A Phase 1/2, First-in-Human Study of the Menin-KMT2A (MLL1) Inhibitor Bleximenib in Participants With Acute Leukemia (cAMeLot-1)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 420
- 试验地点
- 203
- 主要终点
- Phase 1: Part 1: Percentage of Participants with Dose-Limiting Toxicity (DLT)
研究概览
简要总结
The purpose of this study is to determine the recommended Phase 2 dose(s) (RP2D[s]) of bleximenib in phase 1 Part 1 (Dose Escalation) and to determine the safety and tolerability at RP2D in Phase 1 Part 2 (Dose expansion). The purpose of the Phase 2 part of the study is to evaluate the efficacy of bleximenib at the RP2D.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 2 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 2 years to less than (<) 18 years of age (pediatric cohort only), all other cohorts 18 years and above
- •Relapsed or refractory (R/R) acute leukemia and has exhausted, or is ineligible for, available therapeutic options
- •Acute leukemia harboring histone-lysine N-methyltransferase 2A (KMT2A), nucleophosmin 1 gene (NPM1) or nucleoporin 98 gene or nucleoporin 214 gene (NUP98 or NUP214) alterations
- •Participants greater than 18 years are eligible
- •Must have had an initial diagnosis of acute myeloid leukemia (AML) per the WHO 2022 classification criteria and have relapsed/refractory disease
- •AML harboring KMT2A-r (gene rearrangement/translocation) or NPM1 mutations only
- •For Both Phase 1 and 2:
- •Pretreatment clinical laboratory values meeting the following criteria: (a) Hematology: white blood cell (WBC) count <= 20*10^9/liter (L) and (b) renal function; For adult participants, estimated or measured glomerular filtration rate >= 30 milliliter per minute (mL/min) per four variable MDRD equation. For pediatric participants an estimated or measured glomerular filtration rate >=40 mL/min per the CKiD (Chronic Kidney Disease in Children) Schwartz formula
- •Eastern Cooperative Oncology Group (ECOG) performance status grade of 0, 1 or
- •Pediatric participants only: Performance status >=70 by Lansky scale (for participants < 16 years of age) or >=70 Karnofsky scale (for participants >=16 years of age)
- •A female of childbearing potential must have a negative highly sensitive serum beta-human chorionic gonadotropin at screening and within 48 hours prior to the first dose of study treatment
- •Participant must agree to all protocol required contraception requirements and avoid sperm or egg donations or freezing for future reproductive use while on study and for 90 days (males) or 6 months (females) after the last dose of study treatment
排除标准
- •Acute promyelocytic leukemia, diagnosis of Down syndrome associated leukemia or juvenile myelomonocytic leukemia according to World Health Organization (WHO) 2016 criteria
- •Active central nervous system (CNS) disease
- •Prior solid organ transplantation
- •QTc according to Fridericia's formula (QTcF) for males >= 450 millisecond (msec) or for females >= 470 msec. Participants with a family history of Long QT syndrome are excluded
- •Exclusion criteria related to stem cell transplant: a. Received prior treatment with allogenic bone marrow or stem cell transplant <=3 months before the first dose of study treatment ; b. Has evidence of graft versus host disease; c. Received donor lymphocyte infusion <=1 month before the first dose of study treatment; d. Requires immunosuppressant therapy (exception: daily doses <=10 milligrams (mg) prednisone or equivalent are allowed for adrenal replacement)
- •Prior cancer immunotherapy within 4 weeks prior to enrollment or blinatumomab within 2 weeks prior to enrollment. Additional prior cancer therapies must not be given within 4 weeks prior to enrollment or 5 half-lives of the agent (whichever is shorter)
研究组 & 干预措施
Bleximenib
Participants in Phase 1 Part 1 (dose escalation) will receive bleximenib orally. The dose levels will be escalated based on the dose limiting toxicities (DLT) evaluation by Study Evaluation Team (SET) until the recommended Phase 2 Doses (RP2Ds) have been identified. Participants in Phase 1 Part 2 (dose expansion) will receive bleximenib orally at the RP2D(s) determined in Part 1. In Phase 2 participants will receive bleximenib at the RP2D to evaluate anti-leukemia activity and demonstrate acceptable safety at the RP2D(s).
干预措施: Bleximenib (Drug)
结局指标
主要结局
Phase 1: Part 1: Percentage of Participants with Dose-Limiting Toxicity (DLT)
时间窗: Up to 28 days Cycle 1
Percentage of participants with DLT will be assessed accordingly to national cancer institute common terminology criteria for adverse events (NCI-CTCAE) version 5.
Phase 2: Rate of Complete Remission or Complete Remission with Partial Hematologic Recovery (CR/CRh)
时间窗: Up to 4 years and 9 months
Rate of CR/CRh is defined as the percentage of participants achieving a CR or CRh at any time post-treatment.
Phase 1: Number of Participants with Adverse Events (AEs) as a Measure of Safety and Tolerability
时间窗: Up to 4 years and 9 months
An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study.
Phase 1: Number of Participants with AEs by Severity
时间窗: Up to 4 years and 9 months
Severity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Severity scale ranges from Grade 1 (Mild) to Grade 5 (Death). Grade 1= Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Life-threatening and Grade 5= Death related to adverse event.
Phase 1: Number of Participants with Adverse Events (AEs) as a Measure of Safety and Tolerability
时间窗: Up to 4 years and 9 months
An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study.
Phase 1: Number of Participants with AEs by Severity
时间窗: Up to 4 years and 9 months
Severity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Severity scale ranges from Grade 1 (Mild) to Grade 5 (Death). Grade 1= Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Life-threatening and Grade 5= Death related to adverse event.
Phase 1: Part 1: Percentage of Participants with Dose-Limiting Toxicity (DLT)
时间窗: Up to 28 days Cycle 1
Percentage of participants with DLT will be assessed accordingly to national cancer institute common terminology criteria for adverse events (NCI-CTCAE) version 5.
Phase 2: Rate of Complete Remission or Complete Remission with Partial Hematologic Recovery (CR/CRh)
时间窗: Up to 4 years and 9 months
Rate of CR/CRh is defined as the percentage of participants achieving a CR or CRh at any time post-treatment.
次要结局
- Phase 1 and 2: Overall Response Rate (ORR)(Up to 4 years and 9 months)
- Phase 1 and 2: Time To Response (TTR)(Up to 4 years and 9 months)
- Phase 1 and 2: Plasma Concentration of Bleximenib(Up to 4 years and 9 months)
- Phase 2: Duration of Complete Response (CR)/Complete Remission With Partial Hematologic Recovery (CRh)(Up to 4 years and 9 months)
- Phase 2: Time To CR/CRh(Up to 4 years and 9 months)
- Phase 2: Event-free survival (EFS)(Up to 4 years and 9 months)
- Phase 2: Overall survival (OS)(Up to 4 years and 9 months)
- Phase 2: Measurable Residual Disease (MRD) Negativity Among Participants Achieving CR/CRh/CRi(Up to 4 years and 9 months)
- Phase 2: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)(Up to 4 years and 9 months)
- Phase 2: Number of Participants Reporting Transfusion Independence(Up to 4 years and 9 months)
- Phase 1 and 2: Overall Response Rate (ORR)(Up to 4 years and 9 months)
- Phase 1 and 2: Plasma Concentration of Bleximenib(Up to 4 years and 9 months)
- Phase 1: Duration of Response (DOR)(Up to 4 years and 9 months)
- Phase 1 and 2: Time To Response (TTR)(Up to 4 years and 9 months)
- Phase 2: Duration of Complete Response (CR)/Complete Remission With Partial Hematologic Recovery (CRh)(Up to 4 years and 9 months)
- Phase 2: Time To CR/CRh(Up to 4 years and 9 months)
- Phase 2: Event-free survival (EFS)(Up to 4 years and 9 months)
- Phase 2: Overall survival (OS)(Up to 4 years and 9 months)
- Phase 2: Measurable Residual Disease (MRD) Negativity Among Participants Achieving CR/CRh/CRi(Up to 4 years and 9 months)
- Phase 2: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)(Up to 4 years and 9 months)
- Phase 2: Number of Participants Reporting Transfusion Independence(Up to 4 years and 9 months)