Hydroxyurea and/or leukapheresis and/or up to 2 doses of cytarabine if used per institutional SOC for control of leukocytosis are permitted to meet this criterion
- •Not recovered to Grade ≤1 (NCI-CTCAE v5.0) from all nonhematological toxicities except for alopecia
- •Known clinically active human immunodeficiency virus, active hepatitis B or active hepatitis C infection
- •For newly diagnosed cohorts: received prior chemotherapy for leukemia, except hydroxyurea and/or leukapheresis and/or up to 2 doses of cytarabine per institutional standards to control leukocytosis, or prior treatment with all-transretinoic acid for initially suspected acute promyelocytic leukemia
- •For relapsed/refractory cohorts: received chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy that is considered to be investigational < 14 days prior to the first dose of ziftomenib or within 5 drug half-lives prior to the first dose of study drug
- •Uncontrolled intercurrent illness including, but not limited to, cardiac illness as defined in the protocol
- •Mean QT interval corrected for heart rate by Fredericia's formula (QTcF)
- •Arm A and Arm B: >480 ms on triplicate ECGs
- •Arm C: >450 ms on triplicate ECGs
- •Uncontrolled infection
- •Women who are pregnant or lactating
- •An active malignancy and currently receiving chemotherapy for that malignancy or disease that is uncontrolled/progressing
- •Patients who have active GVHD requiring >0.5 mg/kg prednisone or any new or increase in immunosuppressants in the prior 2 weeks for GVHD treatment
研究组 & 干预措施
Dose Escalation: Ziftomenib with Venetoclax and Azacitidine in R/R KMT2A-r (B-1)
Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy
干预措施: Venetoclax (Drug)
Dose Escalation: Ziftomenib with Venetoclax and Azacitidine in R/R NPM1-m (A-1)
Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy
干预措施: Ziftomenib (Drug)
Dose Escalation: Ziftomenib with Venetoclax and Azacitidine in R/R NPM1-m (A-1)
Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy
干预措施: Venetoclax (Drug)
Dose Escalation: Ziftomenib with Venetoclax and Azacitidine in R/R NPM1-m (A-1)
Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy
干预措施: Azacitidine (Drug)
Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in R/R NPM1-m (A-1)
Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy
干预措施: Ziftomenib (Drug)
Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in R/R NPM1-m (A-1)
Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy
干预措施: Venetoclax (Drug)
Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in R/R NPM1-m (A-1)
Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy
干预措施: Azacitidine (Drug)
Dose Escalation: Ziftomenib with 7+3 in 1L NPM1-m/FLT3 wildtype (A-2)
Ziftomenib with 7+3 in newly diagnosed NPM1-m AML patients who are candidates for intensive chemotherapy and must be FLT3 wildtype or ITD ratio <0.05
干预措施: Ziftomenib (Drug)
Dose Escalation: Ziftomenib with 7+3 in 1L NPM1-m/FLT3 wildtype (A-2)
Ziftomenib with 7+3 in newly diagnosed NPM1-m AML patients who are candidates for intensive chemotherapy and must be FLT3 wildtype or ITD ratio <0.05
干预措施: Daunorubicin (Drug)
Dose Escalation: Ziftomenib with 7+3 in 1L NPM1-m/FLT3 wildtype (A-2)
Ziftomenib with 7+3 in newly diagnosed NPM1-m AML patients who are candidates for intensive chemotherapy and must be FLT3 wildtype or ITD ratio <0.05
干预措施: Cytarabine (Drug)
Dose Validation/Expansion: Ziftomenib with 7+3 in 1L NPM1-m/FLT3 wildtype (A-2)
Ziftomenib with 7+3 in newly diagnosed NPM1-m AML patients who are candidates for intensive chemotherapy and must be FLT3 wildtype or ITD ratio <0.05
干预措施: Ziftomenib (Drug)
Dose Validation/Expansion: Ziftomenib with 7+3 in 1L NPM1-m/FLT3 wildtype (A-2)
Ziftomenib with 7+3 in newly diagnosed NPM1-m AML patients who are candidates for intensive chemotherapy and must be FLT3 wildtype or ITD ratio <0.05
干预措施: Daunorubicin (Drug)
Dose Validation/Expansion: Ziftomenib with 7+3 in 1L NPM1-m/FLT3 wildtype (A-2)
Ziftomenib with 7+3 in newly diagnosed NPM1-m AML patients who are candidates for intensive chemotherapy and must be FLT3 wildtype or ITD ratio <0.05
干预措施: Cytarabine (Drug)
Dose Validation/Expansion: Ziftomenib with Venetoclax in R/R NPM1-m (A-3)
Ziftomenib with Venetoclax in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy
干预措施: Ziftomenib (Drug)
Dose Validation/Expansion: Ziftomenib with Venetoclax in R/R NPM1-m (A-3)
Ziftomenib with Venetoclax in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy
干预措施: Venetoclax (Drug)
Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in 1L NPM1-m (A-4)
Ziftomenib with Venetoclax and Azacitidine in newly diagnosed NPM1-m AML patients
干预措施: Ziftomenib (Drug)
Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in 1L NPM1-m (A-4)
Ziftomenib with Venetoclax and Azacitidine in newly diagnosed NPM1-m AML patients
干预措施: Venetoclax (Drug)
Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in 1L NPM1-m (A-4)
Ziftomenib with Venetoclax and Azacitidine in newly diagnosed NPM1-m AML patients
干预措施: Azacitidine (Drug)
Dose Escalation: Ziftomenib with Venetoclax and Azacitidine in R/R KMT2A-r (B-1)
Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy
干预措施: Ziftomenib (Drug)
Dose Escalation: Ziftomenib with Venetoclax and Azacitidine in R/R KMT2A-r (B-1)
Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy
干预措施: Azacitidine (Drug)
Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in R/R KMT2A-r (B-1)
Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy
干预措施: Ziftomenib (Drug)
Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in R/R KMT2A-r (B-1)
Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy
干预措施: Venetoclax (Drug)
Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in R/R KMT2A-r (B-1)
Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy
干预措施: Azacitidine (Drug)
Dose Escalation: Ziftomenib with 7+3 in 1L KMT2A-r (B-2)
Ziftomenib with 7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive chemotherapy
干预措施: Ziftomenib (Drug)
Dose Escalation: Ziftomenib with 7+3 in 1L KMT2A-r (B-2)
Ziftomenib with 7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive chemotherapy
干预措施: Daunorubicin (Drug)
Dose Escalation: Ziftomenib with 7+3 in 1L KMT2A-r (B-2)
Ziftomenib with 7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive chemotherapy
干预措施: Cytarabine (Drug)
Dose Validation/Expansion: Ziftomenib with 7+3 in 1L KMT2A-r (B-2)
Ziftomenib with 7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive therapy
干预措施: Ziftomenib (Drug)
Dose Validation/Expansion: Ziftomenib with 7+3 in 1L KMT2A-r (B-2)
Ziftomenib with 7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive therapy
干预措施: Daunorubicin (Drug)
Dose Validation/Expansion: Ziftomenib with 7+3 in 1L KMT2A-r (B-2)
Ziftomenib with 7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive therapy
干预措施: Cytarabine (Drug)
Dose Validation/Expansion: Ziftomenib with Venetoclax + Azacitidine in 1L KMT2A-r (B-3)
Ziftomenib with Venetoclax and Azacitidine in newly diagnosed KMT2A-r AML patients
干预措施: Ziftomenib (Drug)
Dose Validation/Expansion: Ziftomenib with Venetoclax + Azacitidine in 1L KMT2A-r (B-3)
Ziftomenib with Venetoclax and Azacitidine in newly diagnosed KMT2A-r AML patients
干预措施: Venetoclax (Drug)
Dose Validation/Expansion: Ziftomenib with Venetoclax + Azacitidine in 1L KMT2A-r (B-3)
Ziftomenib with Venetoclax and Azacitidine in newly diagnosed KMT2A-r AML patients
干预措施: Azacitidine (Drug)
Dose Escalation: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1)
Ziftomenib with 7+3 and quizartinib in newly diagnosed NPM1-m and FLT3-ITD+ (with allelic ratio ≥0.05) AML patients who are candidates for IC and eligible to receive FLT3-targeted therapy
干预措施: Ziftomenib (Drug)
Dose Escalation: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1)
Ziftomenib with 7+3 and quizartinib in newly diagnosed NPM1-m and FLT3-ITD+ (with allelic ratio ≥0.05) AML patients who are candidates for IC and eligible to receive FLT3-targeted therapy
干预措施: Daunorubicin (Drug)
Dose Escalation: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1)
Ziftomenib with 7+3 and quizartinib in newly diagnosed NPM1-m and FLT3-ITD+ (with allelic ratio ≥0.05) AML patients who are candidates for IC and eligible to receive FLT3-targeted therapy
干预措施: Cytarabine (Drug)
Dose Escalation: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1)
Ziftomenib with 7+3 and quizartinib in newly diagnosed NPM1-m and FLT3-ITD+ (with allelic ratio ≥0.05) AML patients who are candidates for IC and eligible to receive FLT3-targeted therapy
干预措施: Quizartinib (Drug)
Dose Validation/Expansion: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1)
Ziftomenib with 7+3 and quizartinib in newly diagnosed NPM1-m and FLT3-ITD+ (with allelic ratio ≥0.05) AML patients who are candidates for IC and eligible to receive FLT3-targeted therapy
干预措施: Ziftomenib (Drug)
Dose Validation/Expansion: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1)
Ziftomenib with 7+3 and quizartinib in newly diagnosed NPM1-m and FLT3-ITD+ (with allelic ratio ≥0.05) AML patients who are candidates for IC and eligible to receive FLT3-targeted therapy
干预措施: Daunorubicin (Drug)
Dose Validation/Expansion: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1)
Ziftomenib with 7+3 and quizartinib in newly diagnosed NPM1-m and FLT3-ITD+ (with allelic ratio ≥0.05) AML patients who are candidates for IC and eligible to receive FLT3-targeted therapy
干预措施: Cytarabine (Drug)
Dose Validation/Expansion: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1)
Ziftomenib with 7+3 and quizartinib in newly diagnosed NPM1-m and FLT3-ITD+ (with allelic ratio ≥0.05) AML patients who are candidates for IC and eligible to receive FLT3-targeted therapy
干预措施: Quizartinib (Drug)
结局指标
主要结局
Rate of dose limiting toxicities (DLTs) per dose level (Part 1a only)
时间窗: During the first 28 days of ziftomenib in combination with SOC backbone treatment (1 cycle)
Assessed by the NCI-CTCAE v5.0
Descriptive statistics of adverse events
时间窗: From Cycle 1 Day 1 up to and including 28 days following the end of 36 months of treatment
Assessed by the NCI-CTCAE v5.0
Complete remission (CR) rate
时间窗: Until relapse, new anti-cancer therapy, death, or up to 36 months of treatment, whichever occurs first
Assessed by the ELN 2022 criteria
次要结局
- TI(From 28 days prior to Cycle 1 Day 1 up to and including 28 days following the end of 36 months of treatment)
- Accumulation ratio of ziftomenib and metabolites(Cycle 1; each cycle is 28 days)
- Cmax of quizartinib(Cycle 1; each cycle is 28 days)
- Tmax of quizartinib(Cycle 1; each cycle is 28 days)
- AUCtau of quizartinib(Cycle 1; each cycle is 28 days)
- Median EFS(From Cycle 1 Day 1 to treatment failure, hematologic relapse following CR, or death from any cause, whichever comes first, assessed up to 36 months of treatment)
- Tmax(Cycle 1; each cycle is 28 days)
- AUC0-last(Cycle 1; each cycle is 28 days)
- AUCtau(Cycle 1; each cycle is 28 days)
- AUCtau of venetoclax(Cycle 1; each cycle is 28 days)
- Composite Complete Remission (CRc)(Until relapse, new anti-cancer therapy, death, or up to 36 months of treatment, whichever occurs first)
- EFS(From Cycle 1 Day 1 to treatment failure, hematologic relapse following CR, or death from any cause, whichever comes first, assessed up to 1 year following start of treatment)
- Median DOR(From time of first remission to relapse or death, whichever occurs first, assessed up to 36 months from start of treatment)
- Proportion of patients who undergo HSCT(From Cycle 1 Day 1 until date of HSCT, assessed up to 36 months of treatment)
- Cmax of venetoclax(Cycle 1; each cycle is 28 days)
- AUC0-last of venetoclax(Cycle 1; each cycle is 28 days)
- Morphologic leukemia-free state (MLFS) rate(Until relapse, new anti-cancer therapy, death, or up to 36 months of treatment, whichever comes first)
- Measurable residual disease (MRD)(Until relapse, new anti-cancer therapy, death, or up to 36 months of treatment, whichever occurs first)
- Median OS(From Cycle 1 Day 1 to date of death from any cause, assessed up to 36 months of treatment)
- Proportion of patients alive(From Cycle 1 Day 1 until death from any cause, assessed up to 1 year following start of treatment)
- Cmax(Cycle 1; each cycle is 28 days)
- Tmax of venetoclax(Cycle 1; each cycle is 28 days)
- AUC0-last of quizartinib(Cycle 1; each cycle is 28 days)