An Open-label, Multi-center Phase Ib/II Study of MK-1045 (CN201) in Subjects With Precursor B-cell Acute Lymphoblastic Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 203
- 试验地点
- 21
- 主要终点
- Dose Escalation Phase: Number of Participants who Experience at Least One Adverse Event (AE)
研究概览
简要总结
Researchers are looking for new ways to treat people with a type of blood cancer called precursor B-cell Acute Lymphoblastic Leukemia (B-ALL) that is relapsed- the cancer has come back after treatment, or refractory - the current treatment has stopped working to slow or stop cancer growth. This study will have two parts. In the first part (dose escalation phase) the goal is to learn about the safety of a study treatment, MK-1045, and to find the best dose level of MK-1045 that is tolerated and may work to treat B-ALL. In the second part (Phase II) researchers want to learn how well MK-1045 works to treat B-ALL.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 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
- •The main inclusion criteria include but are not limited to:
- •Adult participants must be age 18 or older
- •Pediatric participants must be at least 2 years old and less than 18 years old.
- •Diagnosis of precursor B-cell acute lymphoblastic leukemia (B-ALL) and have more than 5% blasts in the bone marrow by morphological assessment
- •Participants with Ph-negative B-ALL with any of the following refractory/relapse criteria:
- •Failure to achieve complete remission after initial induction therapy;
- •Failure to achieve complete remission after salvage treatment;
- •Relapse with first remission duration ≤12 months
- •Second or later relapse
- •Relapse after allogeneic HSCT
- •Participants with Ph-positive B-ALL who have received 2 (or more) tyrosine kinase inhibitors (TKIs) and meet the refractory/relapse criteria above or, those with the T315I mutation
排除标准
- •include but are not limited to:
- •History of Burkitt's leukemia.
- •Received anti-CD19 therapy within 3 months prior to entering the study
- •Received allogeneic HSCT within 12 weeks prior to entering the study
- •Received prior treatment with chimeric antigen receptor T cell (CAR-T) within 3 months prior to entering the study
- •History or presence of clinically relevant central nervous system (CNS) pathology
- •History of clinically symptomatic metastases to the central nervous system or meninges, or other evidence of uncontrolled metastases to the CNS or meninges
- •History of immunodeficiency, including history of any positive test result for human immunodeficiency virus (HIV) antibody.
- •History of serious cardiovascular and cerebrovascular disease
- •Has active autoimmune diseases that may relapse
研究组 & 干预措施
MK-1045 : Dose Escalation Phase- Pediatric Cohort
Pediatric participants will receive a target dose level of MK-1045 from 320 μg to 60000 μg, with dosing further based upon weight. MK-1045 will be administered by IV infusion once per week, in treatment cycles defined as 4 weeks of MK-1045 treatment.
干预措施: MK-1045 (Drug)
MK-1045: Dose Escalation Phase- Adult Cohort
Adults in the dose escalation phase will receive a target dose level of MK-1045 from 600 μg to 120,000 μg, administered by intravenous (IV) infusion. MK-1045 will be administered once per week, in treatment cycles defined as 4 weeks of MK-1045 treatment.
干预措施: MK-1045 (Drug)
结局指标
主要结局
Dose Escalation Phase: Number of Participants who Experience at Least One Adverse Event (AE)
时间窗: Up to approximately 24 months
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
Dose Escalation Phase: Number of Participants who Discontinue Study Treatment Due to an AE
时间窗: Up to approximately 21 months
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
Dose Escalation Phase: Number of Participants Who Experience a Dose-limiting Toxicity (DLT)
时间窗: Up to 28 days
A DLT is defined as any of the following toxicities and judged by the investigator to be related to the study drug: Hematologic toxic reactions: If thrombocytopenia, leukopenia, and anemia are caused by primary leukemia, they are not considered as DLTs. Non-Hematologic toxic reactions: Grade 4 non-hematologic toxicity that does not recover to ≤ Grade 2 within 14 days of best supportive therapy. Grade 3 rash, fatigue, fever, or infection will not be classified as DLT; other Grade 3 non-hematologic toxicities that do not recover to ≤ Grade 2 within 14 days of best supportive therapy is considered DLTs. Others that are considered as DLTs: Other toxicities considered clinically significant by the investigator that result in permanent drug withdrawal.
Dose Escalation Phase: Maximum Tolerated Dose (MTD) of MK-1045
时间窗: Up to approximately 21 months
The MTD will be determined based on the incidence of DLT in each dose level. The dose level for which the DLT rate is closest to the target DLT rate (30%) will be selected as the MTD.
Phase II: Complete Remission (CR) Rate
时间窗: Up to approximately 10 weeks
Complete remission is defined as follows: \< 5% blasts in the bone marrow, no circulating lymphoblasts or extramedullary disease, and full recovery of peripheral blood counts: Platelets ≥100×10\^9/L, and absolute neutrophil count (ANC) ≥1.0×10\^9/L. The number of participants with CR will be presented.
次要结局
- Phase II: Concentration at End of Dosing Interval (Ctrough) of MK-1045(At designated time points up to 4 weeks)
- Phase II: Peripheral B Cell Depletion of MK-1045(Baseline and at designated time points up to 4 weeks)
- Dose Escalation Phase: Area Under the Concentration-Time Curve from Time 0 to Last (AUC0-Last) of MK-1045(At designated time points up to approximately 24 weeks)
- Dose Escalation Phase: Area Under the Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of MK-1045(At designated time points up to approximately 24 weeks)
- Dose Escalation Phase: Area Under the Concentration-time Curve From Time 0 to 168 hours (AUC0-168)(At designated time points up to approximately 24 weeks)
- Dose Escalation Phase: AUC From Time 0 to 168 Hours at Steady State (AUC0-tau)(At designated time points up to 24 weeks)
- Dose Escalation Phase: Maximum Serum Drug Concentration (Cmax) of MK-1045(At designated time points up to approximately 32 weeks)
- Dose Escalation Phase: Time to Maximum Serum Drug Concentration of MK-1045(At designated time points up to approximately 24 weeks)
- Dose Escalation Phase: Concentration at End of Dosing Interval (Ctrough) of MK-1045(At designated time points up to approximately 12 months)
- Dose Escalation Phase: Apparent Terminal Half Life (t1/2)(At designated time points up to approximately 24 weeks)
- Dose Escalation Phase: Apparent Clearance (CL) of MK-1045(At designated time points up to approximately 24 weeks)
- Dose Escalation Phase: Apparent Volume of Distribution (Vz) of MK-1045(At designated time points up to approximately 24 weeks)
- Dose Escalation Phase: Apparent Volume of Distribution at Theoretical Steady State (Vss) of MK-1045(At designated time points up to approximately 24 weeks)
- Dose Escalation Phase: Mean Residence Time (MRT) of MK-1045(At designated time points up to approximately 24 weeks)
- Dose Escalation Phase: Peripheral B Cell Depletion of MK-1045(Baseline and at designated time points up to approximately 12 months)
- Dose Escalation Phase: Peripheral Circulating T Cell Activation of of MK-1045(Baseline and at designated time points up to approximately 12 months)
- Dose Escalation Phase: Percentage of Participants with Antidrug Antibodies (ADA) to MK-1045(At designated time points up to approximately 12 months)
- Dose Escalation Phase: Rate of Complete Remission (CR) and Complete Remission with Partial Hematologic Recovery (CRh)(Up to approximately 10 weeks)
- Dose Escalation Phase: Rate of CR, CRh, and Complete Response with Incomplete Hematologic Recovery (CRi)(Up to approximately 10 weeks)
- Dose Escalation Phase: Rate of Minimum Residual Disease (MRD)-negative Complete Remission(Up to approximately 12 months)
- Dose Escalation Phase: Rate of Red Blood Cell and Platelet Transfusion Independence (TI)(Up to approximately 24 months)
- Phase II: Number of Participants Who Experience at Least 1 AE(Up to approximately 24 months)
- Phase II: Number of Participants who Discontinue Study Treatment Due to an AE(Up to approximately 24 months)
- Phase II: Maximum Serum Drug Concentration (Cmax) of MK-1045(At designated time points up to 4 weeks)
- Phase II: Peripheral Circulating T Cell Activation of of MK-1045(Baseline and at designated time points up to 4 weeks)
- Phase II: Concentration of Peripheral Cytokines(Baseline and at designated time points up to 4 weeks)
- Phase II: Percentage of participants with Antidrug Antibodies (ADA) to MK-1045(At designated time points up to 4 weeks)
- Phase II: Rate of CR and CRh(Up to approximately 10 weeks)
- Phase II: Rate of CR/CRh/CRi(Up to approximately 10 weeks)
- Phase II: Rate of Minimum Residual Disease (MRD)-negative Complete Remission(Up to approximately 24 months)
- Phase II: Rate of Red Blood Cell and Platelet TI(Up to approximately 24 months)
- Phase II: Proportion of Participants Undergoing Hematopoietic Stem Cell Transplantation (HSCT)(Up to approximately 24 months)
- Phase II: Duration of CR(Up to approximately 24 months)
- Phase II: Duration of CR/CRh(Up to approximately 24 months)
- Phase II: Duration of CR/CRh/CRi(Up to approximately 24 months)
- Phase II: Relapse-Free Survival (RFS)(Up to approximately 24 months)
- Phase II: Overall Survival (OS)(Up to approximately 24 months)