A Clinical Study of MK-1045 (CN201) in People With Precursor B-cell Acute Lymphoblastic Leukemia (MK-1045-002)
- Registration Number
- NCT05579132
- Lead Sponsor
- MSD R&D (China) Co., Ltd.
- Brief Summary
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
- Detailed Description
This is a multicenter, open-label, Phase Ib/II study in subjects with precursor B-cell acute lymphoblastic leukemia (B-ALL).
This study is designed in 2 parts as described below: Phase Ib (dose escalation and expansion) and Phase II. If in Phase Ib it is observed in adult subjects at doses with manageable risk and antitumor activity, studies in pediatric subjects can be initiated to explore safety and efficacy in pediatric subjects, as well as pharmacokinetic profiles.
For Phase Ib, the dose escalation employs Bayesian optimal interval (BOIN) design. Administered by IV infusion, once every week (QW), will be evaluated to determine the MTD and/or RP2D of CN201.
After RP2D is determined in Phase Ib, the Phase II study will be initiated to further evaluate the safety, tolerance, PK and PD characteristics, and anti-tumor activity of CN201 in subjects with B-ALL. Simon's two-stage minimax design will be employed to preliminarily explore the efficacy of CN201 in treatment of R/R B-ALL.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 203
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description MK-1045: Dose Escalation Phase- Adult Cohort MK-1045 Adults in the dose escalation phase will receive a target dose level of MK-1045 from 600 μg to 90000 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. MK-1045 : Dose Escalation Phase- Pediatric Cohort MK-1045 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.
- Primary Outcome Measures
Name Time Method Dose Escalation Phase: Number of Participants who Experience at Least One Adverse Event (AE) 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 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) 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 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 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.
- Secondary Outcome Measures
Name Time Method 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 Blood samples will be collected to determine the AUC from time 0 to the last concentration that can be accurately measured of MK-1045
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 Blood samples will be collected to determine the AUC0-inf of MK-1045.
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 Blood samples will be collected to determine the AUC from time to 168 hours after the start of infusion of MK-1045
Dose Escalation Phase: AUC From Time 0 to 168 Hours at Steady State (AUC0-tau) At designated time points up to 24 weeks Blood samples will be collected to determine the AUC0 -tau
Dose Escalation Phase: Maximum Serum Drug Concentration (Cmax) of MK-1045 At designated time points up to approximately 32 weeks Blood samples will be collected to determine the maximum serum drug concentration, obtained directly from the measured value of the plasma concentration-time curve
Dose Escalation Phase: Time to Maximum Serum Drug Concentration of MK-1045 At designated time points up to approximately 24 weeks Blood samples will be collected to determine the Tmax of MK-1045
Dose Escalation Phase: Concentration at End of Dosing Interval (Ctrough) of MK-1045 At designated time points up to approximately 12 months Blood samples will be collected to determine the Ctrough of MK-1045
Dose Escalation Phase: Apparent Terminal Half Life (t1/2) At designated time points up to approximately 24 weeks Blood samples will be collected to determine the t1/2 of MK-1045
Dose Escalation Phase: Apparent Clearance (CL) of MK-1045 At designated time points up to approximately 24 weeks Blood samples will be collected to determine the CL of MK-1045
Dose Escalation Phase: Apparent Volume of Distribution (Vz) of MK-1045 At designated time points up to approximately 24 weeks Blood samples will be collected to determine the Vz of MK-1045
Dose Escalation Phase: Apparent Volume of Distribution at Theoretical Steady State (Vss) of MK-1045 At designated time points up to approximately 24 weeks Blood samples will be collected to determine the Vss of MK-1045
Dose Escalation Phase: Mean Residence Time (MRT) of MK-1045 At designated time points up to approximately 24 weeks Blood samples will be collected to determine the MRT of MK-1045
Dose Escalation Phase: Peripheral B Cell Depletion of MK-1045 Baseline and at designated time points up to approximately 12 months B cell depletion will be determined at each timepoint by comparing absolute B cell numbers (as determined by flow cytometry) with those at baseline
Dose Escalation Phase: Peripheral Circulating T Cell Activation of of MK-1045 Baseline and at designated time points up to approximately 12 months Peripheral circulating T cell activation will be determined at each timepoint by comparing absolute T cell numbers and T cell activation markers with those at baseline
Dose Escalation Phase: Percentage of Participants with Antidrug Antibodies (ADA) to MK-1045 At designated time points up to approximately 12 months Blood samples collected at designated timepoints will be used to determine the percentage of participants who develop detectable ADAs to MK-1045
Dose Escalation Phase: Rate of Complete Remission (CR) and Complete Remission with Partial Hematologic Recovery (CRh) 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.
CRh is defined as meeting all of the following criteria:
Satisfaction of all criteria for CR except partial recovery of peripheral blood counts (platelets ≥ 50 ×10\^9/L and ANC ≥ 0.5×10\^9/L). The percentage of participants with CR or CRh will be presented.Dose Escalation Phase: Rate of CR, CRh, and Complete Response with Incomplete Hematologic Recovery (CRi) 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.
CRh is defined as meeting all of the following criteria:
Satisfaction of all criteria for CR except partial recovery of peripheral blood counts (platelets ≥ 50 ×10\^9/L and ANC ≥ 0.5×10\^9/L).
CRi is defined as follows:
\<5% blasts in the bone marrow, No circulating lymphoblasts or extramedullary disease, and platelets \<100×10\^9/L and neutrophils ≥1.0×109/L or platelets ≥100 ×109/L and neutrophils \<1.0×10\^9/L. The percentage of participants with CR, CRh or CRi will be presented.Dose Escalation Phase: Rate of Minimum Residual Disease (MRD)-negative Complete Remission Up to approximately 12 months MRD-negative is defined as less than 0.01% of leukemic cells were detected in bone marrow with a detection sensitivity no less than 10\^-4.
Dose Escalation Phase: Rate of Red Blood Cell and Platelet Transfusion Independence (TI) Up to approximately 24 months TI is defined as no transfusion for a period of at least 1 week (7 days). The percentage of participants having TI will be presented.
Phase II: Number of Participants Who Experience at Least 1 AE 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.
Phase II: Number of Participants who Discontinue Study Treatment Due to an AE 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.
Phase II: Maximum Serum Drug Concentration (Cmax) of MK-1045 At designated time points up to 4 weeks Blood samples will be collected to determine the maximum serum drug concentration, obtained directly from the measured value of the plasma concentration-time curve
Phase II: Peripheral Circulating T Cell Activation of of MK-1045 Baseline and at designated time points up to 4 weeks Peripheral circulating T cell activation will be determined at each timepoint by comparing absolute T cell numbers and T cell activation markers with those at baseline
Phase II: Concentration of Peripheral Cytokines Baseline and at designated time points up to 4 weeks Blood samples will be collected to compare peripheral blood cytokine levels at various time points with those at baseline
Phase II: Percentage of participants with Antidrug Antibodies (ADA) to MK-1045 At designated time points up to 4 weeks Blood samples collected at designated timepoints will be used to determine the percentage of participants who develop detectable ADAs to MK-1045
Phase II: Rate of CR and CRh 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.
CRh is defined as meeting all of the following criteria:
Satisfaction of all criteria for CR except partial recovery of peripheral blood counts (platelets ≥ 50 ×10\^9/L and ANC ≥ 0.5×10\^9/L). The percentage of participants with CR or CRh will be presented.Phase II: Rate of CR/CRh/CRi Up to approximately 10 weeks CR 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.
CRh is defined as meeting all of the following criteria:
Satisfaction of all criteria for CR except partial recovery of peripheral blood counts (platelets ≥ 50 ×10\^9/L and ANC ≥ 0.5×10\^9/L).
CRi is defined as follows:
\<5% blasts in the bone marrow, No circulating lymphoblasts or extramedullary disease, and platelets \<100×10\^9/L and neutrophils ≥1.0×109/L or platelets ≥100 ×109/L and neutrophils \<1.0×10\^9/L. The percentage of participants with CR, CRh or CRi will be presented.Phase II: Rate of Minimum Residual Disease (MRD)-negative Complete Remission Up to approximately 24 months MRD-negative is defined as less than 0.01% of leukemic cells were detected in bone marrow with a detection sensitivity no less than 10\^-4.
Phase II: Rate of Red Blood Cell and Platelet TI Up to approximately 24 months Red Blood Cell and Platelet TI is defined as no transfusion for a period of at least 1 week (7 days). The percentage of participants having TI will be presented.
Phase II: Proportion of Participants Undergoing Hematopoietic Stem Cell Transplantation (HSCT) Up to approximately 24 months The number of participants who undergo a HSCT during study participation will be presented.
Phase II: Duration of CR Up to approximately 24 months For participants who demonstrate a CR (defined as \< 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) , duration of CR is defined as the time from the first documentation of a disease response of CR to the date of the first documented relapse event, or death due to any cause, whichever occurs first
Phase II: Duration of CR/CRh Up to approximately 24 months Duration of CR/CRh is defined as the time from the first documentation of a disease response of CR/CRh to the date of the first documented relapse event, or death due to any cause, whichever occurs first. Only participants who demonstrate a CR (defined as \< 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), or CRh \[satisfaction of all criteria for CR except partial recovery of peripheral blood counts (platelets ≥ 50 ×10\^9/L and ANC ≥ 0.5×10\^9/L)\] will be analyzed.
Phase II: Duration of CR/CRh/CRi Up to approximately 24 months Duration of CR/CRh/CRi is defined as the time from the first documentation of a disease response of CR/CRh/CRi to the date of the first documented relapse event, or death due to any cause, whichever occurs first. Only participants who demonstrate a CR (defined as \< 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), or CRh \[satisfaction of all criteria for CR except partial recovery of peripheral blood counts (platelets ≥ 50 ×10\^9/L and ANC ≥ 0.5×10\^9/L)\], or CRi (\<5% blasts in the bone marrow, No circulating lymphoblasts or extramedullary disease, and platelets \<100×10\^9/L and neutrophils ≥1.0×109/L or platelets ≥100 ×109/L and neutrophils \<1.0×10\^9/L) will be analyzed.
Phase II: Relapse-Free Survival (RFS) Up to approximately 24 months RFS is defined as the time from the first dose of MK-1045 to the first documented relapse, or death due to any cause (whichever occurs first). In participants who achieve CR, CRh or CRi, relapse is defined as either hematological or extramedullary relapse . Hematological relapse is defined as recurrence of blasts in the blood, or \>5% blasts in bone marrow. Extramedullary relapse is defined as recurrence of extramedullary disease after a CR.
Phase II: Overall Survival (OS) Up to approximately 24 months OS is the time from date of first study treatment to the date of death due to any reason.
Phase II: Concentration at End of Dosing Interval (Ctrough) of MK-1045 At designated time points up to 4 weeks Blood samples will be collected to determine the Ctrough of MK-1045
Phase II: Peripheral B Cell Depletion of MK-1045 Baseline and at designated time points up to 4 weeks B cell depletion will be determined at each timepoint by comparing absolute B cell numbers (as determined by flow cytometry) with those at baseline
Trial Locations
- Locations (11)
The Second Affiliated Hospital of Third Military Medical University ( Site 0008)
🇨🇳Chongqing, Chongqing, China
Southern Medical University Nanfang Hospital ( Site 0004)
🇨🇳Guangzhou, Guangdong, China
The Second Hospital of Hebei Medical University ( Site 0003)
🇨🇳Shijiazhuang, Hebei, China
The First Hospital of Harbin ( Site 0005)
🇨🇳Harbin, Heilongjiang, China
Henan Cancer Hospital-hematology department ( Site 0002)
🇨🇳Zhengzhou, Henan, China
Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology
🇨🇳Wuhan, Hubei, China
Tongji Hospital affiliated to Tongji Medical College of HUST ( Site 0006)
🇨🇳Wuhan, Hubei, China
The Affiliated Hospital of Xuzhou Medical University ( Site 0007)
🇨🇳Xuzhou, Jiangsu, China
West China Second University Hospital, Sichuan University ( Site 0011)
🇨🇳Chengdu, Sichuan, China
Hematology Hospital of Chinese Academy of Medical Sciences ( Site 0001)
🇨🇳Tianjin, Tianjin, China
The Children's Hospital of Zhejiang University School of Medicine ( Site 0009)
🇨🇳Hangzhou, Zhejiang, China