An Open-Label, Dose Escalation Phase 1a Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of MK-1045 (CN201) in Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 100
- 试验地点
- 19
- 主要终点
- Number of Participants who Experience a Dose-limiting Toxicity (DLT)
研究概览
简要总结
Researchers are looking for new ways to treat people with relapsed or refractory B-Cell Non-Hodgkin Lymphoma (B-NHL). B-cells are a type of white blood cells that make antibodies and help fight infections. Non-Hodgkin Lymphoma is a type of cancer in the lymphatic system causing enlarged lymph nodes and/or organs in belly or chest. Relapsed means a disease or condition comes back after treatment Refractory means a disease does not respond to treatment or stops responding to a treatment.
MK-1045, the study medicine, is designed to treat relapsed or refractory B-NHL. MK-1045 is an immunotherapy, which is a treatment that helps the immune system fight cancer.
This is the first study in which MK-1045 will be given to people. The goal of this study is to learn about:
- The safety of MK-1045 and how well people tolerate it.
- The highest dose of MK-1045 that is well tolerated.
- How well MK-1045 works to treat relapsed or refractory B-NHL.
详细描述
This study is the first-in-human clinical trial of CN201 to evaluate the safety, tolerability, pharmacokinetic (PK) profile and preliminary efficacy of CN201 in patients with relapsed or refractory B-NHL. This study will provide a basis for further clinical development of CN201.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- •Inclusion Criteria
- •Inclusion Criteria include, but are not limited to:
- •Has relapsed or refractory B-cell Non-Hodgkin's lymphoma (B-NHL) with disease history meeting the following World Health Organization (WHO) diagnostic subtypes of B-NHL that are CD19-positive in pathologic immunohistochemistry test: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) (Grade I to III), marginal zone lymphoma, lymphoplasmacytic lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, and transformed large B-cell lymphoma (During the dose-escalation phase, participants, excluding those treated with Chimeric antigen receptor T-cell (CAR-T) who cannot provide proof of pathologic immunohistochemistry CD19 positivity but have previous proof of CD20 positivity may be considered for enrollment after communication with the sponsor)
- •Relapse is defined as the occurrence of progressive disease (PD) after complete response (CR) or partial response (PR) has been achieved after adequate treatment. Note: For DLBCL participants, relapse must occur after participants undergoing at least two lines of therapy; for other participants, they must undergo at least one line of therapy.
- •Refractory is defined as a situation that there is no standard of care available or that it is not applicable to use standard of care at this stage, including: Participants who are unresponsive to standard of care (e.g., monotherapy or combination therapy containing anti-CD20 monoclonal antibody) and whose best response to standard therapy is PD or stable disease (SD); Participants who are not eligible for autologous hematopoietic stem cell transplantation (ASCT) and have relapsed PD after receiving ASCT; Participants who have failed on chimeric antigen receptor T cell (CAR-T) immunotherapy, but the first dose of the study intervention must be at least 3 months after discontinuation of CAR-T therapy, and CD19 positive expression is still present in tumor tissue.
- •Has at least one evaluable tumor lesion per the Lugano 2014 criteria, i.e., a lymph node lesion > 15 mm in long diameter or an extranodal lesion > 10 mm in long diameter according to computed tomography (CT) cross-sectional imaging or magnetic resonance imaging (MRI)
- •Has an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2 and an estimated survival time of more than 3 months
- •Has essentially normal: bone marrow function; coagulation function; liver function; kidney function; lung function; and heart function
- •Exclusion Criteria
- •Exclusion Criteria include, but are not limited to:
- •Has any other non-Hodgkin lymphoma (NHL) not listed in inclusion criteria
- •Has been treated with anti-CD3/CD19 bispecific antibody (BsAb) prior to first dose of study intervention
- •Has received chemotherapy, endocrine therapy, radiotherapy (palliative radiotherapy 2 weeks prior to the first administration of the investigational drug), or biologic therapy, and small molecule targeted agents within 2 weeks prior to the first administration of the investigational drug or within 5 half-lives of the drug, whichever is shorter
- •Has received anti-CD20 antibody or anti-CD19 antibody within 4 weeks prior to first use of the investigational drug
- •Has received anti-tumor immunotherapy or other unlisted clinical study intervention within 4 weeks prior to the first dose of study intervention, or within 5 half-lives of the drug, whichever is shorter
- •Has undergone any major organ surgery (excluding aspiration biopsy) or significant trauma within 4 weeks prior to the first dose of study intervention or those requiring elective surgeries during the study
- •Has received systemic corticosteroids (prednisone >10 mg/day or equivalent) or other immunosuppressive agents within 14 days prior to the first dose of the study intervention, excluding the following agents: topical, ocular, intra-articular, intranasal, and inhaled corticosteroids, and short-term, prophylactic use of corticosteroids (e.g. to prevent radio contrast agent induced allergic reactions)
- •Has used immunomodulatory agents, including but not limited to thymosin, interleukin-2 (IL-2), interferon (IFN) and anti-tumor Chinese patent drugs or Chinese herbal medicines within 14 days prior to the first dose of study intervention
- •Has had a live attenuated vaccines within 4 weeks prior to the first dose of study intervention
- •Has a central nervous system (CNS) infiltration
- •Has previous or concomitant CNS diseases, including epilepsy, severe brain injury, dementia, Parkinson's disease, cerebellar disorder, organic cerebellar syndrome, or mental diseases
- •Has prior or concomitant malignancies (except cured basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, prostatic intraepithelial neoplasia, and other tumors that have been clinically cured for 5 years as assessed by the investigator)
- •Has uncontrolled active infections currently requiring systemic anti-infective therapy within 3 days prior to first dose
- •Has active hepatitis B and/or hepatitis C. Participants who are positive for antibodies to hepatitis C virus (HCV). Participants who are hepatitis B surface antigen (HBsAg) positive are not allowed to enroll in the dose-escalation period; however, those who were hepatitis B surface antigen (HBsAg)-positive but hepatitis B Virus deoxyribonucleic acid (HBV DNA)-negative and adherent to entecavir antiviral therapy and who agreed to regular monthly monitoring of HBV DNA are allowed to enroll in the dose-expansion period
- •Has a history of immunodeficiency, including testing positive for human immunodeficiency virus (HIV) antibody
- •Has a history of serious cardiovascular and cerebrovascular disease, including but not limited to: severe cardiac rhythm or conduction abnormalities; acute coronary syndrome, congestive heart failure, stroke, or other Grade 3 or higher cardiovascular and cerebrovascular events within 6 months prior to the first dose; ≥ Class II cardiac function as per New York Heart Association (NYHA) functional class or LVEF < 50%; or clinically uncontrollable hypertension
- •Has previous or current interstitial lung disease
- •Has acute graft-versus-host disease (GVHD) or active chronic GVHD at present
- •Has active or history of autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, autoimmune thyroid disease, vasculitis, psoriasis, etc.) that may relapse, or participants who are at risks (e.g., organ transplant requiring immunosuppressive therapy). Participants with the following diseases are allowed to be further screened for enrollment: hypothyroidism managed with hormone replacement therapy only, and skin diseases not requiring systemic treatment (such as vitiligo, psoriasis, or alopecia).
- •Has received immunotherapy with known Grade 3 or higher immune-related adverse events (irAEs)
- •Has non-hematologic adverse reactions from prior anti-tumor therapy have not recovered to Grade ≤ 1 as assessed by National Cancer Institute NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 (excluding toxicities such as alopecia that are assessed by the investigator to have no safety risk)
研究组 & 干预措施
MK-1045 Fixed Dose
Participants will receive MK-1045 via intravenous (IV) infusion on Day 1 of each week for 3 consecutive weeks followed by one week off of each four-week cycle for up to 12 months until discontinuation or death.
干预措施: MK-1045 (Drug)
MK-1045 Step-up Dose
Participants will receive MK-1045 via an IV infusion in a step-up dose with priming once a week (Q1W) for a 3-week cycle for up to 12 months until discontinuation or death.
干预措施: MK-1045 (Drug)
结局指标
主要结局
Number of Participants who Experience a Dose-limiting Toxicity (DLT)
时间窗: Up to ~28 Days
DLT are any of the following drug related (DR) investigator-assessed adverse events: Grade 4 neutropenia that does not recover to Grade ≤ 2 after more than 5 days of supportive care including granulocyte colony-stimulating factor (G-CSF), or ≥ Grade 3 febrile neutropenia; Grade 4 platelet (PLT) decreased, or Grade 3 PLT decreased with bleeding; Grade 4 anemia. Grade 4 non-hematologic toxicity; Grade 3 non-hematologic toxicity that does not recover to Grade ≤ 2 within 3 days after best supportive care (excluding simple laboratory abnormalities without clinical significance as assessed by the investigator). Participants with ≥ Grade 3 tumor lysis syndrome who recover to ≤ Grade 2 within 14 days after optimal supportive therapy will be excluded from the definition of DLT. A DLT was also any other toxic reactions requiring permanent discontinuation of the study intervention.
Number of Participants who Experience an Adverse Event (AE)
时间窗: Up to ~15 months
An AE is defined as any untoward medical event that occurs after a participant receives the investigational drug, which may be manifested as symptoms, signs, diseases, or laboratory abnormalities, but may not necessarily have a causal relationship with the study intervention. The number of participants who experience an AE will be reported.
Number of Participants who Experience a Serious Adverse Events (SAE)
时间窗: Up to ~15 months
An SAE refers to an untoward medical occurrence such as death, life-threatening event, permanent or serious disability or loss of function, need for hospitalization or prolongation of hospitalization after the participant receives the intervention, and congenital abnormalities or birth defects. The number of participants who experience a SAE will be reported.
Number of Participants who Experience a Drug-related Adverse Event (DRAE)
时间窗: Up to ~15 months
An AE is defined as any untoward medical event that occurs after a participant receives the investigational drug, which may be manifested as symptoms, signs, diseases, or laboratory abnormalities, but may not necessarily have a causal relationship with the study intervention. A DRAE is defined as an AE definitely related, probably related, or possibly related to the study intervention. The number of participants who have experienced a DRAE will be reported.
Number of Participants who Experience an AE of Grade 3 or higher
时间窗: Up to ~15 months
An AE is defined as any untoward medical event that occurs after a participant receives the study intervention, which may be manifested as symptoms, signs, diseases, or laboratory abnormalities, but may not necessarily have a causal relationship with the study intervention. AEs are graded on a scale from 1-5 with 1=Mild, 2=Moderate, 3=Severe or medically significant but not immediately life-threatening, 4= Life threatening consequences, and 5=Death due to AE. The number of participants who experience an AE of grade 3 or above will be presented.
Number of Participants who Experience an AE for Each Severity Grade from 1-5
时间窗: Up to ~15 months
An AE is defined as any untoward medical event that occurs after a participant receives the study intervention, which may be manifested as symptoms, signs, diseases, or laboratory abnormalities, but may not necessarily have a causal relationship with the study intervention. AEs are graded on a scale from 1-5 with 1=Mild, 2=Moderate, 3=Severe or medically significant but not immediately life-threatening, 4= Life threatening consequences, and 5=Death due to AE. The number of participants who experience an AE in each category of AEs from 1-5 will be presented.
Number of Participants who Experience a SAE or Serious Drug-related AE
时间窗: Up to ~15 months
An SAE refers to an untoward medical occurrence such as death, life-threatening event, permanent or serious disability or loss of function, need for hospitalization or prolongation of hospitalization after the participant receives the study intervention, and congenital abnormalities or birth defects. A drug related SAE is defined as an SAE definitely related, probably related, or possibly related to the study intervention. The number of participants who experience a SAE or a serious drug-related AE will be reported.
Number of Participants who Experience a Dose Modification Due to an AE or DRAE
时间窗: Up to ~15 months
An AE is defined as any untoward medical event that occurs after a participant receives the study intervention, which may be manifested as symptoms, signs, diseases, or laboratory abnormalities, but may not necessarily have a causal relationship with the study intervention. A drug related AE includes AEs definitely related, probably related, and possibly related to the study intervention. The number of participants who experience a dose modification due to an AE or DRAE will be presented.
Number of Participants who Withdraw from the Study due to an AE or DRAE
时间窗: Up to ~15 months
An AE is defined as any untoward medical event that occurs after a participant receives the study intervention, which may be manifested as symptoms, signs, diseases, or laboratory abnormalities, but may not necessarily have a causal relationship with the study intervention. A drug related AE includes AEs definitely related, probably related, and possibly related to the study intervention. The number of participants who discontinue the study due to an AE will be presented.
Number of Participants who Died due to an AE or DRAE
时间窗: Up to ~15 months
An AE is defined as any untoward medical event that occurs after a participant receives the study intervention, which may be manifested as symptoms, signs, diseases, or laboratory abnormalities, but may not necessarily have a causal relationship with the study intervention. A drug related AE includes AEs definitely related, probably related, and possibly related to the study intervention. The number of participants who died due to an AE or DRAE will be presented.
次要结局
- Mean Change in Serum MK-1045 Concentration After Administration(Baseline and up to 12 months)
- Area Under the Concentration-time Curve (AUC) of MK-1045(Pre-dose and at designated time points post-dose up to 12 months)
- Area Under the Concentration-time Curve from Time 0 to 168 Hours Post Dose (AUC0-168) of MK-1045(Pre-dose and at designated time points post-dose up to 168 hours)
- Area Under the Concentration-time Curve from Time 0 to Last Quantifiable Concentration Post Dose (AUC0-last) of MK-1045(Pre-dose and at designated time points post-dose up to 168 hours)
- Maximum Concentration (Cmax) of MK-1045(Pre-dose and at designated time points post-dose up to 12 months)
- Time to Maximum Concentration (Tmax) of MK-1045(Pre-dose and at designated time points post-dose up to 12 months)
- Terminal Elimination Half-life (T1/2) of MK-1045(Pre-dose and at designated time points post-dose up to 12 months)
- Clearance (CL) of MK-1045(Pre-dose and at designated time points post-dose up to 12 months)
- Concentration at the End of Dosing Interval (Ctrough) of MK-1045(Pre-dose and at designated time points post-dose up to 12 months)
- Area Under the Concentration-time Curve from Time 0 to the Dosing Interval (168 Hours) at Steady State (AUC0-tau) of MK-1045(Pre-dose and at designated time points post-dose up to 168 hours)
- Accumulatio Ratio Based on Cmax (RAC-Cmax) of MK-1045(Pre-dose and at designated time points post-dose up to 12 months)
- Accumulation Ratio Based on AUC0-tau (RAC_AUC0-tau) of MK-1045(Pre-dose and at designated time points post-dose up to 12 months)
- Steady State Clearance (CLss) of MK-1045(Pre-dose and at designated time points post-dose up to 12 months)
- Steady State Apparent Volume of Distribution (Vss) of MK-1045(Pre-dose and at designated time points post-dose up to 12 months)
- Mean Number of B Cells in Peripheral Blood After Administration of MK-1045(Baseline and up to 12 months)
- Mean Number of T cells in Peripheral Blood After Administration of MK-1045(Baseline and up to 12 months)
- Mean Level of T Cell Proliferation After Administration of MK-1045(Baseline and up to 12 months)
- Percentage of Participants who Develop Anti-drug Antibodies (ADA) to MK-1045(Baseline and up to 15 months)
- Objective Response Rate (ORR)(Up to 15 months)
- Duration of Response (DOR)(Up to ~15 months)
- Complete Response Rate (CRR)(Up to ~15 months)
- Duration of Complete Response (DCR)(Up to ~15 months)
- Progression Free Survival (PFS)(Up to ~15 months)
- Accumulatio Ratio Based on Cmax (RAC-Cmax) of MK-1045(Pre-dose and at designated time points post-dose up to 12 months)
- Mean Change in Serum MK-1045 Concentration After Administration(Baseline and up to 12 months)
- Area Under the Concentration-time Curve (AUC) of MK-1045(Pre-dose and at designated time points post-dose up to 12 months)
- Area Under the Concentration-time Curve from Time 0 to 168 Hours Post Dose (AUC0-168) of MK-1045(Pre-dose and at designated time points post-dose up to 168 hours)
- Area Under the Concentration-time Curve from Time 0 to Last Quantifiable Concentration Post Dose (AUC0-last) of MK-1045(Pre-dose and at designated time points post-dose up to 168 hours)
- Maximum Concentration (Cmax) of MK-1045(Pre-dose and at designated time points post-dose up to 12 months)
- Time to Maximum Concentration (Tmax) of MK-1045(Pre-dose and at designated time points post-dose up to 12 months)
- Terminal Elimination Half-life (T1/2) of MK-1045(Pre-dose and at designated time points post-dose up to 12 months)
- Clearance (CL) of MK-1045(Pre-dose and at designated time points post-dose up to 12 months)
- Concentration at the End of Dosing Interval (Ctrough) of MK-1045(Pre-dose and at designated time points post-dose up to 12 months)
- Area Under the Concentration-time Curve from Time 0 to the Dosing Interval (168 Hours) at Steady State (AUC0-tau) of MK-1045(Pre-dose and at designated time points post-dose up to 168 hours)
- Accumulation Ratio Based on AUC0-tau (RAC_AUC0-tau) of MK-1045(Pre-dose and at designated time points post-dose up to 12 months)
- Steady State Clearance (CLss) of MK-1045(Pre-dose and at designated time points post-dose up to 12 months)
- Steady State Apparent Volume of Distribution (Vss) of MK-1045(Pre-dose and at designated time points post-dose up to 12 months)
- Mean Number of B Cells in Peripheral Blood After Administration of MK-1045(Baseline and up to 12 months)
- Mean Number of T cells in Peripheral Blood After Administration of MK-1045(Baseline and up to 12 months)
- Mean Level of T Cell Activation After Administration with MK-1045(Baseline and up to 12 months)
- Mean Level of T Cell Proliferation After Administration of MK-1045(Baseline and up to 12 months)
- Mean Level of Cytokines in Peripheral Blood After Administration of MK-1045(Baseline up to 12 months)
- Percentage of Participants who Develop Anti-drug Antibodies (ADA) to MK-1045(Baseline and up to 15 months)
- Objective Response Rate (ORR)(Up to 15 months)
- Duration of Response (DOR)(Up to ~15 months)
- Complete Response Rate (CRR)(Up to ~15 months)
- Progression Free Survival (PFS)(Up to ~15 months)
- Duration of Complete Response (DCR)(Up to ~15 months)