A Phase 1/2 Open Label, Multi-center Study to Assess the Safety, Tolerability, Pharmacokinetics and Clinical Efficacy of Acalabrutinib in Chinese Adult Subjects With Relapsed or Refractory Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia or Other B-cell Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- AstraZeneca
- 入组人数
- 105
- 试验地点
- 24
- 主要终点
- Phase I: Temporal Change Parameter (TCP) in Systemic Exposure of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib
研究概览
简要总结
This is an open-label, two-part study to assess the safety, tolerability, pharmacokinetics and clinical efficacy of acalabrutinib in Chinese adult subjects with R/R MCL, CLL and other B-cell malignancies. The study is divided into 2 parts: Phase 1 portion and Phase 2 portion.
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
- 18 Years 至 130 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
- •Chinese subjects at least 18 years of age at the time of study entry.
- •Eastern Cooperative Oncology Group (ECOG) performance status of ≤2
- •Adequate hematological and organ function.
- •Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy.
- •Pathologically confirmed MCL, with documentation of chromosome translocation t(11;14) (q13;q32) and/or overexpression of cyclin D1 in association with other relevant markers (eg, CD5, CD19, CD20, PAX5). Disease had relapsed after or been refractory to previous treatment.
- •Diagnosis of CLL that meets published diagnostic criteria. Must have received ≥ 1 prior systemic therapies for CLL.
- •Active disease per iwCLL 2018 criteria that requires treatment. (CLL only)
- •Other relapsed/refractory B-cell malignancies without stand of care (phase 1 only).
排除标准
- •Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject had been disease free for ≥2 years or which would not have limited survival to <2 years.
- •Significant cardiovascular disease.
- •Known central nervous system involvement of lymphoma/leukemia or leptomeningeal disease.
- •Known history of HIV, serologic status reflecting active hepatitis B or C infection.
- •Major surgery within 4 weeks before first dose of study drugs.
- •Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura.
- •Required or received anticoagulation with warfarin or equivalent vitamin K antagonist (eg, phenprocoumon).
- •Prior exposure to a BCR or BCL-2 inhibitor.
- •Use of a strong inhibitor or inducer of CYP3A.
- •Breastfeeding or pregnant.
研究组 & 干预措施
Acalabrutinib
Acalabrutinib will be orally administered until disease progression or unacceptable toxicity.
干预措施: Acalabrutinib (Drug)
结局指标
主要结局
Phase I: Temporal Change Parameter (TCP) in Systemic Exposure of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib
时间窗: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 1 Day 8
Blood samples were collected to determine the TCP of acalabrutinib and ACP-5862 in plasma. The TCP in systemic exposure was calculated as AUCτ (steady state)/AUCinf (first dose). The TCP was determined using non-compartmental method.
Phase I: Accumulation Ratio of AUCτ (Rac AUC) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib
时间窗: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 1 Day 8
Blood samples were collected to determine the Rac AUC of acalabrutinib and ACP-5862 in plasma. The Rac AUC was calculated as AUCτ (steady state)/AUCτ (first dose). The Rac AUC was determined using non-compartmental method.
Phase I: Accumulation Ratio of Cmax (Rac Cmax) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib
时间窗: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 1 Day 8
Blood samples were collected to determine the Rac Cmax of acalabrutinib and ACP-5862 in plasma. The Rac Cmax was calculated as Cmax (steady state)/Cmax (first dose). The Rac Cmax was determined using non-compartmental method.
Phase I: Metabolite/Parent Drug AUCτ Ratio (MRAUCτ) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib
时间窗: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 1 Day 8
Blood samples were collected to determine the MRAUCτ of acalabrutinib and ACP-5862 in plasma. The MRAUCτ was determined using non-compartmental method.
Phase I: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
时间窗: From the first dose administration up to 30 days following the date of last dose of study treatment, approximately 25 months.
An AE is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. A SAE is an AE occurring during any study phase, that fulfils 1 or more of the following criteria: death, life-threatening, in-participant hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, congenital abnormality or birth defect, and an important medical event that may jeopardize the participant or may require medical treatment to prevent 1 of the outcomes listed above. AEs leading to discontinuation of acalabrutinib were those with action taken was 'Drug Permanently Discontinued' for acalabrutinib.
Phase I: Area Under the Plasma Concentration-Time Curve From Zero to Infinity (AUCinf) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib
时间窗: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 0 Day 1
Blood samples were collected to determine the AUCinf of acalabrutinib and ACP-5862 in plasma. The AUCinf was determined using non-compartmental method.
Phase I: Area Under the Plasma Concentration-Time Curve From Zero to 12 Hours (AUC0-12) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib
时间窗: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8 and 12 hours postdose on Cycle 0 Day 1
Blood samples were collected to determine the AUC0-12 of acalabrutinib and ACP-5862 in plasma. The AUC0-12 was determined using non-compartmental method.
Phase I: Area Under the Plasma Concentration-Time Curve From Zero to the Time of the Last Quantifiable Concentration (AUClast) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib
时间窗: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 0 Day 1
Blood samples were collected to determine the AUClast of acalabrutinib and ACP-5862 in plasma. The AUClast was determined using non-compartmental method.
Phase I: Maximum Observed Plasma Drug Concentration (Cmax) of Acalabrutinib and ACP-5862 Post Single and Multiple Dose of Acalabrutinib
时间窗: Single dose: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8 and 12 hours postdose on Cycle 0 Day 1; Multiple dose: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 1 Day 8
Blood samples were collected to determine the Cmax of acalabrutinib and ACP-5862 in plasma. The Cmax was determined using non-compartmental method.
Phase I: Time to Reach Maximum Observed Concentration (Tmax) of Acalabrutinib and ACP-5862 Post Single and Multiple Dose of Acalabrutinib
时间窗: Single dose: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8 and 12 hours postdose on Cycle 0 Day 1; Multiple dose: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 1 Day 8
Blood samples were collected to determine the tmax of acalabrutinib and ACP-5862 in plasma. The tmax was determined using non-compartmental method.
Phase I: Apparent Total Body Clearance of Drug (CL/F) of Acalabrutinib Post Single and Multiple Dose of Acalabrutinib
时间窗: Single dose: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8 and 12 hours postdose on Cycle 0 Day 1; Multiple dose: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 1 Day 8
Urine samples were collected to determine the CL/F of acalabrutinib. The CL/F was determined using non-compartmental method.
Phase I: Apparent Volume of Distribution (Vz/F) of Acalabrutinib Post Single Dose of Acalabrutinib
时间窗: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 0 Day 1
Blood samples were collected to determine the Vz/F of acalabrutinib in plasma. The Vz/F was determined using non-compartmental method.
Phase I: Terminal Elimination Rate Constant (λz) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib
时间窗: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 0 Day 1
Blood samples were collected to determine the λz of acalabrutinib and ACP-5862 in plasma. The λz was determined using non-compartmental method.
Phase I: Terminal Phase Half-Life (t1/2λz) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib
时间窗: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 0 Day 1
Blood samples were collected to determine the t1/2λz of acalabrutinib and ACP-5862 in plasma. The t1/2λz was determined using non-compartmental method.
Phase I: Metabolite/Parent Drug Cmax Ratio (MRCmax) of Acalabrutinib and ACP-5862 Post Single and Multiple Dose of Acalabrutinib
时间窗: Single dose: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8 and 12 hours postdose on Cycle 0 Day 1; Multiple dose: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 1 Day 8
Blood samples were collected to determine the MRCmax of acalabrutinib and ACP-5862 in plasma. The MRCmax was determined using non-compartmental method.
Phase I: Metabolite/Parent Drug AUC Ratio (MRAUCinf) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib
时间窗: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 0 Day 1
Blood samples were collected to determine the MRAUCinf of acalabrutinib in plasma. The MRAUCinf was determined using non-compartmental method.
Phase I: Area Under the Plasma Concentration-Time Curve Across the Dosing Interval (AUCτ) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib
时间窗: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 1 Day 8
Blood samples were collected to determine the AUCτ of acalabrutinib and ACP-5862 in plasma. The AUCτ was determined using non-compartmental method.
Phase I: Minimum Observed Plasma Drug Concentration (Cmin) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib
时间窗: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 1 Day 8
Blood samples were collected to determine the Cmin of acalabrutinib and ACP-5862 in plasma. The Cmin was determined using non-compartmental method.
Phase II: Objective Response Rate (ORR) Assessed by Blinded Independent Central Review (BICR)
时间窗: Response evaluations performed at the end of Cycles 2, 4 and 6; and then every 12 weeks +/- 7 days through Cycle 25, and then every 24 weeks +/- 7 days thereafter. Assessed until 18 December 2023.
The ORR \[based on International workshop on chronic lymphocytic leukemia (iwCLL) 2018 criteria as assessed by the BICR\] was defined as the percentage of participants who achieved a complete response (CR), CR with incomplete marrow recovery (CRi), nodular partial response (nPR), and partial response (PR). The ORR and the corresponding 95% 2-sided confidence interval (CI) of ORR were presented based on Clopper-Pearson exact method.
次要结局
- Phase I: Best Overall Response (BOR) Assessed by Investigator in Participants With R/R CLL(Response evaluations performed at the end of Cycles 2, 4 and 6; and then every 12 weeks +/- 7 days thereafter or more frequently at the investigator's discretion, approximately 25 months)
- Phase I: Best Overall Response Assessed by Investigator in Participants With R/R MCL(Response evaluations performed at the end of Cycles 2, 4 and 6; and then every 12 weeks +/- 7 days thereafter or more frequently at the investigator's discretion, approximately 25 months)
- Phase II: ORR Assessed by Investigator(Response evaluations performed at the end of Cycles 2, 4 and 6; and then every 12 weeks +/- 7 days through Cycle 25, and then every 24 weeks +/- 7 days thereafter. Assessed until 18 December 2023.)
- Phase II: Duration of Response (DoR) Assessed by BICR and Investigator(Response evaluations performed at the end of Cycles 2, 4 and 6; and then every 12 weeks +/- 7 days through Cycle 25, and then every 24 weeks +/- 7 days thereafter. Assessed until 18 December 2023.)
- Phase II: Progression-Free Survival (PFS) Assessed by BICR and Investigator(Response evaluations performed at the end of Cycles 2, 4 and 6; and then every 12 weeks +/- 7 days through Cycle 25, and then every 24 weeks +/- 7 days thereafter. Assessed until 18 December 2023.)
- Phase II: Time to Response (TTR) Assessed by BICR and Investigator(Response evaluations performed at the end of Cycles 2, 4 and 6; and then every 12 weeks +/- 7 days through Cycle 25, and then every 24 weeks +/- 7 days thereafter. Assessed until 18 December 2023.)
- Phase II CLL Only: Time to Next Treatment (TTNT)(Response evaluations performed every 12 weeks +/- 7 days through Cycle 25, and then every 24 weeks +/- 7 days thereafter. Assessed until 18 December 2023.)
- Phase II CLL Only: Percentage of Participants With Minimal Residual Disease (MRD) Negativity(At screening (-28 days) and end of treatment visit. Assessed until 18 December 2023.)
- Phase II: Percentage of Participants With Overall Survival (OS) at Month 6(From the first dose administration up to Month 6)
- Phase II: Plasma Concentration of Acalabrutinib(At 1, 2 and 4 hours post-dose on Day 8, 15 and 22 of Cycle 1)