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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
105
Acalabrutinib 100 mg orally twice daily
Research Site
Beijing, China
Research Site
Beijing, China
Research Site
Beijing, China
Research Site
Changchun, China
Research Site
Changsha, China
Research Site
Changzhou, China
Research Site
Chengdu, China
Research Site
Fuzhou, China
Research Site
Haikou, China
Research Site
Hangzhou, China
...and 13 more locations
Phase I: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
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.
Time frame: From the first dose administration up to 30 days following the date of last dose of study treatment, approximately 25 months.
Phase I: Area Under the Plasma Concentration-Time Curve From Zero to Infinity (AUCinf) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib
Blood samples were collected to determine the AUCinf of acalabrutinib and ACP-5862 in plasma. The AUCinf was determined using non-compartmental method.
Time frame: 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
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
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.
Time frame: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8 and 12 hours postdose on Cycle 0 Day 1
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
Blood samples were collected to determine the AUClast of acalabrutinib and ACP-5862 in plasma. The AUClast was determined using non-compartmental method.
Time frame: 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
Phase I: Maximum Observed Plasma Drug Concentration (Cmax) of Acalabrutinib and ACP-5862 Post Single and Multiple Dose of Acalabrutinib
Blood samples were collected to determine the Cmax of acalabrutinib and ACP-5862 in plasma. The Cmax was determined using non-compartmental method.
Time frame: 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
Phase I: Time to Reach Maximum Observed Concentration (Tmax) of Acalabrutinib and ACP-5862 Post Single and Multiple Dose of Acalabrutinib
Blood samples were collected to determine the tmax of acalabrutinib and ACP-5862 in plasma. The tmax was determined using non-compartmental method.
Time frame: 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
Phase I: Apparent Total Body Clearance of Drug (CL/F) of Acalabrutinib Post Single and Multiple Dose of Acalabrutinib
Urine samples were collected to determine the CL/F of acalabrutinib. The CL/F was determined using non-compartmental method.
Time frame: 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
Phase I: Apparent Volume of Distribution (Vz/F) of Acalabrutinib Post Single Dose of Acalabrutinib
Blood samples were collected to determine the Vz/F of acalabrutinib in plasma. The Vz/F was determined using non-compartmental method.
Time frame: 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
Phase I: Terminal Elimination Rate Constant (λz) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib
Blood samples were collected to determine the λz of acalabrutinib and ACP-5862 in plasma. The λz was determined using non-compartmental method.
Time frame: 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
Phase I: Terminal Phase Half-Life (t1/2λz) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib
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.
Time frame: 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
Phase I: Metabolite/Parent Drug Cmax Ratio (MRCmax) of Acalabrutinib and ACP-5862 Post Single and Multiple Dose of Acalabrutinib
Blood samples were collected to determine the MRCmax of acalabrutinib and ACP-5862 in plasma. The MRCmax was determined using non-compartmental method.
Time frame: 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
Phase I: Metabolite/Parent Drug AUC Ratio (MRAUCinf) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib
Blood samples were collected to determine the MRAUCinf of acalabrutinib in plasma. The MRAUCinf was determined using non-compartmental method.
Time frame: 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
Phase I: Area Under the Plasma Concentration-Time Curve Across the Dosing Interval (AUCτ) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib
Blood samples were collected to determine the AUCτ of acalabrutinib and ACP-5862 in plasma. The AUCτ was determined using non-compartmental method.
Time frame: 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
Phase I: Minimum Observed Plasma Drug Concentration (Cmin) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib
Blood samples were collected to determine the Cmin of acalabrutinib and ACP-5862 in plasma. The Cmin was determined using non-compartmental method.
Time frame: 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
Phase I: Metabolite/Parent Drug AUCτ Ratio (MRAUCτ) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib
Blood samples were collected to determine the MRAUCτ of acalabrutinib and ACP-5862 in plasma. The MRAUCτ was determined using non-compartmental method.
Time frame: 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
Phase I: Temporal Change Parameter (TCP) in Systemic Exposure of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib
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.
Time frame: 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
Phase I: Accumulation Ratio of AUCτ (Rac AUC) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib
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.
Time frame: 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
Phase I: Accumulation Ratio of Cmax (Rac Cmax) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib
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.
Time frame: 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
Phase II: Objective Response Rate (ORR) Assessed by Blinded Independent Central Review (BICR)
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.
Time frame: 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 I: Best Overall Response (BOR) Assessed by Investigator in Participants With R/R CLL
The BOR is best response a participant has had following first dose date but prior to starting any subsequent anticancer therapy up to and including progression or last evaluable assessment in absence of progression. The CR: No lymph nodes \>=1.5 centimeters. The CRi: Participants who fulfill all criteria for CR but have a persistent anemia, thrombocytopenia or neutropenia apparently unrelated to CLL but related to drug toxicity. The nPR: Participants who were in a complete remission but bone marrow nodules can be identified histologically. The PR: Disease \>=50% from baseline. Partial response with lymphocytosis (PRL): Presence of lymphocytosis plus \>=50% reduction in lymphadenopathy and/or in spleen or liver enlargement plus 1 of PR criteria for platelets or hemoglobin must be met. Stable disease (SD): Change of -49% to +49% in lymph nodes. PD: Increase \>=50% from baseline or from response.
Time frame: 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
The BOR is best response a participant has had following first dose date but prior to starting any subsequent anticancer therapy up to and including progression or last evaluable assessment in absence of progression. CR: No lymph nodes \>=1.5 centimeters. PR: Disease \>=50% from baseline. SD: Change of -49% to +49% in lymph nodes. PD: Increase \>=50% from baseline or from response.
Time frame: 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
The ORR (based on iwCLL 2018 criteria as assessed by the Investigator) was defined as the percentage of participants who achieved a CR, CRi, nPR, and PR. The ORR and the corresponding 95% 2-sided CI of ORR were presented based on Clopper-Pearson exact method.
Time frame: 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.
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Phase II: Duration of Response (DoR) Assessed by BICR and Investigator
The DoR (based on iwCLL 2018 criteria as assessed by the BICR and Investigator) was defined as the interval from the first documentation of objective response to the earlier of the first documentation of objective PD or death from any cause. The DoR was calculated using Kaplan-Meier technique.
Time frame: 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
The PFS (based on iwCLL 2018 criteria as assessed by the BICR and Investigator) was defined as the interval from the start of acalabrutinib therapy to the earlier of the first documentation of objective PD or death from any cause. The PFS was calculated using Kaplan-Meier technique.
Time frame: 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
The TTR (based on iwCLL 2018 criteria as assessed by the BICR and Investigator) was defined as the interval between the date of first dose and the date of initial documentation of a response.
Time frame: 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)
The TTNT was defined as the interval from the start of acalabrutinib therapy to institution of non-protocol specified anticancer treatment for CLL or death due to any cause, whichever came first. The TTNT was calculated using Kaplan-Meier technique.
Time frame: 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
The MRD negative rate was defined as the percentage of participants with MRD-negativity (\<1 CLL cell per 10000 leukocytes) measured in the peripheral blood by flow cytometry.
Time frame: 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
The OS was defined as the interval from the start of acalabrutinib therapy to death from any cause. The OS was calculated using Kaplan-Meier technique.
Time frame: From the first dose administration up to Month 6
Phase II: Plasma Concentration of Acalabrutinib
Blood samples were collected to determine the plasma concentration of acalabrutinib.
Time frame: At 1, 2 and 4 hours post-dose on Day 8, 15 and 22 of Cycle 1