Phase 1 Study to Determine the Safety and Tolerability of Ziftomenib Combinations for the Treatment of KMT2A-rearranged or NPM1-mutant Relapsed/Refractory Acute Myeloid Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 171
- 试验地点
- 49
- 主要终点
- Rate of dose limiting toxicities (DLTs) per dose level
研究概览
简要总结
The safety, tolerability, and antileukemic response of ziftomenib in combination with standard of care treatments for patients with relapsed/refractory acute myeloid leukemia will be examined with the following agents: FLAG-IDA, low-dose cytarabine, and gilteritinib.
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
- •Has been diagnosed with relapsed/refractory AML.
- •Has a documented NPM1 mutation or KMT2A rearrangement.
- •Has a documented FLT3 mutation (cA-3 only).
- •Has an Eastern Cooperative Oncology Group (ECOG) Performance status ≤
- •Has adequate hepatic and renal function as defined per protocol.
- •Has an ejection fraction above a protocol defined limit.
- •Participant, or legally authorized representative, must be able to understand and provide written informed consent prior to the first screening procedure.
- •Has agreed to use contraception as defined per protocol.
排除标准
- •Has a diagnosis of acute promyelocytic leukemia or blast chronic myeloid leukemia.
- •Has clinically active central nervous system leukemia.
- •Has an active and uncontrolled infection.
- •Has a mean corrected QT interval (QTcF) > 480ms.
- •Has uncontrolled intercurrent illness, including, but not limited to protocol defined cardiac disease.
- •Has received radiation, chemotherapy, immunotherapy, or any other anticancer therapy including investigational therapy <14 days or within 5 drug half-lives prior to the first dose of study intervention.
- •Has had major surgery within 4 weeks prior to the first dose of study intervention.
- •Has received a hematopoietic stem cell transplant (HSCT) and has not previously had adequate recovery per protocol defined criteria.
- •Has active graft-versus-host disease (GvHD) and or on immunosuppressive drugs for the treatment of GvHD
- •Participant is pregnant or lactating.
研究组 & 干预措施
Phase 1a
Oral ziftomenib; sequential cohorts of escalating dose levels of ziftomenib to identify the safety and tolerability of the combination regimens. Participants will be enrolled in 1 of 5 dose escalation cohorts:
A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA
A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC)
A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib
B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA
B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC)
干预措施: Fludarabine (Drug)
Phase 1a
Oral ziftomenib; sequential cohorts of escalating dose levels of ziftomenib to identify the safety and tolerability of the combination regimens. Participants will be enrolled in 1 of 5 dose escalation cohorts:
A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA
A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC)
A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib
B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA
B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC)
干预措施: Granulocyte colony-stimulating factor (Biological)
Phase 1b
Oral ziftomenib; Following the determination of the maximum tolerated dose in Phase 1a, participants will be enrolled in 1 of 5 dose validation/expansion cohorts:
A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA
A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC)
A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib
B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA
B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC)
干预措施: Idarubicin (Drug)
Phase 1b
Oral ziftomenib; Following the determination of the maximum tolerated dose in Phase 1a, participants will be enrolled in 1 of 5 dose validation/expansion cohorts:
A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA
A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC)
A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib
B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA
B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC)
干预措施: Granulocyte colony-stimulating factor (Biological)
Phase 1b
Oral ziftomenib; Following the determination of the maximum tolerated dose in Phase 1a, participants will be enrolled in 1 of 5 dose validation/expansion cohorts:
A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA
A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC)
A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib
B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA
B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC)
干预措施: Gilteritinib (Drug)
Phase 1a
Oral ziftomenib; sequential cohorts of escalating dose levels of ziftomenib to identify the safety and tolerability of the combination regimens. Participants will be enrolled in 1 of 5 dose escalation cohorts:
A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA
A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC)
A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib
B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA
B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC)
干预措施: Gilteritinib (Drug)
Phase 1b
Oral ziftomenib; Following the determination of the maximum tolerated dose in Phase 1a, participants will be enrolled in 1 of 5 dose validation/expansion cohorts:
A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA
A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC)
A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib
B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA
B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC)
干预措施: Cytarabine (Drug)
Phase 1a
Oral ziftomenib; sequential cohorts of escalating dose levels of ziftomenib to identify the safety and tolerability of the combination regimens. Participants will be enrolled in 1 of 5 dose escalation cohorts:
A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA
A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC)
A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib
B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA
B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC)
干预措施: Ziftomenib (Drug)
Phase 1a
Oral ziftomenib; sequential cohorts of escalating dose levels of ziftomenib to identify the safety and tolerability of the combination regimens. Participants will be enrolled in 1 of 5 dose escalation cohorts:
A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA
A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC)
A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib
B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA
B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC)
干预措施: Cytarabine (Drug)
Phase 1b
Oral ziftomenib; Following the determination of the maximum tolerated dose in Phase 1a, participants will be enrolled in 1 of 5 dose validation/expansion cohorts:
A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA
A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC)
A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib
B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA
B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC)
干预措施: Ziftomenib (Drug)
Phase 1b
Oral ziftomenib; Following the determination of the maximum tolerated dose in Phase 1a, participants will be enrolled in 1 of 5 dose validation/expansion cohorts:
A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA
A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC)
A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib
B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA
B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC)
干预措施: Fludarabine (Drug)
Phase 1a
Oral ziftomenib; sequential cohorts of escalating dose levels of ziftomenib to identify the safety and tolerability of the combination regimens. Participants will be enrolled in 1 of 5 dose escalation cohorts:
A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA
A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC)
A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib
B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA
B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC)
干预措施: Idarubicin (Drug)
结局指标
主要结局
Rate of dose limiting toxicities (DLTs) per dose level
时间窗: During the first 28 days of ziftomenib in combination with SOC treatment (1 cycle)
Assessed by the NCI-CTCAE v5.0
Descriptive statistics of adverse events
时间窗: First dose of ziftomenib up to and including 28 days after last dose of ziftomenib, or if the patient is lost to follow-up, whichever comes first
Assessed by the NCI-CTCAE v5.0
次要结局
- OS(Up to 12 months following discontinuation of treatment)
- Complete remission (CR) rate for cohorts A-1, A-2, B-1, and B-2(Up to 12 months following discontinuation of treatment)
- Gilteritinib AUC(0-last)(Cycle 1 (Each cycle is 28 days))
- Complete remission (CR) / Complete remission with partial hematologic recovery (CRh) rate for cohort A-3(Up to 12 months following discontinuation of treatment)
- Composite complete remission (CRc) rate(Up to 12 months following discontinuation of treatment)
- 6-month OS(Up to 6 months following discontinuation of treatment)
- DOR(Up to 12 months following discontinuation of treatment)
- Ziftomenib Cmax(Cycle 1 (Each cycle is 28 days))
- Gilteritinib Cmax(Cycle 1 (Each cycle is 28 days))
- Morphologic leukemia-free state (MLFS) rate(Up to 12 months following discontinuation of treatment)
- MRD assessment(Up to 12 months following discontinuation of treatment)
- HSCT(Up to 12 months following discontinuation of treatment)
- Ziftomenib AUC(0-last)(Cycle 1 (Each cycle is 28 days))
- Ziftomenib AUC(tau)(Cycle 1 (Each cycle is 28 days))
- Median EFS(Up to 12 months following discontinuation of treatment)
- 6-month EFS(Up to 6 months following discontinuation of treatment)
- Transfusion independence(Up to 12 months following discontinuation of treatment)
- Gilteritinib Tmax(Cycle 1 (Each cycle is 28 days))
- Gilteritinib AUC(tau)(Cycle 1 (Each cycle is 28 days))
- Ziftomenib Tmax(Cycle 1 (Each cycle is 28 days))